WO1999051225A1 - Antidiabetic agents - Google Patents
Antidiabetic agents Download PDFInfo
- Publication number
- WO1999051225A1 WO1999051225A1 PCT/US1999/006767 US9906767W WO9951225A1 WO 1999051225 A1 WO1999051225 A1 WO 1999051225A1 US 9906767 W US9906767 W US 9906767W WO 9951225 A1 WO9951225 A1 WO 9951225A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- nhc
- compound
- group
- accordance
- Prior art date
Links
- 0 C*(CCCC1)C1C(*C1C2CC(C3)C3C(C)(*)CC1)C2C(C(C(O)=C(*)C1=O)=O)=C1O Chemical compound C*(CCCC1)C1C(*C1C2CC(C3)C3C(C)(*)CC1)C2C(C(C(O)=C(*)C1=O)=O)=C1O 0.000 description 3
- BOBGJFFADWBUBA-UHFFFAOYSA-N Cc1c[nH]c2c(C)cccc12 Chemical compound Cc1c[nH]c2c(C)cccc12 BOBGJFFADWBUBA-UHFFFAOYSA-N 0.000 description 2
- DEYSMUBRQRFUIS-UHFFFAOYSA-N COc(c(OC)c1)ccc1C(C(C(O)=C(c1c[nH]c2c1cccc2)C1=O)=O)=C1O Chemical compound COc(c(OC)c1)ccc1C(C(C(O)=C(c1c[nH]c2c1cccc2)C1=O)=O)=C1O DEYSMUBRQRFUIS-UHFFFAOYSA-N 0.000 description 1
- RWXZXCZBMQPOBF-UHFFFAOYSA-N Cc1ccc2nc[nH]c2c1 Chemical compound Cc1ccc2nc[nH]c2c1 RWXZXCZBMQPOBF-UHFFFAOYSA-N 0.000 description 1
- LXFUDECTERGCEE-UHFFFAOYSA-N OC(C(OCC1=O)=O)=C1c(cc1)ccc1I Chemical compound OC(C(OCC1=O)=O)=C1c(cc1)ccc1I LXFUDECTERGCEE-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
- A61K31/10—Sulfides; Sulfoxides; Sulfones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Definitions
- Insulin is a hormone that is necessary for normal carbohydrate, protein and fat metabolism in mammals. Insulin is known to bind to the extracellular domain ( ⁇ -subunits) of its specific receptor. Following insulin binding, conformational changes in the insulin receptor lead to autophosphorylation of the intracellular ⁇ - subunits and stimulation of the receptor's intrinsic tyrosine kinase activity and activation of insulin signal transduction pathway. The activated insulin receptor tyrosine kinase phosphorylates several intermediate substrates (e.g. IRS-1 and SHC). These proximal events lead to activation of additional signaling intermediates such as PI-3- kinase and MAP kinase.
- IRS-1 intermediate substrates
- Type I diabetes or insulin-dependent diabetes
- Type II diabetes or non-insulin-dependent diabetes (NIDDM)
- NIDDM non-insulin-dependent diabetes
- Insulin resistance is a major susceptibility trait for NIDDM and is also a contributing factor in atherosclerosis, hypertension, lipid disorders and polycystic ovarian syndrome.
- NIDDM National Diabetes Management Function
- An exogenous insulin regimen is often required in the treatment of secondary diabetes, i.e., diabetes occurring in relation to other disease states such as pancreatic disease. Insulin is also used in some cases of gestational diabetes to obtain optimum blood glucose control.
- the conventional route of insulin administration is subcutaneously via a needle and syringe. Continuous subcutaneous insulin infusion with an infusion pump is an alternative to conventional injection therapy for achieving normalized levels of blood glucose.
- Thiazolidinediones have been recently described as a class of compounds with a mechanism of action which ameliorates many symptoms of NIDDM. These agents substantially increase insulin sensitivity in muscle, liver and adipose tissue in several NIDDM animal models, resulting in the correction of elevated plasma levels of
- the present invention relates to compounds represented by formula I:
- ring Y represents a 5-6 membered aryl or heteroaryl fused ring, which is optionally substituted with 1-4 groups selected from Ra;
- X represents O, S(O) m or N, wherein m is 0, 1 or 2;
- A represents a member selected from the group consisting of: (a) a 6-10 membered mono-or bicyclic aryl group;
- each R a is independently selected from the group consisting of: halo, -OH, -C 1 2 alkyl(Rb) 3 , -C 2 -io alkenyl(Rb) 3 , -C 2 _io alkynyl(Rb)3, -Cg.io aryl(Rb)3, -heteroaryl(Rb)3 ,-heterocyclyl(Rb)3,
- each Rb is independently selected from: H, OH, halo, -C ⁇ _4 alkyl, -C 2 _4 alkenyl, -C 2 -4 alkynyl, -CF 3 , -OCF 3 , -NO 2 , -N 3 , -CHO, -OC ⁇ _ 6 alkyl, -S(O) m C ⁇ _ 6 alkyl, -NH 2 , -NHC ⁇ _ 6 alkyl, -N(C ⁇ _ 6 alkyl) 2 , -C(O)C ⁇ _ 6 alkyl, -CO H, -C0 2 C ⁇ _ 6 alkyl, -C(O)NH 2 , -C(O)NHC ⁇ _ 6 alkyl, -C(O)N(Ci.
- the present invention relates to compounds of formula I, as well as tautomers, salts, hydrates and prodrugs thereof.
- alkyl and the alkyl portions of aralkyl, alkoxy and the like refer to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 15 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Preferred cycloalkyl groups include cyclopentyl and cyclohexyl.
- Alkyl also includes a straight or branched alkyl group which contains or is interrupted by a cycloalkylene portion. Examples include the following:
- alkylene and monovalent alkyl portion(s) of the alkyl group can be attached at any available point of attachment to the cycloalkylene portion.
- substituted alkyl when substituted alkyl is present, this refers to a straight, branched or cyclic alkyl group as defined above, substituted with 1-3 groups as defined with respect to each variable.
- alkenyl refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 15 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic (non- resonating) carbon-carbon double bonds may be present.
- Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted when a substituted alkenyl group is provided.
- alkynyl refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 15 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present.
- Preferred alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted when a substituted alkynyl group is provided.
- alkoxy refers to those groups of the designated carbon length in either a straight or branched configuration attached through an oxygen linkage and if two or more carbon atoms in length, they may include a double or a triple bond.
- alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, allyloxy, propargyloxy, and the like.
- halo as used herein means fluoro, chloro, bromo or iodo.
- Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and like groups as well as rings which are fused, e.g., naphthyl and the like.
- Aryl thus contains at least one ring having at least 5 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms.
- the preferred aryl groups are phenyl and naphthyl.
- Aryl groups may likewise be substituted.
- Preferred substituted aryls include phenyl and naphthyl substituted with up to three R a groups.
- Heteroaryl is a group containing from 5 to 10 atoms, 1-4 of which are heteroatoms, 0-4 of which heteroatoms are N and 0-1 of which are O or S(O) m , said heteroaryl group being unsubstituted or substituted with up to 3 R a groups; examples are pyrrolyl, furanyl, thienyl, pyridyl, quinolinyl, purinyl, imidazolyl, imidazopyridyl and pyrimidinyl.
- Prodrugs as used herein refer to C 1.4 alkoxy, C1.4 acyloxy, carboxylic acid and phosphate derivatives of the compounds of formula I as well as other compounds which generate quinones in vivo.
- Examples of prodrugs include the following:
- At least one RP represents C1.4 alkyl, C ⁇ _ acyl, CO2H, a phosphate group, a metal complex, such as a chelating metal, or another group which generates the quinone in vivo.
- Ra groups are present, and each Ra is independently selected from the group consisting of: halo, -OH, -C ⁇ _i2 alk l(Rb) 3 , -C 2 -io alkenyl(Rb) 3 , -C 2 _io alkynyl(Rb) 3 , -C ⁇ -lO aryl(Rb) 3 , -heteroaryl(Rb) 3 ,-heterocyclyl(Rb) 3 ,
- each Rb is independently selected from: H, OH, halo, -C ⁇ .4 alkyl, -C 2 _4 alkenyl, -C 2 -4 alkynyl, -CF 3 , -OCF 3 , -NO 2 , -N3, -CHO,
- A represents a member selected from the group consisting of: a 5-10 membered mono-or bicyclic aryl group or a 9-10 membered bicyclic heteroaryl group, attachment to which is through a 6 membered ring, the heteroaryl groups having 1-4 heteroatoms selected from O, S(O) m and N, said aryl and heteroaryl groups being optionally substituted with 1-3 Ra groups.
- A represents a 9-10 membered bicyclic heteroaryl group, attachment to which is through a 6 membered ring, the heteroaryl group having 1-4 heteroatoms selected from O, S(O) m and N, said heteroaryl group being optionally substituted with 1-3 Ra groups.
- A represents a 9-10 membered bicyclic heteroaryl group, attachment to which is through a 6 membered ring, the heteroaryl group having 1-4 heteroatoms selected from O, S(O) m and N, said heteroaryl group being optionally substituted with 1-3 Ra groups.
- all other variables are as originally defined. Examples of preferred values of A which are 9-10 membered bicyclic heteroaryl groups include the following:
- A represents a 5-6 membered isolated monocyclic heteroaryl group, having 1-3 heteroatoms selected from O, S(O) m and N, optionally substituted with 1-3 Ra groups.
- preferred 5-6 membered isolated monocyclic heteroaryl groups include pyrrole, imidazole, triazole, pyridine, pyrimidine, pyrazine, furan, thiophene, oxazole and thiazole.
- Ra groups attached, said Ra groups being selected from the group consisting of: halo, -C ⁇ .12 alkyl(Rb) 3 , -NH 2 , -NHC ⁇ _ 6 alkyl(Rb) 3 , -N(C!_ 6 alkyl(Rb) 3 ) 2 , -N 3 , -OC ⁇ _ 6 alkyl(Rb) 3 , -S(O) m H, -S(O) m C ⁇ _ 6 alkyl(Rb) 3 , -C(O)C 1 .
- each Rb is independently selected from: H, OH, halo, -CF 3 , -OCF3, -NO 2 , -N 3 , -OC ⁇ _ 6 alkyl, -S(O) m C ⁇ . 6 alkyl, -NH 2 , -NHC1.6 alkyl, -N(C!. 6 alkyl) 2 , -C(O)C ⁇ . 6 alkyl, -CO 2 H, -CO 2 C ⁇ .
- A represents a phenyl ring, unsubstituted or substituted with 1-3 Ra moieties selected from the group consisting of: halo, -C ⁇ _ ⁇ 2 alkyl(Rb) 3 , -NH 2 , -NHC ⁇ .6 alkyl(Rb) 3 , -N(C ⁇ _ 6 alkyl(Rb) 3 ) 2 , -N 3 , -OC ⁇ _ 6 alkyl(Rb) 3 , -S(O) m H, -S(O) m C 1 . 6 alkyl(Rb) 3 ,-C(O)C ⁇ .
- each Rb is independently selected from: H, OH, halo, -CF 3 , -OCF3, -NO 2 , -N3, -OCL6 alkyl, -S(O) m C ⁇ _ 6 alkyl, -NH 2 , -NHCi.6 alkyl, -N(C ⁇ . 6 alkyl) 2 , -C(O)C ⁇ _ 6 alkyl, -CO 2 H, -CO 2 C ⁇ . 6 alkyl,
- Ra groups are present in the molecule and are selected from the group consisting of: halo, -C ⁇ _ ⁇ 2 alkyl(Rb)3, -NH2, -NHC ⁇ _6 alkyl(Rb) 3 , -N(C ⁇ _ 6 alkyKRb ⁇ , -N 3 , -OC ⁇ _ 6 alkyl(Rb) 3 , -S(O) m H, -S(O) m C 1 .
- each Rb is independently selected from: H, OH, halo, -CF3, -OCF3, -NO 2 , -N 3 , -OC1.6 alkyl, -S(O) m C ⁇ _ 6 alkyl, -NH 2 ,
- Protecting groups may be chosen with,e.g., reference to Greene, T.W., et al., Protective Groups in Organic Synthesis. John Wiley & Sons, Inc., 1991.
- the blocking groups are readily removable, i.e., they can be removed, if desired, by procedures which will not cause cleavage or other disruption of the remaining portions of the molecule. Such procedures include chemical and enzymatic hydrolysis, treatment with chemical reducing or oxidizing agents under mild conditions, treatment with fluoride ion, treatment with a transition metal catalyst and a nucleophile, and catalytic hydrogenation.
- Non-limiting examples of suitable hydroxyl protecting groups are: trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl, p-
- Non-limiting examples of suitable carboxyl protecting groups are benzhydryl, o-nitrobenzyl, p-nitrobenzyl, 2- naphthylm ethyl, allyl, 2-chloroallyl, benzyl, 2,2,2-trichloroethyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 2- (trimethylsilyl)ethyl, phenacyl, p-methoxybenzyl, acetonyl, p- methoxyphenyl, 4-pyridylmethyl and t-butyl.
- salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
- Representative salts and esters include the following:
- the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are contemplated to be within the scope of the present invention. Therefore, where a compound is chiral, the separate enantiomers, substantially free of the other, are included within the scope of the invention; further included are all mixtures of the two enantiomers. Also included within the scope of the invention are polymorphs and hydrates of the compounds of the instant invention. Asymmetric centers may be present in the compounds of the instant invention depending upon the nature of the various substituents on the molecule. Each such asymmetric center will
- Tautomeric forms of the compounds of formula I are also included herein.
- Tautomeric forms as used herein refer to structures which differ by the shift of double bonds and concommitant displacement of hydrogen atoms.
- the present invention also provides a method for treating or preventing the onset of diabetes mellitis in a mammalian patient which comprises administering to said mammal a compound of formula I in an amount which is effective for modulating insulin receptor tyrosine kinase activity.
- the present invention further provides a method for reducing blood glucose levels in a mammalian patient in need thereof, which comprises administering to said mammal a glucose reducing effective amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate or tautomer thereof, in an amount which is effective for modulating insulin receptor tyrosine kinase activity.
- a glucose reducing effective amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate or tautomer thereof in an amount which is effective for modulating insulin receptor tyrosine kinase activity.
- Yet another aspect of the present invention provides pharmaceutical compositions containing a compound of formula I and a pharmaceutically acceptable carrier.
- the term "to modulate insulin receptor tyrosine kinase activity” includes activating insulin receptor tyrosine kinase, stimulating insulin receptor tyrosine phosphorylation, or enhancing the effect of insulin to stimulate insulin receptor tyrosine kinase activity or insulin signal transduction pathway.
- the ability of the compound to modulate insulin receptor tyrosine activity may be determined using the methods described herein. Briefly, Chinese Hamster Ovary (CHO) cells expressing human insulin receptor are plated and treated with insulin and/or test agents. CHO.T cells are one type of CHO cells that express human insulin receptor. The treated cells are lysed, and the insulin receptor is purified. The level of tyrosine phosphorylation of the receptor is determined using an anti-phosphotyrosine antibody conjugated to alkaline phosphatase and its chromogenic substrate.
- IRTK 20 - receptor tyrosine kinase activity
- the concept of altered levels of insulin, biological activity of insulin, and levels of insulin sensitivity includes impaired insulin production and/or activity, lower than normal levels of endogenous insulin, resistance to normal or elevated level of insulin, which may be due to insufficient insulin receptor expression, reduced insulin-binding affinity, or any abnormality at any step along the insulin signaling pathway.
- the compounds of formula I modulate insulin receptor tyrosine kinase activity and are thus useful in the treatment, prevention, amelioration, suppression or control of diseases, disorders or conditions that are characterized by altered insulin levels, biological activity of insulin, insulin sensitivity, or a combination thereof.
- diseases or disorders include diabetes mellitus (Type I and Type II), atherosclerosis, hypertension, lipid disorders, obesity, polycystic ovarian syndrome, and other conditions associated with insulin deficiency or insulin resistance.
- These compounds are also useful in the treatment or prevention of hyperglycemia or for controlling blood glucose levels in an animal suffering from Type I or Type II diabetes mellitus. Without being bound by a particular theory, it is believed that the compounds stimulate insulin receptor tyrosine kinase activity.
- these compounds stimulate tyrosine phosphorylation of insulin receptor ⁇ subunit and insulin receptor substrate- 1 as well as activity of phosphoinositide-3-kinase. These compounds have the properties of an insulin mimetic and insulin sensitizing agent.
- the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Although the compounds may be administered by any conventional mode of administration, including intravenous, intramuscular, subcutaneous, oral, topical, etc.; oral administration is preferred.
- the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
- the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligrams to about 50 milligrams.
- the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
- compositions which comprise a compound of formula I and a pharmaceutically acceptable carrier.
- composition is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
- the pharmaceutical compositions of the present invention encompass any composition made by admixing a
- compositions of the present invention comprise a compound of formula I as an active ingredient, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
- the compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administrations, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
- the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
- a compound of the invention can be combined with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
- the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
- any of the usual pharmaceutical media may be employed.
- oral liquid preparations such as suspensions, elixirs and solutions
- water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used; or in the case of oral solid preparations such as powders, capsules and tablets, carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be included.
- carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be included.
- tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed.
- tablets may be coated by standard aqueous or nonaqueous techniques.
- the active ingredient may also be administered by controlled release means and/or delivery devices.
- compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion.
- Such compositions may be prepared by any conventional method.
- the compositions are prepared by admixing the active ingredient with a liquid or finely divided solid or both, and then, if necessary, shaping the product into the desired preparation.
- a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet contains from about 1 mg to about 500 mg of the active ingredient and each cachet or capsule contains from about 1 to about 500 mg of the active ingredient.
- Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of these active compounds in water suitably mixed with a surfactant such as hydroxypropylcellulose.
- Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
- the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- the carrier can be a solvent or dispersion medium containing, for
- Suitable topical formulations include transdermal devices, aerosols, creams, ointments, lotions, dusting powders, and the like. These formulations may be prepared via conventional methods containing the active ingredient. To illustrate, a cream or ointment is prepared by mixing sufficient quantities of hydrophilic material and water, containing from about 0.5-90% by weight of the compound, in sufficient quantities to produce a cream or ointment having the desired consistency.
- Pharmaceutical compositions suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of the combination with the softened or melted carrier(s) followed by chilling and shaping moulds.
- the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
- additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
- the compounds of the present invention may be used in combination with other drugs.
- Such other drugs may be administered, by a route and in an amount commonly used, contemporaneously or sequentially.
- a pharmaceutical composition containing such other drugs in addition to the compound of the invention is preferred. Accordingly, the pharmaceutical
- compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of formula I.
- active ingredients include, but are not limited to anti diabetic agents such as insulin, sulfonylureas, biguanides (such as metformin) ⁇ -glucosidase inhibitors (such as acarbose), and peroxisome proliferator-activater receptor ⁇ agonists such as the glitazones (thiazolidinediones such as pioglitazone, troglitazone, MCC-555, and BRL49653); cholesterol lowering agents such as HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and others), sequestrants (cholestyramine, colestipol and dialkylaminoalkyl derivatives of a cross-linked dextran), nico
- anti diabetic agents such as insulin, sul
- oxalate group can be achieved using alkyl oxalyl chloride, such as ethyl oxalyl chloride. Ring closure can be effected by DBU or its equivalent to afford intermediate 5, which can be used for the synthesis of the compounds of Formula I as shown in Scheme 3.
- the intermediates of Formula 10 can be prepared similarly to intermediates of Formula 5, starting from acids 6.
- Intermediates of Formula 5 can be coupled to intermediates of Formula 11 to afford compounds of Formula 12 under acidic conditions (see Liebigs Ann. Chem. 177-194 (1986)).
- the aldehydes of Formula 11 are commercially available, known in the literature or can be prepared following literature methods. Rearrangement of compounds 12 to the products of Formula I can be effected using an alkoxide base such as sodium methoxide and sodium ethoxide.
- compounds of Formula I can be prepared starting from intermediates of Formula 10 and aldehydes of Formula 13.
- Aldehyde 13 is commercially available, known in the literature or can be prepared following literature methods described for analogous compounds. Condensation of compounds 10 and 13 leads to products of Formula 14, which can be rearranged using alkoxide bases.
- Example 2 Using the procedure set forth in Example 1, and starting from the compound of preparative example 2 and l-methylindole-3- carboxaldehyde the target compound was prepared.
- Example 2 Using the procedure set forth in Example 1, and starting from the compound of Preparative Example 1 and l-methylindole-3- carboxaldehyde, the target compound was prepared.
- Example 2 Using the procedure set forth in Example 1, and starting from the compound of Preparative Example 4 and 8- quinolinecarboxaldehyde, the target compound was prepared.
- CHO.T cells which overexpress human insulin receptor are cultured in Hams F12 medium supplemented with 10% fetal calf serum, fungizone, penicillin and streptomycin at approximately 1.5 x 10 ⁇ cells/well.
- the 96-well plates are incubated for approximately 24 h at 37°C, which is when the cells reached confluency. The cells are washed
- phosphate buffered saline PBS
- Insulin and/or test compounds are added to the wells, and the cells are incubated for an additional 20 min at 37°C.
- the cells are washed three times with PBS and lysates are prepared.
- the lysates are transferred to a second 96 well plate.
- the wells of the second plate are precoated with monoclonal anti-insulin receptor antibody.
- Antibody is diluted to a final concentration of approximately 4 mcg/mL in 20 mM NaHCO3, pH 9.6. Approximately 50 mcL of diluted antibody solution is added to each well.
- the lysates are incubated for 16 h at 4°C to immunopurify the insulin receptor.
- the washed plates are incubated for 5 h at 4°C with monoclonal antiphosphotyrosine antibody conjugated to alkaline phosphatase (Transduction Laboratories).
- the unbound antibody is removed and chromogenic substrate of alkaline phosphotase is added to the wells. Signals are detected at 405 nm with a microtiter plate reader.
- CHO.T cells (approximately 1.5 x 10 ⁇ cells/well) were cultured in Hams F12 medium supplemented with 10% fetal calf serum, fungizone, penicillin and streptomycin. The 96-well plates are incubated for approximately 24 h at 37°C, which is when the cells reached confluency. The cells are washed with phosphate buffered saline (PBS) three times and then incubated in serum-free medium for 3 h at 37°C. Insulin and/or test compounds are added to the wells, and the cells are incubated for an additional 20 min at 37°C. The cells are washed three times with PBS and lysates are prepared. The lysates are transferred to a second 96 well plate. The wells of the second plate are precoated with monoclonal anti-insulin receptor antibody. Antibody is diluted to a final
- the insulin receptor tyrosine kinase activity twenty microliters of the kinase reaction mixture (50 mM Hepes, pH 7.6, 150 mM NaCl, 5 mM MgCl , 5 mM MnCl , 0.1% Triton X-100, 1 mg/ml poly(Glu:Tyr)(4:l), 2 m Ci of carrier-free [g- 32 P]ATP) is added to each well of the 96-well plates and the incubation is continued at 25°C for 40 min. The reaction is terminated by addition of 50 ml 100 mM phosphoric acid. The mixture is transferred to Multiscreen PH plates and washed. The radioactivities associated with the wells are determined using a Topcount. The insulin receptor tyrosine kinase activities stimulated by test agents are compared to that stimulated by insulin.
- GST-IRTK glutathione S-transferase fusion protein containing intracellular domain of the insulin receptor
- a substrate protein (histone H2B) (0.35 ⁇ g/ ⁇ l final concentration) was then added and the incubation was continued at 25 C for 15 min and terminated by the addition of 50 mM EDTA.
- the reaction mixtures were separated by SDS-PAGE followed by immunoblotting.
- the blots were probed with a monoclonal anti- phosphotyrosine antibody and developed using the ECF reagents.
- the level of tyrosine phosphorylation of GST-IRTK and histone H2B was determined using image analyses.
- histone H2B and 32- ⁇ -ATP were added to the reaction mixtures.
- the samples were analyzed by SDS-PAGE followed by autoradiography.
- mice Genetically altered obese diabetic mice (db/db) (male, 7-9 weeks old) are housed (7-9 mice/cage) under standard laboratory conditions at 22 C and 50% relative humidity, and maintained on a diet of Purina rodent chow and water ad libitum. Prior to treatment, blood is collected from the tail vein of each animal and blood glucose concentrations are determined using One Touch BasicGlucose Monitor System (Lifescan). Mice that have plasma glucose levels between 250 to 500 mg/dl are used.
- Each treatment group consists of seven mice that are distributed so that the mean glucose levels are equivalent in each group at the start of the study, db/db mice are dosed orally by gavage with either vehicle (containing 0.5% methylcellulose ) or test compound from 0.2 to 30 mg/kg in a volume of 10 ml/kg.
- Blood is sampled from the tail vein hourly for 4 hours and at 24, 30 h post-dosing and analyzed for blood glucose concentrations. Food is withdrawn from 0-4 h post dosing and reintroduced thereafter. Individual body weights and mean food consumption (each cage) are also measured after 24 h. Significant differences between groups (comparing drug-treated to vehicle-treated) are evaluated using Student t-test. While certain preferred embodiments are described in detail, numerous alternative embodiments are contemplated as falling within the invention. Consequently, the claims are not to be limited to the specific teachings herein.
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002328607A CA2328607A1 (en) | 1998-04-02 | 1999-03-29 | Antidiabetic agents |
EP99915076A EP1067925A4 (en) | 1998-04-02 | 1999-03-29 | Antidiabetic agents |
AU33680/99A AU748432B2 (en) | 1998-04-02 | 1999-03-29 | Antidiabetic agents |
JP2000541996A JP2002510623A (en) | 1998-04-02 | 1999-03-29 | Antidiabetic drugs |
Applications Claiming Priority (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US8039898P | 1998-04-02 | 1998-04-02 | |
US60/080,398 | 1998-04-02 | ||
GBGB9812208.8A GB9812208D0 (en) | 1998-06-05 | 1998-06-05 | Antidiabetic agents |
GB9812208.8 | 1998-06-05 | ||
US9613598P | 1998-08-10 | 1998-08-10 | |
US60/096,135 | 1998-08-10 | ||
GBGB9823088.1A GB9823088D0 (en) | 1998-10-21 | 1998-10-21 | Antidiabetic agents |
GB9823088.1 | 1998-10-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999051225A1 true WO1999051225A1 (en) | 1999-10-14 |
Family
ID=27451793
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1999/006767 WO1999051225A1 (en) | 1998-04-02 | 1999-03-29 | Antidiabetic agents |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1067925A4 (en) |
JP (1) | JP2002510623A (en) |
AU (1) | AU748432B2 (en) |
CA (1) | CA2328607A1 (en) |
WO (1) | WO1999051225A1 (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6528037B2 (en) | 2000-10-11 | 2003-03-04 | Telik, Inc. | Method for determining whether a compound is an insulin receptor kinase activator |
US6660763B2 (en) | 1996-11-13 | 2003-12-09 | Sugen, Inc. | Bis-indolylquinone compounds |
US6750240B2 (en) | 1996-11-13 | 2004-06-15 | Sugen, Inc. | Methods of using bis-indolylquinones |
EP2305352A1 (en) | 2004-04-02 | 2011-04-06 | Merck Sharp & Dohme Corp. | 5-alpha-reductase inhibitors for use in the treatment of men with metabolic and anthropometric disorders |
WO2012027331A1 (en) | 2010-08-27 | 2012-03-01 | Ironwood Pharmaceuticals, Inc. | Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders |
WO2013138352A1 (en) | 2012-03-15 | 2013-09-19 | Synergy Pharmaceuticals Inc. | Formulations of guanylate cyclase c agonists and methods of use |
WO2014197720A2 (en) | 2013-06-05 | 2014-12-11 | Synergy Pharmaceuticals, Inc. | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
US11471455B2 (en) | 2018-10-05 | 2022-10-18 | Annapurna Bio, Inc. | Compounds and compositions for treating conditions associated with APJ receptor activity |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9897565B1 (en) | 2012-09-11 | 2018-02-20 | Aseko, Inc. | System and method for optimizing insulin dosages for diabetic subjects |
US9171343B1 (en) | 2012-09-11 | 2015-10-27 | Aseko, Inc. | Means and method for improved glycemic control for diabetic patients |
US9486580B2 (en) | 2014-01-31 | 2016-11-08 | Aseko, Inc. | Insulin management |
US9233204B2 (en) | 2014-01-31 | 2016-01-12 | Aseko, Inc. | Insulin management |
US11081226B2 (en) | 2014-10-27 | 2021-08-03 | Aseko, Inc. | Method and controller for administering recommended insulin dosages to a patient |
JP6989262B2 (en) | 2014-10-27 | 2022-01-05 | アセコー インコーポレイテッド | Subcutaneous outpatient management |
JP6858751B2 (en) | 2015-08-20 | 2021-04-14 | アセコー インコーポレイテッド | Diabetes Management Therapy Advisor |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5583149A (en) * | 1994-01-06 | 1996-12-10 | Bristol-Myers Squibb Company | Antimigraine derivatives of indolylcycloalkanylamines |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5786488A (en) * | 1996-11-13 | 1998-07-28 | Sugen, Inc. | Synthetic methods for the preparation of indolyquinones |
-
1999
- 1999-03-29 EP EP99915076A patent/EP1067925A4/en not_active Withdrawn
- 1999-03-29 WO PCT/US1999/006767 patent/WO1999051225A1/en not_active Application Discontinuation
- 1999-03-29 JP JP2000541996A patent/JP2002510623A/en not_active Withdrawn
- 1999-03-29 CA CA002328607A patent/CA2328607A1/en not_active Abandoned
- 1999-03-29 AU AU33680/99A patent/AU748432B2/en not_active Ceased
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5583149A (en) * | 1994-01-06 | 1996-12-10 | Bristol-Myers Squibb Company | Antimigraine derivatives of indolylcycloalkanylamines |
Non-Patent Citations (1)
Title |
---|
See also references of EP1067925A4 * |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6660763B2 (en) | 1996-11-13 | 2003-12-09 | Sugen, Inc. | Bis-indolylquinone compounds |
US6750240B2 (en) | 1996-11-13 | 2004-06-15 | Sugen, Inc. | Methods of using bis-indolylquinones |
US6528037B2 (en) | 2000-10-11 | 2003-03-04 | Telik, Inc. | Method for determining whether a compound is an insulin receptor kinase activator |
EP2305352A1 (en) | 2004-04-02 | 2011-04-06 | Merck Sharp & Dohme Corp. | 5-alpha-reductase inhibitors for use in the treatment of men with metabolic and anthropometric disorders |
WO2012027331A1 (en) | 2010-08-27 | 2012-03-01 | Ironwood Pharmaceuticals, Inc. | Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders |
WO2013138352A1 (en) | 2012-03-15 | 2013-09-19 | Synergy Pharmaceuticals Inc. | Formulations of guanylate cyclase c agonists and methods of use |
EP3708179A1 (en) | 2012-03-15 | 2020-09-16 | Bausch Health Ireland Limited | Formulations of guanylate cyclase c agonists and methods of use |
EP4309673A2 (en) | 2012-03-15 | 2024-01-24 | Bausch Health Ireland Limited | Formulations of guanylate cyclase c agonists and methods of use |
WO2014197720A2 (en) | 2013-06-05 | 2014-12-11 | Synergy Pharmaceuticals, Inc. | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
US11471455B2 (en) | 2018-10-05 | 2022-10-18 | Annapurna Bio, Inc. | Compounds and compositions for treating conditions associated with APJ receptor activity |
US11944622B2 (en) | 2018-10-05 | 2024-04-02 | Annapurna Bio, Inc. | Compounds and compositions for treating conditions associated with APJ receptor activity |
Also Published As
Publication number | Publication date |
---|---|
EP1067925A4 (en) | 2003-04-16 |
AU3368099A (en) | 1999-10-25 |
JP2002510623A (en) | 2002-04-09 |
AU748432B2 (en) | 2002-06-06 |
CA2328607A1 (en) | 1999-10-14 |
EP1067925A1 (en) | 2001-01-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10442782B2 (en) | Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof | |
AU748432B2 (en) | Antidiabetic agents | |
US20230271935A1 (en) | Ire1 small molecule inhibitors | |
US20090054484A1 (en) | Substituted heteroaryl benzofuran acids | |
EP3681862B1 (en) | Beta-hydroxy heterocyclic amines and their use in the treatment of hyperglycaemia | |
US20140329795A1 (en) | Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof | |
JP2000297075A (en) | Composition for treatment and prophylaxis of diabetic complication | |
US7446112B2 (en) | Modulators of muscarinic receptors | |
JP2022525795A (en) | Heterocyclolyl (phenyl) methanol compound useful for the treatment of hyperglycemia | |
US10385036B2 (en) | Sulfonamide-substituted indole modulators of RORC2 and methods of use thereof | |
JP4601038B2 (en) | Indolylmaleimides | |
CN108299420B (en) | Pentacyclic compounds as selective estrogen receptor down-regulators and uses thereof | |
US6077849A (en) | Antidiabetic agents | |
US8680150B2 (en) | Small molecule hematopoietic growth factor mimetic compounds that activate hematopoietic growth factor receptors | |
EP0718290B1 (en) | Carboxyalkyl heterocyclic derivatives | |
CN110709393A (en) | Inhibitors of LDHA activity | |
RU2355686C2 (en) | Glutamine fructose-6-phosphate amidotransferase inhibitors | |
US20100222394A1 (en) | Method for producing pyrazol-3-yl-benzamide derivative | |
JPWO2002043760A1 (en) | Sugar metabolism activator | |
US6281234B1 (en) | (2-Acylaminothiazole-4-yl)acetic acid derivative | |
US4378369A (en) | Esters of 2,5-anhydro-D-mannitol | |
WO2021003398A1 (en) | Inhibitors of low molecular weight protein tyrosine phosphatase (lmptp) and uses thereof | |
SK5442002A3 (en) | Aromatic di-keto derivatives, processes for their production and their use as a pharmaceutical | |
TW202404977A (en) | A pyrimido five-membered heterocyclic compound, its preparation method and use | |
CN103957905A (en) | Cycloalkane carboxylic acid derivatives as CXCR3 receptor antagonists |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AL AM AU AZ BA BB BG BR BY CA CN CU CZ EE GD GE HR HU ID IL IN IS JP KG KR KZ LC LK LR LT LV MD MG MK MN MX NO NZ PL RO RU SG SI SK SL TJ TM TR TT UA US UZ VN YU ZA |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW SD SL SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 33680/99 Country of ref document: AU |
|
ENP | Entry into the national phase |
Ref document number: 2328607 Country of ref document: CA Ref country code: CA Ref document number: 2328607 Kind code of ref document: A Format of ref document f/p: F |
|
ENP | Entry into the national phase |
Ref country code: JP Ref document number: 2000 541996 Kind code of ref document: A Format of ref document f/p: F |
|
NENP | Non-entry into the national phase |
Ref country code: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1999915076 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1999915076 Country of ref document: EP |
|
WWG | Wipo information: grant in national office |
Ref document number: 33680/99 Country of ref document: AU |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1999915076 Country of ref document: EP |