Invented by Donna Yu, James Lester Figarola, Donald David, City of Hope
The City of Hope invention works as followsThe invention provides complexes of TGR5 and metformin, or analogues thereof, that can be used to treat diseases such as diabetes, cardiovascular disease and cancer.
Background for TGR5-agonist complexes to treat diabetes and cancer
Diabetes mellitus is a major health epidemic categorized into two subclasses: type 1, known as insulin dependent diabetes mellitus (IDDM), and type 2, noninsulin dependent diabetes mellitus (NIDDM).1 Type 2 diabetes is a chronic and progressive metabolic disorder of carbohydrate and lipid metabolism and accounts for nearly 90% of diabetes mellitus and results from impaired insulin secretion and reduced peripheral insulin sensitivity?a burgeoning, worldwide health problem affecting almost twenty-six million people in the United States.2 Current oral therapies for this disease are limited by availability of effective medications, including, for example, insulin secretagogues, such as sulfonylureas; activators of the peroxisome proliferator-activated receptor-? (?PPAR-??) (?PPAR-??) After long-term administration, all of the oral hypoglycemic drugs fail. The current treatments have a number of deficiencies, including hypoglycemic events, weight gain and gastrointestinal issues, edema over time, and loss in responsiveness.
Metformin, a common medication used to treat diabetes, is widely available. Metformin has recently been studied as a possible anticancer agent. Studies suggest that cancer patients, whether or not they have diabetes, may benefit from lowering their insulin levels. In 1995, the United States Food and Drug Administration approved metformin as an oral hypoglycemic. Metformin, given alone or with insulin and a sulfonylurea, reduces hyperglycemia by decreasing hepatic sugar output and increasing glucose uptake in skeletal muscles. Metformin HCl, however, has a poor oral bioavailability of only about 50% due to its poor absorption by the lower gastrointestinal tract. There is therefore a need for new therapies to treat diabetes and cancer, as well as compositions that have a greater bioavailability for patients with diabetes and associated diseases. Herein are provided solutions to these problems and others in the art.
The complexes are useful in treating diabetes, fatty liver, cancer, and cardiovascular disease.
The complexes described include metformin, metformin analogs and a TGR5-ligand. A complex includes a TGR5-ligand and a non-covalently bonded metformin or analogue. “In another aspect, a complex is formed between a TGR5 and a metformin analog or analogue. The TGR5 is non-covalently bonded to the metformin.
Also provided are pharmaceutical compositions. A pharmaceutical composition includes a TGR5-ligand and a pharmaceutically accepted excipient.
Herein are described methods of treating cancer. In one aspect is a method for treating cancer by administering a therapeutically effective combination of a TGR5-ligand and a metformin, or analogue thereof to a patient in need.
The present invention includes methods of treating diabetes, and diseases associated with it. A method is described in one aspect for treating diabetes by administering an effective therapeutic dose of metformin, metformin analogs and TGR5 ligands to a patient. A method is described in another aspect for treating a metabolic disorder associated with diabetes. The subject receiving the treatment will be administered a combination of metformin, metformin analog and TGR5 ligand. In another aspect is a method of treating hyperglycemia, insulin resistance, hyperinsulinemia, dyslipidemia, hypertriglyceridemia, hypertension, fibrinolysis, or endothelial dysfunction by administering a combined therapeutically effective amount of a metformin or metformin analogue and a TGR5 ligand as described herein. Another aspect relates to a method for reducing bloodpressure by administering the combined therapeutically-effective amount of metformin, metformin analog and TGR5 as described herein. Another aspect of the invention is a method for decreasing glycated haemoglobin (HbA1c), by administering combined therapeutically-effective amounts of metformin, metformin analog and TGR5 as described. “In another aspect, a method for reducing the weight of the liver or kidneys is described by administering a TGR5-ligand and a metformin/metformin analogue in a therapeutically effective combination.
Also provided are methods to treat cardiovascular disease. The method of treating cardiovascular disease is described in one aspect. It involves administering a therapeutically effective dose of metformin, metformin analogs or TGR5 ligand to a patient in need.
The present invention also provides methods for treating polycystic Ovarian Syndrome. A method is described in one aspect for treating polycystic Ovarian Syndrome in a patient by administering the therapeutically effective amounts of metformin, metformin analogs and TGR5 ligand.
Unless defined differently, technical and science terms used herein will have the same meaning that a person with ordinary skill in this field would understand. See, e.g., Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY 2nd ed., J. Wiley & Sons (New York, N.Y. 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, N Y 1989). In the practice of this invention, any methods, materials and devices similar to or equivalent to those described in the present disclosure can be used. These definitions have been provided to help you understand certain terms that are used often in this disclosure. They are not intended to limit the scope.
The abbreviations herein are used in the context of chemical and biological arts. The chemical formulae and structures described herein have been constructed in accordance with the standard rules for chemical valency that are known to the chemical arts.
The chemically identical substitutes would be the same if the formula was written right to left. For example, “OCH2” is equivalent to “CH2O”.
The term “alkyl” is used to describe a straight (i.e., unbranched) or branched carbon chain (or carbon), or a combination thereof. This can be fully saturated, mono- or polyunsaturated and include divalent radicals. By itself or in conjunction with another substituent (unless otherwise stated), the term “alkyl” means a straight or branched (i.e. unbranched) carbon chain, or carbon, or a combination thereof. The carbon can be mono-, polyunsaturated, or fully saturated. It may also include divalent and multivalent radicals. Alkyl does not undergo cyclization. Saturated hydrocarbon radicals can include groups like methyl, (cyclohexyl), ethyl n, propyl t, butyl isopropyl n, sec-butyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl is abutyl isobutyl isobutyl isobutyl isobutyl isobutyl Unsaturated alkyl groups are those that have one or more triple or double bonds. alkene, alkyne). Unsaturated alkyl groups can include vinyl, 2-propenyl and crotyl. Also, 2,4-pentadienyl and 3-(1,4 pentadienyl), as well as higher homologs. Alkoxy is a group of alkyls attached to the rest of the molecule by an oxygen linker.
The term “alkylene” is used to describe a divalent radical derived from an alkyl, as exemplified by the example but not limited to?CH2CH2CH2CH2? By itself or in conjunction with another substituent (unless otherwise stated), the term ‘alkylene’ means a divalent radical that is derived from an allyl. An example, but not exclusive to, this radical would be?CH2CH2CH2CH2?”. Alkyl groups (or alkylenes) typically have between 1 and 24 carbon atoms. In the present invention, those having 10 or less carbon atoms are preferred. A “lower alkyl” A?lower-alkyl? It is an alkyl group with a shorter chain, usually having 8 or fewer carbons. The term “alkenylene” is used. By itself or in conjunction with another substitute, the term?alkenylene’ means, unless stated otherwise, a divalent radical deriving from an alkene.
The term “heteroalkyl” is used to describe a stable straight or branched chain, or combinations thereof, that includes at least one carbon atom and at least one heteroatom selected from the group consisting of O. N. P. Si. S. By itself or when combined with another term, the term “heteroalkyl” means, unless stated otherwise, a straight or branched stable chain or combinations thereof that includes at least one Carbon atom and one heteroatom chosen from the group consisting O, N. P. Si. and S. The nitrogen and sulfur atoms can optionally also be oxidized and the nitrogen heteroatom optionally quatemized. Heteroalkyl does not undergo cyclization. Examples include, but are not limited to:?CH2?CH2?O-CH3,??N(CH3)?CH3,??CH2??S??CH2??CH3,???CH2??S(O)2??CH3,???CH2??S??CH2??CH3,???CH2??S??CH2??CH3,???CH2??S??CH2??CH3, ##CH2??CH2??S(O)2??CH3,???CH2??S?CH2?CH2?CH2?! Examples include but are not restricted to: CH2?CH2 – O?CH3, Two or three heteroatoms can be consecutive. For example, “?CH2?”NH?OCH3” and “?CH2?”O?Si?CH3)3.
The term “heteroalkylene” is also used in this way. “Similarly, the term?heteroalkylene,? and ?CH2?S?CH2?CH2?NH?CH2?. Heteroatoms may also occupy one or both chain termini for heteroalkylene groups (e.g. alkyleneoxy and alkylenedioxy; alkyleneamino and alkylenediamino). For alkylene or heteroalkylene groups, the direction of writing the formula for the linking group does not imply any orientation. The formula?C (O)2R??, for example, represents both?C (O)2R?? and?C(O]2R?? The formula?C(O2)2R?? R?C(O2)2? and?C(O2)2R?? As mentioned above, heteroalkyl group, as used in this document, includes those groups attached to the rest of the molecule via a heteroatom such as ‘C(O),R’, ‘C(O),NR?, NR?R?, SR?, or?SO2R” When ‘heteroalkyl’ is used, it means that the group attached to the remainder of a molecule through a heteroatom. Examples include?C(O)R?,?C(O)NR? When?heteroalkyl? If the term ‘heteroalkyl’ is recited, followed by a list of specific heteroalkyl groups such as?NR??R? The terms?NR?R? and ‘heteroalkyl’ are not mutually exclusive or redundant. To add clarity, we list the heteroalkyl group names. The term “heteroalkyl” is used to describe this. The term?heteroalkyl? “The term ‘heteroalkyl group’ is not meant to exclude specific heteroalkyl groups, such as?NR?R??
The term ‘cycloalkyl’ is used to describe a group of compounds. “The terms?cycloalkyl? and?heterocycloalkyl?, either alone or in combination with other terms, mean unless otherwise stated cyclic versions of?alkyl? By themselves or when combined with other terms, these terms refer to cyclic versions?alkyl,? By themselves or in combination with other terms, unless otherwise stated, cyclic versions of?alkyl? respectively. A heteroatom may also occupy the same position as the heterocycle when it is attached to the rest of the molecule for heterocycloalkyl. Both cycloalkyl (and heterocycloalkyl) are non-aromatic. Examples of cycloalkyl are, but not limited to cyclopropyl cyclobutyl cyclopentyl cyclohexyl 1-cyclohexenyl 3-cyclohexenyl cycloheptyl and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A ‘cycloalkylene’ and a ?heterocycloalkylene,? “A divalent radical is a divalent radical that can be used alone or in combination with another substituent. It can be derived from either a cycloalkyl or heterocycloalkyl.
The term halo is used to describe a halogen lamp. or ?halogen,? By themselves or in conjunction with another substitute, fluorine or chlorine atoms, bromine atoms, or iodine are meant, unless stated otherwise. Also, terms like haloalkyl are used. Monohaloalkyl, as well as polyhaloalkyl are included in terms such as?haloalkyl? The term “halo(C1 – C4)alkyl” is an example. includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
The term “acyl” means, unless otherwise stated,?C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl; substituted or unsubstituted heteroalkyl; substituted and/or nonsubstituted heterocycloalkyl; substituted and/or nonsubstituted heterocycloalkyl. “The term?acyl?
The term “aryl” means, unless otherwise stated, a polyunsaturated aromatic hydrocarbon substituent. This can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e. a fused ring aryl) or linked covalent “The term?aryl?” means, unless stated otherwise, a polyunsaturated aromatic hydrocarbon substitute, which can either be a single or multiple ring (preferably between 1 and 3 rings), that is fused together or covalently linked. A fused ring is a group of rings that are fused together, where at least one ring is an aryl. The term “heteroaryl” is used. The term?heteroaryl’ refers to aryl rings (or groups) containing at least one heteroatom, such as N, O or S. Optionally, the nitrogen and sulfur are oxidized and the nitrogen is optionally quatternized. The term “heteroaryl” is used to describe this. The term?heteroaryl’ includes fused ring groups heteroaryl (i.e. multiple rings fused, where at least one of those rings is a ring heteroaromatic). A 5,6-fused heteroarylene is two rings fused together where one ring contains 5 members and the second ring 6 members. At least one of these rings must be a heteroaryl group. A 6,6-fused heteroarylene is the same thing. It refers to two rings that are fused, one with 6 members and one with 6 members. At least one of these rings must be a heteroaryl. A 6,5-fused heteroarylene is two rings fused, one with 6 members, the other with 5 members. At least one of these rings will be a heteroaryl. A heteroaryl group may be attached to a molecule via a heteroatom or carbon. Examples of aryls and heteroaryls include phenyls, 1-naphthyls, 2-naphthyls, 4-biphenyls, 1-pyrrolyls, 2-pyrrolyls, 3-pyrrolyls, 3-pyr The group of acceptable substitutes is described below. An?arylene’? A?arylene? As a single substituent or in combination with another, a divalent radical is derived from aryls and heteroaryls. Examples of non-limiting heteroaryl groups are pyridinyl and pyrimidinyl. “The examples above can be substituted, unsubstituted, and the divalent radicals are non-limiting examples for heteroarylene.
A fused ring of heterocycloalkyl and aryl” is an aryl fused with a heterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl. A fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl. Fused ring heterocycloalkyl-aryl, fused ring heterocycloalkyl-heteroaryl, fused ring heterocycloalkyl-cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substituents described herein.
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