WO1999002152A1 - Utilisation de 3,4-diphenylchromanes pour la preparation d'une composition pharmaceutique permettant d'augmenter l'insulinosensitivite - Google Patents

Utilisation de 3,4-diphenylchromanes pour la preparation d'une composition pharmaceutique permettant d'augmenter l'insulinosensitivite Download PDF

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Publication number
WO1999002152A1
WO1999002152A1 PCT/DK1998/000315 DK9800315W WO9902152A1 WO 1999002152 A1 WO1999002152 A1 WO 1999002152A1 DK 9800315 W DK9800315 W DK 9800315W WO 9902152 A1 WO9902152 A1 WO 9902152A1
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WO
WIPO (PCT)
Prior art keywords
formula
diphenylchroman
pharmaceutically acceptable
acceptable salt
mammal
Prior art date
Application number
PCT/DK1998/000315
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English (en)
Inventor
Michael Shalmi
Martin William Edwards
Original Assignee
Novo Nordisk A/S
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to AU84338/98A priority Critical patent/AU8433898A/en
Publication of WO1999002152A1 publication Critical patent/WO1999002152A1/fr

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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
    • A61K31/395—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

Definitions

  • the present invention relates to the use of compounds of the general formula I for increasing insulin sensitivity.
  • the present invention also embraces pharmaceutical compositions comprising these compounds and methods of using the compounds and their pharmaceutical compositions.
  • the present invention relates to use of compounds of the general formula I for reducing blood glucose levels in humans, particularly those afflicted with diabetes.
  • Diabetes mellitus is a systemic disease characterized by disorders in the actions of insulin and other regulatory hormones in the metabolism of carbohydrates, fats and proteins, and in the structure and function of blood vessels.
  • the primary symptom of diabetes is hyperglycemia, often accompanied by glucosuria, the presence in urine of large amounts of glucose, and polyuria, the excretion of large volumes of urine. Additional symptoms arise in chronic or long standing diabetes. These symptoms include degeneration of the walls of blood vessels. Although many different organs are affected by these vascular changes, the nerves, eyes and kidneys appear to be the most susceptible. As such, long-standing diabetes mellitus, even when treated with insulin, is a leading cause of blindness.
  • Type I diabetes is of juvenile onset, ke- tosis-prone, develops early in life with much more severe symptoms and has a near- certain prospect of later vascular involvement. Control of this type of diabetes is difficult and requires exogenous insulin administration.
  • Type II diabetes mellitus is of adult onset, ketosis-resistant, develops later in life, is milder and has a more gradual onset.
  • One of the most significant advancements in the history of medical science came in 1922 when Banting and Best demonstrated the therapeutic effects of insulin in diabetic dogs.
  • Banting and Best demonstrated the therapeutic effects of insulin in diabetic dogs came in 1922 when Banting and Best demonstrated the therapeutic effects of insulin in diabetic dogs.
  • a clear picture of the basic biochemical defects of the disease is not known, and diabetes remains a serious health problem. It is believed that two percent of the United States' population is afflicted with some form of diabetes.
  • the introduction of orally effective hypoglycemic agents was an important development in the treatment of hyperglycemia.
  • Centchroman has also been investigated as an anti-cancer agent for treatment of advanced breast cancer (Misra et al., Int J Cancer 43 (1989), 781 - 783. Recently, centchroman as a race- mate has been found as a potent cholesterol lowering pharmaceutical agent expressed by a significant decrease of the serum concentrations (S.D. Bain et aj., J Min Bon Res 9 (1994), S 394). It is preferred to use the compounds of formula I in the trans configuration. The I enantiomeric forms are preferred over racemic mixtures.
  • the 3,4-diarylchromans are prepared according to known methods, such as those disclosed in U.S. Patent No. 3,340,276 to Carney et aj., U.S. Patent No. 3,822,287 to Bolger, and Ray et al., J Med Chem 19 (1976), 276 - 279, the contents of which are incorporated herein by reference. Conversion of the cis isomer to the trans configuration by means of an organometallic base-catalyzed rearrangement is disclosed in U.S. Patent No. 3,822,287.
  • the optically active d- and l-enantiomers may be prepared as disclosed by Salman et aj. in U.S. Patent No.
  • levormeloxifene the compound of formula II is referred to as levormeloxifene.
  • levormeloxifene is obtained as the free base and the hydrochloride salt.
  • Levormeloxifene, ( - ) - 3R,4R - trans- 7-methoxy-2,2- dimethyl-3-phenyl-4- ⁇ 4-[2-(pyrrolidin-1-yl)ethoxy]phenyl ⁇ chromane is a particular preferred compound.
  • Levormeloxifene may be used in human and veterinary medicine for the regulation of bone metabolism.
  • osteoporosis including post-menopausal osteoporosis and glucocorticoid-related osteoporosis
  • Paget ' s disease hyperparathyroidism
  • hypercalcemia of malignancy other conditions characterized by excessive rates of bone resorption and/or decreased rates of bone formation.
  • insulin sensitizers in particular thiazolidinediones, and there use in treating diabetes mellitus, in particular NIDDM. Insulin sensitizers lowers blood glucose without stimulating insulin secretion, and in some instances even lowers insulin levels in mammals.
  • the 3,4-diphenylchromans of formula I, and in particular levormeloxifene may be administered to mammals, such as humans, to increase insulin sensitivity and/or reduce hyperinsulineamia and/or reduce blood glucose concentrations.
  • 3,4- diphenylchromans can be used for treating hyperinsulineamia, hyperglycemia and for increasing insulin sensitivity in mammals.
  • This invention provides the use of 3,4-diphenylchromans of formula I, and in particular levormeloxifene, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for reducing blood glucose concentrations, for treating hyperinsulineamia and/or for treating conditions associated with insulin resistance in mammals, such as humans.
  • the term “treating” or “treatment” is also intended to comprise prophylactic treatment, that is prevention of a disease before its outbreak.
  • the current invention concerns the discovery that the compounds of formula I are useful in mammalian patients with a decreased insulin sensitivity and accompanying hyperinsulineamia in order to revert the metabolic imbalance this condition is associated with.
  • the methods of treatment provided by this invention are practiced by administering to a mammal, eg. a human (male or female), in need of a dose of a 3,4- diphenylchroman of formula I or a pharmaceutically acceptable salt thereof, that is effective to modulate, in particular increase, insulin sensitivity and/or reduce hyperinsulineamia.
  • Preferred 3,4-diphenylchromans of formula I for use in accordance with the present invention comprises centchroman as a racemic mixture, in particular (+/-)-3,4-trans-7- methoxy-2,2-dimethyl-3-phenyl-4- ⁇ 4-[2-(pyrrolidin-1-yl)ethoxy]phenyl ⁇ chromane, and most preferred is levormeloxifene.
  • 3,4-diphenylchromans of formula I may be prepared in the form of pharmaceutically acceptable salts, especially acid-addition salts, including salts of organic acids and mineral acids.
  • salts include salts with non-toxic organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, gluconic acid, malic acid, maleic acid, tartaric acid, citric acid, ascorbic acid, benzoic acid, salicylic acid, embonic acid, methanesulphonic acid and malonic acid.
  • Suitable inorganic acid-addition salts include salts with non-toxic acids such as hydrochloric, hydro- bromic, sulphuric and phosphoric acids and the like.
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • a preferred pharmaceutically acceptable salt of 3,4-diphenylchromans of formula I are the fumarate salt, particularly preferred is levormeloxifene hydrogen fumarate.
  • Another preferred pharmaceutically acceptable salt of 3,4-diphenylchromans of formula I are the maleate salt, particularly preferred is levormeloxifene hydrogen maleate.
  • 3,4-diphenylchromans of formula I and their pharmaceutically acceptable salts are also useful for treating conditions associated with insulin resistance.
  • Conditions associated with insulin resistance can result from disorders such as diabetes mellitus and its chronic complications, obesity, hyperlipidemias and dyslipidemias, athero- sclerosis, hypertension, cardiovascular disease, AIDS, cancer, wasting/cachexia, sepsis, trauma associated with burns, malnutrition and stress; aging, lupus and other autoimmune diseases, endocrine disease, hyperuricemia, polycystic ovary syndrome and complications arising from athletic activity or inactivity.
  • 3,4-diphenylchromans of formula I and their pharmaceutically acceptable salts are formulated with a pharmaceutically acceptable carrier to provide a medicament for parenteral, oral, nasal, rectal, subdermal or in- tradermal or transdermal administration according to conventional methods.
  • Formulations may further include one or more diluents, fillers, emulsifiers, preservatives, buffers, excipients, etc. and may be provided in such forms as liquids, powders, emulsions, suppositories, liposomes, transdermal patches, controlled release, dermal implants, tablets, etc.
  • the 3,4-diphenylchromans of formula I may be prepared in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences, Gennaro, ed., Mack Publishing Co., Easton, PA, 1990. Oral administration is preferred.
  • the active 3,4-diphenylchroman of formula I is prepared in a form suitable for oral administration, such as a tablet or capsule.
  • a pharmaceutically acceptable salt of a 3,4-diphenylchroman of formula I is combined with a carrier and moulded into a tablet.
  • Suitable carriers in this regard in- elude starch, sugars, dicalcium phosphate, calcium stearate, magnesium stearate and the like.
  • Such compositions may further include one or more auxiliary substances, such as wetting agents, emulsifiers, preservatives, stabilizers, colouring additives, etc.
  • compositions containing a 3,4-diphenylchroman of formula I may be administered one or more times per day or week.
  • An effective amount of such a pharmaceutical composition is the amount required to treat hyperglycemia, to treat conditions associated with insulin resistance, to increase insulin sensitivity, to reduce blood glucose levels and/or reduce hyperinsulineamia, according to this invention. Such amounts will depend, in part, on the particular condition to be treated, age, weight, and general health of the patient, and other factors evident to those skilled in the art.
  • a typical daily dose will contain a nontoxic dosage range of from about 0.001 to about 75 mg/kg patient per day of a 3,4-diphenylchroman of formula I, in particular levormeloxifene.
  • compositions containing a 3,4-diphenylchroman of formula I may be administered in unit dosage form one or more times per day or week. In the alternative, they may be provided as controlled release formulations suitable for dermal implantation. Implants are formulated to provide release of active compound over the desired period of time, which can be up to several years. Controlled-release formulations are disclosed by, for example, Sanders et al.. J Pharm Sci 73 (1964), 1294 - 1297, 1984; U.S. Patent Specification No. 4,489,056; and U.S. Patent Specification No. 4,210,644, which are incorporated herein by reference.
  • the ability of the compounds of formula I, and in particular levormeloxifene to increase insulin sensitivity was determined by testing the efficacy of the compounds in vivo in mammals.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation de composés de formule générale (I) permettant d'augmenter l'insulinosensitivité.
PCT/DK1998/000315 1997-07-10 1998-07-07 Utilisation de 3,4-diphenylchromanes pour la preparation d'une composition pharmaceutique permettant d'augmenter l'insulinosensitivite WO1999002152A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU84338/98A AU8433898A (en) 1997-07-10 1998-07-07 Use of 3,4-diphenylchromans for the manufacture of a pharmaceutical composition for increasing insulin sensitivity

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DK84097 1997-07-10
DK0840/97 1997-07-10
US5330597P 1997-07-21 1997-07-21
US60/053,305 1997-07-22

Publications (1)

Publication Number Publication Date
WO1999002152A1 true WO1999002152A1 (fr) 1999-01-21

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AU (1) AU8433898A (fr)
WO (1) WO1999002152A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001001969A2 (fr) * 1999-07-06 2001-01-11 Endorecherche, Inc. Methodes de traitement et/ou de suppression de la prise de poids

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4544555A (en) * 1974-05-21 1985-10-01 Gastaud Jean M 3,20-Diketo, 6-methyl, 17-alpha-hydroxy 19-norpregna 4,6-diene, its esters and the uses thereof
WO1996022092A1 (fr) * 1995-01-20 1996-07-25 Novo Nordisk A/S Utilisation des 3,4-diphenylchromanes pour la preparation d'une composition pharmaceutique destinee au traitement preventif ou curatif de l'obesite

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4544555A (en) * 1974-05-21 1985-10-01 Gastaud Jean M 3,20-Diketo, 6-methyl, 17-alpha-hydroxy 19-norpregna 4,6-diene, its esters and the uses thereof
WO1996022092A1 (fr) * 1995-01-20 1996-07-25 Novo Nordisk A/S Utilisation des 3,4-diphenylchromanes pour la preparation d'une composition pharmaceutique destinee au traitement preventif ou curatif de l'obesite

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001001969A2 (fr) * 1999-07-06 2001-01-11 Endorecherche, Inc. Methodes de traitement et/ou de suppression de la prise de poids
WO2001001969A3 (fr) * 1999-07-06 2001-08-02 Endorech Inc Methodes de traitement et/ou de suppression de la prise de poids
JP2003503446A (ja) * 1999-07-06 2003-01-28 アンドルシェルシュ・インコーポレイテッド 体重増加の処置方法および／または抑制方法
US6710059B1 (en) 1999-07-06 2004-03-23 Endorecherche, Inc. Methods of treating and/or suppressing weight gain
JP4790178B2 (ja) * 1999-07-06 2011-10-12 アンドルシェルシュ・インコーポレイテッド 体重増加の処置方法および／または抑制方法
AU2009200258B2 (en) * 1999-07-06 2012-01-12 Endorecherche, Inc. Methods of treating and/or suppressing weight gain

Also Published As

Publication number Publication date
AU8433898A (en) 1999-02-08

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