Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
  • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
  • C07D217/18—Aralkyl radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
  • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
  • C07D217/18—Aralkyl radicals
  • C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine

Definitions

• the present invention relates to the field of ⁇ 3-Adrenoreceptor agonists and to methods of their preparation, formulation and use to stimulate, regulate and modulate metabolism of fats in adipose tissues in animals, particularly humans and other mammals. More particularly, the present invention relates to the field of treating obesity and overweight conditions in animals, particularly humans and other mammals and associated effects of conditions associated with obesity and overweight, including Type II diabetes mellitus (non-insulin dependent diabetes), insulin resistance, glucose intolerance, hypothyroidism, morbid obesity, and the like.
• Type II diabetes mellitus non-insulin dependent diabetes
• insulin resistance glucose intolerance
• hypothyroidism morbid obesity, and the like.
• ⁇ -Adrenoreceptor sub-type ⁇ 3- Adrenoreceptors.
• the specific structure of the ⁇ 3-Adrenoreceptor has not been characterized, but it has been demonstrated to be a distinct cellular structure, distinguishable from the ⁇ i-Adrenoreceptor and the ⁇ 2-Adrenoreceptor sites previously identified.
• Another object of the present invention is the provision of safe and effective ⁇ 3 Adrenoreceptor formulations for administration to stimulate, regulate and modulate metabolism of fats in adipose tissues in animals, particularly humans and other mammals.
• Still another object of the present invention is to provide safe and effective administration of ⁇ 3-Adrenoreceptor agonists for stimulating, regulating and modulating metabolism of fats in adipose tissues in animals, particularly humans and other mammals.
• Yet another object of the present invention is to provide a safe and effective regimen for causing and promoting weight loss in humans, and for the maintenance of healthy and personally desired body fat levels.
• Still another object of the present invention is to provide safe and effective adjuncts to the husbandry of domesticated animals for the production of low fat dietary meats for human consumption.
• the primary objective of the present invention is to provide for weight and body fat regulation through modalities which are effective and safe.
• the present invention provides a clear path to safe and effective regulation of body weight and body fat which is safe and effective, which can provide significant and long lasting relief from the health consequences of overweight and obesity and the conditions associated therewith, and from the disease conditions which are aggravated by overweight and obesity.
• Compounds which are highly potent and highly specific ⁇ 3-Adrenoreceptor agonists are provided.
• the compounds are formulated into pharmaceutical preparations and administered for stimulating, regulating and modulating metabolism of fats in adipose tissues in animals, particularly humans and other mammals.
• the compounds of the invention have the structure:
• Ri and R_ are each independently members selected from the group consisting of H, OH, Cl, NO2, CH3SO2NH, NH2, CH3O and weak acids of the structure R7-NH, where R7 is an acyl group, wherein at least one of Ri and R2 is OH. It is generally preferred that R2 be OH.
• R3, R4 and Rs are variously and independently members selected from I, Br, Cl, F, OCH3, CH3, alkyl, alkylaryl, aminoalkyl, thioalkyl, and O-alkyl.
• R4 and R5 are each a halogen, the same or different.
• R- is an acid moiety which forms an acid salt with the NH group.
• Re is desirably HCl or (COOH) 2 .
• racemic mixtures are active, selective, and bioavailable, we have found that the isolated isomers are ordinarily of more particular interest.
• the S(-) isomers are preferred, as they will be found to have the highest selectivity and the highest bioavailability.
• the R(+) isomers are also of interest, as the R-isomers are in some cases easier to isolate.
• the compounds are formulated into pharmaceutical carriers to serve as highly selective, effective and safe ⁇ 3-Adrenoreceptor agonists to provide long term weight control.
• compositions are administered to control body fat levels, and to maintain acceptable body fat levels over time.
• compositions are administered to attain desirably low fat content in carcass meats intended for human consumption.
• the compounds of the present invention the method of their synthesis, their formulation into pharmaceutical compositions suitable for administration, and the method of their use for stimulating, regulating and modulating metabolism of fats in adipose tissues in animals, particularly humans and other mammals..
• the highly desirable goals of stimulating, regulating and modulating metabolism of fats in adipose tissues in animals, particularly humans and other mammals through the modality of administering a pharmaceutical formulation of one or more compounds which are ⁇ - Adrenoreceptor selective agonists is provided.
• the regulatory and modulatory effect of the compounds of the present invention are dependent on continued administration over time, and the attainment of an equilibrium state which is believed to be dose dependent. In that fashion, the present invention affords the control of body fat in animals, particularly humans and other mammals, over sustained periods, at desirable levels of body fat and /or body mass indices, as defined in the medical literature.
• the compounds of the present invention attain the high affinity for the ⁇ - Adrenoreceptor, the low affinity for the ⁇ i Adrenoreceptor and the ⁇ Adrenoreceptor required for effective selectivity and freedom from adverse side effects, and high levels of agonist activity to make the compounds effect in their required role in fat metabolism.
• Adrenaline to exemplify the biochemical action of these catechol amine hormones, is a primary agonist for these receptors in the body, and activates metabolic processes within the cells to which it binds.
• Adrenaline is associated with specific cellular processes which are dependent upon the nature of the cell to which it is bound.
• the action of adrenaline on the cell is to activate an enzyme within the cell, adenylate cyclase.
• the adenylate cyclase in turn catalyses further reactions within the target cell, typically beginning an enzyme cascade until the enzyme is broken down or deactivated by cellular regulatory mechanisms.
• the primary action of adenylate cyclase is the conversion of ATP to cAMP (cyclic adenosine monophosphate or "cyclic adenylate").
• the cAMP activates, in turn, an enzyme cascade which catalyses the conversion of glycogen into glucose and inhibits the conversion of glucose into glycogen, greatly increasing extra-cellular levels of blood glucose in the body.
• cAMP triggers the breakdown of glycogen into lactate and ATP, providing high levels of ATP to support high levels of muscular activity.
• the effect is hypertensive and is accompanied by vasodilation throughout the body, increasing blood flow and transport of blood glucose to the cells.
• ⁇ -blockers are among the commonly prescribed drugs in the field of cardiology. For the hypertensive patient, competitive binding of the blocking agent to the ⁇ Adrenoreceptors modulates and limits the additional hypertensive action of adrenaline on the heart muscle.
• the ⁇ -blockers may be employed in combination with vasodilators, decreasing the resistance to blood flow peripherally without increasing the heart rate and strength of contraction. A reduction in blood pressure and the work requirement on the heart muscle results.
• cAMP acts to cause bronchodilation which, when combined with increased blood flow, supplies higher levels of oxygen transport.
• epinephrine is widely employed to stimulate bronchodilation in the treatment of asthma and allergenic reactions which constrict the bronchia.
• Adrenoreceptor agonists and blockers have been known for some time, and have proved to be a fruitful field for drug development.
• Adrenoreceptor agonists and blockers are both competitive and non-competitive (non-equilibrium) binding agents. Some of such agents are ubiquitous in their action, while others exhibit varying degrees of selectivity for the two sub-types (and hence in the action response produced).
• Trimetoquinol is a potent nonspecific ⁇ -adrenoceptor ( ⁇ -AR) agonist clinically used in Japan as a bronchorelaxant.
• ⁇ -AR nonspecific ⁇ -adrenoceptor
• catecholamine hormones such as epinephrine, norepinephrine, dopamine, and the ⁇ -adrenoceptor agonist isoproterenol
• catecholamine hormones such as epinephrine, norepinephrine, dopamine, and the ⁇ -adrenoceptor agonist isoproterenol
• isoproterenol is incorporated within the tetrahydroisoquinoline nucleus of trimetoquinol.
• Aspll3 with Asnll3 abolished receptor binding of trimetoquinol and its analogs.
• Fraundorfer, P. F. "Functional and biochemical Characterization of trimetoquinol (TMQ) analog interactions with ⁇ -adrenergic receptor subtypes" Ph. D.
• trimetoquinol analogs may interact with the same amino acid residues in the binding site as isoproterenol, the contribution of catechol interactions with these mutated ⁇ Adrenoreceptors is less significant in terms of ligand binding and may well be overshadowed by the binding contributions of the trimethoxybenzyl group of trimetoquinol.
• trimetoquinol analogs interact with an auxiliary site through the substituted benzyl group in addition to the binding site shared by catecholamines. This subsite can be used to advantage in the development of more site-selective agents.
• the high potency of compound 2 seems to suggest that this auxiliary site is hydrophobic in nature.
• the complementary binding sites for trimetoquinol analogs are essentially unknown.
• compound 2 is a more potent TP receptor antagonist than trimetoquinol further suggesting that 1- benzyl ring modifications are appropriate to develop agents with greater selectivity on ⁇ -Adrenoreceptor versus TP receptors and vice versa.
• Adrenoreceptor and ⁇ Adrenoreceptor agonists include Isoproterenol, X and Y, having the structures:
• the present invention is based on the provision of ⁇ 3-Adrenoreceptor agonists in pharmaceutically acceptable carrier formulations for administration to stimulate, regulate and modulate metabolism of fats in adipose tissues in animals, particularly humans and other mammals.
• the present invention additionally provides a method for safe and effective administration of ⁇ 3-Adrenoreceptor agonists for stimulating, regulating and modulating metabolism of fats in adipose tissues in animals, particularly humans and other mammals.
• Compounds which are highly potent and highly specific ⁇ 3-Adrenoreceptor agonists are provided.
• the compounds are formulated into pharmaceutical preparations and administered for stimulating, regulating and modulating metabolism of fats in adipose tissues in animals, particularly humans and other mammals.
• the compounds of the invention have the structure:
• Ri and R2 are each independently members selected from the group consisting of H, OH, Cl, NO2, CH3S02NH, NH2, CH3O and weak acids of the structure R7-NH, where R7 is an acyl group, wherein at least one of Ri and R2 is OH. It is generally preferred that R2 be OH.
• R3, R. and R5 are variously and independently members selected from I, Br, Cl, F, OCH3, CH3, alkyl, alkylaryl, aminoalkyl, thioalkyl, and O-alkyl.
• R4 and R5 are each a halogen, the same or different.
• R5 is an acid moiety which forms an acid salt with the NH group.
• Re is desirably HCl or (COOH) 2 .
• racemic mixtures are active, selective, and bioavailable, we have found that the isolated isomers are ordinarily of more particular interest.
• the S(-) isomers are preferred, as they will be found to have the highest selectivity and the highest bioavailability.
• the R(+) isomers are also effective.
• the compounds of the present invention be further qualified and limited to those with high bioavailability, high selectivity and high activity for the ⁇ 3-Adrenoreceptor.
• selectivity is highest for the S-isomers, and these are generally preferred for these reasons.
• preferred species are the following:
• moieties X, Y, and Z are variously and independently members selected from I, Br, Cl, F, OCH3, CH3, alkyl, alkylaryl, aminoalkyl, thioalkyl, and O-alkyl.
• X and Z are each a halogen, the same or different:
• Formula C-R Preferred species of these structures having particularly good properties include the following compounds:
• the tetrahydroisoquinolines 6a-c were synthesized from the O-methyl or O-benzyl protected catecholamines 3a or 3b, respectively, and 4- nitrophenylacetic acid (4a) or 3,5-bis-trifluoromethylphenylacetic acid (4b) using methods described previously. Clark, M. T.; Adejare, A.; Shams, G.; Feller, D. R.; Miller, D. D. "5-fluoro- and 8- fluorotrimetoquinol: selective beta 2-adrenoceptor agonists" / Med Chem 1987, 30, 86-90.; Harrold, M. W.; Gerhardt, M. A.; Romstedt, K.; Feller, D.
• Isolation of the stereo isomers is performed by known techniques, including recrystallization, column separation using HPLC, adsorption chromotography, and the like.

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• 2001
  • 2001-03-29 EP EP01964673A patent/EP1373212A4/de not_active Withdrawn
  • 2001-03-29 AU AU87298/01A patent/AU782148B2/en not_active Ceased
  • 2001-03-29 WO PCT/US2001/010376 patent/WO2001074782A1/en active IP Right Grant

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