Novel pyridine-based thyroid receptor ligands are provided which have the general formula I

This invention relates to novel pyridine-based compounds which are thyroid receptor ligands and are preferably selective for the thyroid hormone receptor xcex2. Further, the present invention relates to methods for using such compounds and to pharmaceutical compositions containing such compounds.
While the extensive role of thyroid hormones in regulating metabolism in humans is well recognized, the discovery and development of new specific drugs for improving the treatment of hyperthyroidism and hypothyroidism has been slow. This has also limited the development of thyroid agonists and antagonists for treatment of other important clinical indications, such as hypercholesterolemia, obesity and cardiac arrhythmias.
Thyroid hormones affect the metabolism of virtually every cell of the body. At normal levels, these hormones maintain body weight, metabolic rate, body temperature and mood, and influence blood levels of serum low density lipoprotein (LDL). Thus, in hypothyroidism there is weight gain, high levels of LDL cholesterol, and depression. In hyperthyroidism, these hormones lead to weight loss, hypermetabolism, lowering of serum LDL levels, cardiac arrhythmias, heart failure, muscle weakness, bone loss in postmenopausal women, and anxiety.
Thyroid hormones are currently used primarily as replacement therapy for patients with hypothyroidism. Therapy with L-thyroxine returns metabolic functions to normal and can easily be monitored with routine serum measurements of levels of thyroid-stimulating hormone (TSH), thyroxine (3,5,3xe2x80x2,5xe2x80x2-tetraiodo-L-thyronine, or T4) and triiodothyronine (3,5,3xe2x80x2-triiodo-L-thyronine, or T3). However, replacement therapy, particularly in older individuals, may be restricted by certain detrimental effects from thyroid hormones.
In addition, some effects of thyroid hormones may be therapeutically useful in non-thyroid disorders if adverse effects can be minimized or eliminated. These potentially useful influences include weight reduction, lowering of serum LDL levels, amelioration of depression and stimulation of bone formation. Prior attempts to utilize thyroid hormones pharmacologically to treat these disorders have been limited by manifestations of hyperthyroidism, and in particular by cardiovascular toxicity.
Development of specific and selective thyroid hormone receptor ligands, particularly agonists of the thyroid hormone receptor could lead to specific therapies for these common disorders, while avoiding the cardiovascular and other toxicity of native thyroid hormones. Tissue-selective thyroid hormone agonists may be obtained by selective tissue uptake or extrusion, topical or local delivery, targeting to cells through other ligands attached to the agonist and targeting receptor subtypes. Thyroid hormone receptor agonists that interact selectively with the xcex2-form of the thyroid hormone receptor offers an especially attractive method for avoiding cardio-toxicity.
Thyroid hormone receptors (TRs) are, like other nuclear receptors, single polypeptide chains. The various receptor forms appear to be products of two different genes xcex1 and xcex2. Further isoform differences are due to the fact that differential RNA processing results in at least two isoforms from each gene. The TRxcex11, TRxcex21 and TRxcex22 isoforms bind thyroid hormone and act as ligand-regulated transcription factors. In adults, the TRxcex21 isoform is the most prevalent form in most tissues, especially in the liver and muscle. The TRxcex12 isoform is prevalent in the pituitary and other parts of the central nervous system, does not bind thyroid hormones, and acts in many contexts as a transcriptional repressor. The TRxcex11 isoform is also widely distributed, although its levels are generally lower than those of the TRxcex21 isoform. Whereas many mutations in the TRxcex2 gene have been found and lead to the syndrome of generalized resistance to thyroid hormone, mutations leading to impaired TRxcex1 function have not been found.
A growing body of data suggests that many or most effects of thyroid hormones on the heart, and in particular, on the heart rate and rhythm, are mediated through the xcex1-form of the TRxcex11 isoform, whereas most actions of the hormone such as on the liver, muscle and other tissues, are mediated more through the xcex2-forms of the receptor. Thus, a TRxcex2-selective agonist might not elicit the cardiac rhythm and rate influences of the hormones, but would elicit many other actions of the hormones. Applicants believe that the xcex1-form of the receptor is primarily associated with heart rate function for the following reasons:
1) tachycardia is very common in the syndrome of generalized resistance to thyroid hormone in which there are defective TRxcex2-forms, and high circulating levels of T4 and T3;
2) there was a tachycardia in the only described patient with a double deletion of the TRxcex2 gene (Takeda et al, J. Clin. Endrocrinol. and Metab. 1992, Vol. 74, p. 49);
3) a double knockout TRxcex1 gene (but not xcex2-gene) in mice resulted in a slower mouse heart rate, as compared to control mice; and
4) western blot analysis of human myocardial TRs show presence of the TRxcex11, TRxcex12 and TRxcex22 proteins, but not TRxcex21.
If these indications are correct, then it may be possible that a TRxcex2-selective agonist could be used to mimic a number of thyroid hormone actions, while having a lesser effect on the heart. Such a compound may be used for: (1) replacement therapy in elderly subjects with hypothyroidism who are at risk for cardiovascular complications; (2) replacement therapy in elderly subjects with subclinical hypothyroidism who are at risk for cardiovascular complications; (3) obesity; (4) hypercholesterolemia due to elevations of plasma LDL levels; (5) depression; and (6) osteoporosis in combination with a bone resorption inhibitor.
In accordance with the illustrative embodiments and demonstrating features of the present invention, compounds are provided which are thyroid receptor ligands, and have the general formula I
wherein
X is oxygen (xe2x80x94Oxe2x80x94), sulfur (xe2x80x94Sxe2x80x94), sulfoxide (xe2x80x94S(O)xe2x80x94), sulfonyl (xe2x80x94SO2xe2x80x94), CR8R8xe2x80x2 or NR8;
Y is oxygen (xe2x80x94Oxe2x80x94), xe2x80x94NR8, xe2x80x94CH2xe2x80x94 or sulfur (xe2x80x94Sxe2x80x94);
Z is a bond or substituted or unsubstituted C1-4 alkyl;
R1 is halogen, trifluoromethyl, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted amide, sulfone, sulfonamide, aryloxy or C3-7 cycloalkyl, wherein said aryl, heteroaryl or cycloalkyl ring(s) are attached or fused to the aromatic ring;
R1a is hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R2 and R3 are each independently hydrogen, halogen, substituted or unsubstituted C1-4 alkyl or substituted or unsubstituted C3-5 cycloalkyl, wherein at least one of R2 and R3 being other than hydrogen;
R4 is hydrogen, halogen, amino, Oxe2x80x94R7, Sxe2x80x94R7 or C1-4 alkyl;
R5 is hydroxyl (xe2x80x94OH), carboxylic acid (xe2x80x94COOH), sulfonic acid (xe2x80x94SO2OH) or phosphonic acid (xe2x80x94PO3H2);
R6 is hydrogen, alkyl, alkanoyl or aroyl (such as acetyl or benzoyl);
R7 is hydrogen or C1-4 alkyl;
R8 for each occurrence is independently hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, aryl or substituted aryl, arylalkyl or substituted arylalkyl, alkoxy or hydroxyl; and
R8xe2x80x2 is hydrogen, a bond, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, aryl or substituted aryl, arylalkyl or substituted arylalkyl, alkoxy or hydroxyl, or R8 and R8xe2x80x2 together form a carbonyl (xe2x80x94COxe2x80x94).
The definition of formula I above includes all prodrug-esters, stereoisomers and pharmaceutically acceptable salts of formula I.
The compounds of formula I are thyroid hormone receptor ligands and include compounds which are, for example, selective agonists, partial agonists, antagonists or partial antagonists of the thyroid receptor. Preferably, the compounds of formula I possess activity as agonists of the thyroid receptor, preferably selective agonists of the thyroid receptor-beta, and may be used in the treatment of diseases or disorders associated with thyroid receptor activity. In particular, the compounds of formula I may be used in the treatment of diseases or disorders associated with metabolism dysfunction or which are dependent upon the expression of a T3 regulated gene, such as obesity, hypercholesterolemia, atherosclerosis, cardiac arrhythmias, depression, osteoporosis, hypothyroidism, goiter, thyroid cancer, glaucoma, skin disorders or diseases and congestive heart failure.
The present invention provides for compounds of formula I, pharmaceutical compositions employing such compounds and for methods of using such compounds. In particular, the present invention provides for a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, alone or in combination with a pharmaceutically acceptable carrier.
Further, in accordance with the present invention, a method is provided for preventing, inhibiting or treating the progression or onset of diseases or disorders associated with the thyroid receptor, particularly, the thyroid receptor-beta, such as the diseases or disorders defined above and hereinafter, wherein a therapeutically effective amount of a compound of formula I is administered to a mammalian, i.e., human patient in need of treatment.
The compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more other agent(s) active in the therapeutic areas described herein.
In addition, a method is provided for preventing, inhibiting or treating the diseases as defined above and hereinafter, wherein a therapeutically effective amount of a combination of a compound of formula I and another compound of the invention and/or another type of therapeutic agent, is administered to a mammalian patient in need of treatment.
Preferably, compounds of this invention include embodiments of formula I wherein
X is oxygen, sulfur, sulfoxide, sulfonyl, xe2x80x94CH2xe2x80x94 or xe2x80x94NHxe2x80x94;
Y is oxygen or xe2x80x94NHxe2x80x94;
R1 is halogen, substituted or unsubstituted C1-6 alkyl, C3-7 cycloalkyl, substituted aryl, aryloxy, substituted amide, sulfone or sulfonamide, wherein R1 is attached ortho to the R6Oxe2x80x94 group;
R2 and R3 are each independently iodo, bromo, chloro or fluoro;
R4 is hydrogen, fluoro, chloro, amino, xe2x80x94OCH3, hydroxyl (xe2x80x94OH) or methyl;
R5 is carboxylic acid; and
R6 is hydrogen.
Other preferred embodiments of the invention include compounds of formula I wherein
X is carbonyl, CHR8 or NR8;
Y is oxygen or xe2x80x94NHxe2x80x94;
R1 is halogen, substituted or unsubstituted C1-6 alkyl, substituted aryl, substituted amide, sulfone, sulfonamide or C3-7 cycloalkyl;
R2 and R3 are independently bromo, chloro or methyl;
R4 is hydrogen, fluoro, chloro, hydroxyl, amino, methoxy or methyl;
R5 is a carboxylic acid; and
R6 is hydrogen.
Further preferred embodiments of the invention include compounds of formula I having the structure:
wherein
Y is oxygen or xe2x80x94NHxe2x80x94.
R1a is hydrogen, methyl or ethyl;
R2 and R3 are halogen;
R4 is hydrogen, halogen, amino, xe2x80x94OCH3 or hydroxyl; and
R10 is hydrogen, halogen or substituted or unsubstituted C1-4 alkyl.
The following abbreviations have the indicated meanings:
Ar=aryl
Bn=benzyl
DMF=N,N-dimethylformamide
DMSO=dimethyl sulfoxide
Et=ethyl
EtOAc=ethyl acetate
g=gram(s)
h or hr=hour(s)
Me=methyl
M+H=parent plus a proton
min=minute(s)
mL=milliliter
mg=milligram(s)
mol=moles
mmol=millimole(s)
M=molar
Ph=phenyl
RT=room temperature
HPLC=high performance liquid chromatography
NMR=nuclear magnetic resonance
THF=tetrahydrofuran
TFA=trifluoroacetic acid
xcexcL=microliter
The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.
The term xe2x80x9cthyroid receptor ligandxe2x80x9d as used herein is intended to cover any moiety which binds to a thyroid receptor. The ligand may act as an agonist, an antagonist, a partial agonist or a partial antagonist. Another term for xe2x80x9cthyroid receptor ligandxe2x80x9d is xe2x80x9cthyromimeticxe2x80x9d.
Unless otherwise indicated, the term xe2x80x9calkyldxe2x80x9d as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons, containing 1 to 12 carbons in the normal chain, preferably 1 to 4 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, or isobutyl, pentyl, hexyl, isohexyl, heptyl; 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl. xe2x80x9cSubstituted alkylxe2x80x9d includes an alkyl group optionally substituted with one or more functional groups which are commonly attached to such chains, such as, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, hydroxy, cyano, nitro, amino, halo, carboxyl or alkyl ester thereof and/or carboxamide, substituted or unsubstituted.
Unless otherwise indicated, the term xe2x80x9calkoxyxe2x80x9d refers to alkyl-Oxe2x80x94. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.
The term xe2x80x9carylxe2x80x9d or xe2x80x9cArxe2x80x9d as employed herein alone or as part of another group refers to monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl including l-naphthyl and 2-naphthyl). xe2x80x9cSubstituted arylxe2x80x9d includes an aryl group optionally substituted through available carbon atoms with one or more groups selected from hydrogen, halo, substituted or unsubstituted alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, hydroxy, amino, nitro, cyano and/or any of the alkyl substituents set out herein.
The term xe2x80x9calkanoylxe2x80x9d refers to alkyl-C(O)xe2x80x94.
The term xe2x80x9caroylxe2x80x9d refers to aryl-C(O)xe2x80x94.
Unless otherwise indicated, the term xe2x80x9caryloxyxe2x80x9d as employed herein, alone or as part of another group, denotes xe2x80x94ORxe2x80x94 wherein R is aryl as defined herein.
The term xe2x80x9cheteroarylxe2x80x9d means a 5- or 6-membered aromatic heterocyclic ring which contains one or more heteroatoms selected from nitrogen, sulfur, oxygen and/or a SO or SO2 group. Such rings may be fused to another aryl or heteroaryl ring and include possible N-oxides. xe2x80x9cSubstituted heteroarylxe2x80x9d includes a heteroaryl group optionally substituted with one or more substituents, such as those described for substituted alkyl and/or substituted aryl.
The term xe2x80x9caminoxe2x80x9d as used herein refers to xe2x80x94NRARB where RA and RB are independently hydrogen, or RA and/or RB may optionally be a substituent, such as aryl, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, cyano, nitro, carboxyl, halo, alkylthio, heteroaryl, heterocycle, heterocycle(aryl) carboalkyl and the like.
The term xe2x80x9csubstituted amidexe2x80x9d as used herein refers to an amide linkage: xe2x80x94C(O)NR where R is hydrogen or may optionally be a substituent, such as aryl, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, cyano, nitro, amino, carboxyl, halo, alkylthio, heteroaryl, heterocycle carboalkyl and the like.
The term xe2x80x9csulfonamidexe2x80x9d as used herein refers to a sulfonamide linkage: xe2x80x94SO2NRRxe2x80x2 where R and Rxe2x80x2 are independently hydrogen, or one or both of R and Rxe2x80x2 may optionally be substituents, such as any of the substituents described in the definition of substituted alkyl or substituted amino.
The term xe2x80x9csulfonexe2x80x9d as used herein refers to a sulfone linkage: xe2x80x94SO2R where R is hydrogen or may optionally be a substituent, such as aryl, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, cyano, nitro, amino, carboxyl, halo, alkylthio, heteroaryl, heterocycle carboalkyl and the like.
The term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocycloxe2x80x9d as used herein, represents a 5- to 7-membered monocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from N, O or S. Exemplary monocyclic heterocyclo groups include 2- and 3-thienyl, 2- and 3-furyl, 2-, 3-, and 4-pyridyl and imidazolyl. The term heterocycle or heterocyclic ring also includes bicyclic rings wherein the five- or six-membered ring containing oxygen and/or sulfur and/or nitrogen atoms as defined above is fused to a benzene ring and the bicyclic ring is attached by way of an available atom. Exemplary bicyclic heterocycle groups include 4-, 5-, 6- or 7-indolyl, 4-, 5-, 6-, or 7-isoindolyl, 5-, 6-, 7- or 8-quinolinyl, 5-, 6-, 7- or 8-isoquinolinyl and 4-, 5-, 6- or 7-benzothiazoyl. xe2x80x9cSubstituted heterocycloxe2x80x9d includes a heterocyclo group optionally substituted with one or more substituents, such as those described for substituted alkyl and/or substituted aryl.
Unless otherwise indicated, the term xe2x80x9calkenylxe2x80x9d as used herein refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 2 to 8 carbons in the normal chain, which include one or more double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like. xe2x80x9cSubstituted alkenylxe2x80x9d includes an alkenyl group optionally substituted with one or more substituents, such as those described for substituted alkyl and/or substituted aryl.
The term xe2x80x9carylalkylxe2x80x9d refers to alkyl groups as described above having an aryl substituent. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl and the like. xe2x80x9cSubstituted arylalkylxe2x80x9d includes an arylalkyl group optionally substituted with one or more substituents, such as those described for substituted alkyl and/or substituted aryl.
The term xe2x80x9ccycloalkylxe2x80x9d or xe2x80x9ccycloalkenylxe2x80x9d as used herein includes saturated or partially saturated (containing one or more double bonds) cyclic hydrocarbon groups containing 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. xe2x80x9cSubstituted cycloalkylxe2x80x9d or xe2x80x9csubstituted cycloalkenylxe2x80x9d include a cycloalkyl or cycloalkenyl group optionally substituted with one or more substituents, such as those described for substituted alkyl and/or substituted aryl.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as used herein alone or as part of another group-refers to chlorine, bromine, fluorine and iodine, with chlorine or bromine being preferred.
The (CH2)n group is an alkyl group that includes 0 to 4 carbons in the normal chain which may include 1, 2, or 3 alkyl substituents.
The term xe2x80x9ccarbonylxe2x80x9d, as used herein, refers to a xe2x80x94C(O)xe2x80x94 group.
The compounds of formula I can be present as salts, which are also within the scope of this invention. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred. If the compounds of formula I have, for example, at least one basic center, they can form acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, (for example aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as (C1-C4) alkyl or arylsulfonic acids which are unsubstituted or substituted, for example by halogen, for example methyl- or p-toluene-sulfonic acid. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. The compounds of formula I having at least one acid group (for example COOH) can also form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di or tri-lower alkylamine, for example ethyl, tertbutyl, diethyl, diisopropyl, triethyl, tributyl or dimethyl-propylamine, or a mono, di or trihydroxy lower alkylamine, for example mono, di or triethanolainine. Corresponding internal salts may furthermore be formed. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds of formula I or their pharmaceutically acceptable salts, are also included.
Preferred salts of the compounds of formula I which contain a basic group include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate or nitrate.
Preferred salts of the compounds of formula I which contain an acid group include sodium, potassium and magnesium salts and pharmaceutically acceptable organic amines.
The compounds of formula I may also have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., the compound of formula I) is a prodrug within the scope and spirit of the invention.
Various forms of prodrugs are well known in the art. A comprehensive description of prodrugs and prodrug derivatives may be found in:
a.) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31, (Academic Press, 1996);
b.) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); and
c.) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pgs 113-191 (Harwood Academic Publishers, 1991).
Said references are incorporated herein by reference.
Embodiments of prodrugs suitable for use in the present invention include lower alkyl esters, such as ethyl ester, or acyloxyalkyl esters such as pivaloyloxymethyl (POM).
An administration of a therapeutic agent of the invention includes administration of a therapeutically effective amount of the agent of the invention. The term xe2x80x9ctherapeutically effective amountxe2x80x9d as used herein refers to an amount of a therapeutic agent to treat or prevent a condition treatable by administration of a composition of the invention. That amount is the amount sufficient to exhibit a detectable therapeutic or preventative or ameliorative effect. The effect may include, for example, treatment or prevention of the conditions listed herein. The precise effective amount for a subject will depend upon the subject""s size and health, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration. Thus, it is not useful to specify an exact effective amount in advance.
The compounds of formula I of the invention can be prepared as shown in the following reaction schemes and description thereof, as well as by relevant published literature procedures that may be used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter and in the working Examples. Protection and deprotection in the Schemes below may be carried out by procedures generally known in the art. For example, see T. W. Greene and P. G. M. Wuts, xe2x80x9cProtecting Groups in Organic Synthesisxe2x80x9d, 3rd Edition, (Wiley, 1999), incorporated herein by reference.
Scheme 1 depicts a general synthetic approach to compounds of formula I wherein X=O, S or NR8, which utilizes the displacement reaction of an appropriately substituted phenol, thiophenol or aniline 1 such as 3-isopropyl-4-methoxyphenol or 4-methoxynaphthol with a pentasubstituted pyridine 2 such as 3,5-dichloro-2,4,6-trifluoropyridine or pentafluoro pyridine to provide intermediate 3. In structure 1 and all other applicable structures contained in further schemes described below, the term xe2x80x9cPGxe2x80x9d refers to a protecting group appropriate for the functional group indicated (in this instance, for a phenolic oxygen). Subsequent displacement of the 2-fluoro and 6-fluoro substituents on the pyridine 3 with nucleophiles 4 and reactant HR4 sequentially provide intermediates 5 and 6 respectively. Examples of suitable nucleophiles 4 include, but are not limited to, glycine methyl ester and methyl glycolate. Examples of reactant HR4 include, but are not limited to, alkylthiol, sodium alkoxide, alkylamine, or benzylamine. Compounds of formula I wherein X is sulfoxide or sulfonyl can be derived from intermediates 5 or 6 when X is S, via oxidation with an oxidating agent, for example mCPBA. Further protecting group and functional group manipulation of intermediates 5 or 6 will provide the compounds of formula I where X is O, S, NR8, sulfoxide and sulfonyl.
For example, where intermediate 1 is 3-isopropyl-4-methoxy phenol (X is oxygen) and intermediate 2 is 3, 5-dichloro-2,4,6-trifluoro pyridine (R2 and R3 are chlorine), the resulting intermediate 3 would be the corresponding diaryl ether where X=O and R2=R3=Cl. The 2-fluoro substituent of this intermediate can be readily displaced with nucleophile 4 where Y is O, NR8, CH2 or sulfur, such as an amine or alkoxide, to form intermediate 5. The 6-fluoro substituent of the resulting amino or alkoxypyridine 5 can then be further displaced with a third nucleophile, such as ethylthiol in presence of potassium carbonate to provide the intermediate 6. Deprotection or Raney-Nickel desulfurization of 5 and/or 6 would provide the desired compounds of formula I wherein R4=F or H.
Poly-substituted prime rings may be prepared by using commerically available polysubstituted phenols as illustrated below in Scheme 1 b where X represents a halogen.
Alternatively, poly-substitutions can be achieved by halogenation of intermediate Ia or its acyl derivative, intermediate Iia, followed by hydrolysis. Conversion of the halogens (X) to an alkyl, aryl or heteroaryl may be achieved by subsequent Steele or Suzuki coupling reactions with tetraalkyltin or aryl boronic acid reagents.
Scheme 2 depicts another general synthetic approach to produce the compounds of formula I wherein X=O in which the position adjacent (ortho) to Oxe2x80x94PG (R1=H) can be functionalized via sulfonation/sulfonylation, brominalion or formylation to provide intermediate 7, 8 and 9. Conversion of CHO to COOH and to N-substituted amide may be carried out by methods well known in the art, such as oxidation of the formyl group of intermediate 9 to form intermediate 10. Carbodiimide promoted coupling of an amine with the resulting carboxylic acid of intermediate 10 provides intermediate 11 wherein R1=an amide. Subsequent displacement of the 2-fluoro substituent of 11 with an amine or alkoxide 4, where Y=NH or O, as described in the description of Scheme 1, provides intermediate 5. Displacement of the 2-fluoro substituent of 8 with 4 provides 12. Subsequent Suzuki coupling of the aryl bromide 12 with substituted phenylboronic acid provides 5 wherein R1=Aryl.
Chloronation of the aryl sulfonic acid 7 wherein R1=OH, followed by addition of an amine or aniline provides the aryl sulfonamide intermediate 13. Displacement of the 2 fluoro substituent of 13 or 7 wherein R1=Ar, with 4 provides 5 wherein R1=sulfonamide or sulfone.
Scheme 2b depicts Baeyer-Villiger oxidation of the intermediate 9 followed by hydrolysis provides 14. Treatment of 14 with aryl boronic acids under Evan""s conditions (see D. A. Evans et al., Tetrahedron Lett., 39, 2937-2940, 1998) provides intermediate 15. Subsequent displacement of the 2-fluoro substituent of 15 with 4 provides 5 wherein R1=aryloxy. Further protecting group and functional group manipulation of the intermediate 5 will provide the desired compounds of formula I where X is oxygen.
Alternatively, compounds of formula I in which X is CR8R8xe2x80x2 or CO may be prepared as shown in Scheme 3. Conversion of 2 to 18 may be achieved via displacement of the 4-fluoro substituent of 2 with 16 followed by displacement of the 2-fluoro substituent of 17 with nucledphile 4. Oxidation of 18 provides 19. Deprotection and functional group manipulation of 19 provides compounds of formula I wherein X is CO. Alternatively, reductive deoxygenation of 19 affords 20. Deprotection of 20 provides intermediate 22. Alternatively, Wittig olefination of 19 provides intermediate 21. Hydrogenation, deprotection and functional group manipulation of 21 provides intermediate 22. Deprotection and functional group manipulation of 22 provides compounds of formula I where X is CR8R8xe2x80x2.
Further methods applicable to the synthesis of compounds of formula I in which X=O and R2 and R3 are independently varied as hydrogen, halogen and alkyl are described in Li et al., WO 99/00353.
All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The compounds of the present invention can have asymmetric centers at any of the carbon atoms including any one of the R substitutents. Consequently, compounds of formula I can exist in enantiomeric or diasteromeric forms or in mixtures thereof. The processes for preparation can utilize racemates, enantiomers or diasteromers as starting materials. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods. For example, chromatographic or fractional crystallization.
A. Utilities
The compounds of the present invention are thyroid receptor ligands, and include compounds which are, for example, selective agonists, partial agonists, antagonists or partial antagonists of the thyroid receptor. Preferably compounds of the present invention possess activity as agonists of the thyroid receptor, preferably selective agonists of the thyroid receptor-beta, and may be used in the treatment of diseases or disorders associated with thyroid receptor activity. In particular, compounds of the present invention may be used in the treatment of diseases or disorders associated with metabolism dysfunction or which are dependent upon the expression of a T3 regulated gene.
Accordingly, the compounds of the present invention can be administered to mammals, preferably humans, for the treatment of a variety of conditions and disorders, including, but not limited to hypothyroidism; subclinical hyperthyroidism; non-toxic goiter; atherosclerosis; thyroid hormone replacement therapy (e.g., in the elderly); malignant tumor cells containing the thyroid receptor; papillary or follicular cancer; maintenance of muscle strength and function (e.g., in the elderly); reversal or prevention of frailty or age-related functional decline (xe2x80x9cARFDxe2x80x9d) in the elderly (e.g., sarcopenia); treatment of catabolic side effects of glucocorticoids; prevention and/or treatment of reduced bone mass, density or growth (e.g., osteoporosis and osteopenia); treatment of chronic fatigue syndrome (CFS); accelerating healing of complicated fractures, e.g. distraction osteogenesis; in joint replacement; eating disorders (e.g., anorexia); treatment of obesity and growth retardation associated with obesity; treatment of depression, nervousness, irritability and stress; treatment of reduced mental energy and low selfesteem (e.g., motivation/assertiveness); improvement of cognitive function (e.g., the treatment of dementia, including Alzheimer""s disease and short term memory loss); treatment of catabolism in connection with pulmonary dysfunction and ventilator dependency; treatment of cardiac dysfunction (e.g., associated with valvular disease, myocardial infarction, cardiac hypertrophy or congestive heart failure); lowering blood pressure; protection against ventricular dysfunction or prevention of reperfusion events; treatment of hyperinsulinemia; stimulation of osteoblasts, bone remodeling and cartilage growth; regulation of food intake; treatment of insulin resistance, including NIDDM, in mammals (e.g., humans); treatment of insulin resistance in the heart; treatment of congestive heart failure; treatment of musculoskeletal impairment (e.g., in the elderly); improvement of the overall pulmonary function; skin disorders or diseases, such as glucocorticoid induced dermal atrophy, including restoration of dermal atrophy induced by topical glucocorticoids, and the prevention of dermal atrophy induced by topical glucocorticoids (such as the simultaneous treatment with topical glucocorticoid or a pharmacological product including both glucocorticoid and a compound of the invention), the restoration/prevention of dermal atrophy induced by systemic treatment with glucocdrticoids, restoration/prevention of atrophy in the respiratory system induced by local treatment with glucocorticoids, UV-induced dermal atrophy, dermal atrophy induced by aging (wrinkles, etc.), wound healing, keloids, stria, cellulite, roughened skin, actinic skin damage, lichen planus, ichtyosis, acne, psoriasis, Dernier""s disease, eczema, atopic dermatitis, chloracne, pityriasis and skin scarring.
The term treatment is also intended to include prophylactic treatment.
In addition, the conditions, diseases, and maladies collectively referenced to as xe2x80x9cSyndrome Xxe2x80x9d or Metabolic Syndrome as detailed in Johannsson J. Clin. Endocrinol. Metab., 82, 727-34 (1997), may be treated employing the compounds of the invention.
B. Combinations
The present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, a therapeutically effective amount of at least one of the compounds of formula I, alone or in combination with a pharmaceutical carrier or diluent. Optionally, compounds of the present invention can be used alone, in combination with other compounds of the invention, or in combination with one or more other therapeutic agent(s), e.g., an antidiabetic agent or other pharmaceutically active material.
The compounds of the present invention may be employed in combination with other modulators and/or ligands of the thyroid receptor or other suitable therapeutic agents useful in the treatment of the aforementioned disorders including: anti-diabetic agents; anti-osteoporosis agents; anti-obesity agents; growth promoting agents (including growth hormone secretagogues); anti-inflammatory agents; anti-anxiety agents; anti-depressants; anti-hypertensive agents; cardiac glycosides; cholesterol/lipid lowering agents; appetite suppressants; bone resorption inhibitors; thyroid mimetics (including other thyroid receptor agonists); anabolic agents; and anti-tumor agents.
Examples of suitable anti-diabetic agents for use in combination with the compounds of the present invention include biguanides (e.g., metformin or phenformin), glucosidase inhibitors (e.g., acarbose or miglitol), insulins (including insulin secretagogues or insulin sensitizers), meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, gliclazide, chlorpropamide and glipizide), biguanide/glyburide combinations (e.g., Glucovance(copyright)), thiazolidinediones (e.g., troglitazone, rosiglitazone and pioglitazone), PPAR-alpha agonists, PPAR-gamma agonists, PPAR alpha/gamma dual agonists, SGLT2 inhibitors, glycogen phosphorylase inhibitors, inhibitors of fatty acid binding protein (aP2), glucagon-like peptide-1 (GLP-1), and dipeptidyl peptidase IV (DP4) inhibitors.
Examples of suitable anti-osteoporosis agents for use in combination with the compounds of the present invention include alendronate, risedronate, PTH, PTH fragment, raloxifene, calcitonin, RANK ligand antagonists, calcium sensing receptor antagonists, TRAP inhibitors, selective estrogen receptor modulators (SERM) and AP-1 inhibitors.
Examples of suitable anti-obesity agents for use in combination with the compounds of the present invention include aP2 inhibitors, PPAR gamma antagonists, PPAR delta agonists, beta 3 adrenergic agonists, such as AJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other known beta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615, 5,491,134, 5,776,983 and 5,488,064, a lipase inhibitor, such as orlistat or ATL-962 (Alizyme), a serotonin (and dopamine) reuptake inhibitor, such as sibutramine, topiramate (Johnson and Johnson) or axokine (Regeneron), other thyroid receptor beta drugs, such as a thyroid receptor ligand as disclosed in WO 97/21993 (U. Cal SF), WO 99/00353 (KaroBio) and GB98/284425 (KaroBio), and/or an anorectic agent, such as dexamphetamine, phentermine, phenylpropanolamine or mazindol.
The compounds of the present invention may be combined with growth promoting agents, such as, but not limited to, TRH, diethylstilbesterol, theophylline, enkephalins, E series prostaglandins, compounds disclosed in U.S. Pat. No. 3,239,345, e.g., zeranol, and compounds disclosed in U.S. Pat. No. 4,036,979, e.g., sulbenox or peptides disclosed in U.S. Pat. No. 4,411,890.
The compounds of the invention may also be used in combination with growth hormone secretagogues such as GHRP-6, GHRP-1 (as described in U.S. Pat. No. 4,411,890 and publications WO 89/07110 and WO 89/07111), GHRP-2 (as described in WO 93/04081), NN703 (Novo Nordisk), LY444711 (Lilly), MK-677 (Merck), CP424391 (Pfizer) and B-HT920, or with growth hormone releasing factor and its analogs or growth hormone and its analogs or somatomedins including IGF-1 and IGF-2, or with alpha-adrenergic agonists, such as clonidine or serotinin 5-HTD agonists, such as sumatriptan, or agents which inhibit somatostatin or its release, such as physostigmine and pyridostigmine. A still further use of the disclosed compounds of the invention is in combination with parathyroid hormone, PTH(1-34) or bisphosphonates, such as MK-217 (alendronate).
A still further use of the compounds of the invention is in combination with estrogen, testosterone, a selective estrogen receptor modulator, such as tamoxifen or raloxifene, or other androgen receptor modulators, such as those disclosed in Edwards, J. P. et al., Bio. Med. Chem. Let., 9, 1003-1008 (1999) and Hamann, L. G. et al., J. Med. Chem., 42, 210-212 (1999).
A further use of the compounds of this invention is in combination with steriodal or non-steroidal progesterone receptor agonists (xe2x80x9cPRAxe2x80x9d), such as levonorgestrel, medroxyprogesterone acetate (MPA).
Examples of suitable anti-inflammatory agents for use in combination with the compounds of the present invention include prednisone, dexamethasone, Enbrel(copyright), cyclooxygenase inhibitors (i.e., COX-1 and/or COX-2 inhibitors such as NSAIDs, aspirin, indomethacin, ibuprofen, piroxicam, Naproxen(copyright), Celebrex(copyright), Vioxx(copyright)), CTLA4-Ig agonists/antagonists, CD40 ligand antagonists, IMPDH inhibitors, such as mycophenolate (CellCept(copyright)), integrin antagonists, alpha-4 beta-7 integrin antagonists, cell adhesion inhibitors, interferon gamma antagonists, ICAM-1, tumor necrosis factor (TNF) antagonists (e.g., infliximab, OR1384), prostaglandin synthesis inhibitors, budesonide, clofazimine, CNI-1493, CD4 antagonists (e.g., priliximab), p38 mitogen-activated protein kinase inhibitors, protein tyrosine kinase (PTK) inhibitors, IKK inhibitors, and therapies for the treatment of irritable bowel syndrome (e.g., Zelmac(copyright) and Maxi-K(copyright) openers such as those disclosed in U.S. Pat. No. 6,184,231 B1).
Example of suitable anti-anxiety agents for use in combination with the compounds of the present invention include diazepam, lorazepam, buspirone, oxazepam, and hydroxyzine pamoate.
Examples of suitable anti-depressants for use in combination with the compounds of the present invention include citalopram, fluoxetine, nefazodone, sertraline, and paroxetine.
For the treatment of skin disorders or diseases as described above, the compounds of the present invention may be used alone or optionally in combination with a retinoid, such as tretinoin, or a vitamin D analog.
Examples of suitable anti-hypertensive agents for use in combination with the compounds of the present invention include beta adrenergic blockers, calcium channel blockers (L-type and T-type; e.g. diltiazem, verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g., sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), Dual ET/AII antagonist (e.g., compounds disclosed in WO 00/01389), neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilat and gemopatrilat), and nitrates.
Examples of suitable cardiac glycosides for use in combination with the compounds of the present invention include digitalis and ouabain.
Examples of suitable cholesterol/lipid lowering agents for use in combination with the compounds of the present invention include HMG-COA reductase inhibitors, squalene synthetase inhibitors, fibrates, bile acid sequestrants, ACAT inhibitors, MTP inhibitors, lipooxygenase inhibitors, an ileal Na+/bile acid cotransporter inhibitor, cholesterol absorption inhibitors, and cholesterol ester transfer protein inhibitors (e.g., CP-529414).
MTP inhibitors which may be employed herein in combination with one or more compounds of formula I include MTP inhibitors as disclosed in U.S. Pat. Nos. 5,595,872, 5,739,135, 5,712,279, 5,760,246, 5,827,875, 5,885,983 and 5,962,440 all incorporated herein by reference.
A preferred MTP inhibitor is 9-[4-[4-[[2-(2,2,2-Trifluoroethoxy)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide
The HMG CoA reductase inhibitors which may be employed in combination with one or more compounds of formula I include mevastatin and related compounds as disclosed in U.S. Pat. No. 3,983,140, lovastatin (mevinolin) and related compounds as disclosed in U.S. Pat. No. 4,231,938, pravastatin and related compounds such as disclosed in U.S. Pat. No. 4,346,227, simvastatin and related compounds as disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171. Further HMG CoA reductase inhibitors which may be employed herein include fluvastatin, disclosed in U.S. Pat. No. 5,354,772, cerivastatin disclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080, atorvastatin disclosed in U.S. Pat. Nos. 4,681,893, 5,273,995, 5,385,929 and 5,686,104, pyrazole analogs of mevalonolactone derivatives as disclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactone derivatives, as disclosed in PCT application WO 86/03488, 6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivatives thereof, as disclosed in U.S. Pat. No. 4,647,576, Searle""s SC-45355 (a 3-substituted pentanedioic acid derivative) dichloroacetate, imidazole analogs of mevalonolactone, as disclosed in PCT application WO 86/07054, 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives, as disclosed in French Pat. No. 2,596,393, 2,3-disubstituted pyrrole, furan and thiophene derivatives, as disclosed in European Patent Application No. 0221025, naphthyl analogs of mevalonolactone, as disclosed in U.S. Pat. No. 4,686,237, octahydronaphthalenes, such as disclosed in U.S. Pat. No. 4,499,289, keto analogs of mevinolin (lovastatin), as disclosed in European Patent Application No.0,142,146 A2, as well as other known HMG CoA reductase inhibitors.
The squalene synthetase inhibitors which may be used in combination with the compounds of the present invention include, but are not limited to, xcex1-phosphono-sulfonates disclosed in U.S. Pat. No. 5,712,396, those disclosed by Biller et al, J. Med. Chem., 1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid (phosphinylmethyl)phosphonates, terpenoid pyrophosphates disclosed by P. Ortiz de Montellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyl diphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs as disclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293, phosphinylphosphonates reported by McClard, R. W. et al, J. A. C. S., 1987, 109, 5544 and cyclopropanes reported by Capson, T. L., PhD dissertation, June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp 16, 17, 40-43, 48-51, as well as other squalene synthetase inhibitors as disclosed in U.S. Pat. No. 4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K., Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2, 1-40 (1996).
Bile acid sequestrants which may be used in combination with the compounds of the present invention include cholestyramine, colestipol and DEAE-Sephadex (Secholex(copyright), Policexide(copyright)), as well as lipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide (Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinic acid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin, poly(diallylmethylamine) derivatives such as disclosed in U.S. Pat. No. 4,759,923, quaternary amine poly(diallyldimethylammonium chloride) and ionenes such as disclosed in U.S. Pat. No. 4,027,009, and other known serum cholesterol lowering agents.
ACAT inhibitors suitable for use in combination with compounds of the invention include ACAT inhibitors as described in, Drugs of the Future 24, 9-15 (1999), (Avasimibe); xe2x80x9cThe ACAT inhibitor, Cl-1011 is effective in the prevention and regression of aortic fatty streak area in hamstersxe2x80x9d, Nicolosi et al, Atherosclerosis (Shannon, Irel). (1998), 137(1), 77-85; xe2x80x9cThe pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoB100-containing lipoproteinxe2x80x9d, Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1), 16-30; xe2x80x9cRP 73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitorxe2x80x9d, Smith, C., et al, Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50; xe2x80x9cACAT inhibitors: physiologic mechanisms for hypolipidemic and anti-atherosclerotic activities in experimental animalsxe2x80x9d, Krause et al, Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A., Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, Boca Raton, Fla.; xe2x80x9cACAT inhibitors: potential anti-atherosclerotic agentsxe2x80x9d, Sliskovic et al, Curr. Med. Chem. (1994), 1(3), 204-25; xe2x80x9cInhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 6. The first water-soluble ACAT inhibitor with lipid-regulating activity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of a series of substituted N-phenyl-Nxe2x80x2-[(1-phenylcyclopentyl)methyl]ureas with enhanced hypocholesterolemic activityxe2x80x9d, Stout et al, Chemtracts: Org. Chem. (1995), 8(6), 359-62.
Examples of suitable cholesterol absorption inhibitor for use in combination with the compounds of the invention include SCH48461 (Schering-Plough), as well as those disclosed in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998).
Examples of suitable ileal Na+/bile acid cotransporter inhibitors for use in combination with the compounds of the invention include compounds as disclosed in Drugs of the Future, 24, 425-430 (1999).
Examples of suitable thyroid mimetics for use in combination with the compounds of the present invention include thyrotropin, polythyroid, KB-130015, and dronedarone.
Examples of suitable anabolic agents for use in combination with the compounds of the present invention include testosterone, TRH diethylstilbesterol, estrogens, xcex2-agonists, theophylline, anabolic steroids, dehydroepiandrosterone, enkephalins, E-series prostagladins, retinoic acid and compounds as disclosed in U.S. Pat. No. 3,239,345, e.g., Zeranol(copyright); U.S. Pat. No. 4,036,979, e.g., Sulbenox(copyright) or peptides as disclosed in U.S. Pat. No. 4,411,890.
The aforementioned patents and patent applications are incorporated herein by reference.
The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians"" Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
Where the compounds of the invention are utilized in combination with one or more other therapeutic agent(s), either concurrently or sequentially, the following combination ratios and dosage ranges are preferred:
When combined with a hypolypidemic agent, an antidepressant, a bone resorption inhibitor and/or an appetite suppressant, the compounds of formula I may be employed in a weight ratio to the additional agent within the range from about 500:1 to about 0.005:1, preferably from about 300:1 to about 0.01:1.
Where the antidiabetic agent is a biguanide, the compounds of formula I may be employed in a weight ratio to biguanide within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 2:1.
The compounds of formula I may be employed in a weight ratio to a glucosidase inhibitor within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 50:1.
The compounds of formula I may be employed in a weight ratio to a sulfonylurea in the range from about 0.01:1 to about 100:1, preferably from about 0.2:1 to about 10:1.
The compounds of formula I may be employed in a weight ratio to a thiazolidinedione in an amount within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 5:1.
The thiazolidinedione may be employed in amounts within the range from about 0.01 to about 2000 mg/day, which may optionally be administered in single or divided doses of one to four times per day.
Further, where the sulfonylurea and thiazolidinedione are to be administered orally in an amount of less than about 150 mg, these additional agents may be incorporated into a combined single tablet with a therapeutically effective amount of the compounds of formula I.
Metformin, or salt thereof, may be employed with the compounds of formula I in amounts within the range from about 500 to about 2000 mg per day, which may be administered in single or divided doses one to four times daily.
The compounds of formula I may be employed in a weight ratio to a PPAR-alpha agonist, a PPAR-gamma agonist, a PPAR-alpha/gamma dual agonist, an SGLT2 inhibitor and/or an aP2 inhibitor within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 5:1.
An MTP inhibitor may be administered orally with the compounds of formula I in an amount within the range of from about 0.01 mg/kg to about 100 mg/kg and preferably from about 0.1 mg/kg to about 75 mg/kg, one to four times daily.
A preferred oral dosage form, such as tablets or capsules, may contain the MTP inhibitor in an amount of from about 1 to about 500 mg, preferably from about 2 to about 400 mg, and more preferably from about 5 to about 250 mg; administered on a regimen of one to four times daily.
For parenteral administration, the MTP inhibitor may be employed in an amount within the range of from about 0.005 mg/kg to about 10 mg/kg and preferably from about 0.005 mg/kg to about 8 mg/kg, administered on a regimen of one to four times daily.
A HMG CoA reductase inhibitor may be administered orally with the compounds of formula I within the range of from about 1 to 2000 mg, and preferably from about 4 to about 200 mg.
A preferred oral dosage form, such as tablets or capsules, will contain the HMG CoA reductase inhibitor in an amount from about 0.1 to about 100 mg, preferably from about 5 to about 80 mg, and more preferably from about 10 to about 40 mg.
A squalene synthetase inhibitor may be administered with the compounds of formula I within the range of from about 10 mg to about 2000 mg and preferably from about 25 mg to about 200 mg.
A preferred oral dosage form, such as tablets or capsules, will contain the squalene synthetase inhibitor in an amount of from about 10 to about 500 mg, preferably from about 25 to about 200 mg.
The compounds of formula I of the invention can be administered orally or parenterally, such as subcutaneously or intravenously, as well as by nasal application, rectally or sublingually to various mammalian species known to be subject to such maladies, e.g., humans, in an effective amount within the dosage range of abut 0.01 xcexcg/kg to about 1000 xcexcg/kg, preferably about 0.1 xcexcg/kg to 100 xcexcg/kg, more preferably about 0.2 xcexcg/kg to about 50 xcexcg/kg (or form about 0.5 to 2500 mg, preferably from about 1 to 2000 mg) in a regimen of single, two or four divided daily doses.
The compounds of the formula I can be administered for any of the uses described herein by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents. The present compounds can, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The present compounds can also be administered liposomally.
Exemplary compositions for oral administration include suspensions which can contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which can contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The compounds of formula I can also be delivered through the oral cavity by sublingual and/or buccal administration. Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms which may be used. Exemplary compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG). Such formulations can also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (e.g. Carbopol 934). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
Exemplary compositions for nasal aerosol or inhalation administration include solutions in saline which can contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
Exemplary compositions for parenteral administration include injectable solutions or suspensions which can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer""s solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor.
Exemplary compositions for rectal administration include suppositories which can contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug.
Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).
It will be understood that the specific dose level and frequency of dosage for any particular subject can be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition.

Abstract: wherein:

Abstract: X is oxygen (xe2x80x94Oxe2x80x94), sulfur (xe2x80x94Sxe2x80x94), sulfoxide (xe2x80x94S(O)xe2x80x94), sulfonyl (xe2x80x94SO2xe2x80x94), CR8R8 or NR8;

Abstract: Y is xe2x80x94NR8, oxygen (xe2x80x94Oxe2x80x94), xe2x80x94CH2xe2x80x94 or sulfur (xe2x80x94Sxe2x80x94);

Abstract: Z is a bond or substituted or unsubstituted C1-4 alkyl; and

Abstract: wherein the substituents are as described herein.

Abstract: In addition, a method is provided for preventing, inhibiting or treating diseases or disorders associated with metabolism dysfunction or which are dependent upon the expression of a T3 regulated gene, wherein a compound as described above is administered in a therapeutically effective amount.


An assembly for mounting in a side wall opening of a catch basin side wall and convertible into a trap for reducing the amount of matter being carried out of the catch basin by drainage water exiting the catch basin. The assembly includes a first trap member having a first wall and an outlet opening formed in the first wall and a second trap member releasably and sealingly engageable with the first trap member. The second trap member has a second wall spaced from the first wall when so attached. The assembly further includes a filter assembly releasably attachable to one of the first and second trap members, and having a filter member being made to capture matter entrained in drainage water. When the assembly is assembled, mounted in the side wall opening, and converted into a trap by providing the inlet opening in the second wall at a position below the outlet opening, there is defined a water flow path extending from the catch basin interior, through the inlet opening and then through the outlet opening, and the filter member is positioned across the water flow path to capture matter entrained in drainage water flowing along the path. The inlet opening is sized, shaped and configured to restrict water flow through the assembly to promote settlement of matter in the catch basin. Also provided is a method of capturing matter entrained in drainage water exiting a catch basin including mounting a filter member releasably to the catch basin side wall downstream of the side wall opening, the filter member being made to remove matter from drainage water flowing through the filter member.

The present invention relates to traps for mounting in a side wall opening of a catch basin side wall.
Catch basins are large concrete structures buried in the ground and used to collect drainage water. They typically have an opening in one side wall to which may be coupled an outflow or outlet pipe of a drainage system. A trap is often provided at the opening in order to prevent floating pollutants, such as gas, oil, leaves and branches, from entering the outlet pipe and possibly plugging the pipe. Such traps may also provide a water xe2x80x9cplugxe2x80x9d for preventing sewer gases from entering the catch basin from the outlet pipe. This reduces offensive odors in the area of the catch basin.
A problem with prior art traps is that they are not particularly effective in filtering or removing matter such as dirt, debris and pollutants from drainage water entering the catch basin. Examples of matter include cigarette butts, fallen leaves, woods, plastic, bottles, trash, sand, and silt, bacteria, heavy metals, nutrients, and hydrocarbons, such as oil and grease. The matter is often carried with the drainage water out of the catch basin and enters lakes and river beds, which can be harmful to aquatic life. Furthermore, outlet pipes downstream of the catch basin may become clogged resulting in costly clean-up operations.
Another problem with conventional traps is that they tend to permit water to flow at too great a rate through the catch basins during periods of heavy rainfall. In some municipalities, drainage water from catch basins combine with sewage water to be collectively treated at sewage treatment facilities. When water entering the sewage treatment plant exceeds its capacity, excess water may go untreated and be discharged into rivers and lakes, resulting in environmental damage.
U.S. Pat. No. 6,126,817 issued Oct. 3, 2000 to Duran discloses traps having flow regulating means which promote the settlement of entrained particles in catch basins. However, the traps are relatively complicated in their design which adds to manufacturing costs. Moreover, the traps are not constructed to remove finer particles such as silt or clay or non-settling pollutants such as hydrocarbons.
The present invention provides a trap which is intended to remedy the above problems and has additional advantages, as will become apparent below.
In accordance with a first aspect of the invention, there is provided an assembly for mounting in a side wall opening of a catch basin side wall and convertible into a trap for reducing the amount of matter being carried out of the catch basin by drainage water exiting the catch basin, said assembly being sealingly attachable across said side wall opening and comprising:
a first trap member having a first wall and an outlet opening formed in said first wall, said first trap member being sealingly attachable to an outlet pipe with said outlet opening in communication with the interior of the pipe;
a second trap member releasably and sealingly engageable with said first trap member and having a second wall spaced from said first wall when so attached; and
a filter assembly releasably attachable to one of said first and second trap members, said filter assembly having a filter member made to capture matter entrained in drainage water;
wherein, when the assembly is assembled, mounted in said side wall opening, and converted into a trap by providing said inlet opening in said second wall at a position below said outlet opening, there is defined a water flow path extending from the catch basin interior, through said inlet opening and then through said outlet opening, and said filter member is positioned across said water flow path to capture matter entrained in drainage water flowing along said path.
The invention also provides an assembly according to the first aspect converted into a trap. When so converted, the second wall has an inlet opening for communicating with the interior of the catch basin. The inlet opening may be sized, shaped and configured to restrict water flow through the assembly to promote settlement of matter in the catch basin.
The second wall may be provided with cutting guides for use in cutting the inlet opening.
In accordance with a second aspect, there is provided a method of capturing matter entrained in drainage water exiting from a catch basin into an outlet pipe through a side wall opening in the catch basin. The method comprises providing a trap that includes an outer trap member having a first wall and an outlet opening formed in the first wall, an inner trap member releasably engaged with the outer trap member and having a second wall defining an inlet opening, and a filter member having an open end and an opposite closed end. The trap is mounted in the side wall opening so that the outer trap member is attached to the outlet pipe and the open end of the filter member is coupled releasably to an inner surface of the outer trap member downstream of the side wall opening. Again, the filter member is made to capture matter from drainage water flowing through the filter member.
Traps according to the present invention have several advantages. First, positioning the filter assembly near the side wall opening of the catch basin, allows the catch basin to be easily cleaned using a conventional vacuum truck. The hose of a vacuum truck can be simply inserted into the catch basin to suck up sediment and debris, without fear of damaging the filter assembly. In contrast, conventional filter assemblies are often mounted near the inlet of the catch basin or within the catch basin itself. In these situations, the filter may be damaged by the hose of a vacuum truck during cleaning. Also, in some cases, the catch basin must be redesigned to accommodate the filter assembly. Furthermore, cleaning such conventional filter assemblies often involves lifting the assemblies out of the catch basin from above, a process which can be time consuming and cumbersome.
Second, by restricting the flow of water through the trap, more particulates are retained in the catch basin as mentioned above. This prevents the downstream clogging of outlet and sewer pipes, and the deposit of sediment in water ways or water bodies such as rivers and lakes.
Third, the present assembly allows for much flexibility, being adaptable after installation to suit site specific needs. The filter assembly and inner trap member may be removed after the trap has been installed to provide a catch basin which functions as though no trap were present. This is useful in situations in which a trap is needed initially but not later. For example, during construction, the inner trap component and filter may be required to keep the large amount of exposed sediment from entering the drainage or sewer system. However, when construction is complete, a catch basin without a trap, or with a trap but without a filter assembly, may be adequate in removing smaller amounts of sediment entering the catch basin. Conversely, the filter assembly and inner trap member may be added to the outer trap member long after the outer trap member has been mounted in the side wall of a catch basin. This is useful in situations in which no trap is needed initially but is needed later. For example, a gas station could be built in an existing community near a catch basin with no trap. With the outer trap member already installed in the catch basin side wall, one could simply mount the inner trap member to the outer trap member during construction of the gas station to provide a trap suitable for catching large sediments resulting from construction. A filter assembly suitable for capturing particulate matter could also be mounted to catch finer sediments. Later, when the gas station is operational, the filter assembly may be replaced with another filter assembly having a hydrocarbon filter to filter gasoline and oil from drainage water entering the trap from the gas station.
A fourth arguable advantage is that the catch basin will xe2x80x9cback upxe2x80x9d when the filter is clogged thereby providing a visual indicator that the filter needs replacement. This is in contrast with some conventional filter assemblies which provide overflow openings to allow water to flow into the drainage system when the filter is clogged, thus carrying dirt, debris and other pollutants with it.


A cable assembly for supporting a seed chuck in a crystal puller to grow monocrystalline ingots according to the Czochralski method comprises a cable adapted for generally vertical movement within the crystal puller relative to a source of molten material. A chuck support is connected to an end of the cable within the crystal puller and is configured for supporting the seed chuck. The chuck support is constructed of a refractory material having a high creep rupture strength and comprises an elongate shank having an upper end and a lower end and an enlarged end member at the lower end of the shank. A coupling is constructed of a malleable material and is deformable into engagement with the end of the cable and the upper end of the shank to join the chuck support to the cable. The elongate shank spaces the coupling from the enlarged end member of the chuck support so that during operation of the crystal puller the coupling is substantially further above the molten source material than the chuck support as the cable assembly pulls the growing ingot upward within the crystal puller.

The present invention relates generally to crystal growing apparatus used in growing monocrystalline ingots, and more particularly to a cable assembly for use in such crystal growing apparatus.
Single crystal silicon, which is the starting material for most semiconductor electronic component fabrication, is commonly prepared by the so-called Czochralski ("Cz") method. The growth of a crystal ingot is most commonly carried out in a crystal pulling furnace or crystal puller. In this method, polycrystalline silicon ("polysilicon") is charged to a crucible and melted by a heater surrounding the outer surface of the crucible side wall. A cable assembly comprised of a shank and a cable wound on a drum supports a seed chuck capable of holding a seed crystal therein. The seed crystal is brought into contact with the molten silicon and a single crystal ingot is grown by slow extraction via the cable assembly. After formation of a neck is complete, the diameter of the crystal ingot is enlarged by decreasing the pulling rate and/or the melt temperature until the desired or target diameter is reached. The cylindrical main body of the crystal which has an approximately constant diameter is then grown by controlling the pull rate and the melt temperature while compensating for the decreasing melt level. Near the end of the growth process, the crystal diameter must be reduced gradually to form an end-cone. Typically, the end-cone is formed by increasing the pull rate and heat supplied to the crucible. When the diameter becomes small enough, the ingot is then separated from the melt.
Conventional cable assemblies used in crystal pullers comprise a tungsten cable and a chuck support constructed of a malleable material, such as a non-magnetic austenitic stainless steel or a malleable tungsten alloy. The chuck support includes a shank swaged to the end of the cable extending within the crystal puller and a ball, sized larger than the shank, attached to the end of the shank opposite the cable. The chuck support is malleable so that the shank can be swaged on the end of the cable to connect the chuck support to the cable. The seed chuck is supported by the ball of the chuck support and hangs down therefrom such that the ball of the chuck support carries the weight of the seed chuck and growing ingot. The weight is then distributed up the shank to the cable.
Recent advances in crystal puller design and semiconductor wafer processing have led to more severe mechanical and thermal loads on the cable assembly. The creep rupture strength of the material used to form the chuck support is not sufficiently great to withstand the environment in the new puller. The chuck support tends to fail at the crosssection between the ball and the shank at mechanical and thermal loads well below loads that would cause the tungsten cable to fail. The chuck support has thus become the limiting factor in the usage lifetime of the cable assembly for growing silicon ingots. More particularly, the lifetime of the conventional cable assembly has been cut in half, from being useful in growing about twenty ingots down to being used in the growth of only about ten silicon ingots. The thickness of the shank cannot be increased to overcome this limitation because the shank must remain sufficiently malleable for swaging to the cable to form a strong joint. For similar reasons, the conventional chuck support cannot be constructed of near pure tungsten, which has a higher creep rupture strength under the severe thermal loading within the crystal puller, because it is not sufficiently malleable for swaging the shank to the cable.


The container closure (1) consists of a spout (2) intended to be connected to a container and of a cap (3) that closes the spout. The latter is provided with two wings (6). From a sealing closed position, the cap (3) is movable by a twisting movement of less than 180 degrees to a released position in which it can be withdrawn from the spout (2). Stop means arranged on the spout (2) and on the cap (3) define the closed position. In addition, a locking member (11) may be provided in the cap (3) which only allows opening the latter after the rupture of a predetermined breaking point (18).

Known container closures have a screw cap that is generally provided with a tamper-evident tear-off ring. The screw cap allows reclosing the container after first time opening. However, the known screw caps have the disadvantage that they can be swallowed, particularly by children. Therefore, measures have been sought to exclude this dangerous swallowing risk. The reference EP2653404A1 shows a known solution where the cap is simply enlarged. A disadvantage of this solution is the substantially higher material consumption for the manufacture of the cap, in particular. Another problem that may arise, however, is the torque applied when the cap is reclosed which, due to the enlarged diameter, is much higher than in the known small screw caps and may cause the thread to be destroyed. Another disadvantage of this solution is that the tamper-evident seal formed by an axially removable tear-off ring under the edge of the cap is partly hidden and thus not visible at first sight.
Another solution to the problem of the swallowing risk is described in the reference US2004/238564A1. The described cap is provided with two lateral wing-like blades which prevent swallowing. The cap is integrally connected to a tubular spout and is separated therefrom by being twisted or broken off along a weakening line. To be reclosed, the cap is inverted and a lid portion integrated therein is pushed over the spout. In alternative solutions, a plug that is pushed into the opening at the end of the spout is provided instead of a lid. Both solutions are disadvantageous for hygienic reasons as the mentioned opening or plug, respectively, is exposed to the surroundings and thus to impurities before first-time opening.
Other solutions such as the one described in the reference EP2253555B1 combine a screw cap with wing-like enlargements. These entail the disadvantage that the orientation of the wings is rather coincidental when the screw closure is tightened and thus sealing. For automatically processing pouches where the spout is welded in between sheets in a defined position, however, it is indispensable that the wings are always aligned in parallel to the empty pouch so that they will not occupy too much space in the corresponding magazines or cause disturbances during the transport of the pouches.
On the background of this prior art it is the object of the invention to suggest a container closure where the cap has a defined rotational position relative to the spout in the closed condition.


The present invention is directed to a height adjustable water heater stand which includes a drainage system. The water heater stand includes a height adjustable base, an arcuate support surface and retention lip having a punch-out portion to provide for a drain pipe attachment.

This invention relates to a height adjustable stand, and more particularly, to a height adjustable stand having a drainage system therein for support of a water heater.
Water heaters are typically positioned within a limited space of a dwelling and on a floor adjacent the garage. For example, the water heater is placed in a closet with a central heating unit wherein the closet may or may not be built on a raised platform.
Gasoline and other flammable liquids are commonly stored within the garage, and most commonly in cans on the garage floor. Not infrequently, these flammable liquids are spilled or leaked onto the garage floor and fumes emanating from these liquids tend to hover and travel low to the garage floor and into the area where the water heater is housed. There have been a number of accidents involving water heaters wherein a pilot light of the water heater is an instrument which ignites these fumes resulting in explosion and/or fire.
Additionally, a drain is normally formed in the floor of the closet which houses the water heater to catch leakage from the water heater. However, the location of the drain varies. Leaks can occur on a point of the water heater which directs water away from the drain creating a mess and defeating the purpose of the drain.
Attempts have been made at providing a water heater stand. Such attempts have failed to provide uniformity to the industry in meeting basic safety standards for supporting the water heater under dry or wet conditions. Such attempts also lack height adjustability, fail to provide for leakage, or are designed to inhibit manuverability for assembly and positioning within small work areas.
One type of strand described in U.S. Pat. No. 4,267,998 is directed to a wooden stand which requires on-site assembly. Such a stand lacks drainage directability, height adjustability and is susceptible to weakening from moisture.
Another type of stand disclosed in U.S. Pat. No. 5,199,676 is directed to a sheet-like metal stand which requires assembly at the site. Similarly, this stand lacks drainage directability and height adjustability.
There exists a need for a relatively inexpensive stand which can elevate the water heater and associated pilot light above the garage floor and/or air region of concern. There is also need for a height adjustable stand in order to raise the water heater a desired height while allowing accommodation of the water heater within the housing environment. Still there is another need to have a stand which is easy to install within a limited work space wherein the water heater is housed. There is also a need for a stand to include a drainage system. Finally, there is a need to provide a safe water heater stand which solves the above needs and brings uniformity to the industry.


A portable toothbrush holding device for sanitarily holding a toothbrush having a generally planar shape manufactured from a rigid polymer, such as acrylic resin, embodying a predefined shape with at least one linear edge for resting on a planar surface such as a counter or lavatory basin. The toothbrush holder comprises one or more holes there through for the passage of a toothbrush handle. The distal end of the toothbrush handle rests upon the surface such as a counter or lavatory basin, while the bristle end of the toothbrush is elevated off the counter surface due to the propping action of the toothbrush holder, positioned proximate to the bristle end of the toothbrush.

The present invention relates to a toothbrush holder. More specifically this invention relates to a portable toothbrush holder for sanitarily holding a toothbrush, and protecting the bristles.
Toothbrushes have become an important device for maintaining oral hygiene, and preventing diseases of the gums and teeth. Due to their intra-oral use, it is important to maintain sanitation, and prevent contact with potential disease and bacteria covered surfaces found around a lavatory basin wherein one would typically use a toothbrush. Often, the toothbrush is laid upon the rim of a lavatory basin, which allows contact of the bristle portion of the brush with the surface of the lavatory basin, providing for the transfer of bacteria from the basin surface to the brush, and subsequently, to the users mouth. Furthermore, due to the design of most toothbrushes, they are prone to falling off surfaces such as the lavatory basin, and coming in contact with the floor, which is another highly potential bacterial carrier.
In addition to possible contamination resulting from simply resting a toothbrush on a counter or basin, over time the bristle elements of the brush may become deformed, or worn from repeated falls from the basin, and possible breakage of the toothbrush may result, shortening the useful life for the toothbrush.
A toothbrush is routinely taken along on trips so that oral hygiene can be continued while away from home. During travel, the toothbrush is usually protected by a travel container. To conserve space, the travel container closely conforms to the external shape of the toothbrush. Once at the destination, the toothbrush is removed from the travel container and stored, often on the lavatory basin itself, resulting in exposure to unknown and possibly unsanitary bacteria or disease. The present invention overcomes these shortcomings in providing a portable toothbrush stand that is simple to manufacture and allows for the sanitary protection of a toothbrush.
Briefly described, the present invention comprises a portable toothbrush holder, suitable for home use or travel, whereby a toothbrush can be held in a clean environment with the bristles of the brush exposed for drying.
It is an object of the present invention to provide for a sanitary means of holding a toothbrush, upon a surface being a high potential bacterial carrier such as a lavatory basin.
It is another object of the present invention to provide a compact, easily transportable means of holding a toothbrush sanitarily for use in travel.
Still another object of the invention is to provide a new and improved toothbrush holder which affords less susceptibility to contamination and damage of toothbrush bristles attributed to falling off a lavatory sink basin onto the floor.
A further object of the invention to provide a new and improved toothbrush holder for preventing the contamination and deformation of toothbrush bristles, that is both economic and simple to manufacture.
The foregoing objects of the present invention are accomplished in the preferred embodiment of the invention by a generally planar toothbrush holder, comprised of a predetermined polymer such as acrylic, and having a predefined shape with at least one linear edge, or in the alternative, at least two corresponding points for resting on a surface such as a counter or sink basin. The toothbrush holder further comprises one or more holes there through for the passage of a toothbrush handle. When the toothbrush is stored, the distal end of the toothbrush handle rests upon the surface such as a counter or lavatory basin, while the bristle end of the toothbrush is elevated off the counter surface due to the propping action of the toothbrush holder, positioned proximate to the bristle end of the toothbrush.
Further areas of applicability of the present invention will become apparent from the detailed description provided hereinafter. It should be understood that the detailed description and specific examples, while indicating the preferred embodiment of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.


Two mower-conditioner lugged rollers provided with a four-gear timing system that allows the rollers to separate while still maintaining the timing.

1. Field of the Invention
This invention relates generally to mower-conditioners and more particularly to a timing system for the rollers of a mower-conditioner to prevent interference of lugs from one roller to another.
2. Description of the Related Art
The rollers of mower-conditioners allow hay or other forage to pass between an upper and a lower roller to be crimped just before it is formed into a windrow so that it will dry more quickly. These rollers typically have intermeshing lugs thereon, for example as shown in U.S. Pat. No. 5,056,302 to Rosenbahn et al. It is important that the lugs of the upper roller fit in the depressions of the lower roller and vice versa when these rollers are close together so that the lugs of one roller do not interfere with the lugs of an adjacent roller. To solve this problem, timing gears have been devised as in the aforementioned patent to Rosenbalm et al. It has been determined however that if a large item passes between the rollers, on the gear end, the gear end of the rollers separate to allow the item to pass, and the opposite end stays together. As the separation of the rollers begins, the gear located on the upper roller proceeds to pass over the adjacent gear, this causes the upper roller to rotate with respect to the lower roller i.e. the upper roller timing gear "Walks" with respect to another. This ruins the timing and makes the intermeshing lugs on the roller's far side collide, possibly damaging the rollers, the gears, etc.
Accordingly, there is a need to solve the aforementioned problem in the prior art.

Apparatus for preventing interference of intermeshing lugs on separable rollers


An apparatus and method for diagnosing whether a charging and discharging switching element provided on a charging and discharging path of a battery pack operates normally. A charging and discharging switching unit having a charging and discharging switch and a fuse is installed on a charging and discharging path between a battery cell and a pack terminal. The apparatus includes a first diagnosing path a second diagnosing path, a third diagnosing path, an integrated diagnosing path having a diagnosis switching unit and a diagnosis resistor, a voltage measuring unit, and a control unit configured to turn on and off the diagnosis switching unit and determine whether the charging and discharging switching unit is operating abnormally based on the diagnosis voltage measured by the voltage measuring unit.

Recently, as the demand for portable electronic products such as laptops, video cameras and portable telephones has rapidly increased and storage batteries for energy storage, robots, satellites, or the like have been developed in earnest, high-performance secondary batteries capable of being repeatedly charged and discharged are being actively studied.
Accordingly, as technology development and demand for mobile devices, electric vehicles, hybrid electric vehicles, power storage devices, uninterruptible power supplies, and the like increase, the demand for secondary batteries as an energy source is rapidly increasing. In particular, secondary batteries used in electric vehicles or hybrid electric vehicles are high-power, high-capacity secondary batteries, and many studies are being conducted thereon.
Currently commercialized secondary batteries include nickel-cadmium batteries, nickel-hydrogen batteries, nickel-zinc batteries, lithium secondary batteries, and the like. Among them, the lithium secondary batteries are spotlighted because they ensure free charging and discharging due to substantially no memory effect compared to nickel-based secondary batteries, as well as very low discharge rate and high energy density.
The lithium secondary battery mainly uses lithium-based oxide and carbon material as positive electrode active material and negative electrode active material, respectively. The lithium secondary battery includes an electrode assembly in which a positive electrode plate and a negative electrode plate respectively coated with a positive electrode active material and a negative electrode active material are arranged with a separator interposed therebetween, and an exterior, namely a battery case, for hermetically receiving the electrode assembly together with electrolyte.
At least one secondary battery may be included in a battery pack as a battery cell, and the secondary battery may be charged and discharged through a charging and discharging path to function as a substantial power source for the battery pack. At this time, a charging and discharging switching unit for opening and closing the charging and discharging path may be installed between the secondary battery, namely the battery cell, and a pack terminal of the battery pack. In particular, the charging and discharging switching unit may include a charging and discharging switch and a fuse. The charging and discharging switch is controlled by a control unit provided to the battery pack to turn on and off the charging and discharging path. As the charging and discharging switch, a mechanical switch such as a contactor or an electronic switch such as a MOSFET may be used. In addition, when overcurrent flows in the charging and discharging path, the fuse may be disconnected to irreversibly block the charging and discharging path.
The charging and discharging switch or the fuse is an element that selectively allows a charging and discharging current to flow, while rapidly blocking the flow of current when an abnormal situation occurs, and may be regarded as a very important component in the battery pack. If an abnormality occurs in the charging and discharging switch or the fuse not to properly permit or block the flow of the charging and discharging current, the battery pack may be damaged, and also a device or user connected to the battery pack may be seriously damaged. In particular, in the case of a middle-sized or large-sized battery pack used in devices such as an electric vehicle or an energy storage system (ESS), which have been used more and more in recent years, a very large current may flow in the charging and discharging path. Thus, if the flow of the charging and discharging current is not blocked in time, the battery pack may be damaged, and also the corresponding device may be damaged or ignited. Moreover, in the case of the electric vehicle, most users are riding therein in use, and the electric vehicle moves at a high speed. Thus, if the current is not properly turned on/off, the users may be injured along with material damage.
Therefore, it is necessary to accurately diagnose whether the charging and discharging switch or the fuse is operating normally. In this aspect, various techniques have been proposed for diagnosing whether the charging and discharging switching element such as the charging and discharging switch or the fuse provided to the charging and discharging path of the battery pack operates normally. However, effective techniques for diagnosing the charging and discharging switching element have not been proposed. For example, in the case of conventional diagnostic techniques, a circuit structure or a result calculation process is complicated, which however still have many problems such as difficulty in quick processing, many errors, requirement for a high-performance control device for accurate processing, an uneasy manufacturing process, or high manufacture cost.


A refrigeration apparatus cabinet has an outer shell and an inner liner to define an insulation space therebetween. The shell has a deck including an enlarged opening. A conduit extends downwardly along a rear wall of the liner, with a distal end extending through the deck opening. A foil access cover is adhered to the deck about the opening to cover the opening, with the conduit extending outwardly from the space. A body of foamed-in-place insulation is provided in the space, with the access cover sealing the deck opening to prevent leakage of the foamed-in-place insulation.

In one conventional method of forming a refrigeration apparatus cabinet, a liner is spaced from a shell and foamed-in-place insulation is formed therebetween. To provide electrical power to electrical apparatus within the refrigeration cabinet, or to connect components within the sealed refrigeration system, a tunnel is provided between the shell and the liner. The conductors or tubing mounted at a rear wall of the shell pass through the tunnel into the cabinet.
In some instances, it is desirable to provide the conductors or tubing in the space between the shell and the liner embedded in the foamed-in-place insulation. While the routing of the conductors or tubing in the space is straightforward, problems result where these devices exit the space. Particularly, a process opening must be provided in the shell, commonly in the deck. However, expanding foam insulation tends to escape through any opening. To prevent such escape, foam stops must be provided for stopping the foaming action at the opening. Moreover, any covering of such openings must be satisfactory to meet U.L. requirements for a metal barrier.
The present invention is directed to solving one or more of the problems discussed above in a novel and simple manner.

Foil access cover for refrigeration deck


A subcutaneous sling for neck lift surgery. The sling comprises a sling body, shaped to fit in a submental triangle of a patient undergoing neck lift surgery, comprising a narrow anterior edge for anchoring near the chin of the patient. The sling comprises two lateral sling extensions, each coupled to a respective side edge of two sides of the sling body, each projecting away from the center of the sling body in a posterior lateral orientation of between 45 and 90 degrees from the anterior-posterior axis, and curved slightly towards the narrow anterior edge to fit the submandibular triangle and extend to near each ear of the patient. The sling body is at least 4 centimeters long in the anterior-posterior dimension, and the ends of the two lateral sling extensions are at least 14 centimeters distant from each other.

In plastic surgery, a neck lift, or lower rhytidectomy, is a surgical procedure that improves visible signs of aging in the jawline and neck. A neck lift may remove excess fat and skin in the lower face that creates jowls, remove fatty deposits under the chin, tighten loose neck skin, adjust muscle banding in the neck, for example that create abnormal contours, and/or the like. Factors that cause the need for a neck lift may include heredity, gravity, environmental conditions, stress, and/or the like. These factors may cause excess wrinkling of the neck skin, such as referred to colloquially as "turkey wattle" or a double chin, and impair jowl lines.
Other procedures related to lower rhytidectomy are cervicoplasty and platysmaplasty, which are correction of submental ptosis sometimes necessary to reverse the effects of aging. Cervicoplasty and platysmaplasty may be performed together with facial rhytidectomy, when surgeons may need to address the cervical region.
Originating from the pectoralis major muscle fascia, the platysma is a layer of muscle that has multiple insertions. Moving anterior to posterior, the muscle is anchored to the mentum and the inferior mandibular border and meets the orbicularis oris laterally and then the depressor anguli oris. Platysmal meshing with the depressor anguli oris contributes to the superficial muscular aponeurotic system (SMAS), highlighting its importance when attempting to reverse facial aging.
A neck lift may be performed by a horizontal submental incision for lipectomy, with excision or plication of hypertrophic anterior platysmal bands, and wide subcutaneous cervical dissection. This may correct fasciocutaneous ligaments extending from the dermis to the facial fascia, and osseocutaneous ligaments extend from the dermis to the periosteum.
Adipose tissue may comprise subcutaneous and subplatysmal fat tissue. Increased amounts of subcutaneous fat may be observed with weight gain, aging, lipodystrophies, and/or the like. Subplatysmal fat is far more vascular and fibrous than subcutaneous fat and is visualized after incising the platysma muscle. This difference may result in reduced efficacy of liposuction of subplatysmal fat.
The foregoing examples of the related art and limitations related therewith are intended to be illustrative and not exclusive. Other limitations of the related art will become apparent to those of skill in the art upon a reading of the specification and a study of the figures.