EP1135119A1 - Composes hypoglycemiants et hypolipemiants - Google Patents

Composes hypoglycemiants et hypolipemiants

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Publication number
EP1135119A1
EP1135119A1 EP99957542A EP99957542A EP1135119A1 EP 1135119 A1 EP1135119 A1 EP 1135119A1 EP 99957542 A EP99957542 A EP 99957542A EP 99957542 A EP99957542 A EP 99957542A EP 1135119 A1 EP1135119 A1 EP 1135119A1
Authority
EP
European Patent Office
Prior art keywords
olide
carbon
hydroxy
group
eudesma
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99957542A
Other languages
German (de)
English (en)
Other versions
EP1135119A4 (fr
Inventor
Dilip Wagle
Sheng Ding Fang
Ihor Terleckyj
John Resek
Jack Egan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Synvista Therapeutics Inc
Original Assignee
Alteon Inc
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Filing date
Publication date
Application filed by Alteon Inc filed Critical Alteon Inc
Publication of EP1135119A1 publication Critical patent/EP1135119A1/fr
Publication of EP1135119A4 publication Critical patent/EP1135119A4/fr
Withdrawn legal-status Critical Current

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/92—Naphthofurans; Hydrogenated naphthofurans
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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

Definitions

  • the present invention relates to methods of reducing hyperhpidemia and hyperglycemia, as well as to certain compounds and compositions
  • type II diabetes while genetic mutations can cause certain subsets of the disease (e.g., maturity-onset diabetes of the young, or MODY), the most common form of the disease involves resistance to the action of insulin on insulin-target tissues, and is associated with obesity, predominately of abdominal origin In addition to elevated glucose levels, circulating levels of triglycerides, cholesterol and non-esterified fatty acids (NEFA) are elevated during a fasting period Persons afflicted with diabetes are predisposed to the development of cardiovascular disorders, which is the main cause of morbidity and mortality for this disease. Resistance to insulin action occurs not only in hyperglycemic states but also in Syndrome X, an insulin-resistant disorder characterized by hyperinsulinemia and dyslipidemia.
  • Syndrome X an insulin-resistant disorder characterized by hyperinsulinemia and dyslipidemia.
  • Oral antihyperglycemic agents such as the sulfonylureas and biguanides, promote improvements in elevated lipid levels through overcoming the associated state of insulin-resistance, either by potentiating the endogenous release of insulin from the ⁇ - cells of the pancreas, as in the case of the sulphonylureas, or by enhancing glucose disposal and reducing gluconeogenesis, as in the case of biguanides.
  • Other approaches to controlling the elevated lipids and glucose have involved the use of broad acting oral antihyperglycemics such as the thiazolidinedione class of agents which lower fatty acids and improve the insulin-resistant state of insulin responsive tissues.
  • non-este ⁇ fied fatty acids appear to play a role in promoting the diabetic and/or the hyperhpidemic, insulin-resistant, state Elevated free fatty acids arise from either the excess body burden of adipose tissue in the obese state or from uncontrolled breakdown of t ⁇ glyce ⁇ des in adipose tissue, a major insulin-target tissue, or both
  • elevated levels of free fatty acids have been shown to acutely induce insulin resistance in muscle, the major glucose utilizing tissue of the body, where a direct effect on glucose transport in muscle is observed
  • fatty acids affect liver metabolism to increase hepatic glucose output
  • elevated fatty acids induce impaired ⁇ - cell functioning by lessening the secretion of insulin from ⁇ - cells in response to a glucose stimulus Attempts to reduce fatty acid levels have included the development of thermogenic agents (73 agonists) which are believed to function by stimulating brown adipose tissue to oxidize fatty acids and thus clear them from the circulation Alternatively, removing
  • hpolytic inhibitors that inhibit adipose tissue breakdown of t ⁇ glyce ⁇ des are known as hpolytic inhibitors. It is toward the development of new methods and agents for lowering circulating hpids to treat hyperhpidemic disorders or for lowering circulatory glucose to treat hyperglycemia, diabetes and associated disorders that the present invention is directed Summary Of The Invention
  • the invention relates to lipid-lowering or glucose-lowering methods and compounds, particularly hpid-lowermg or glucose-lowering compounds, with an A-B ring structure of the following Formula I
  • the present invention to provides, among other things methods for lowering lipid levels in a mammal to treat or prevent the development of pathology associated with elevated lipid levels; compounds which inhibit the enzyme hormone- sensitive lipase and inhibit lipolysis; agents and methods for the treatment of insulin resistance and Syndrome X; methods for lowering glucose levels in a mammal in order to treat or prevent the development of pathology associated with hyperglycemia, methods for treating impaired glucose tolerance associated with fasting or prandial hyperglycemia, normoglycemia, or insulin resistance, for example to delay or prevent the onset of non-insulin-dependent diabetes mellitus.
  • methods for lowering lipid levels in a mammal or lowering glucose levels in a mammal comprising administering to said mammal an effective amount of a composition comprising a compound of the formula.
  • the invention relates to a method for lowering blood lipid levels or lowering blood glucose in a mammal comprising administering to the mammal a lipid-lowering or glucose-lowering effective amount of one or more compounds with an A-B ring structure, the compounds of Formula I, wherein the dotted line between carbons 5 and 6, the dotted line between carbon 4 and R 2 , and the dotted line between carbon 1 1 and R 3 each independently represent an optional double bond from the respective numbered carbon to a linked carbon; wherein R 1 is hydrogen, hydroxy, a lower alkanoyloxy or an aroyloxy group (wherein aryl of aroyloxy can be substituted by one or more lower alkyl, lower alkoxy, halo, trifluoromethyl, di(lower)alkylamino, hydroxy, nitro or C1-C3 alkylenedioxy groups), wherein X is hydroxy or, together with Y is oxy linking carbon 8 and carbon 12, wherein Y is hydroxy or an ammo group
  • the invention also relates to a compound (and pharmaceutical compositions thereof) of Formula I, wherein the dotted line between carbons 5 and 6 the dotted line between carbons 4 and R , and the dotted line between carbon 1 1 and R 3 each independently represent an optional double bond from the respective numbered carbon to a linked carbon, wherein R 1 is hydrogen, hydroxy, a lower alkanoyloxy or an aroyloxy group (wherein aryl of aroyloxy can be substituted by one or more lower alkyl, lower alkoxy, halo, trifluoromethyl, d ⁇ (lower)alkylam ⁇ no, hydroxy, nitro or C 1 -C3 alkylenedioxy groups), wherein X is hydroxy or, together with Y is oxy linking carbon 8 and carbon 12, wherein Y is hydroxy or an amino group that can be mono or di-substituted with lower alkyl, where the lower alkyls can be joined to form a five or six-membered ring, wherein
  • the hydrogen substituents at positions 5, 7 and 8 are alpha relative to the A-B ring structure
  • X is hydroxy
  • R ! is a lower alkanoyloxy group, for example, selected from the group consisting of acetoxy, propanoyloxy, isobutyryloxy, and cyclopropanoyloxy
  • the compound is, for example, selected from the group consisting of 2 -acetoxy-5,7,8 H- eudesma-4( 15), 1 1 ( 13)-d ⁇ en-8, 12-ol ⁇ de, 2 ⁇ -propanoyloxy-5,7,8 ⁇ H-eudesma- 4(15),l l(13)-d ⁇ en-8, 12-ohde, 2 ⁇ -cyclopropanoyloxy-5,7,8 H-eudesma-4(15), l 1 (13)- d ⁇ en-8,12-ohde, 2 ⁇ -acetoxy-4,5,7,8, l l ⁇ H
  • (1) X is oxy, (2) R 1 is lower alkanoyloxy or aroyloxy, with the proviso that when R 2 is methylene linked to C4 by a double bond, R 3 is methylene linked to Cl 1 by a double bond, then R 1 is not ethanoyl, and (3) wherein R 2 and R 3 are each independently a lower alkyl group or a lower alkenyl group with the unsaturation limited to the linkage to carbon 4 or carbon 1 1
  • (1) X is oxy, (2) R 1 is lower alkanoyloxy or aroyloxy, and (3) wherein R 2 and R 3 are each independently a lower alkyl group or a lower alkenyl group with the unsaturation limited to the linkage to carbon 4 or carbon 1 1
  • the lower alkyl and alkenyl groups contain one to six carbons Lower alkenyl groups are defined in conjunction with the backbone structures of Formula I, such that a methylene group has its unsaturation in conjunction with, for example, carbon 4 or carbon 11
  • at least one or both of R 1 and R 2 are methyl or methylene (both bonds in a double bond to carbon 4 or carbon 11)
  • the lower alkanoyloxy groups referred to above contain one or two to six carbon atoms and include methanoyloxy, ethanoyloxy or acetoxy, propanoyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, and the corresponding branched-chain isomers thereof
  • Also included among the alkanoyloxy groups herein are those comprising substituted and unsubstituted cycloalkyl groups, such as cyclopropanoyloxy, cyclobutanoyloxy, cyclopentanoyloxy,
  • the lower alkyl groups include methyl, ethyl, propyl, butyl, pentyl, heyxl, and the corresponding brnached- chain isomers thereof.
  • the aryl groups are C6-C10 aromatic groups, or a heteroaromatic groups with 5 to 10 ring atoms, of which, preferably, up to two (2) are heteroatoms selected from nitrogen, oxygen or sulfur.
  • the lower alkyl groups referred to above include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the corresponding branched-chain isomers thereof.
  • the bond linking groups R 2 and R 3 can be a single or double bond, and the alkyl groups described herein can be bonded to carbons 4 and 1 1 , respectively, by means of a single or double bond.
  • Non-limiting examples of compounds in which R 1 is hydrogen include salts, such as sodium salts, of: 8 ⁇ -hydroxy-4,7,8 ⁇ H-eudesama-5, l l(13)-dien-12-oic acid; 8 ⁇ -hydroxy-5,7,8,l l ⁇ H-eudesam-4(15)-en-12-oic acid; 8 ⁇ -hydroxy- 4,5,7,8, l l ⁇ H-eudesman-12-oic acid; 2 ⁇ -hydroxy-4(15), l l(13)eudesmadien-12,8-olide.
  • salts such as sodium salts
  • Non-limiting examples of compounds in which R 1 is hydroxy include salts, such as sodium or hydrochloride salts, of: 2 ⁇ ,8 ⁇ -dihydroxy-2 ⁇ -4,5, 7,8,1 l ⁇ H-eudesaman-12-oic acid; 2 ⁇ ,8 ⁇ -dihydroxy-4(15)l l(13)-eudesamadien-12-oic acid; 2 ⁇ -benzoyl- 8 ⁇ -hydroxy-2 ⁇ ,4,5, 7,8,1 l ⁇ H-eudesaman-12-oic acid; l-[2 ⁇ -hydroxy-l 1,12-dihydro- 5,7,8 H-eudesm-4(15)-en-8,12-olidyl]-pyrrolidine; and l-[2 ⁇ -benzoyloxy-l l,12- dihydro-5,7,8 ⁇ H-eudesm-4(15)-en-8,12-olidyl]-pyrrolidine.
  • salts such as sodium or hydrochloride salts
  • R is a lower alkanoyloxy group
  • Compounds in which R is a lower alkanoyloxy group include but are not limited to 2 ⁇ -acetoxy-5,7,8 H-eudesma-4(15),l l(13)-dien-8,12-olide; 2 ⁇ -propanoyloxy-5,7,8 ⁇ H-eudesma-4(15), l l (13)-dien-8,12-olide; 2 ⁇ -isobutyryloxy- 5,7,8 ⁇ H-eudesma-4(15),l l(13)-dien-8,12-olide; ⁇ -cyclopropanoyloxy-5,7,8 ⁇ H- eudesma-4(15), l l(13)-dien-8,12-olide; 2 ⁇ - acetoxy-4,5,7,8, 1 l H-eudesman-8,12- olide; and 2 ⁇ -cyclopropanoyloxy-5, 7,8,1 l
  • Rl is a aroyloxy group
  • compounds in which Rl is a aroyloxy group include, for example, 2 ⁇ -benzoyloxy- 5.7,8 ⁇ H-eudesma-4(15), l l(13)-dien-8,12-olide, 2 ⁇ -furoyloxy-5,7,8 ⁇ H-eudesma- 4( 15), 1 1 ( 13 )-dien-8, 12-olide, 2 ⁇ -benzoyloxy-4,5, 7,8, 1 l ⁇ H-eudesman-8,12-olide, and 2 ⁇ - benzoyloxy-5, 7,8, 1 l ⁇ H-eudesm-4(15)-en-8, l 2-olide
  • the compounds of the present invention upon administration to hyperhpidemic mammals, exact positive effects on circulating lipid levels Furthermore, in vitro, the compounds specifically inhibit an enzyme, hormone-sensitive lipase (HSL), and inhibit lipolysis in a whole-cell model In vivo, the compounds described herein
  • the compounds of the present invention are prepared from synthetic starting materials or those isolated from natural sources
  • One particular starting material with double bonds between carbons 4 and 15, and between carbons 1 1 and 13, 2 ⁇ -hydroxy-5,7,8 ⁇ H-eudesma-4(15), l l(13)-dien-8, 12-olide can be synthesized by the procedure described by Tomioka et al. (1984, Tetrahedron Letters 25 333-336) or isolated and purified from the plant Iva microcephala or other plants, as described by Herz et al (1962, J. Org. Chem.
  • the alkanoyloxy and aroyloxy derivatives of 2-hydroxy compounds are prepared by synthetic procedures known to one of ordinary skill, for example, 2 ⁇ -propanoyloxy-5,7,8 ⁇ H-eudesma-4(l 5), 1 l(13)-dien-8,l 2-olide and 2 ⁇ -benzoyloxy-5,7,8 ⁇ H-eudesma-4(l 5), l l(13)-dien-8, l 2-olide are prepared from 2 ⁇ -hydroxy-5,7,8 ⁇ H-eudesm-4(15), l l(13)-dien-8,12-olide by reaction with propanecarbonyl chloride and benzoyl chloride, respectively
  • a dien such as 2 ⁇ -
  • Open ring compounds can be synthesized by hydrolysis of the corresponding lactone
  • the 2 ⁇ isomer can be prepared from the corresponding 2 ⁇ isomer using the Mitsunobu reaction (Mitsunobu et al , 1967, Bull Chem Soc Japan 40 935)
  • Representative compounds of the present invention include 2 ⁇ -cyclohexanecarbonyloxy-4,5,7,8, 1 l ⁇ H-eudesman-8,12-ohde 2 ⁇ -cyclopentanecarbonyloxy-4,5,7,8, 1 l ⁇ H-eudesman-8, 12-ohde 2 ⁇ -cyclobutanecarbonyloxy-4,5,7,8, 1 l ⁇ H-eudesman-8, 12-ohde 2 ⁇ -(2'-naphthoyloxy)5,7,8, l l ⁇ H-eudesm-4(15)-en-8,12-ohde
  • the compounds of the present invention can be isolated and purified by established methods to yield pharmaceutically acceptable material for administration to mammals.
  • the compounds for use in the methods of the present invention can be, and are preferably, administered as a medicament, i.e., a pharmaceutical composition.
  • a medicament i.e., a pharmaceutical composition.
  • Preferred are oral and intraperitoneal dosage forms of the compounds.
  • compositions used in the methods of this invention for administration to animals and humans comprise the compound of the present invention in combination with a pharmaceutical carrier or excipient.
  • the medicament can be in the form of tablets (including lozenges and granules), dragees, capsules, pills, ampoules or suppositories comprising the compound of the invention.
  • “Medicament” as used herein means physically discrete coherent portions suitable for medical administration.
  • “Medicament in dosage unit form” as used herein means physically discrete coherent units suitable for medical administration, each containing a daily dose or a multiple (up to four times) or a sub-multiple (down to a fortieth) of a daily dose of the active compound of the invention in association with a carrier and/or enclosed within an envelope.
  • the medicament contains a daily dose or, for example, a half, a third or a quarter of a daily dose will depend on whether the medicament is to be administered once or, for example, twice, three times or four times a day, respectively.
  • the compositions are formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredients.
  • Tablets, coated tablets, capsules, ampoules and suppositories are examples of preferred dosage forms according to the invention. It is only necessary that the active ingredient constitute an effective amount, i.e., such that a suitable effective dosage will be consistent with the dosage form employed in single or multiple unit doses.
  • the exact individual dosages, as well as daily dosages will, of course, be determined according to standard medical principles under the direction of a physician or veterinarian.
  • the compounds of the present invention can also be administered as suspensions, solutions and emulsions of the active compound in aqueous or non-aqueous diluents, syrups, granulates or powders.
  • Diluents that can be used in pharmaceutical compositions (e.g., granulates) containing the active compound adapted to be formed into tablets, dragees, capsules and pills include, without limitation, the following: (a) fillers and extenders, e.g., starch, sugars, mannitol and silicic acid; (b) binding agents, e.g., carboxymethyl cellulose and other cellulose derivatives, alginates, gelatine and polyvinyl pyrrolidone; (c) moisturizing agents, e.g., glycerol; (d) disintegrating agents, e.g., agar-agar, calcium carbonate and sodium bicarbonate; (e) agents for retarding dissolution, e.g., paraffin; (f) resorption accelerators, e.g., quaternary ammonium compounds; (g) surface active agents, e.g., cetyl alcohol, glycerol monostearate; (h) adsor
  • the tablets, dragees, capsules and pills comprising the active compound can have the customary coatings, envelopes and protective matrices, which can contain opacifiers They can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time
  • the coatings, envelopes and protective matrices can be made, for example, from polymeric substances or waxes
  • the compounds of the present invention can also be made up in microencapsulated form together with one or several of the above-mentioned diluents
  • the diluents to be used in pharmaceutical compositions adapted to be formed into suppositories can, for example, be the usual water-soluble diluents, such as polyethylene glycols and fats (e g , cocoa oil and high esters, e g , C14-alcohol with C16-fatty acid) or mixtures of these diluents
  • the pharmaceutical compositions can also contain coloring agents and preservatives, as well as perfumes and flavoring additions (e g , peppermint oil and eucalyptus oil), and sweetening agents, (e g , saccharin and aspartame)
  • the pharmaceutical compositions will generally contain from 0 5 to 90% of the active ingredient by weight of the total composition
  • the pharmaceutical compositions and medicaments can also contain other pharmaceutically active compounds Any diluent in the medicaments of the present invention can be any of those mentioned above in relation to the pharmaceutical compositions
  • Such medicaments can include solvents of molecular weight less than 200 as the sole diluent It is envisaged that the compounds of the present invention will be administered perorally, parenterally (for example, intramuscularly, intraperitoneally, subcutaneously, transdermally or intravenously), rectally or topically, preferably orally or parenterally, especially perhngually, or intravenously
  • the dosage rate e g , 0 5 to 500 mg/kg of body weight
  • the dosage rate will be a function of the nature and body weight of the human or animal subject to be treated, the individual reaction of this subject to the treatment, type of formulation in which the active ingredient is administered, the mode in which the administration is carried out and the point in the progress of the disease or interval at which it is to be administered
  • the compounds of the present invention intervene in the hpolysis of stored t ⁇ glyce ⁇ des and their metabolism into fatty acids and glycerol
  • elevated glucose levels can be reduced
  • the metabolism of fat provides three times as much caloric energy as do carbohydrates or proteins
  • free fatty acids undergo ⁇ - oxidation, which consequently inhibits glycolysis by negative feedback mechanisms while simultaneously promoting gluconeogenesis
  • the released glycerol is utilized as a three-carbon substrate in gluconeogenesis thus cont ⁇ buting to an increased level of hepatic glucose output
  • enhanced hpolysis of stored t ⁇ glyce ⁇ des in adipose tissue occurs after prolonged periods of fasting, and is quickly suppressed following ingestion of a meal by the actions of
  • the anti-hpolytic effect of the compounds of the present invention in adipose tissue results in a reduction of plasma free fatty acids and glycerol concentrations
  • a reversal from gluconeogenesis to glycolysis in the liver can be achieved due to the decreased availability of fatty acids as a fuel source, with an eventual lowe ⁇ ng of plasma glucose levels as the is once again reestablished as the primary energy source
  • Lowering of free fatty acids has an additional impact on the function of the pancreas In the ⁇ — cell, elevations of free fatty acids cause an impairment in the insulin secretory mechanisms, as demonstrated by Unger (1995, Diabetes 44 863-870), with compounds demonstrating NEFA lowering properties preventing and restoring proper ⁇ -cell functioning
  • the compounds of the present invention thus achieve a lowering or normalization of elevated blood glucose and insulin levels, and amelioration of the insulin-resistant state of muscle in addition to their beneficial effect on circulating hpids
  • Type II diabetes the insulin regulatory mechanism for hpolysis does not function properly Due to the state of insuhn-resistance, and despite the elevation of insulin levels over the normal range in certain instances, the inhibition of hormone- sensitive lipase activity is severely diminished such that the lipolytic activity on stored t ⁇ glyce ⁇ des is enhanced, resulting in highly elevated fasting plasma NEFA levels.
  • recent experimental evidence suggests that a transient state of insuhn-resistance can be achieved in normal, non-diabetic individuals following the direct infusion of NEFA into the circulatory system This data would support a pathological role for elevated plasma NEFA in Type II diabetes
  • the exact etiology for the development of adult-onset Type II diabetes is unknown However, it is correlated with marked obesity since 70% of this patient population can be categorized as being obese under the general criterion set forth by American Diabetes Association, National Institutes of Health guidelines As such, non-human mammals exhibiting a similar pathophysiological profiles serve as appropriate models for
  • Animal models displaying these overall characteristics include the ob/ob and KK/Ay strains of mice, and the Zucker fa fa (ZDF) rat
  • the ob/ob mouse begins to develop a diabetic profile at 4 weeks of age Plasma glucose values increase up until 9- 10 weeks, at which time the levels begin to plateau
  • the ob/ob mouse displays elevated levels of NEFA, triglyceride production, and an insulin-resistant state
  • a parallel increase in plasma insulin levels occurs as a consequence of hyperglycemia As plasma insulin levels peak, an improvement in hyperglycemia is seen
  • the amount of insulin present is not sufficient to completely normalize the insulin-resistant state during an oral glucose tolerance test
  • KK/Ay is similar to the ob/ob with some differences being noted
  • the onset of the Type II profile occurs much later, roughly 3-4 months of age, and persists for as long as 1 year
  • Both mouse models display hype ⁇ nsuhnemia, hyperglycemia, insuhn-resistance and dyshpidemia similar to that seen in the clinical setting
  • the ZDF rat is also similar to the ob/ob and KK/Ay mouse in that all the general attributes of the Type Il-hke profile with one added exception
  • the ZDF rat displays a progressive decline in the ability to secrete insulin from the ⁇ - cell beginning at 10 weeks of age, resulting in a state of hypoinsuhnemia
  • this condition is similar in profile to a subtype of Type II diabetic patients which fail to respond to certain classes of pharmacological agents, such as the sulfonylureas, and can require insulin therapy
  • the present invention can be better understood by reference to the following non-hmiting Examples, which are provided as exemplary of the invention The following examples are presented in order to more fully illustrate the preferred embodiments of the invention They should in no way be construed, however, as limiting the broad scope of the invention
  • the flower heads, leaves, and tender stems of plants were dried, ground, and extracted in Soxhlet extractor with a mixture of petroleum ether and ether (2 1 v/v) with stirring for 5 hrs.
  • the crude 2- hydroxy-5,7,8 ⁇ -eudesm-4(l 5), 1 1(13)-dien-8, 12-olide started precipitating out in 2 hrs
  • the extract was allowed to cool at room temperature overnight, and then filtered, washed with the same mixture of solvent to obtain crude 2-hydroxy-5,7,8 ⁇ -eudesm- 4(15),l l(13)-dien-8,12-olide (2.93% yield)
  • the crude 2-hydroxy-5,7,8 ⁇ -eudesm- 4(15), l l(13)-dien-8, 12-olide was crystallized from a mixture of CH2C12, ether, and petroleum ether to obtain 2-hydroxy-5,7,8 ⁇ -eudesm-4(15),l l(13)-dien-8, 12-olide
  • the CH 2 C1 2 solution was evaporated in vacuo to give the crude product (7.0 g), which was purified by Silica gel column chromatography eluted with CH 2 C1 2 and 1 % MeOH-CH 2 Cl successively.
  • the product (5.08g) was crystallized from a mixture of CH 2 C1 , ether, and petroleum ether to obtain 2 ⁇ -benzoyloxy-5,7,8 ⁇ H-eudesma-4(15), l l(13)-d ⁇ en-8, 12-olide (4.5 g, 79.3%); m.p. 127-129°C. Estimated purity 99.9% by HPLC.
  • reaction mixture was filtered and concentrated in vacuo.
  • the residue was washed with ice water to get a white powder product, 2 ⁇ hydroxy-4,5, 7,8, 1 l ⁇ H-eudesman-8, 12-olide (3.36 g, 82.7%); m.p. 154-155°C.
  • the compounds of the present invention can be formulated for oral pharmaceutical administration to a patient in need of blood glucose lowering as follows Component mg/tablet
  • Compound of the invention 50 starch 50 mannitol 75 magnesium stearate 2 stearic acid 5
  • the compound, a portion of the starch and the lactose are combined and wet granulated with starch paste.
  • the wet granulation is placed on trays and allowed to dry overnight at a temperature of 45°C
  • the dried granulation is comminuted in a comminutor to a particle size of approximately 20 mesh
  • Magnesium stearate, stearic acid and the balance of the starch are added and the entire mix blended prior to compression on a suitable tablet press
  • the tablets are compressed at a weight of 232 mg using a 11/32 inch punch with a hardness of 4 kg. These tablets will disintegrate within a half hour according to the method described in USP XVI Example 4: Hormone-Sensitive Lipase
  • hormone-sensitive lipase Potential to directly inhibit the activity of hormone-sensitive lipase is determined in an in vitro purified enzyme system.
  • Recombinant hormone-sensitive lipase protein isolated from a bacterial expression vector was pre-incubated with a compound of the invention (e.g , 100 ⁇ M) prior to the addition of substrate, emulsified triolein phosphatidylcholine/phosphatidylinositol (PC/PI), to initiate the reaction.
  • PC/PI emulsified triolein phosphatidylcholine/phosphatidylinositol
  • Pharmacological specificity is determined by incubating test compound with other mammalian and non-mammalian lipase enzyme systems to assess inhibition of activity.
  • the assay was conducted using triolein concentrations from 42 ⁇ M to 835 ⁇ M.
  • Example 7 Further Enzyme Evaluations To demonstrate that the specificity of the compounds of the present invention toward hormone sensitive lipase, 2 ⁇ -benzoyloxy-5,7,8 ⁇ H-eudesma- 4(15),1 1(13)-dien-8, 12-olide was evaluated for inhibition of Candida rugosa lipase toward emulsified Triolein substrate PC/PI As shown in Table 2 below, 2 ⁇ - benzoyloxy-5, 7, 8 ⁇ H-eudesma-4(15), l l(13)-dien-8, 12-olide did not inhibit enzyme activity
  • any in vitro assay for hpolysis was developed using 3T3-L1 cells
  • the 3T3-L1 adipocytes were permeabilized with digitonin and preincubated with the compounds of the present invention
  • the hormone sensitive lipase was activated with cAMP, which resulted in the hydrolysis of triglycerides to free fatty acids and glycerol
  • the liberated glycerol in the supernatant is quantified by a fluorescent assay performed in Microfluor B flat bottom plates
  • adipocytes are used 14 days after differentiation is initiated
  • the media is carefully removed from the adipocytes
  • Thecells are then gently washed twice with 300 ⁇ l of PBS
  • the cells are incubated with 0 2 ml of a permeabilization buffer consisting of lOmM sodium phosphate, 150 mM sodium chloride, pH 7 4, 1% fatty-acid-free BSA, and digitonin (10 mg/ml)
  • an additional 0 2 ml of permeabilization buffer containing the test compound was added and the cells were incubated for an additional 30 minutes
  • the buffer is then removed completely and replaced with 200 ⁇ l of permeabilization buffer containing test compounds and 200 ⁇ l of permeabilization buffer containing N 6 -benzoyloxy-cAMP (0 6 mJVl), 8-t hi methyl -c AMP (0 6 mJVl), 2 mM ATP and 4 mM
  • the reaction bufer consists of Kinase Buffer, pH 7 0 (2 mM MgC12, 100 mM Triethanolamine, 2 mg/ml fatty acid free BSA), 130 ⁇ M ATP, 2 units/ml Glycerol kinase and 1 unit/ml glycerol phosphate oxidase.
  • 50 ul of reaction buffer is added to 50 ul of supernatant from the hpolysis assay.
  • a standard curve ranging from 0 -12,000 pmoles is generated with standard glycerol diluted in permeabilization buffer.
  • the plates are sealed and incubated at 37°C for 30 minutes.
  • the reaction results in conversion of glycerol to dihydroxyacetone phosphate and hydrogen peroxide
  • the hydrogen peroxide released is estimated using Quanta Blu flurorgenic substrate (Pierce, Rockford, IL) and HRP 50 ⁇ l of Quanta Blu Working solution is added to the samples and standards followed by the addition of 50 ul of 250 units/ml HRP
  • Quanta Blu Working solution is made by mixing 9 parts Quanta Blu substrate solution (Pierce, Quanta Blu Fluororgenic Peroxidase substrate kit, cat #15169) and 1 part Kinase buffer (2 mM MgC12, 100 mM Triethanolamine, 2 mg/ml fatty acid free BSA), pH 7 0
  • the plates are sealed and incubated at 37°C for 30 minutes
  • the reaction is stopped by adding 50 ul / well Quanta Blu Stop solution (Pierce, Quanta Blu Fluorogenic Peroxidase Kit.
  • the relative fluorescence units (RFU's) of the product are measured at an excitation and emission of 320 nm and 405 nm respectively, and corrected for background fluorescence
  • the final data is expressed as percent inhibition of hpolysis In the calculation, cAMP stimulation of Hpolysis is considered as 100%) stimulation, or conversely as 0% inhibition
  • the final data is expressed as a percent inhibition calculated as follows
  • mice Male, C57/B16J lean mice were purchased from Jackson Laboratories, Bar Harbor, Maine. Animals were housed and maintained in accordance with NIH guidelines and had free access to water and food ad libitum Test compounds of the present invention were suspended in 0 25%) methylcellulose (w/v in distilled water) and stored at -20°C in single use aliquots. Animals received a daily dose via the intraperitoneal route of administration for 2 weeks. After the last dose, animals were fasted overnight. On the following morning, a 250 ⁇ l blood sample was drawn via the retro-orbital sinus into a tube containing an EDTA-saline solution and centrifuged at 1,200 x g for 15 min.
  • the plasma fraction was analyzed for non-esterified free fatty acid content (NEFA) using the NEFA C diagnostic kit (WAKO Chemicals USA, Richmond, VA), and glycerol with the triglyceride GPO-Trinder diagnostic kit (Sigma) modified for use on a BM Hitachi 911 clinical chemistry analyzer.
  • NEFA C diagnostic kit WAKO Chemicals USA, Richmond, VA
  • glycerol with the triglyceride GPO-Trinder diagnostic kit (Sigma) modified for use on a BM Hitachi 911 clinical chemistry analyzer.
  • mice Male, KK/Ay mice were purchased from Clea Japan USA, Pennington, NJ. At 4 months of age, animals received daily intraperitoneal administration of 2 ⁇ - benzoyloxy-5,7,8 ⁇ H-eudesma-4(15), l l(13)-dien-8, 12-olide for 2 weeks. As described in Example 10, fasting plasma NEFA values were obtained. In addition, cholesterol and triglycerides were measured using BM reagent assay kits on a BM Hitachi 91 1 clinical chemistry analyzer.
  • mice receiving a 2 ⁇ -benzoyloxy-5,7,8 ⁇ H-eudesma- 4(15),1 l(13)-dien-8, 12-olide The data demonstrate significant reductions in NEFA, triglycerides, cholesterol and glycerol in mice receiving a 2 ⁇ -benzoyloxy-5,7,8 ⁇ H-eudesma- 4(15),1 l(13)-dien-8, 12-olide.
  • Plasma glucose levels were measured using a Boehringer Mannheim reagent assay kits on a Boehringer Mannheim Hitachi 91 1 clinical chemistry analyzer. Control mice showed a fasting plasma glucose level of 184 ⁇ 24 mg/dL, whereas animals dosed with the test compound showed a plasma glucose level of 90 ⁇ 29 mg/dL (p ⁇ 0.01).
  • Example 12 Effects in fasted ob/ob mice
  • mice Male, C57/B16J ob/ob mice were purchased from Jackson Laboratories (Bar Harbor, Maine). At 8-9 weeks of age, animals received daily compound administration via the intraperitoneal route of injection for a 2 week period at the indicated doses. Test compounds of the present invention were prepared as previously described in Example 10. At either 2 or 4 weeks of treatment, animals were fasted overnight and plasma NEFA levels determined as described in Example 1 1. The data are expressed as a percent reduction compared to animals that received vehicle alone. The test compounds elicited reductions in NEFA levels in treated animals.
  • Glucose levels were measured using a Johnson & Johnson One-Touch Glucometer from a 20 ⁇ l blood sampled collected via the retro-orbital sinus with a heparinized micro-capillary tube. -_>_> -
  • KK/Ay mice were administered compound as described in the foregoing Examples After 2 weeks of treatment, an oral glucose tolerance test (OGTT) was performed in the fasting state by administering a 2 gm/kg glucose solution prepared in deionized water to overnight fasted animals, and measuring venous glucose from the tip of the tail at regularly scheduled time points
  • OGTT oral glucose tolerance test
  • data obtained from young, non-diabetic C57/B16J mice is included for comparison
  • Calculation of the area under the curve (AUC) displayed in Table 2 was performed using a rectangular summation procedure incorporated within the P ⁇ zm data software analysis program (Graphpad, Sorrento, CA.)
  • Example 15 Effects on normog
  • mice Female ob/ob mice were administered compound as described above After 5-6 weeks of dosing, an OGTT was performed as previously described in Example 14
  • the initial fasting glucose values were obtained from non-diabetic mice
  • the compound of the present invention elicits a significant normalization of glucose disposal in this state

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Abstract

L'invention concerne, en autres choses, des méthodes et des composés hypolipémiants et hypoglycémiants, en particulier des composés hypolipémiants ou hypoglycémiants ayant une structure de cyle A-B (I), dans laquelle la ligne pointillée entre les atomes de carbone 5 et 6, la ligne pointillée entre l'atome de carbone 4 et R2 ainsi que la ligne pointillée entre l'atome de carbone 11 et R3 représentent chacune indépendamment une double liaison optionnelle à partir de l'atome de carbone à numéro respectif à un atome de carbone lié, et dans laquelle X représente hydroxy, ou avec Y, il représente oxy liant l'atome de carbone 8 et l'atome de carbone 12.
EP99957542A 1998-11-12 1999-11-10 Composes hypoglycemiants et hypolipemiants Withdrawn EP1135119A4 (fr)

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US19050798A 1998-11-12 1998-11-12
US19735298A 1998-11-20 1998-11-20
US197352 1998-11-20
PCT/US1999/026563 WO2000027388A1 (fr) 1998-11-12 1999-11-10 Composes hypoglycemiants et hypolipemiants

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CA2286451A1 (fr) 1999-10-14 2001-04-14 Grant A. Mitchell Induction de l'infertilite chez les males au moyen d'une lipase hormonosensible
WO2004111006A1 (fr) * 2003-06-12 2004-12-23 Novo Nordisk A/S Carbamates de phenyle para-substitues en tant qu'inhibiteurs de la lipase hormono-sensible
EP1636201A1 (fr) * 2003-06-12 2006-03-22 Novo Nordisk A/S Carbamates de phenyle para-substitues en tant qu'inhibiteurs de la lipase hormono-sensible
JP2008535775A (ja) * 2004-12-23 2008-09-04 ハーフテン，キャロライン ヴァン カロメリア・アマラントイデス（ｃａｌｏｍｅｒｉａａｍａｒａｎｔｈｏｉｄｅｓ）から単離した治療化合物
AU2005317748B8 (en) * 2004-12-23 2011-07-21 Caroline Van Haaften Therapeutic compounds isolated from Calomeria amaranthoides
CN114886889A (zh) * 2022-04-27 2022-08-12 清华大学 土木香内酯或其衍生物在制备用于预防或治疗肥胖的药物、保健品或食品中的用途

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EP0597107A1 (fr) * 1991-10-17 1994-05-18 Shionogi & Co., Ltd. Analogue de lignane, sa production et medicament hypolipidemiant

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US5917084A (en) * 1996-07-03 1999-06-29 Millennium Pharmaceuticals, Inc. Antifungal agents

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EP0597107A1 (fr) * 1991-10-17 1994-05-18 Shionogi & Co., Ltd. Analogue de lignane, sa production et medicament hypolipidemiant

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Title
See also references of WO0027388A1 *

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MXPA01004830A (es) 2002-09-18
AU1522600A (en) 2000-05-29
NZ511572A (en) 2003-06-30
AU761878B2 (en) 2003-06-12
CA2350213A1 (fr) 2000-05-18

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