WO2007146965A2 - Compounds for the treatment of periodontal disease - Google Patents
Compounds for the treatment of periodontal disease Download PDFInfo
- Publication number
- WO2007146965A2 WO2007146965A2 PCT/US2007/071049 US2007071049W WO2007146965A2 WO 2007146965 A2 WO2007146965 A2 WO 2007146965A2 US 2007071049 W US2007071049 W US 2007071049W WO 2007146965 A2 WO2007146965 A2 WO 2007146965A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- substituted
- alkyl
- unsubstituted
- compound
- species
- Prior art date
Links
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- 208000028169 periodontal disease Diseases 0.000 title claims abstract description 18
- 238000011282 treatment Methods 0.000 title abstract description 15
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- 238000000034 method Methods 0.000 claims abstract description 102
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 47
- 229910052739 hydrogen Inorganic materials 0.000 claims description 47
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
- 150000002367 halogens Chemical class 0.000 claims description 42
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- 150000003839 salts Chemical class 0.000 claims description 35
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- WGIWBXUNRXCYRA-UHFFFAOYSA-H trizinc;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Zn+2].[Zn+2].[Zn+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O WGIWBXUNRXCYRA-UHFFFAOYSA-H 0.000 description 1
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- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
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- 229940118696 vibrio cholerae Drugs 0.000 description 1
- PGOLTJPQCISRTO-UHFFFAOYSA-N vinyllithium Chemical compound [Li]C=C PGOLTJPQCISRTO-UHFFFAOYSA-N 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
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- 150000003712 vitamin E derivatives Chemical class 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
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- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 235000019235 yellow 2G Nutrition 0.000 description 1
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- 239000011746 zinc citrate Substances 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/58—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing atoms other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur or phosphorus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/69—Boron compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
Definitions
- Periodontitis Bacterial infections of the mouth include inflammation of the gum, gingivitis, and inflammation of the periodontium, periodontitis. Plaque bacteria and bacterial toxins that accumulate below the gum- line may cause inflammation of the gums, termed gingivitis. Inflammation of the gingiva involves influx of lymphocytes and macrophages into the gum tissue and their release of proinflammatory cytokines (TNFa and ILIb) and matrix metalloproteases (MMPs). Periodontitis, or Pyorrhea, is a disease involving chronic inflammation of the gums (gingiva), often persisting unnoticed for years or decades in a patient, that results in loss of connective tissue and/or bone supporting the teeth.
- TNFa and ILIb proinflammatory cytokines
- MMPs matrix metalloproteases
- Periodontitis is the second most important cause, after tooth decay, of tooth loss.
- the invention provides an oral care composition comprising a compound described herein.
- the oral care composition is a member selected from a mouthwash, dentifrice, liquid whitener, chewing gum, dissolvable, partially dissolvable or non-dissolvable film or strip, wipe or towelette, implant, dental floss.
- the oral care composition is a member selected from a toothpaste, prophylactic paste, tooth polish, gel, professional gel and other related products applied by dentists, as well as mouth wash, mouth rinse, dental floss, chewing gum, lozenge, tablet, edible food product and the like.
- the dentifrice is a member selected from a powder, toothpaste and dental gel.
- the compound is present in a therapeutically effective amount. In an exemplary embodiment, the compound is present in an amount of from about 0.1% wgt of compound/wgt of oral care composition to about 5% wgt of compound/wgt of oral care composition. In an exemplary embodiment, the compound is present in an amount of from about 0.3% wgt of compound/wgt of oral care composition to about 0.6% wgt of compound/wgt of oral care composition.
- the compound is present in the range of about (all percentages are in wgt of compound/wgt of oral care composition) 0.3 % to about 5 %, including about 0.4%, about 0.6%, about 0.8%, about 1%, about 1.5, about 2%, about 2.5 %, about 3 %, about 3.5 %, about 4%, and the like.
- the compound is present in the range of about 2 % to about 10 %.
- the compound is present in the range of about 2 % to about 4 %.
- the compound is present in the range of about 2.5 % to about 6 %.
- the compound is present in the range of about 0.1 % to about 1 %.
- E is OH
- R is H
- R* and R** are independently selected from substituted or unsubstituted phenyl.
- R* and R** are independently selected from 4-alkyl, 3- halogen phenyl and 4-halogen, 3-alkyl phenyl.
- R* and R** are 4-methyl, 3-chloro phenyl.
- the compound is a member selected from 3-hydroxypyridine-2-carbonyloxy-bis (3- chloro-4-methylphenyl)-borane or (bis(3-Chloro4-methylphenyl)borinic acid 3- hydroxypicolinate ester), l,3-dihydro-5-fluoro-l-hydroxy-2,l-benzoxaborole, and 5- (4-cyanophenoxy)-l,3-dihydro-l-hydroxy-2,l-benzoxaborole.
- the compound is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4- methylphenyl)-borane.
- the compound is 3- hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl)-borane and the compound is present in an amount of from about 0.1% wgt/wgt to about 5% wgt/wgt. In another exemplary embodiment, the compound is 3-hydroxypyridine-2- carbonyloxy-bis (3-chloro-4-methylphenyl)-borane and the compound is present in an amount of from about 0.3% wgt/wgt to about 0.6% wgt/wgt.
- the compound described herein has antibacterial properties. In another exemplary embodiment, the compound described herein has anti-inflammatory properties. In an exemplary embodiment, the compound described herein has both anti-bacterial and anti-inflammatory properties. In an exemplary embodiment, the compound described herein has both anti-bacterial and anti-inflammatory properties, and is S-hydroxypyridine-l-carbonyloxy-bis (3-chloro- 4-methylphenyl)-borane.
- the invention provides a method for killing a microorganism or inhibiting the growth of a microorganism, comprising contacting said microorganism with a therapeutically effective amount of a compound described herein, thereby killing or inhibiting the growth of the microorganism.
- the microorganism is a member selected from Actinobacillus species, Porphyromonas species, Tannerella species, Prevotella species, Eubacterium species, Treponema species, Bulleidia species, Mogibacterium species, Slackia species, Campylobacter species, Eikenella species, Peptostreptococcus species, Peptostreptococcus species, Capnocytophaga species, Fusobacterium species, Porphyromonas species and Bacteroides species.
- the microorganism is a member selected from Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythensis, Prevotella intermedia, Eubacterium nodatum, Treponema denticola, Bulleidia extructa, Mogibacterium timidum, Slackia exigua, Campylobacter rectus, Eikenella corrodens, Peptostreptococcus micros, Peptostreptococcus anaerobius, Capnocytophaga ochracea, Fusobacterium nucleatum, Porphyromonas asaccharolytica and Bacteroides for sythus .
- the compound of use in the method has a structure described above.
- the compound of use in the method is a member selected from 3-hydroxypyridine-2-carbonyloxy-bis (3- chloro-4-methylphenyl)-borane or (bis(3-chloro-4-methylphenyl)borinic acid 3- hydroxypicolinate ester), l,3-dihydro-5-fluoro-l-hydroxy-2,l-benzoxaborole, and 5- (4-cyanophenoxy)-l,3-dihydro-l-hydroxy-2,l-benzoxaborole.
- the compound of use in the method is 3-hydroxypyridine-2- carbonyloxy-bis (3-chloro-4-methylphenyl)-borane.
- the invention provides a method for treating or preventing periodontal disease in a human or an animal, comprising administering to the human or the animal a therapeutically effective amount of a compound described herein, thereby treating or preventing said periodontal disease.
- the periodontal disease is a member selected from gingivitis, periodontitis and juvenile/acute periodontitis.
- the compound of use in the method has a structure described above.
- the compound of use in the method is a member selected from 3-hydroxypyridine-2-carbonyloxy-bis (3- chloro-4-methylphenyl)-borane or (bis(3-chloro-4-methylphenyl)borinic acid 3- hydroxypicolinate ester), l,3-dihydro-5-fluoro-l-hydroxy-2,l-benzoxaborole, and 5- (4-cyanophenoxy)-l,3-dihydro-l-hydroxy-2,l-benzoxaborole.
- the compound of use in the method is 3-hydroxypyridine-2- carbonyloxy-bis (3-chloro-4-methylphenyl)-borane.
- a compound of use in the compositions and methods described herein has a structure according to Formula I:
- R a is a member selected from a negative charge, a salt (I) counterion, H, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
- M is a member selected from oxygen, sulfur and NR 2a .
- R 2a is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
- J is a member selected from (CR 3a R 4a ) ni and CR 5a .
- R 3a , R 4a , and R 5a are members independently selected from H, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
- the index nl is an integer selected from 0 to 2.
- R 6a , R 7a , and R 8a are members independently selected from H, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
- the index ml is an integer selected from 0 and 1.
- A is a member selected from CR 9a and N.
- D is a member selected from CR 1Oa and N.
- E is a member selected from CR l la and N.
- G is a member selected from CR 12a and N.
- R 9a , R 1Oa , R l la and R 12a are members independently selected from H, OR* a , NR* a R** a , SR* a , -S(O)R* a , -S(O) 2 R* a , -S(O) 2 NR* 11 R** a , -C(O)R* a , -C(O)OR* a , - C(O)NR* a R** a , nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
- Each R* a and R** a are members independently selected from H, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
- the combination of nitrogens (A + D + E + G) is an integer selected from 0 to 3.
- a member selected from R 3a , R 4a and R 5a and a member selected from R 6a , R 7a and R 8a , together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring.
- R 3a and R 4a together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring.
- R 6a and R 7a together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring.
- R 9a and R 1Oa together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring.
- R 1Oa and R l la together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring.
- R l la and R 12a together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring.
- a compound of use in the compositions and methods described herein has a structure according to Formula IX:
- R 20 , R 21 and R 22 are members independently selected from a negative charge, a salt counterion, H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
- a compound of use in the compositions and methods described herein has a structure according to Formula XI:
- the microorganism is implicated in periodontal disease.
- the microorganism is a member selected from a virus, bacteria, fungus, yeast or parasite.
- the bacteria is a member selected from Actinobacillus species, Porphyromonas species, Tannerella species, Prevotella species, Eubacterium species, Treponema species, Bulleidia species, Mogibacterium species, Slackia species, Campylobacter species, Eikenella species, Peptostreptococcus species, Peptostreptococcus species, Capnocytophaga species, Fusobacterium species, Porphyromonas species and Bacteroides species.
- the bacteria is a member selected from Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Tannerella for sythensis, Prevotella intermedia, Eubacterium nodatum, Treponema denticola, Bulleidia extructa, Mogibacterium timidum, Slackia exigua, Campylobacter rectus, Eikenella corrodens, Peptostreptococcus micros, Peptostreptococcus anaerobius, Capnocytophaga ochracea, Fusobacterium nucleatum, Porphyromonas asaccharolytica and Bacteroides for sythus.
- the invention provides a method of treating or preventing periodontal disease in an animal, said method comprising administering to the animal a therapeutically effective amount of a boron-containing compound described herein.
- the animal is a human.
- the periodontal disease is a member selected from gingivitis, periodontitis, and juvenile/acute periodontitis.
- the invention provides an oral care composition comprising a boron-containing compound described herein. This oral care composition can be used to treat periodontal disease.
- FIG. 1 displays the results of testing several boron-containing compounds of the invention against several bacteria which are implicated in periodontal disease.
- FIG. 2 displays exemplary compounds of the invention.
- FIG. 3 displays exemplary compounds of the invention.
- substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents, which would result from writing the structure from right to left, e.g., -CH 2 O- is intended to also recite -OCH 2 -.
- poly as used herein means at least 2.
- a polyvalent metal ion is a metal ion having a valency of at least 2.
- Moiety refers to the radical of a molecule that is attached to another moiety.
- alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. Ci-Cio means one to ten carbons).
- saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n- heptyl, n-octyl, and the like.
- An unsaturated alkyl group is one having one or more double bonds or triple bonds.
- alkyl groups examples include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4- pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
- alkyl unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below, such as “heteroalkyl.”
- Alkyl groups that are limited to hydrocarbon groups are termed "homoalkyl".
- alkylene by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified, but not limited, by - CH 2 CH 2 CH 2 CH 2 -, and further includes those groups described below as “heteroalkylene.”
- an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention.
- a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
- alkoxy alkylamino and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.
- heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and at least one heteroatom.
- the heteroatoms can be selected from the group consisting of B, O, N and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
- the heteroatom(s) B, O, N and S may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
- Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 .
- heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
- heteroalkylene groups heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).
- no orientation of the linking group is implied by the direction in which the formula of the linking group is written.
- the formula -C(O) 2 R'- represents both -C(O) 2 R'- and -R 5 C(O) 2 -.
- cycloalkyl and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
- heterocycloalkyl examples include, but are not limited to, 1 -(1,2,5,6- tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2-piperazinyl, and the like.
- halo or halogen
- haloalkyl by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
- terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
- halo(Ci-C 4 )alkyl is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
- aryl means, unless otherwise stated, a polyunsaturated, aromatic, substituent that can be a single ring or multiple rings (preferably from 1 to 3 rings), which are fused together or linked covalently.
- heteroaryl refers to aryl groups (or rings) that contain from one to four heteroatoms.
- the heteroatom is selected from B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
- a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
- Non- limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3- pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4- oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-
- aryl when used in combination with other terms (e.g. , aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
- arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g.
- benzyl, phenethyl, pyridylmethyl and the like including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2- pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like).
- a carbon atom e.g., a methylene group
- an oxygen atom e.g., phenoxymethyl, 2- pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like.
- R', R", R'" and R" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g. , aryl substituted with 1-3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups.
- each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present.
- R' and R" When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring.
- -NR 'R is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl.
- alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) and acyl (e.g., -C(O)CH 3 , -C(O)CF 3 , - C(O)CH 2 OCH 3 , and the like).
- haloalkyl e.g., -CF 3 and -CH 2 CF 3
- acyl e.g., -C(O)CH 3 , -C(O)CF 3 , - C(O)CH 2 OCH 3 , and the like.
- substituents for the aryl and heteroaryl groups are generically referred to as "aryl group substituents.”
- Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(0)-(CRR') q -U-, wherein T and U are independently -NR-, -0-, -CRR'- or a single bond, and q is an integer of from 0 to 3.
- two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula - A-(CH 2 ) r -B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR'- or a single bond, and r is an integer of from 1 to 4.
- One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
- two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula - (CRR') s -X-(CR"R'")d-, where s and d are independently integers of from O to 3, and X is -0-, -NR'-, -S-, -S(O)-, -S(O) 2 -, or -S(O) 2 NR'-.
- the substituents R, R', R" and R'" are preferably independently selected from hydrogen or substituted or unsubstituted (Ci-C 6 )alkyl.
- Ring means a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
- a ring includes fused ring moieties. The number of atoms in a ring is typically defined by the number of members in the ring. For example, a "5- to 7-membered ring” means there are 5 to 7 atoms in the encircling arrangement. The ring optionally included a heteroatom. Thus, the term “5- to 7- membered ring” includes, for example pyridinyl and piperidinyl.
- the term “ring” further includes a ring system comprising more than one "ring", wherein each "ring” is independently defined as above.
- heteroatom includes atoms other than carbon (C) and hydrogen (H). Examples include oxygen (O), nitrogen (N) sulfur (S), silicon (Si), germanium (Ge), aluminum (Al) and boron (B).
- R is a general abbreviation that represents a substituent group that is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocycloalkyl groups.
- an effective amount of a drug, formulation, or permeant is meant a sufficient amount of a active agent to provide the desired local or systemic effect.
- a “Topically effective,” “Cosmetically effective,” “pharmaceutically effective,” or “therapeutically effective” amount refers to the amount of drug needed to effect the desired therapeutic result.
- Topicically effective refers to a material that, when applied to the skin, nail, hair, claw or hoof produces a desired pharmacological result either locally at the place of application or systemically as a result of transdermal passage of an active ingredient in the material.
- Cosmetically effective refers to a material that, when applied to the skin, nail, hair, claw or hoof, produces a desired cosmetic result locally at the place of application of an active ingredient in the material.
- salts are meant to include salts of the compounds of the invention which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
- base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
- pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
- acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
- inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and
- salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., Journal of Pharmaceutical Science 66: 1-19 (1977)).
- Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
- the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compounds in the conventional manner.
- the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
- the present invention provides compounds which are in a prodrug form.
- Prodrugs of the compounds or complexes described herein readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment.
- Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
- Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are encompassed within the scope of the present invention.
- the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
- the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine- 125 ( 125 I) or carbon- 14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
- pharmaceutically acceptable carrier or “pharmaceutically acceptable vehicle” refers to any formulation or carrier medium that provides the appropriate delivery of an effective amount of a active agent as defined herein, does not interfere with the effectiveness of the biological activity of the active agent, and that is sufficiently non-toxic to the host or patient.
- Representative carriers include water, oils, both vegetable and mineral, cream bases, lotion bases, ointment bases and the like. These bases include suspending agents, thickeners, penetration enhancers, and the like. Their formulation is well known to those in the art of cosmetics and topical pharmaceuticals. Additional information concerning carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005) which is incorporated herein by reference.
- “Pharmaceutically acceptable topical carrier” and equivalent terms refer to pharmaceutically acceptable carriers, as described herein above, suitable for topical application.
- An inactive liquid or cream vehicle capable of suspending or dissolving the active agent(s), and having the properties of being nontoxic and non-inflammatory when applied to the skin, nail, hair, claw or hoof is an example of a pharmaceutically- acceptable topical carrier. This term is specifically intended to encompass carrier materials approved for use in topical cosmetics as well.
- compositions refers to preservatives, antioxidants, fragrances, emulsif ⁇ ers, dyes and excipients known or used in the field of drug formulation and that do not unduly interfere with the effectiveness of the biological activity of the active agent, and that is sufficiently non-toxic to the host or patient.
- Additives for topical formulations are well-known in the art, and may be added to the topical composition, as long as they are pharmaceutically acceptable and not deleterious to the epithelial cells or their function. Further, they should not cause deterioration in the stability of the composition.
- inert fillers for example, inert fillers, anti- irritants, tackifiers, excipients, fragrances, opacifiers, antioxidants, gelling agents, stabilizers, surfactant, emollients, coloring agents, preservatives, buffering agents, other permeation enhancers, and other conventional components of topical or transdermal delivery formulations as are known in the art.
- the terms “enhancement,” “penetration enhancement” or “permeation enhancement” relate to an increase in the permeability of the skin, nail, hair, claw or hoof to a drug, so as to increase the rate at which the drug permeates through the skin, nail, hair, claw or hoof.
- the enhanced permeation effected through the use of such enhancers can be observed, for example, by measuring the rate of diffusion of the drug through animal or human skin, nail, hair, claw or hoof using a diffusion cell apparatus.
- a diffusion cell is described by Merritt et ah, J of Controlled Release, 1:161-162 (1984).
- the term “permeation enhancer” or “penetration enhancer” intends an agent or a mixture of agents, which, alone or in combination, act to increase the permeability of the skin, nail, hair or hoof to a drug.
- excipients is conventionally known to mean carriers, diluents and/or vehicles used in formulating drug compositions effective for the desired use.
- Topical administration refers to the application of a pharmaceutical agent to the external surface of the skin, nail, hair, claw or hoof, such that the agent crosses the external surface of the skin, nail, hair, claw or hoof and enters the underlying tissues.
- Topical administration includes application of the composition to intact skin, nail, hair, claw or hoof, or to a broken, raw or open wound of skin, nail, hair, claw or hoof.
- Topical administration of a pharmaceutical agent can result in a limited distribution of the agent to the skin and surrounding tissues or, when the agent is removed from the treatment area by the bloodstream, can result in systemic distribution of the agent.
- Transdermal delivery refers to the diffusion of an agent across the barrier of the skin, nail, hair, claw or hoof resulting from topical administration or other application of a composition.
- stratum corneum acts as a barrier and few pharmaceutical agents are able to penetrate intact skin.
- the epidermis and dermis are permeable to many solutes and absorption of drugs therefore occurs more readily through skin, nail, hair, claw or hoof that is abraded or otherwise stripped of the stratum corneum to expose the epidermis.
- Transdermal delivery includes injection or other delivery through any portion of the skin, nail, hair, claw or hoof or mucous membrane and absorption or permeation through the remaining portion.
- Absorption through intact skin, nail, hair, claw or hoof can be enhanced by placing the active agent in an appropriate pharmaceutically acceptable vehicle before application to the skin, nail, hair, claw or hoof.
- Passive topical administration may consist of applying the active agent directly to the treatment site in combination with emollients or penetration enhancers.
- transdermal delivery is intended to include delivery by permeation through or past the integument, i.e. skin, nail, hair, claw or hoof.
- microbial infection refers to any infection of a host tissue by an infectious agent including, but not limited to, viruses, bacteria, mycobacteria, fungus and parasites (see, e.g., Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson et al, eds., 12th ed. 1991); Williams et al, J. of Medicinal Chem. 42:1481-1485 (1999), herein each incorporated by reference in their entirety).
- microbial infection refers to any infection of a host tissue by an infectious agent including, but not limited to, viruses, bacteria, mycobacteria, fungus and parasites (see, e.g., Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson et al, eds., 12th ed. 1991); Williams et al, J. of Medicinal Chem. 42:1481-1485 (1999), herein each incorporated by reference in their entirety).
- Bio medium refers to both in vitro and in vivo biological milieus.
- exemplary in vitro “biological media” include, but are not limited to, cell culture, tissue culture, homogenates, plasma and blood. In vivo applications are generally performed in mammals, preferably humans.
- MIC or minimum inhibitory concentration
- Also of use in the present invention are compounds that are poly- or multivalent species, including, for example, species such as dimers, trimers, tetramers and higher homo logs of the compounds of use in the invention or reactive analogues thereof.
- the poly- and multi-valent species can be assembled from a single species or more than one species of the invention.
- a dimeric construct can be "homo-dimeric” or "heterodimeric.”
- poly- and multi-valent constructs in which a compound of the invention or a reactive analogue thereof, is attached to an oligomeric or polymeric framework e.g., polylysine, dextran, hydroxyethyl starch and the like
- an oligomeric or polymeric framework e.g., polylysine, dextran, hydroxyethyl starch and the like
- the framework is preferably polyfunctional (i.e. having an array of reactive sites for attaching compounds of use in the invention). Moreover, the framework can be derivatized with a single species of the invention or more than one species of the invention. [0063] Moreover, the present invention includes the use of compounds within the motif set forth in the formulas contained herein, which are functionalized to afford compounds having water-solubility that is enhanced relative to analogous compounds that are not similarly functionalized. Thus, any of the substituents set forth herein can be replaced with analogous radicals that have enhanced water solubility.
- a hydroxyl group with a diol, or an amine with a quaternary amine, hydroxy amine or similar more water- soluble moiety.
- additional water solubility is imparted by substitution at a site not essential for the activity towards the editing domain of the compounds set forth herein with a moiety that enhances the water solubility of the parent compounds.
- Methods of enhancing the water- solubility of organic compounds are known in the art. Such methods include, but are not limited to, functionalizing an organic nucleus with a permanently charged moiety, e.g., quaternary ammonium, or a group that is charged at a physiologically relevant pH, e.g.
- carboxylic acid amine
- Other methods include, appending to the organic nucleus hydroxyl- or amine- containing groups, e.g. alcohols, polyols, polyethers, and the like.
- Representative examples include, but are not limited to, polylysine, polyethyleneimine, poly(ethyleneglycol) and poly(propyleneglycol).
- Suitable functionalization chemistries and strategies for these compounds are known in the art. See, for example, Dunn, R. L., et al, Eds. POLYMERIC DRUGS AND DRUG DELIVERY SYSTEMS, ACS Symposium Series Vol. 469, American Chemical Society, Washington, D.C. 1991.
- This invention provides boron-containing compounds which are useful in the treatment of microorganisms located in the oral cavities of animals.
- the compounds are also useful in treating periodontal disease.
- the invention comprises a compound having the structure according to the following formulae: wherein B is boron, 0 is oxygen, R* and R** are each independently selected from substituted or unsubstituted alkyl (C1-C4), substituted or unsubstituted cycloalkyl (C 3 - C 7 ), substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted heteroaryl.
- the index z is 0 or 1 and when z is 1, A is CH, CR 10 or N.
- D is N, CH, or CR 12 .
- E is H, OH, alkoxy or 2-(morpholino)ethoxy, CO 2 H or C ⁇ 2 alkyl.
- R* and/or R** are the same or are different, preferably wherein one of R* and R** is a substituted or unsubstituted alkyl (Ci-C 4 ) or R* and R** are each a substituted or unsubstituted alkyl (Ci-C 4 ).
- R* and/or R** are the same or are different, preferably wherein one of R* and R** is a substituted or unsubstituted cycloalkyl (C3-C7) or R* and R** are each a substituted or unsubstituted cycloalkyl (C3-C7).
- R* and/or R** are the same or are different, preferably wherein one of R* and R** is a substituted or unsubstituted alkenyl or R* and R** are each a substituted or unsubstituted alkenyl.
- the alkenyl has the structure 2
- R* and/or R** are the same or are different, preferably wherein one of R* and R** is a substituted or unsubstituted alkynyl or R* and R** are each a substituted or unsubstituted alkynyl.
- the alkynyl has the structure 3
- R* and/or R** are the same or are different, preferably wherein one of R* and R** is a substituted or unsubstituted phenyl or R* and R** are each a substituted or unsubstituted phenyl but excluding compounds of formula 1 wherein z is 1, A is CR 10 , D is CR 12 , J is CR 10 and excluding compounds of formula 2 wherein the combination of substituents is such that z is 1, A is CR 10 , D is CR 12 , m is 2, and G is H or methyl or ethyl.
- G is also not propyl.
- such excluded compounds although not being claimed as novel, may find use in one or more of the methods of the invention, preferably for treatment against infection, most preferably in treatment against fungal infection. In a preferred embodiment, only novel compounds of the invention are contemplated for such uses.
- novel compounds of the invention do not include quinaldine derivatives, such as 2-methylquinoline, wherein R 9 is methyl, A z is CH, D is CH, J is CH and R 11 is hydrogen. However, such compounds may be useful in the methods of the invention.
- a preferred embodiment is a compound of a formula described herein, such as formula 1, 2a, 2b, 2c or 2d, wherein R* and R** are each other than a phenyl or substituted phenyl.
- Another preferred embodiment is a compound of a formula described herein, such as formula 1, 2a, 2b, 2c or 2d, wherein one of R* or R** is benzyl or substituted benzyl.
- the compound has a formula described herein, such as formula 1, 2a, 2b, 2c or 2d, wherein z is 1, E is N- (morpholinyl)ethoxy or alkoxy greater than C 4 .
- the phenyl has the structure 4
- One highly preferred embodiment is a compound of a formula described herein, such as formula 1, 2a, 2b, 2c or 2d, wherein R* is 3 -fluorophenyl, R** is A- chlorophenyl, R 9 is H, R 11 is H, A z is CH, D is CH, J is CH and may be called (3- fluorophenyl)(4-chlorophenyl)borinic acid 8-hydroxyquinoline ester.
- Another preferred embodiment is a compound of a formula described herein, such as formula 1, 2a, 2b, 2c or 2d, wherein R* and R** are each 3-(4,4- dimethyloxazolidin-2-yl)phenyl, R 9 is H, R 11 is H, A z is CH, D is CH, J is CH and may be called bis(3-(4,4-dimethyloxazolidin-2-yl)phenyl)borinic acid 8- hydroxyquinoline ester.
- An additional preferred embodiment is a compound of a formula described herein, such as formula 1, 2a, 2b, 2c or 2d, wherein R* is 3 -fluorophenyl, R** is cyclopropyl, R 9 is H, R 11 is H, A z is CH, D is CH, J is CH and referred to as (3- fluorophenyl)(cyclopropyl)borinic acid 8-hydroxyquinoline ester.
- a highly preferred embodiment is a compound of a formula described herein, such as formula 1, 2a, 2b, 2c or 2d, wherein R* is 4-(N,N-dimethyl)- aminomethylphenyl, R** is 4-cyanophenyl, R 9 is H, R 11 is H, A z is CH, D is CH, J is CH and is referred to as (4-(N,N-dimethyl)-aminomethylphenyl)(4- cyanophenyl)borinic acid 8-hydroxyquinoline ester.
- R* and/or R** are the same or are different, preferably wherein one of R* and R** is a substituted or unsubstituted benzyl or R* and R** are each a substituted or unsubstituted benzyl.
- the benzyl has the structure 5
- One preferred embodiment is a compound of a formula described herein, such as formula 1, 2a, 2b, 2c or 2d, R* and/or R** are the same or are different, preferably wherein one of R* and R** is a substituted or unsubstituted heterocycle or R* and R** are each a substituted or unsubstituted heterocycle.
- the heterocycle has the structure 6
- a highly preferred embodiment is a compound of a formula described herein, such as formula 1, 2a, 2b, 2c or 2d, wherein R* is pyrid-3-yl, R** is A- chlorophenyl, R 9 is H, R 11 is H, A z is CH, D is CH, and J is CH (named (pyrid-3- yl)(4-chlorophenyl)borinic acid 8-hydroxyquinoline ester).
- a highly preferred embodiment is a compound of a formula described herein, such as formula 1, 2a, 2b, 2c or 2d, wherein R* is 5-cyanopyrid-3-yl, R** is vinyl, R 9 is H, R 11 is H, A z is CH, D is CH, and J is CH (named (5-cyanopyrid-3- yl)(vinyl)borinic acid 8-hydroxyquinoline ester).
- One preferred embodiment is a compound of a formula described herein, such as formula 1, 2a, 2b, 2c or 2d, wherein R 9 is H, R 11 is H, A z is CH, D is CH, and J is CH.
- such solvent structures can especially insinuate themselves into at least some of the compounds of the invention, especially between the boron and nitrogen atoms, to increase the ring size of such compounds by one or two atoms.
- the boron ring of a structure of the invention comprises 5 atoms, including, for example, the boron, a nitrogen, an oxygen and 2 carbons, insinuation of a solvent atom between the boron and nitrogen would afford a 7 membered ring.
- hydroxyl and amino solvents may afford structures containing an oxygen or nitrogen between the ring boron and nitrogen atoms to increase the size of the ring.
- Such structures are expressly contemplated by the present invention, preferably where R*** is H or alkyl.
- Reaction scheme A demonstrates the synthesis of the intermediate borinic acids, and their subsequent conversion to the desired borinic acid complexes.
- R* and R** are identical, the reaction of two equivalents of an arylmagnesium halide (or aryllithium) with trialkyl borate, followed by acidic hydrolysis affords the desired borinic acid 5.
- the borinic acid complexes are obtained from the precursor borinic acids by reaction with one equivalent of the desired heterocyclic ligand in suitable solvents (i.e., ethanol, isopropanol, dioxane, ether, toluene, dimethylformamide, N-methylpyrrolidone, or tetrahydrofuran).
- suitable solvents i.e., ethanol, isopropanol, dioxane, ether, toluene, dimethylformamide, N-methylpyrrolidone, or tetrahydrofuran.
- compounds of the invention may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms.
- These compounds can be, for example, racemates or optically active forms.
- the single enantiomers, i.e., optically active forms can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.
- the invention provides a compound having a structure according to Formula I:
- R la is a member selected from a negative charge, a salt counterion, H, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
- M is a member selected from oxygen, sulfur and NR 2a .
- R 2a is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
- J is a member selected from (CR 3a R 4a ) n i and CR 5a .
- R 3a , R 4a , and R 5a are members independently selected from H, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
- the index nl is an integer selected from 0 to 2.
- R 6a , R 7a , and R 8a are members independently selected from H, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
- the index ml is an integer selected from 0 and 1.
- A is a member selected from CR 9a and N.
- D is a member selected from CR 1Oa and N.
- E is a member selected from CR l la and N.
- G is a member selected from CR 12a and N.
- R 9a , R 1Oa , R l la and R 12a are members independently selected from H, OR* a , NR* a R** a , SR* a , -S(O)R* a , -S(O) 2 R* a , -S(O) 2 NR* a R** a , -C(O)R* a , -C(O)OR* a , - C(0)NR* a R** a , nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
- Each R* a and R** a are members independently selected from H, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
- the combination of nitrogens (A + D + E + G) is an integer selected from 0 to 3.
- a member selected from R 3a , R 4a and R 5a and a member selected from R 6a , R 7a and R 8a , together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring.
- R 3a and R 4a together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring.
- R 6a and R 7a together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring.
- R 9a and R 1Oa together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring.
- R 1Oa and R l la together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring.
- R l la and R 12a together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring.
- the compound has a structure according to Formula (Ia):
- each R 3a and R 4a is a member independently selected from H, cyano, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, trifluoromethyl, substituted or unsubstituted hydroxymethyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenyl, substituted or unsubstituted mercaptomethyl, substituted or unsubstituted mercaptoalkyl, substituted or unsubstituted aminomethyl, substituted or unsubstituted alkylaminomethyl, substituted or unsubstituted dialkylaminomethyl, substituted or unsubstituted arylaminomethyl, substituted or unsubstituted indolyl and substituted or unsubstituted amido.
- each R 3a and R 4a is a member independently selected from cyano, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, trifluoromethyl, substituted or unsubstituted hydroxymethyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenyl, substituted or unsubstituted mercaptomethyl, substituted or unsubstituted mercaptoalkyl, substituted or unsubstituted aminomethyl, substituted or unsubstituted alkylaminomethyl, substituted or unsubstituted dialkylaminomethyl, substituted or unsubstituted arylaminomethyl, substituted or unsubstituted indolyl, substituted or unsubstituted amido.
- each R 3a and R 4a is a member selected from H, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted butyl, substituted or unsubstituted t-butyl, substituted or unsubstituted phenyl and substituted or unsubstituted benzyl.
- R 3a and R 4a is a member selected from methyl, ethyl, propyl, isopropyl, butyl, t-butyl, phenyl and benzyl.
- R 3a is H and R 4a is a member selected from methyl, ethyl, propyl, isopropyl, butyl, t-butyl, phenyl and benzyl.
- R 3a is H and R 4a is H.
- each R 9a , R 1Oa , R l la and R 12a is a member independently selected from H, OR* a , NR*R** a , SR* a , -S(O)R* a , -S(O) 2 R* a , -S(O) 2 NR* a R** a , -C(O)R* a , -C(O)OR* a , -C(O)NR* a R** a , halogen, cyano, nitro, substituted or unsubstituted methoxy, substituted or unsubstituted methyl, substituted or unsubstituted ethoxy, substituted or unsubstituted ethyl, trifluoromethyl, substituted or unsubstituted hydroxymethyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted benzy
- R 9a , R 1Oa , R l la and R 12a are selected from the previous list of substituents with the exception of -C(O)R* a , - C(O)OR* a , -C(O)NR* a R** a .
- R 9a , R 1Oa , R lla and R 12a are members independently selected from fluoro, chloro, bromo, nitro, cyano, amino, methyl, hydroxylmethyl, trifluoromethyl, methoxy, trifluoromethyoxy, ethyl, diethylcarbamoyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidinyl, piperizino, piperizinyl, piperizinocarbonyl, piperizinylcarbonyl, carboxyl, 1-tetrazolyl, 1- ethoxycarbonylmethoxy, carboxymethoxy, thiophenyl, 3-(butylcarbonyl) phenylmethoxy, lH-tetrazol-5-yl, 1-ethoxycarbonylmethyloxy-, 1- ethoxycarbonylmethyl-, 1-ethoxycarbonylmethyl-, 1-ethoxycarbony
- the compound according to Formula (I) or Formula (Ia) is a member selected from:
- the compound has a structure according to one of Formulae I-Io with substituent selections for R 9a , R 1Oa , R l la and R 12a including all the possiblities contained in paragraph 90 except for H.
- the compound has a structure according to one of Formulae Ib-Io with substituent selections for R 9a , R 1Oa , R l la and R 12a including all the possiblities contained in paragraph 91 except for H.
- the compound has a formula according to Formulae (Ib)-(Ie) wherein R la is a member selected from H, a negative charge and a salt counterion and the remaining R group (R 9a in Ib, R 1Oa in Ic, R lla in Id, and R 12a in Ie) is a member selected from fluoro, chloro, bromo, nitro, cyano, amino, methyl, hydroxylmethyl, trifluoromethyl, methoxy, trifluoromethyoxy, ethyl, diethylcarbamoyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidinyl, piperizino, piperizinyl, piperizinocarbonyl, piperizinylcarbonyl, carboxyl, 1-tetrazolyl, 1- ethoxycarbonylmethoxy, carboxymethoxy, thiopheny
- the compound has a formula according to
- R , 1a a is a member selected from H, a negative charge and a salt counterion and each of the remaining two R groups (R 9a and R 1Oa in If, R 9a and R l la in Ig, R 9a and R 12a in Ih, R 1Oa and R l la in Ii, R 1Oa and R 12a in Ij, R lla and R 12a in Ik) is a member independently selected from fluoro, chloro, bromo, nitro, cyano, amino, methyl, hydroxylmethyl, trifluoromethyl, methoxy, trifluoromethyoxy, ethyl, diethylcarbamoyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidinyl, piperizino, piperizinyl, piperizinocarbonyl, piperizinylcarbonyl, carboxyl, 1-
- the compound has a formula according to Formulae (H)-(Io) wherein R la is a member selected from H, a negative charge and a salt counterion and each of the remaining three R groups (R 9a , R 1Oa , R l la in (II), R 9a , R 1Oa , R 12a in (Im), R 9a , R l la , R 12a in (In), R 1Oa , R l la , R 12a in (Io)) is a member independently selected from fluoro, chloro, bromo, nitro, cyano, amino, methyl, hydroxylmethyl, trifluoromethyl, methoxy, trifluoromethyoxy, ethyl, diethylcarbamoyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidinyl, piperizino, piperizinyl, piperiz
- R 7b is a member selected from H, methyl, ethyl and phenyl.
- R 10b is a member selected from H, OH, NH 2 , SH, halogen, substituted or unsubstituted phenoxy, substituted or unsubstituted phenylalkyloxy, substituted or unsubstituted phenylthio and substituted or unsubstituted phenylalkylthio.
- R l lb is a member selected from H, OH, NH 2 , SH, methyl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenylalkyloxy, substituted or unsubstituted phenylthio and substituted or unsubstituted phenylalkylthio.
- R lb is a member selected from a negative charge, H and a salt counterion.
- R 10b and R l lb are H.
- the compound cannot have a structure according to Formula (Ix) wherein one member selected from R 10b and R l lb is H and the other member selected from R 10b and R llb is a member selected from halo, methyl, cyano, methoxy, hydroxymethyl and p-cyanophenyloxy.
- R 10b and R l lb are members independently selected from fluoro, chloro, methyl, cyano, methoxy, hydroxymethyl, and p-cyanophenyl.
- the compound cannot have a structure according to Formula (Ix) wherein R lb is a member selected from a negative charge, H and a salt counterion; R 7b is H; R 10b is F and R l lb is H.
- R lb and R 12b along with the atoms to which they are attached, are joined to form a phenyl group.
- R 10b is a member selected from H, halogen, CN and substituted or unsubstituted Ci_4 alkyl.
- a structure does not have the which is a member selected from Formulae (I) to (Io) at least one member selected from R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a , R 1Oa , R l la and R 12a is nitro, cyano or halogen.
- W is a member selected from (CR 3a R 4a ) n i, wherein nl is 0, J is a member selected from (CR 6a R 7a ) mh wherein ml is 1, A is CR 9a , D is CR 1Oa , E is CR l la , G is CR 12a , the R 9a is not halogen, methyl, ethyl, or optionally joined with R 1Oa to form a phenyl ring; R 1Oa is not unsubstituted phenoxy, C(CH 3 ) 3 , halogen, CF 3 , methoxy, ethoxy, or optionally joined with R 9a to form a phenyl ring; R l la is not halogen or optionally joined with R 1Oa to form a phenyl ring; and R 12a is not halogen.
- W is a member selected from (CR 3a R 4a ) n i, wherein nl is 0, J is a member selected from (CR 6a R 7a ) m i, wherein ml is 1, A is CR 9a , D is CR 1Oa , E is CR lla , Gl is CR 12a , then neither R 6a nor R 7a are halophenyl.
- W is a member selected from (CR 3a R 4a ) n i, wherein nl is 0, J is a member selected from (CR 6a R 7a ) m i, wherein ml is 1, A is CR 9a , D is CR 1Oa , E is CR lla , G is CR 12a , and R 9a , R 1Oa and R lla are H, then R 6a , R 7a and R 12a are not H.
- the compound of the invention has a structure which is a member selected from:
- R g is halogen.
- R a , R b , R c , R d and R e are members independently selected from a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
- there is a proviso that the compound is not a member selected from
- the compound has a structure is a member selected from:
- R a , R d and R e are each members indepenently selected from:
- R b and R c are members independently selected from H, methyl,
- R b is H and R c is a member selected from
- R b and R c are, together with the nitrogen to which they are attached, optionally joined to form a member selected from
- R a is a member selected from
- R d is a member selected from
- R e is a member selected from
- the compound is a member selected from
- the compound has a structure which is described in Figure 2. In an exemplary embodiment, the compound has a structure which is described in Figure 3.
- the compound has a structure according to a member selected from Formulae I(b), I(c), I(d), and I(e) wherein said remaining R group (R 9a for I(b), R 1Oa for I(c), R l la for I(d) and R 12a for I(e)) is carboxymethoxy.
- the compound has a structure which is a member selected from Formulae (If) - (Ik), wherein either R 9a a or R , 10a a for Formula (If), either R 9a or R l la for Formula (Ig), either R 9a or R 12a for Formula (Ih), either R 1Oa or R lla for Formula (Ii), either R 1Oa or R 12a for Formula (Ij), either R lla or R 12a for Formula (Ik) is halogen, and the other substituent in the pairing (ex. if R 9a is F in Formula (If), then R 1Oa is selected from the following substituent listing), is a member selected from NH 2 , N(CH 3 )H, and N(CH 3 ) 2 .
- the compound has a structure which is a member selected from:
- R* and R** are members selected from: H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
- the compound is a member selected from
- R , 1a a is a member selected from a negative charge, H and a salt counterion.
- the compound has a structure which is a member selected from:
- the compounds and embodiments described above in Formulae (I)-(Io) can form a hydrate with water, a solvate with an alcohol (e.g. methanol, ethanol, propanol); an adduct with an amino compound (e.g. ammonia, methylamine, ethylamine); an adduct with an acid (e.g. formic acid, acetic acid); complexes with ethanolamine, quinoline, amino acids, and the like.
- an alcohol e.g. methanol, ethanol, propanol
- an amino compound e.g. ammonia, methylamine, ethylamine
- an acid e.g. formic acid, acetic acid
- complexes with ethanolamine, quinoline, amino acids, and the like e.g. formic acid, acetic acid
- the compound has a structure according to Formula (Ip):
- R x2 is a member selected from substituted or unsubstituted C1-C5 alkyl and substituted or unsubstituted C1-C5 heteroalkyl.
- R y2 and R z2 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. **A1-M1 are undefined?
- the compound has a structure according to Formula (Iq):
- R x2 is a member selected from substituted or unsubstituted C1-C5 alkyl and substituted or unsubstituted C 1 -C 5 heteroalkyl.
- R y2 and R z2 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
- At least one member selected from R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a , R 1Oa , R l la and R 12a is a member selected from nitro, cyano and halogen.
- the compound has a structure which is a member selected from the following Formulae:
- the compound has a formula according to Formulae (Ib)-(Ie) wherein at least one member selected from R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a , R 1Oa , R l la and R 12a is a member selected from nitro, cyano, fluro, chloro, bromo and cyanophenoxy.
- the compound is a member selected from
- the compound is a member selected from
- R > 6b , r R, 9b , r R, 10b , n Rllb and R , 12b have the same substituent listings as described for Formulae (Ix) and (Iy) above.
- the invention provides poly- or mutli- valent species of the compounds of the invention.
- the invention provides a dimer of the compounds described herein.
- the invention provides a dimer of the compounds described herein.
- the invention provides a dimer of a compound which is a member selected from C1-C96.
- the dimer is a member selected from
- the invention provides an anhydride of the compounds described herein. In an exemplary embodiment, the invention provides an anhydride of the compounds described herein. In an exemplary embodiment, the invention provides an anhydride of a compound which is a member selected from Cl- C96. In an exemplary embodiment the anhydride is a member selected from
- the invention provides a trimer of the compounds described herein. In an exemplary embodiment, the invention provides a trimer of the compounds described herein. In an exemplary embodiment, the invention provides a trimer of a compound which is a member selected from C1-C96. In an exemplary embodiment the trimer is a member selected from
- R lOa a is a member selected from
- R , 15 is a member selected from CN, COOH and - R, 1 1 6 0 and R 1 17 ' are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
- the index p is an integer selected from 1 to 5.
- the index z is an integer selected from 1 to 8.
- X is a member selected from S and O.
- the compound has a structure according to Formula (VIII): wherein R , 4a a is a member selected from substituted or unsubstituted aryl and substituted or unsubstituted arylalkyl.
- R 1Oa is a member selected from H, halogen, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkoxy, substituted or unsubstituted arylthio and substituted or unsubstituted arylalkylthio.
- the compound has a structure compound is a member selected from:
- the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
- the invention provides compounds useful in the methods which have a structure according to Formula IX:
- R 20 , R 21 and R 22 are members independently selected from a negative charge, a salt counterion, H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
- the compound has a structure according to Formula (X):
- the compounds of the invention can form a hydrate with water, solvates with alcohols such as methanol, ethanol, propanol, and the like; adducts with amino compounds, such as ammonia, methylamine, ethylamine, and the like; adducts with acids, such as formic acid, acetic acid and the like; complexes with ethanolamine, quinoline, amino acids, and the like.
- alcohols such as methanol, ethanol, propanol, and the like
- amino compounds such as ammonia, methylamine, ethylamine, and the like
- acids such as formic acid, acetic acid and the like
- complexes with ethanolamine, quinoline, amino acids, and the like complexes with ethanolamine, quinoline, amino acids, and the like.
- the compound has a structure which is a member selected from 5-Chloro-l,3-dihydro-l -hydroxy-2,l-benzoxaborole (Cl), 1,3- Dihydro-l-hydroxy-2,l-benzoxaborole (C2), 5-Fluoro-l,3-dihydro-l-hydroxy-3- methyl-2, 1 -benzoxaborole (C3), 6-Fluoro- 1 -hydroxy- 1 ,2,3 ,4-tetrahydro-2, 1 - benzoxaborine (C4), 5,6-Difluoro-l,3-dihydro-l-hydroxy-2,l-benzoxaborole (C5), 5- Cyano-1 ,3-dihydro- 1 -hydroxy-2, 1 -benzoxaborole (C6), 1 ,3-Dihydro-l -hydroxy-5- methoxy-2, 1 -benzoxaborole
- the compound has a structure which is a member selected from the following compounds:
- the invention provides compounds useful in the methods
- the symbol X represents bromo or iodo.
- the symbol Y is selected from H, lower alkyl, and arylalkyl.
- the symbol Z is selected from H, alkyl, and aryl.
- the symbol PG represents protecting group.
- the symbols A, D, E, G, R x , R y , R z , R la , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a , R 1Oa , R l la , and R 12a can be used to refer to the corresponding symbols in the compounds described herein.
- Step 1 and 2 compounds 1 or 2 are converted into alcohol 3.
- step 1 compound 1 is treated with a reducing agent in an appropriate solvent.
- Suitable reducing agents include borane complexes, such as borane-tetrahydrofuran, borane-dimethylsulfide, combinations thereof and the like.
- Lithium aluminum hydride, or sodium borohydride can also be used as reducing agents.
- the reducing agents can be used in quantities ranging from 0.5 to 5 equivalents, relative to compound 1 or 2.
- Suitable solvents include diethyl ether, tetrahydrofuran, 1,4- dioxane, 1 ,2-dimethoxyethane, combinations thereof and the like. Reaction temperatures range from 0 0 C to the boiling point of the solvent used; reaction completion times range from 1 to 24 h.
- Step 2 the carbonyl group of compound 2 is treated with a reducing agent in an appropriate solvent.
- Suitable reducing agents include borane complexes, such as borane-tetrahydrofuran, borane-dimethylsulfide, combinations thereof and the like.
- Lithium aluminum hydride, or sodium borohydride can also be used as reducing agents.
- the reducing agents can be used in quantities ranging from 0.5 to 5 equivalents, relative to compound 2.
- Suitable solvents include lower alcohol, such as methanol, ethanol, and propanol, diethyl ether, tetrahydrofuran, 1 ,4-dioxane and 1 ,2- dimethoxyethane, combinations thereof and the like.
- Reaction temperatures range from 0 0 C to the boiling point of the solvent used; reaction completion times range from 1 to 24 h.
- Step 3 the hydroxyl group of compound 3 is protected with a protecting group which is stable under neutral or basic conditions.
- the protecting group is typically selected from methoxymethyl, ethoxyethyl, tetrahydropyran-2-yl, trimethylsilyl, te/t-butyldimethylsilyl, tributylsilyl, combinations thereof and the like.
- methoxymethyl compound 3 is treated with 1 to 3 equivalents of chloromethyl methyl ether in the presence of a base.
- Suitable bases include sodium hydride, potassium te/t-butoxide, tertiary amines, such as diisopropylethylamine, triethylamine, l,8-diazabicyclo[5,4,0]undec-7-ene, and inorganic bases, such as sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, combinations thereof and the like.
- the bases can be used in quantities ranging from 1 to 3 equivalents, relative to compound 3. Reaction temperatures range from 0 0 C to the boiling point of the solvent used; preferably between 0 and 40 0 C; reaction completion times range from 1 h to 5 days.
- compound 3 is treated with 1 to 3 equivalents of 3,4-dihydro-2H-pyran in the presence of 1 to 10 mol% of acid catalyst.
- acid catalysts include pyridinium/?-toluenesulfonic acid, /?-toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid, hydrogen chloride, sulfuric acid, combinations thereof and the like.
- Suitable solvents include dichloromethane, chloroform, tetrahydrofuran, 1 ,4-dioxane, 1 ,2-dimethoxyethane, toluene, benzene, and acetonitrile combinations thereof and the like.
- Reaction temperatures range from 0 0 C to the boiling point of the solvent used; preferably between 0 and 60 0 C, and is complete in Ih to 5 days.
- compound 3 is treated with 1 to 3 equivalents of chlorotrialkylsilyane in the presence of 1 to 3 equivalents of base.
- bases include tertiary amines, such as imidazole, diisopropylethylamine, triethylamine, 1,8- diazabicyclo[5,4,0]undec-7-ene, combinations thereof and the like.
- Reaction temperatures range from 0 0 C to the boiling point of the solvent used; preferably between 0 and 40 0 C; reaction completion times range from 1 to 48 h.
- Step 4 compound 4 is converted into boronic acid (5) through halogen metal exchange reaction.
- Compound 4 is treated with 1 to 3 equivalents of alkylmetal reagent relative to compound 4, such as n-butyllithium, sec-butyllithium, tert- butyllithium, isopropylmagnesium chloride or Mg turnings with or without an initiator such as diisobutylaluminum hydride (DiBAl), followed by the addition of 1 to 3 equivalents of trialkyl borate relative to compound 4, such as trimethyl borate, triisopropyl borate, or tributyl borate.
- alkylmetal reagent such as n-butyllithium, sec-butyllithium, tert- butyllithium, isopropylmagnesium chloride or Mg turnings with or without an initiator such as diisobutylaluminum hydride (DiBAl)
- TriBAl diisobutylalum
- Suitable solvents include tetrahydrofuran, ether, 1 ,4-dioxane, 1 ,2-dimethoxyethane, toluene, hexanes, combinations thereof and the like.
- Alkylmetal reagent may also be added in the presence of trialkyl borate.
- the addition of butyllithium is carried out at between -100 and 0 0 C, preferably at between -80 and -40 0 C.
- the addition of isopropylmagnesium chloride is carried out at between -80 and 40 0 C, preferably at between -20 and 30 0 C.
- the addition of Mg turnings, with or without the addition of DiBAl, is carried out at between -80 and 40 0 C, preferably at between -35 and 30 0 C.
- the addition of the trialkyl borate is carried out at between -100 and 20 0 C. After the addition of trialkyl borate, the reaction is allowed to warm to room temperature, which is typically between -30 and 30 0 C. When alkylmetal reagent is added in the presence of trialkyl borate, the reaction mixture is allowed to warm to room temperature after the addition. Reaction completion times range from 1 to 12 h. Compound 5 may not be isolated and may be used for the next step without purification or in one pot.
- Step 5 the protecting group of compound 5 is removed under acidic conditions to give compound of the invention.
- Suitable acids include acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, p- toluenesulfonic acid and the like.
- the acids can be used in quantities ranging from 0.1 to 20 equivalents, relative to compound 5.
- the protecting group is trialkylsilyl
- basic reagents such as tetrabutylammonium fluoride, can also be used.
- Suitable solvents include tetrahydrofuran, 1 ,4-dioxane, 1 ,2-dimethoxyethane, methanol, ethanol, propanol, acetonitrile, acetone, combination thereof and the like.
- Reaction temperatures range from 0 0 C to the boiling point of the solvent used; preferably between 10 0 C and reflux temperature of the solvent; reaction completion times range from 0.5 to 48 h.
- the product can be purified by methods known to those of skill in the art.
- the invention provides a method of making a tetrahydropyran-containing boronic ester, said ester having a structure according to the following formula:
- R 1 and R 2 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
- R 1 and R 2 together with the atoms to which they are attached, can be optionally joined to form a 4- to 7- membered ring.
- R 9a , R 1Oa , R l la and R 12a are members independently selected from H, OR*, NR*R**, SR*, -S(O)R*, -S(O) 2 R*, -S(0) 2 NR*R**, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
- R* and R** is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
- the method comprises: a) subjecting a first compound to Grignard or organolithium conditions, said first compound having a structure according to the following formula:
- halogen is a member selected from iodo and bromo.
- the borate ester is a member selected from B(OR ⁇ 2 (OR 2 ), wherein R 1 and R 2 are each members independently selected from H, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted butyl, substituted or unsubstituted t-butyl, substituted or unsubstituted phenyl and substituted or unsubstituted benzyl.
- R 1 and R 2 together with the atoms to which they are joined, can optionally form a member selected from substituted or unsubstituted dioxaborolane, substituted or unsubstituted dioxaborinane and substituted or unsubstituted dioxaborepane.
- the borate ester is a member selected from B(OR ⁇ 2 (OR 2 ), wherein R 1 and R 2 , together with the atoms to which they are joined, form a member selected from dioxaborolane, substituted or unsubstituted tetramethyldioxaborolane, substituted or unsubstituted phenyldioxaborolane, dioxaborinane, dimethyldioxaborinane and dioxaborepane.
- the Grignard or organolithium conditions further comprise diisobutyl aluminum hydride.
- the temperature of the Grignard reaction does not exceed about 35°C.
- the temperature of the Grignard reaction does not exceed about 40 0 C. In another exemplary embodiment, the temperature of the Grignard reaction does not exceed about 45°C. In an exemplary embodiment, step (b) is performed at a temperature of from about -30 0 C to about -20 0 C. In another exemplary embodiment, step (b) is performed at a temperature of from about -35°C to about -25°C. In another exemplary embodiment, step (b) is performed at a temperature of from about -50 0 C to about -0 0 C. In another exemplary embodiment, step (b) is performed at a temperature of from about -40 0 C to about -20 0 C. In another exemplary embodiment, the tetrahydropyran-containing boronic ester is
- the invention provides a method of making a compound having a structure according to the following formula
- said method comprising: a) subjecting a first compound to Grignard or organolithium conditions, said first compound having a structure according to the following formula:
- the compound is l,3-dihydro-5-fluoro-l-hydroxy-2,l-benzoxaborole.
- the compound is purified by recrystallization from a recrystallization solvent, wherein said recrystallization solvent essentially does not contain acetonitrile. In an exemplary embodiment, the recrystallization solvent contains less than 2% acetonitrile.
- the recrystallization solvent contains less than 1% acetonitrile. In an exemplary embodiment, the recrystallization solvent contains less than 0.5% acetonitrile. In an exemplary embodiment, the recrystallization solvent contains less than 0.1% acetonitrile. In an exemplary embodiment, the recrystallization solvent contains toluene and a hydrocarbon solvent. In an exemplary embodiment, the recrystallization solvent contains about 1 :1 toluene: hydrocarbon solvent. In an exemplary embodiment, the recrystallization solvent contains about 2:1 toluene: hydrocarbon solvent. In an exemplary embodiment, the recrystallization solvent contains about 3:1 toluene: hydrocarbon solvent.
- the recrystallization solvent contains about 4:1 toluene: hydrocarbon solvent.
- the hydrocarbon solvent is a member selected from heptane, octane, hexane, pentane and nonane.
- the recrystallization solvent is 3:1 toluene: heptane.
- Step 6 compound 2 is converted into boronic acid (6) via a transition metal catalyzed cross-coupling reaction.
- Compound 2 is treated with 1 to 3 equivalents of bis(pinacolato)diboron or 4,4,5,5-tetramethyl-l,3,2-dioxaborolane in the presence of transition metal catalyst, with the use of appropriate ligand and base as necessary.
- Suitable transition metal catalysts include palladium(II) acetate, palladium(II) acetoacetonate, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, [1,1 ' -bis(diphenylphosphino)ferrocen] dichloropalladium(II), combinations thereof and the like.
- the catalyst can be used in quantities ranging from 1 to 5 mol% relative to compound 2.
- Suitable ligands include triphenylphosphine, tri(o-tolyl)phosphine, tricyclohexylphosphine, combinations thereof and the like.
- the ligand can be used in quantities ranging from 1 to 5 equivalents relative to compound 2.
- Suitable bases include sodium carbonate, potassium carbonate, potassium phenoxide, triethylamine, combinations thereof and the like.
- the base can be used in quantities ranging from 1 to 5 equivalents relative to compound 2.
- Suitable solvents include ⁇ /,N-dimethylformamide, dimethylsufoxide, tetrahydrofuran, 1,4-dioxane, toluene, combinations thereof and the like.
- Reaction temperatures range from 20 0 C to the boiling point of the solvent used; preferably between 50 and 150 0 C; reaction completion times range from 1 to 72 h.
- Pinacol ester is then oxidatively cleaved to give compound 6.
- Pinacol ester is treated with sodium periodate followed by acid.
- Sodium periodate can be used in quantities ranging from 2 to 5 equivalents relative to compound 6.
- Suitable solvents include tetrahydrofuran, 1 ,4-dioxane, acetonitrile, methanol, ethanol, combinations thereof and the like.
- Suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid combinations thereof and the like. Reaction temperatures range from 0 0 C to the boiling point of the solvent used; preferably between 0 and 50 0 C; reaction completion times range from 1 to 72 h.
- Step 7 the carbonyl group of compound 6 is treated with a reducing agent in an appropriate solvent to give a compound of the invention.
- Suitable reducing agents include borane complexes, such as borane-tetrahydrofuran, borane- dimethylsulfide, combinations thereof and the like.
- Lithium aluminum hydride, or sodium borohydride can also be used as reducing agents.
- the reducing agents can be used in quantities ranging from 0.5 to 5 equivalents, relative to compound 6.
- Suitable solvents include lower alcohol, such as methanol, ethanol, and propanol, diethyl ether, tetrahydrofuran, 1 ,4-dioxane and 1 ,2-dimethoxyethane, combinations thereof and the like.
- Reaction temperatures range from 0 0 C to the boiling point of the solvent used; reaction completion times range from 1 to 24 h.
- compounds of the invention can be prepared in one step from compound 3.
- Compound 3 is mixed with trialkyl borate then treated with alkylmetal reagent.
- Suitable alkylmetal reagents include n-butyllithium, sec- butyllithium, tert-butyllithium combinations thereof and the like.
- Suitable trialkyl borates include trimethyl borate, triisopropyl borate, tributyl borate, combinations thereof and the like.
- the addition of butyllithium is carried out at between -100 and 0 0 C, preferably at between -80 and -40 0 C.
- the reaction mixture is allowed to warm to room temperature after the addition. Reaction completion times range from 1 to 12 h.
- the trialkyl borate can be used in quantities ranging from 1 to 5 equivalents relative to compound 3.
- the alkylmetal reagent can be used in quantities ranging from 1 to 2 equivalents relative to compound 3.
- Suitable solvents include tetrahydrofuran, ether, 1,4-dioxane, 1,2-dimethoxyethane, toluene, hexanes, combinations thereof and the like. Reaction completion times range from 1 to 12 h.
- a mixture of compound 3 and trialkyl borate can be refluxed for 1 to 3 h and the alcohol molecule formed upon the ester exchange can be distilled out before the addition of alkylmetal reagent.
- N-bromosuccinimide can be used in quantities ranging from 0.9 to 1.2 equivalents relative to compound 7.
- Suitable solvents include carbon tetrachloride, tetrahydrofuran, 1,4-dioxane, chlorobenzene, combinations thereof and the like. Reaction temperatures range from 20 0 C to the boiling point of the solvent used; preferably between 50 and 150 0 C; reaction completion times range from 1 to 12 h.
- Step 11 the bromomethylene group of compound 8 is converted to the benzyl alcohol 3.
- Compound 8 is treated with sodium acetate or potassium acetate. These acetates can be used in quantities ranging from 1 to 10 equivalents relative to compound 8.
- Suitable solvents include tetrahydrofuran, 1,4-dioxane, N, N- dimethylformamide, JV,iV-dimethylacetamide, JV-methylpyrrolidone, dimethylsulfoxide, combinations thereof and the like.
- Reaction temperatures range from 20 0 C to the boiling point of the solvent used; preferably between 50 and 100 0 C; reaction completion times range from 1 to 12 h.
- the resulting acetate is hydro lyzed to compound 3 under basic conditions.
- Suitable bases include sodium hydroxide, lithium hydroxide, potassium hydroxide, combinations thereof and the like.
- the base can be used in quantities ranging from 1 to 5 equivalents relative to compound 8.
- Suitable solvents include methanol, ethanol, tetrahydrofuran, water, combinations thereof and the like. Reaction temperatures range from 20 0 C to the boiling point of the solvent used; preferably between 50 and 100 0 C; reaction completion times range from 1 to 12 h.
- compound 8 can be directly converted into compound 3 under the similar condition above.
- Steps 3 through 5 convert compound 3 into a compound of the invention.
- Suitable solvents include tetrahydrofuran, 1 ,2-dimethoxyethane, 1,4-dioxane, ether, toluene, hexane, N,N- dimethylformamide, combinations thereof and the like.
- Reaction temperatures range from 0 0 C to the boiling point of the solvent used; preferably between 0 and 30 0 C; reaction completion times range from 1 to 12 h.
- the enolether formed is hydro lyzed under acidic conditions. Suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, and the like.
- Suitable solvents include tetrahydrofuran, 1,2- dimethoxy ethane, 1,4-dioxane, methanol, ethanol, combination thereof and the like.
- Reaction temperatures range from 20 0 C to the boiling point of the solvent used; preferably between 50 and 100 0 C; reaction completion times range from 1 to 12 h.
- Steps 2 through 5 convert compound 9 into a compound of the invention.
- R 1 H I or II, Rl / H
- compound (Ia) is converted into its aminoalcohol complex (Ib).
- Compound (Ia) is treated with HOR 1 NR ⁇ R 113 .
- the aminoalcohol can be used in quantities ranging from 1 to 10 equivalents relative to compound (Ia).
- Suitable solvents include methanol, ethanol, propanol, tetrahydrofuran, acetone, acetonitrile, 1,2-dimethoxyethane, 1,4-dioxane, toluene, ⁇ /, ⁇ /-dimethylformamide, water, combination thereof and the like.
- Reaction temperatures range from 20 0 C to the boiling point of the solvent used; preferably between 50 and 100 0 C; reaction completion times range from 1 to 24 h.
- the compounds of the invention can be converted into hydrates and solvates by methods similar to those described above.
- the invention provides compounds useful in the methods which have a structure according to Formula XI:
- R lc is substituted or unsubstituted alkyl (Ci - C 4 ). In an exemplary embodiment of Formula (XI), R lc is substituted or unsubstituted alkyloxy. In an exemplary embodiment of Formula (XI), R lc is substituted or unsubstituted cycloalkyl (C3 - C 7 ). In an exemplary embodiment of Formula (XI), R lc is substituted or unsubstituted alkenyl. In a further exemplary embodiment thereof, the substituted alkenyl has the structure
- R lc is a substituted or unsubstituted alkynyl.
- the substituted alkynyl has the structure
- R 23c is defined as before.
- R lc is substituted or unsubstituted aryl.
- the substituted aryl has the structure
- R lc is a substituted or unsubstituted aralkyl.
- the substituted aralkyl has the structure wherein R 28c , R 29c , R 30c , R 31c and R 32c are defined as before, and nl is an integer selected from 1 to 15.
- R lc is a substituted or unsubstituted heteroaryl.
- heteroaryl has the structure
- the structures of the invention also permit solvent interactions that may afford structures (Formula XVII) that include atoms derived from the solvent encountered by the compounds of the invention during synthetic manipulations and therapeutic uses.
- Structure XVII arises from the formation of a dative bond between the solvent(s) with the Lewis acidic boron center.
- solvent complexes could be stable entities with comparative bioactivities.
- Such structures are expressly contemplated by the present invention where R 40c is H or alkyl.
- the invention provides a structure which is a member selected from Formula (Ic), (lie) and (IIIc):
- M is a member selected from H, halogen, -OCH 3 , and -CH 2 -O-CH 2 -O-CH 3 .
- M 1 is a member selected from halogen, -CH 2 OH, and - OCH 3 .
- X is a member selected from O, S, and NR XC .
- R xc is a member selected from H and substituted or unsubstituted alkyl.
- R lc , R 3c , R 4c , R 2c and R 5c are members independently selected from H, OH, NH 2 , SH, CN, NO 2 , SO 2 , OSO 2 OH, OSO 2 NH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
- R 41c is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl and substituted or unsubstituted vinyl.
- the compounds of the invention can form a hydrate with water, solvates with alcohols such as methanol, ethanol, propanol, and the like; adducts with amino compounds, such as ammonia, methylamine, ethylamine, and the like; adducts with acids, such as formic acid, acetic acid and the like; complexes with ethanolamine, quinoline, amino acids, and the like.
- alcohols such as methanol, ethanol, propanol, and the like
- amino compounds such as ammonia, methylamine, ethylamine, and the like
- acids such as formic acid, acetic acid and the like
- complexes with ethanolamine, quinoline, amino acids, and the like complexes with ethanolamine, quinoline, amino acids, and the like.
- the compound has a structure which is a member selected from 2-(3-Chlorophenyl)-[l,3,2]-dioxaborolane, (3- Chlorophenyl)(4 ' -fluoro-(2 ' -(methoxymethoxy)-methyl)-phenyl)-borinic acid, 1 -(3 - Chlorophenyl)-5-fluoro- 1 ,3-dihydrobenzo[c][ 1 ,2]oxaborole, 1 -(3-Chlorophenyl)-6- fluoro-l,3-dihydrobenzo[c][l,2]oxaborole, l-(3-Chlorophenyl)-l,3- dihydrobenzo[c][l,2]oxaborole, 5-Chloro-l-(3-Fluorophenyl)-l,3- dihydrobenzo[c]
- the present invention provides an oral care composition comprising a compound of the invention.
- the compound is a boron-containing compound described herein.
- the compound is a member selected from 3-hydroxypyridine-2- carbonyloxy-bis (3-chloro-4-methylphenyl)-borane (bis(3-Chloro4- methylphenyl)borinic acid 3-hydroxypicolinate ester), l,3-dihydro-5-fluoro-l- hydroxy-2,l-benzoxaborole, and 5-(4-cyanophenoxy)-l,3-dihydro-l-hydroxy-2,l- benzoxaborole.
- the compound is 3- hydroxypyridine-2-carbonyloxy-bis (3 -chloro-4-methylphenyl)-borane (bis(3 - Chloro4-methylphenyl)borinic acid 3-hydroxypicolinate ester).
- These oral care compositions are of use in the methods of the invention.
- An oral care composition of the present invention can take any physical form suitable for application to an oral surface.
- the composition can be a liquid solution suitable for irrigating, rinsing or spraying; a dentifrice such as a powder, toothpaste or dental gel; a liquid suitable for painting a dental surface (e.g., a liquid whitener); a chewing gum; a dissolvable, partially dissolvable or non-dissolvable film or strip (e.g., a whitening strip); a wafer; a wipe or towelette; an implant; a dental floss; toothpastes, prophylactic pastes, tooth polishes, gels, professional gels and other related products applied by dentists, as well as mouth washes, mouth rinses, dental flosses, chewing gums, lozenges, tablets, edible food products, Periochips for insertion into periodontal pockets (made of material such as chlorihexidine gluconate) and the like.
- the composition can contain active and/or carrier ingredients additional to those recited above.
- a compound described herein in the oral care composition can be encapsulated in a material called a microsphere.
- This material can act as a slow-release mechanism for the compound.
- the microsphere is at least partially constructed from chitosan.
- 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4- methylphenyl)-borane is encapsulated in a microsphere in an oral care composition. Additional descriptions of microencapsulated materials are described in Govender et al, Journal of Microencapsulation, 23(7): Nov. 2006, pp 750-761, which is herein incorporated by reference.
- the composition is adapted for application to an oral surface of a small domestic animal, for example a cat or a dog.
- a composition is typically edible or chewable by the animal, and can take the form, for example, of a cat or dog food, treat or toy.
- the composition of any of the embodiments described above is a mouthwash or rinse, an oral spray, a dentifrice, an oral strip, a liquid whitener or a chewing gum.
- Rinses include liquids adapted for irrigation by means of devices such as high-pressure water jets.
- Dentifrices include without limitation toothpastes, gels and powders.
- a "liquid whitener” herein encompasses semi-liquid compositions such as gels as well as flowable liquids, so long as the composition is capable of application to a dental surface by painting with a brush or other suitable device.
- “Painting" in the present context means application of a thin layer of the composition to the dental surface.
- the composition is a toothpaste or gel dentifrice.
- a composition of the invention can comprise, in addition to the boron- containing compound described herein, a vitamin or vitamin derivative or antioxidant component or one or more active agents ("actives").
- useful actives are those addressing, without limitation, appearance and structural changes to teeth, treatment and prevention of plaque, calculus, dental caries, cavities, abscesses, inflamed and/or bleeding gums, gingivitis, oral infective and/or inflammatory conditions in general, tooth sensitivity, halitosis and the like.
- a composition of the invention can contain one or more actives such as whitening agents, fluoride ion sources, antimicrobial agents additional to the boron- containing compound described herein, desensitizing agents, anticalculus (tartar control) agents, stannous ion sources, zinc ion sources, sialagogues, breath-freshening agents, antiplaque agents, anti-inflammatory agents additional to any boron- containing compound that has anti-inflammatory properties, periodontal agents, analgesics and nutrients. Actives should be selected for compatibility with each other and with other ingredients of the composition.
- Actives useful herein are normally present in the composition in amounts selected to be safe and effective, i.e., amount sufficient to provide a desired benefit, for example a therapeutic, prophylactic, nutritive or cosmetic effect, when the composition is used repeatedly as described herein, without undue side effects such as toxicity, irritation or allergic reaction, commensurate with a reasonable benefit/risk ratio.
- a safe and effective amount will usually, but not necessarily, fall within ranges approved by appropriate regulatory agencies.
- a safe and effective amount in a specific case depends on many factors, including the particular benefit desired or condition being treated or sought to be prevented, the particular subject using, or being administered, the composition, the frequency and duration of use, etc.
- Actives are typically present in a total amount of about 0.01% to about 80%, for example about 0.05% to about 60%, about 0.1% to about 50%, or about 0.5% to about 40%, by weight of the composition.
- One or more actives, including the boron-containing compound described herein, can optionally be present in encapsulated form in the composition.
- beads containing one or more actives can be adapted to rupture during brushing or chewing to release the active(s) to the oral surface.
- the composition of the invention may include any of the components conventionally present or desirable in an oral care product.
- the composition may include a whitening agent, such as peroxy compounds, chlorine dioxide, chlorites and hypochlorites, a polymer-peroxide complex, polyvinylpyrrolidone-hydrogen peroxide (PVP-H 2 O 2 ) complex; a source of fluride ions (monofluorophosphate and fluorosilicate salts, antibacterial agents.
- Active agents such as antibacterial agents may be includes, including, for example, those listed in U.S. Pat. No. 5,776,435 to Gaffar et al., the contents of which are incorporated herein by reference.
- the composition may further include a tooth anti- sensitivity agent, a sialagogue (saliva stimulating agent), a breath-freshening agent, an antiplaque or plaque disrupting agent.
- diluents for optional inclusion in a composition of the invention are diluents, abrasives, bicarbonate salts, pH modifying agents, surfactants, foam modulators, thickening agents, viscosity modifiers, humectants, sweeteners, flavorants and colorants.
- One carrier material, or more than one carrier material of the same or different classes, can optionally be present.
- Water is a preferred diluent and in some compositions such as mouthwashes and whitening liquids may be accompanied by an additional solvent, such as an alcohol, e.g., ethanol.
- the composition may contain abrasives, pH modifying agents, surfactants, foam modulators, thickening agents, viscosity modifiers, humectants, sweeteners, flavorants, colorants.
- the invention further provides a method of oral care comprising a step of applying a composition as described herein to an oral surface of a subject.
- the composition is a toothpaste or gel dentifrice
- the applying step comprises brushing the surface, for example a dental surface and a periodontal surface adjacent thereto, with the dentifrice.
- a method of inhibiting inflammation in an oral tissue of a subject comprises applying to an oral surface proximal to the tissue a compound of the invention.
- the compound is a member selected from 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl)-borane (bis(3- Chloro4-methylphenyl)borinic acid 3-hydroxypicolinate ester), l,3-dihydro-5-fluoro- 1 -hydroxy-2, 1 -benzoxaborole, and 5-(4-cyanophenoxy)- 1 ,3-dihydro-l -hydroxy-2, 1 - benzoxaborole.
- the compound is 3- hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl)-borane.
- a method of promoting oral health in a subject comprises applying to an oral surface of the subject a compound of the inventions.
- Practice of a method of the invention can promote any aspect or aspects of oral health.
- a method can promote periodontal and/or gingival health, for instance by reducing bacterial infection and/or inflammation.
- such a method can provide a breath- freshening benefit, for instance through antibacterial and/or antioxidant activity.
- a method can promote tooth retention, for instance by reducing or preventing dental caries and preventing destruction of the bone matrix that holds the tooth in place.
- such a method can provide an anti-plaque benefit.
- such a method can reduce damage to oral tissues from free radicals, including those occurring as a result of contact with tobacco smoke or polluted air.
- cardiovascular disease including atherosclerosis, coronary heart disease (CHD) and stroke; diabetes; respiratory infections including bacterial pneumonia; preterm low birth weight; stomach ulcers; bacteremia; infective endocarditis; prosthetic device infection; chronic obstructive pulmonary disease (COPD); and brain abscesses.
- Practice of the methods can consist of a single application as described herein, or can comprise repeated such applications. In one embodiment a method as described herein is repeated at regular intervals, for example twice or once daily, twice or once weekly, twice or once monthly, in a program or regimen conducted at home and/or in a professional or clinical setting.
- the subject in any of the above methods can be a human or non-human mammal, for example a dog, cat, horse or exotic mammal.
- the subject is a small domestic animal, for example a cat or a dog, and the composition, in the form of a food, treat or toy, is given to the animal to chew.
- compositions of this invention can further include a variety of other components, including hydrophilic liquid vehicles, including but not limited to glycerin, propylene glycol, polyethylene glycol, and hydrophobic liquid vehicles such as triglyceride, diglyceride, and organic oils including mineral oil, essential oils, and fatty vegetable oils.
- hydrophilic and hydrophobic liquid vehicles can be used either singly or in combination and preferably, can be added in a proportion of from about 2 to about 50 wt. % (in the case of compositions comprising liquid vehicles), especially from about 10 to about 35 wt. % based on the whole composition.
- the composition of the present invention for the oral cavity may preferably be formulated into a use form such as gel, liquid, or paste.
- the oral care compositions of the present invention can also contain flavor components, typically in the form of natural flavors or aroma oils and/or herbal extracts and oils. These flavor components can serve not only to give a palatable flavor to the oral care composition, but can act as natural antibacterial agents and preservatives at the same time.
- oils suitable for use in the present invention include but are not limited to citric oil, lemon oil, lime oil, lemongrass oil, orange oil, sweet orange oil, grapefruit oil, pomegranate oil, apricot oil extract, tangerine extract, tangelo oil, peppermint oil, spearmint oil, sage oil, rosemary oil, cinnamon oil, winter green oil, clove oil, eucalyptus oil, ginger oil, sassafras oil, menthol, arvensis mint oil, synthetic mint flavors and oils, carvone, eugenol, methyleugenol, methyl salicylate, methyl eugenol, thymol, anethole, millefolium extract, chamomile, lavender oil, myrrh, eugenol, tea tree oil, sage oil, mallow, limonene, ocimene, n-decyl alcohol, citronellol, ⁇ -terpineol,
- Silica abrasives can also be incorporated into the oral care composition of the present invention, without detracting from the scope of the invention.
- Specific silica abrasives suitable for use with the present invention include but are not limited to silica gels, precipitated silicas, silicates, and hydrated silica.
- Silica gels suitable for use with the present invention are hydrogels, hydrous gels, xerogels, and aerogels, such as those known in the art and described in U.S. Pat. No. 6,440,397.
- Precipitated silicas are those known in the art, such as the suitable oral care-type precipitated silicas described in U.S. Pat. No. 5,589,160.
- Suitable silicates are any of those naturally occurring or synthetic silicates suitable for use with oral care compositions. These silica abrasives can be used singly or in combination.
- An exemplary silica abrasive for use with the present invention includes silica gels. The silica abrasives can be used together with the calcium salt or in lieu of the calcium salt component.
- Water can optionally be incorporated into the oral care compositions of the present invention, such as toothpastes and mouthwashes.
- Water used in the preparation of commercially suitable oral care compositions should preferably be deionized and free of organic impurities.
- Water can generally comprise about 0% to about 40% by weight of the toothpaste compositions herein.
- the oral care composition of the present invention can further contain a variety of optional ingredients and vehicles generally used for preparations for use in the oral cavity, such as toothpastes and mouthwashes.
- optional components include, but are not limited to, such components as abrasives, surfactants, thickening agents, buffers, humectants, preservatives, and antibiotic and anti-caries agents. All of these additives, described in further detail below, are generally usual and would be known to one of skill in the art.
- Dental abrasives useful in the dentifrice compositions of the present invention include a variety of different materials known in the art.
- the abrasive material should be one which is compatible with the composition of interest and does not excessively abrade dentin.
- Suitable abrasives include for example, silicas including gels and precipitates; insoluble polymetaphosphate, hydrated alumina, resinous abrasives such as polymerized resins (e.g. ureas, melamines, cross-linked epoxides, phenolics, and the like), and mixtures thereof.
- humectant Another optional component of the oral care compositions of the present invention is a humectant.
- the humectant serves to keep compositions such as toothpaste compositions from hardening upon exposure to air, and to give mouthwash and toothpaste compositions a moist feel to the mouth.
- Certain humectants can also impart desirable sweetness of flavor to toothpaste and mouthwash compositions.
- Suitable humectants for use in compositions of the present invention include edible polyhydric alcohols such as glycerin, sorbitol, xylitol, polyethylene glycol, and propylene glycol.
- compositions of the present invention can also optionally contain sweeteners such as saccharin sodium, acesulfame potassium, glycyrrhizin, perillartine, thaumatin, aspartylphenylalanyl methyl ester and xylitol.
- sweeteners such as saccharin sodium, acesulfame potassium, glycyrrhizin, perillartine, thaumatin, aspartylphenylalanyl methyl ester and xylitol.
- Buffering agents are another optional component of the oral care compositions of the present invention.
- the buffering agents serve to retain the pH of the compositions within the preferred range.
- Suitable buffering agents for use in dentifrice compositions of the present invention include soluble phosphate salts.
- preservatives such as those that prevent microbial growth in the oral care compositions.
- Suitable preservatives include but are not limited to methylparaben, propylparaben, bezoates, and alcohols such as ethanol.
- Binders and thickeners can also optionally be used in the oral care compositions of the present invention, particularly in toothpaste compositions.
- Preferred binders and thickening agents include, but are not limited to, carrageenan (e.g. Viscarin, Irish moss, and the like); cellulose derivatives such as hydroxyethyl cellulose, sodium carboxymethyl cellulose, and sodium carboxymethyl hydroxypropyl cellulose, carboxyvinyl polymers; natural gums such as karaya gum, gum Arabic, and tragacanth; polysaccharide gums such as xanthan gum; fumed silica; and colloidal magnesium aluminum silicate.
- Compositions of the present oral care compositions can also optionally contain a surfactant.
- Suitable surfactants are those which are reasonably stable and preferably form suds (bubbles) throughout the pH range of the dentifrice compositions.
- Surfactants can also be added to act as solubilizing agents to help retain sparingly soluble components in solutions or mixtures.
- Surfactants useful in the dentifrice compositions as sudsing agents can be soaps, polysorbates, poloxamers, and synthetic detergents that are anionic, nonionic, cationic, zwitterionic, or amphoteric, and mixtures thereof.
- the oral care compositions of the present invention can also optionally comprise anti-caries agents.
- Preferred anti-caries agents are water-soluble fluoride ion sources.
- the number of such fluoride ions sources is great and well known to those of skill in the art, and includes those disclosed in U.S. Pat. No. 3,535,421.
- Exemplary fluoride ion source materials include sodium fluoride, potassium fluoride, sodium monofluorophosphate and mixtures thereof.
- Antimicrobial and anti-plaque agents can also optionally be present in the oral care compositions of the present condition.
- Such agents may include: triclosan (5-chloro-2-(2,4-dichlorophenoxy)-phenol); chlorhexidine; chlorhexidine digluconate (CHX); alexidine, hexetidine (HEX); sanguinarine (SNG); benzalkonium chloride; salicylanilide; domiphen bromide; cetylpyridiniumchloride (CPC); tetradecylpyridinium chloride (TPC); N-tetra-decyl-4-ethylpyridinium chloride (TDEPC); octenidine; delmopinol; octapinol, and other piperidino derivatives; spyware/stannous ion agents; antibiotics such as augmentin, amoxicillin, tetracycline, deoxycycline, minocycline, and metronid
- Oral care compositions of the present invention can also optionally include one or more anticalculus (anti-tartar) agents.
- Anticalculus agents which may be useful in the dentifrice compositions of the present invention include antimicrobials such as chlorhexidine, niddamycin, and triclosan, metals and metal salts such as zinc citrate, Vitamin C, bisphosphonates, triclosanpyrophosphates, pyrophosphates, polyphosphates, polyacrylates and other polycarboxylates, polyepoxysuccinates, ethyenediaminetetraacetic acid (EDTA), nitrilotriacetic acid and related compounds, polyphosphonates, and polypyrophosphates such as sodium hexametaphosphate, as well as other anticalculus agents known to those of skill in the art, such as those described in K. J. Fairbrother et al., "Anticalculus agents," Journal of Clinical Periodontology Vol. 27, pp. 2
- Nutrients and vitamins can also optionally be added to the oral care compositions of the present invention.
- agents can include folates, retinoids (Vitamin A), Vitamin B (Bi-thyamin, B 2 -riboflavin, B 3 -niacine, B 5 -pantothenic acid, B ⁇ -pyridoxine, Bybiotin, Bg/Bg/Bc-folic acid, Bi 2 -cyanocobalamin), Vitamin C (ascorbic acid, sodium ascorbate), Vitamin E, Vitamin E analogs (dl- ⁇ -tocopherol acetate, tocopherol succinate, tocopherol nicotinate)and zinc.
- miscellaneous additives can also be optionally formulated into the oral care compositions of the present invention, such as tooth desensitizing agents (e.g. potassium and strontium salts), condensed anti-tartar agents such as sodium and potassium tetrapyrophosphate, whitening agents such as aluminum oxide and calcium peroxide, debriding agents such as sodium bicarbonate, pigments and dyes, such as Blue 15-C174160, Green 7-C174260, Reds 4-CI12085 and 40 CI16035, Yellows 115 CI47005:l and 5 CI19140, and Carmine 5 CI16035), as well as additives such as mica and sparkles.
- tooth desensitizing agents e.g. potassium and strontium salts
- condensed anti-tartar agents such as sodium and potassium tetrapyrophosphate
- whitening agents such as aluminum oxide and calcium peroxide
- debriding agents such as sodium bicarbonate
- pigments and dyes such as Blue 15-C174160, Green
- the invention provides a method for inhibiting the growth, or killing, a microorganism, preferably a bacteria, fungus, virus, yeast or parasite, comprising contacting the organism with a compound of the invention.
- a microorganism preferably a bacteria, fungus, virus, yeast or parasite
- the compound is a boron-containing compound described herein.
- the microorganism is in the oral cavity of an animal, which is a member selected from human, cattle, deer, reindeer, goat, honey bee, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, camel, yak, elephant, ostrich, otter, chicken, duck, goose, guinea fowl, pigeon, swan, and turkey.
- the animal is a human.
- the method is used in vitro, for example, to eliminate microbial contaminants in a cell culture.
- the compound is a member selected from 3- hydroxypyridine-2-carbonyloxy-bis (3 -chloro-4-methylphenyl)-borane (bis(3 - Chloro4-methylphenyl)borinic acid 3-hydroxypicolinate ester), l,3-dihydro-5-fluoro- 1 -hydroxy-2, 1 -benzoxaborole, and 5-(4-cyanophenoxy)- 1 ,3-dihydro-l -hydroxy-2, 1 - benzoxaborole.
- the compound is 3- hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl)-borane.
- the microorganism is a member selected from a fungus and a yeast.
- the fungus or yeast is a member selected from Candida species, Trichophyton species, Microsporium species, Aspergillus species, Cryptococcus species, Blastomyces species, Cocciodiodes species, Histoplasma species, Paracoccidiodes species, Phycomycetes species, Malassezia species, Fusarium species, Epidermophyton species, Scytalidium species, Scopulariopsis species, Alternaria species, Penicillium species, Phialophora species, Rhizopus species, Scedosporium species and Zygomycetes class.
- the fungus or yeast is a member selected from Aspergilus fumigatus (A.fumigatus), Blastomyces dermatitidis, Candida Albicans (C albicans, both fluconazole sensitive and resistant strains), Candida glabrata (C glabrata), Candida krusei (C krusei), Cryptococcus neoformans (C neoformans), Candida parapsilosis (C parapsilosis), Candida tropicalis (C tropicalis), Cocciodiodes immitis, Epidermophyton floccosum (E.floccosum), Fusarium solani (F.
- Aspergilus fumigatus A.fumigatus
- Blastomyces dermatitidis Candida Albicans (C albicans, both fluconazole sensitive and resistant strains
- Candida glabrata C glabrata
- Candida krusei C krusei
- the fungus or yeast is a member selected from Trichophyton concentricum, T. violaceum, T. schoenleinii, T. verrucosum, T. soudanense, Microsporum gypseum, M. equinum, Candida guilliermondii, Malassezia globosa, M. obtuse, M. restricta, M. slooffiae, and Aspergillus flavus .
- the fungus or yeast is a member selected from dermatophytes, Trichophyton, Microsporum, Epidermophyton Aspergillus, Blastomyces, Candida, Coccidioides, Cryptococcus, Hendersonula, Histoplasma, Paecilomyces, Paracoccidioides, Pneumocystis, Trichosporium and yeast-like fungi.
- the microorganism is a bacteria.
- the bacteria is a gram-positive bacteria.
- the gram-positive bacteria is a member selected from Staphylococcus species, Streptococcus species, Bacillus species, Mycobacterium species, Cory neb acterium species (Propionibacterium species), Clostridium species, Actinomyces species, Enterococcus species and Streptomyces species.
- the bacteria is a gram-negative bacteria.
- the gram-negative bacteria is a member selected from Acinetobacter species, Neisseria species, Pseudomonas species, Brucella species, Agrobacterium species, Bordetella species, Escherichia species, Shigella species, Yersinia species, Salmonella species, Klebsiella species, Enterobacter species, Haemophilus species, Pasteurella species, Streptobacillus species, spirochetal species, Campylobacter species, Vibrio species and Helicobacter species.
- the bacterium is a member selected from Propionibacterium acnes; Staphylococcus aureus; Staphylococcus epidermidis, Staphylococcus saprophyticus; Streptococcus pyogenes; Streptococcus agalactiae; Streptococcus pneumoniae; Enterococcus faecalis; Enterococcus faecium; Bacillus anthracis; Mycobacterium avium-intracellulare; Mycobacterium tuberculosis, Acinetobacter baumanii; Cory neb acterium diphtheria; Clostridium perfringens; Clostridium botulinum; Clostridium tetani; Neisseria gonorrhoeae; Neisseria meningitidis; Pseudomonas aeruginosa; Legionella pneumophila; Escherichia coli;
- the bacteria is a member selected from acid- fast bacterium, including Mycobacterium species; bacilli, including Bacillus species, Coryneb acterium species (also Propionibacterium) and Clostridium species; filamentous bacteria, including Actinomyces species and Streptomyces species; bacilli, such as Pseudomonas species, Brucella species, Agrobacterium species, Bordetella species, Escherichia species, Shigella species, Yersinia species, Salmonella species, Klebsiella species, Enterobacter species, Haemophilus species, Pasteurella species, and Streptobacillus species; spirochetal species, Campylobacter species, Vibrio species; and intracellular bacteria including Rickettsiae species and Chlamydia species.
- acid- fast bacterium including Mycobacterium species
- bacilli including Bacillus species, Coryneb acterium species (also Propionibacterium) and Clo
- the compounds of use in the invention are active against a variety of bacterial organisms. They are active against both Gram positive and Gram negative aerobic and anaerobic bacteria, including staphylococci, for example S. aureus; enterococci, for example E.faecalis; streptococci, for example S. pneumoniae; haemophili, for example H. influenza; Moraxella, for example M. catarrhalis; and Escherichia, for example E. coli.
- the compounds of use in the present invention are also active against mycobacteria, for example M. tuberculosis.
- the compounds of use in the present invention are also active against intercellular microbes, for example Chlamydia and Rickettsiae.
- the compounds of use in the present invention are also active against mycoplasma, for example M. pneumoniae.
- compounds of use in this invention are active against staphylococci organisms such as S. aureus and coagulase negative strains of staphylocci such as S. epidermidis which are resistant (including multiply-resistant) to other anti-bacterial agents, for instance, ⁇ -lactam antibiotics such as, for example, methicillin, acrolides, aminoglycosides, and lincosamides.
- staphylococci organisms such as S. aureus and coagulase negative strains of staphylocci such as S. epidermidis which are resistant (including multiply-resistant) to other anti-bacterial agents, for instance, ⁇ -lactam antibiotics such as, for example, methicillin, acrolides, aminoglycosides, and lincosamides.
- Compounds of use in the present invention are therefore useful in the treatment of MRSA, MRCNS and MRSE.
- Compounds of use in the present invention are also active against vancomycin resistant strains of
- the bacteria is a member selected from Actinobacillus species, Porphyromonas species, Tannerella species, Prevotella species, Eubacterium species, Treponema species, Bulleidia species, Mogibacterium species, Slackia species, Campylobacter species, Eikenella species, Peptostreptococcus species, Peptostreptococcus species, Capnocytophaga species, Fusobacterium species, Porphyromonas species and Bacteroides species.
- the bacteria is a member selected from Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythensis, Prevotella intermedia, Eubacterium nodatum, Treponema denticola, Bulleidia extructa, Mogibacterium timidum Slackia exigua, Campylobacter rectus, Eikenella corrodens, Peptostreptococcus micros, Peptostreptococcus anaerobius, Capnocytophaga ochracea, Fusobacterium nucleatum, Porphyromonas asaccharolytica and Bacteroides for sythus.
- the compound is a member selected from 3-hydroxypyridine-2-carbonyloxy-bis (3- chloro-4-methylphenyl)-borane (bis(3-Chloro4-methylphenyl)borinic acid 3- hydroxypicolinate ester), l,3-dihydro-5-fluoro-l-hydroxy-2,l-benzoxaborole, and 5- (4-cyanophenoxy)-l,3-dihydro-l-hydroxy-2,l-benzoxaborole.
- the compound is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4- methy lpheny l)-borane .
- the microorganism is a virus.
- the virus is a member selected from hepatitis A-B-C, human rhinoviruses, Yellow fever virus, human respiratory coronaviruses, Severe acute respiratory syndrome (SARS), respiratory syncytial virus, influenza viruses, parainfluenza viruses 1-4, human immunodeficiency virus 1 (HIV-I), human immunodeficiency virus 2 (HIV-2), Herpes simplex virus 1 (HSV-I), Herpes simplex virus 2 (HSV-2), human cytomegalovirus (HCMV), Varicella zoster virus, Epstein-Barr (EBV), polioviruses, coxsackieviruses, echoviruses, rubella virus, neuroderma-tropic virus, variola virus, papoviruses, rabies virus, dengue virus, and West Nile virus.
- the virus is a member selected from picornaviridae, flaviviridae, coronaviridae, paramyxoviridae, orthomyxoviridae, retroviridae, herpesviridae and hepadnaviridae.
- the virus is a member selected from a virus included in the following table: Table A. Viruses
- HCV Human respiratory coronavirus
- SAR Severe acute respiratory syndrome
- Bunyavirus - Bunyamwera BUN
- HTN Hantavirus - Hantaan
- HIV-I Human immunodeficiency virus 1
- HIV-2 Retroviridae Human immunodeficiency virus 2 (HIV -2)
- Papovaviridae Pediatric viruses that reside in kidney Adenoviridae Human respiratory distress and some deep-seated eye infections
- HSV-I Herpes simplex virus 1
- HSV-2 Herpes simplex virus 2
- HBV Hepatitis B virus
- HCV Hepatitis C virus
- the compounds of the invention are useful for the treatment of diseases of both animals and humans, involving parasites, including protozoa and helminths.
- parasites include, among others, Entamoeba, Leishmania, Toxoplasma, Trichinella and Schistosoma.
- the parasite is a member selected from Plasmodium falciparum, P. vivax, P. ovale P. malariae, P. berghei, Leishmania donovani, L. infantum, L. chagasi, L. mexicana, L. amazonensis, L. venezuelensis, L. tropics, L. major, L. minor, L.
- aethiopica L. Biana braziliensis, L. (V.) guyanensis, L. (V.) panamensis, L. (V.) peruviana, Trypanosoma brucei rhodesiense, T. brucei gambiense, T. cruzi, Giardia intestinalis, G. lambda, Toxoplasma gondii, Entamoeba histolytica, Trichomonas vaginalis, Pneumocystis carinii, and Cryptosporidium parvum.
- the disease caused by the parasite is a member selected from malaria, Chagas' disease, Leishmaniasis, African sleeping sickness (African human trypanosomiasis), giardiasis, toxoplasmosis, amebiasis and cryptosporidiosis.
- the invention provides a method of treating or preventing periodontal disease, or both.
- the method includes administering to the animal a therapeutically effective amount of a compound of the invention.
- the compound is a member selected from a boron-containing compound described herein, sufficient to treat or prevent said disease.
- the compound is a member selected from 3-hydroxypyridine- 2-carbonyloxy-bis (3-chloro-4-methylphenyl)-borane (bis(3-Chloro4- methylphenyl)borinic acid 3-hydroxypicolinate ester), l,3-dihydro-5-fluoro-l- hydroxy-2,l-benzoxaborole, and 5-(4-cyanophenoxy)-l,3-dihydro-l-hydroxy-2,l- benzoxaborole.
- the compound is 3- hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl)-borane.
- the animal is a member selected from human, cattle, deer, reindeer, goat, honey bee, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, camel, yak, elephant, ostrich, otter, chicken, duck, goose, guinea fowl, pigeon, swan, and turkey.
- the animal is a human.
- the animal is a member selected from a human, cattle, goat, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, chicken and turkey.
- the infection is a member selected from a gingivitis, periodontitis or juvenile/acute periodontitis.
- Additional examples of compounds which can be produced by this method include 2-bromo-4-(3-cyanophenoxy)benzyl alcohol; 2-bromo-4-(4- chlorophenoxy)benzyl alcohol; 2-bromo-4-phenoxybenzyl alcohol; 2-bromo-5-(3,4- dicyanophenoxy)benzyl alcohol; 2-(2-bromo-5-fluorophenyl)ethyl alcohol; 2-bromo- 5-fluorobenzyl alcohol; and l-bromo-2-naphthalenemethanol.
- Additional examples of compounds which can be produced by this method include 2-bromo-l-(methoxymethoxymethyl)benzene; 2-bromo-5 -methyl- 1 - (methoxymethoxymethyl)benzene; 2-bromo-5 -(methoxymethoxymethyl)- 1 - (methoxymethoxymethyl)benzene; 2-bromo-5 -fluoro- 1 -
- the organic layer was washed with water and brine, and dried on anhydrous sodium sulfate.
- the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) followed by trituration with ethyl acetate to give the target compound (55 mg, 23%).
- Additional examples of compounds which can be produced by this method include 2-bromo-5-(4-cyanophenoxy)benzyl alcohol.
- Examples 1-7 can be used to formulate the following compounds. Where available, melting point characterization is provided for these compounds.
- Exemplary starting material (2-bromo-4-(4- fluorophenylthio)phenyl)methanol.
- M.P. 158-163 0 C.
- Exemplary starting material 2-(4-bromo-3- (hydroxymethyl)phenoxy)- 1 -(piperidin- 1 -yl)ethanone .
- Exemplary starting material (2-bromo-4-(4-(pyridin-2- yl)piperazin- 1 -yl)phenyl)methanol.
- Exemplary starting material (2-bromo-4-(lH-indol-l- yl)phenyl)methanol.
- Exemplary starting material 6-(4-bromo-3- (hydroxymethyl)phenoxy)nicotinonitrile.
- M.P. 135-141 0 C.
- Exemplary starting material 3-(l-(3-bromo-4- (hydroxymethyl)phenyl)-lH-indol-3-ylthio)propanenitrile.
- Exemplary starting material (2-bromo-4-(5-methoxy- 1 H-indol- 1 -yl)phenyl)methanol.
- Exemplary starting material (2-bromo-4-(5-methoxy- 3-(phenylthio)- 1 H-indol- 1 -yl)phenyl)methanol.
- Exemplary starting material 4-(l- hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-7-yloxy)benzonitrile.
- Exemplary starting material (2-bromo-4-(4-(pyrimidin-2- yl)piperazin- 1 -yl)phenyl)methanol.
- Exemplary starting material (2-bromo-3- fluorophenyl)methanol.
- Exemplary starting material (2-bromo-4-(4- (trifluoromethyl)phenoxy)phenyl)methanol.
- Exemplary starting material N-(4-bromo-3- (hydroxymethyl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide.
- Exemplary starting material (2-bromo-4-(4- (trifluoromethyl)phenylthio)phenyl)methanol.
- This compound was made from 2-bromobenzylalcohol in the same manner as compound 5b and used for the next step without purification.
- This compound was synthesized from 21b in a similar manner to 22a and used for the next step without purification.
- the (hetero)aryl-bromide or iodide was dissolved in dry THF (20-30 mL/g) under nitrogen and degassed. The solution was cooled to -78°C in an acetone/dry ice bath and n-, sec- or tert-butyllithium in THF or other solvent (1.2-2.4 molar equivalents) was added to the cooled solution dropwise (generally causing the solution to turn deep yellow). The boronic acid ethylene glycol ester (1 molar equivalent) was dissolved in dry THF or diethyl ether (2-10 mL/g) under nitrogen.
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Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002654449A CA2654449A1 (en) | 2006-06-12 | 2007-06-12 | Compounds for the treatment of periodontal disease |
AU2007257689A AU2007257689A1 (en) | 2006-06-12 | 2007-06-12 | Compounds for the treatment of periodontal disease |
MX2008015918A MX2008015918A (en) | 2006-06-12 | 2007-06-12 | Compounds for the treatment of periodontal disease. |
EP07812123A EP2044091A4 (en) | 2006-06-12 | 2007-06-12 | COMPOUNDS FOR TREATING A PERIODONTAL DISEASE |
BRPI0713010-4A BRPI0713010A2 (en) | 2006-06-12 | 2007-06-12 | compounds for the treatment of periodontal disease |
IL195571A IL195571A0 (en) | 2006-06-12 | 2008-11-27 | Compounds for the treatment of periodontal disease |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US80450406P | 2006-06-12 | 2006-06-12 | |
US60/804,504 | 2006-06-12 | ||
US82389306P | 2006-08-29 | 2006-08-29 | |
US60/823,893 | 2006-08-29 |
Publications (2)
Publication Number | Publication Date |
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WO2007146965A2 true WO2007146965A2 (en) | 2007-12-21 |
WO2007146965A3 WO2007146965A3 (en) | 2008-12-04 |
Family
ID=38832802
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2007/071049 WO2007146965A2 (en) | 2006-06-12 | 2007-06-12 | Compounds for the treatment of periodontal disease |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP2044091A4 (en) |
KR (1) | KR20090029797A (en) |
AU (1) | AU2007257689A1 (en) |
BR (1) | BRPI0713010A2 (en) |
CA (1) | CA2654449A1 (en) |
IL (1) | IL195571A0 (en) |
MX (1) | MX2008015918A (en) |
RU (1) | RU2008152367A (en) |
WO (1) | WO2007146965A2 (en) |
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CA2654449A1 (en) | 2007-12-21 |
WO2007146965A3 (en) | 2008-12-04 |
IL195571A0 (en) | 2009-09-01 |
BRPI0713010A2 (en) | 2012-10-09 |
RU2008152367A (en) | 2010-07-20 |
EP2044091A4 (en) | 2010-08-04 |
AU2007257689A1 (en) | 2007-12-21 |
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MX2008015918A (en) | 2009-01-14 |
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