WO2000047206A1 - Utilisation de derives de pyrrolidine pour la preparation d'une composition pharmaceutique destinee au traitement ou a la prevention de l'obesite ou a la regulation de l'appetit - Google Patents

Utilisation de derives de pyrrolidine pour la preparation d'une composition pharmaceutique destinee au traitement ou a la prevention de l'obesite ou a la regulation de l'appetit Download PDF

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Publication number
WO2000047206A1
WO2000047206A1 PCT/DK2000/000055 DK0000055W WO0047206A1 WO 2000047206 A1 WO2000047206 A1 WO 2000047206A1 DK 0000055 W DK0000055 W DK 0000055W WO 0047206 A1 WO0047206 A1 WO 0047206A1
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WIPO (PCT)
Prior art keywords
dihydroxy
hydroxymethylpyrrolidine
hydroxymethyl
hydroxy
pyrrolidine
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PCT/DK2000/000055
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English (en)
Inventor
Jeppe Sturis
Marit Kristiansen
Christina Bjenning
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Novo Nordisk A/S
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Publication date
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to JP2000598158A priority Critical patent/JP2002536410A/ja
Priority to EP00903558A priority patent/EP1150674A1/fr
Priority to AU25357/00A priority patent/AU2535700A/en
Publication of WO2000047206A1 publication Critical patent/WO2000047206A1/fr

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    • 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
    • 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
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • pyrrolidine derivatives for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of obesity or appetite regulation.
  • the present invention relates to the use of compounds of the general formula I for the treatment or prophylaxis of obesity or appetite regulation.
  • the present invention also embraces use of glycogen phosphorylase inhibitors for the treatment or prophylaxis of obesity or appetite regulation and methods of using the compounds and their pharmaceutical compositions.
  • Obesity is a well-known risk factor for the development of many very common diseases such as atherosclerosis, hypertension and diabetes. The incidence of obese people and thereby also these diseases is increasing throughout the entire industrialised world. Due to its indirect but important effect as a risk factor in mortal and common diseases it will be important to find treatment for obesity or appetite regulation.
  • the term obesity implies an excess of adipose tissue.
  • obesity is best viewed as any degree of excess adiposity that imparts a health risk.
  • the cut off between normal and obese individuals can only be approximated, but the health risk imparted by the obesity is probably a continuum with increasing adiposity.
  • the Framingham study demonstrated that a 20% excess over desirable weight clearly imparted a health risk.
  • BMI body mass index
  • the regulation of feeding behaviour is incompletely understood. Certain is that brain neuro- chemicals located in specific hypothalamic nuclei regulate onset and termination of feeding. Several regulatory processes may influence these hypothalamic centres: Metabolic signals such as postprandial increases in plasma glucose and insulin; meal-induced gastric distension is another possible inhibitory factor. Local control by brain neurochemicals and cate- cholamines/beta3-adrenoceptors (inhibits feeding and stimulates energy expenditure). Psychological, social, and genetic factors also influence food intake.
  • initial weight loss is not an optimal therapeutic goal. Rather, the problem is that most obese patient eventually regain their weight.
  • An effective means to establish and/or sustain weight loss is the major challenge in the treatment of obesity today.
  • compositions and methods that are useful for the treatment or prophylaxis of obesity or appetite regulation.
  • One object of the present invention is to provide compounds which can effectively be used for the treatment or prophylaxis of obesity or appetite regulation.
  • Glycogen phosphorylase inhibitors constitute a class of compounds which have use in the treatment of diabetes mellitus.
  • Substituted N-(indole-2-carbonyl)-glycinamides acting as glycogen phosphorylase inhibitors are disclose in PCT-publication No. WO96/39384, WO96/39385 and in EP-A-0 846 464, all hereby incorporated by reference.
  • Piperidine and pyrrolidine compounds acting as glycogen phosphorylase inhibitors are disclose in PCT-publication No. WO 95/24391 , WO 97/09040, WO98/40353 and WO 98/50359, all hereby incorporated by reference.
  • glycogen phosphorylase inhibitor may be used as a compound (active agent) of this invention.
  • Such inhibitors can readily by determined by those skilled in the art.
  • Phosphorylase can either be purchased from Sigma or extracted from rat livers according to Stalmans et. al. (Eur.J.Bio-chem. 49 (1974), 415). The activity of phosphorylase can be de- termined as described by Bergmeyer (1983; in: Meth. of Enzymatic Analysis, 2, 293-295, Weinheim, (ed.) Verlag Chemie).
  • a compound is considered to be a potent glycogen phosphorylase inhibitor if the IC50 value is less than 10 ⁇ M.
  • glycogen phosphorylase inhibitors are described above, however, other glycogen phosphorylase inhibitors will be known to those skilled in the art, such as 1-[N-(5-chloroindole-2-carbonyl)-3-(4-fluorophenyl)- L-Alanyl]-4-hydroxypiperidine and (3R,4R,5R)-5-hydroxymethyl-3,4-piperidinediol.
  • the present invention is based in part on the discovery that a representative glycogen phosphorylase inhibitor, 2-alkylpyrrolidine, (2R,3R,4R)-3,4-dihydroxy-2-hydroxymethylpyrrolidine is effective in appetite regulation and against obesity, in Sprague Dawley rats and in Zucker Diabetic Fatty (ZDF) rats.
  • ZDF rats are generally recognised models of hyperphagia, obesity and diabetes.
  • glycogen phosphorylase inhibitors and the 2-alkylpyrrolidine of formula I are useful as therapeutic appetite regulation agents and therapeutic agent against obesity in mammals, including primates such as humans.
  • the present invention is furthermore useful in treatment or prophylaxes of diseases were lowering of the lipid content in the blood is beneficial such as dyslipidemia, hypertriglyc- eridemia, hyperlipidemia, hyperlipoproteinaemia, cardiovascular diseases and hypertension.
  • the present invention provides the use of a compound of the general formula (I)
  • R ' is hydrogen, acyl, alkene, cycloalkyl or alkyl which optionally is substituted with one or more of the following groups: hydroxy, alkoxy, amino, N-alkylamino, N,N-dialkylamino, halogen, cycloalkyl, optionally substituted phenyl or alkoxycarbonyl, R 2 is hydrogen or alkyl,
  • R and R4 which are the same or different, independent of each other, is hydrogen, halogen, hydroxy, mercapto or amino which is optionally substituted with alkyl or aralkyl, and
  • R ⁇ is alkyl substituted with hydroxy, halogen, amino, N-alkylamino, N,N-dialkylamino or mercapto, or pharmaceutically acceptable salts or hydrates thereof including any of the optical isomers or mixtures thereof, for the manufacture of a medicament for the treatment or prophylaxis of obesity or appetite regulation.
  • alkyl when used alone or in combination with another moiety, is a straight or branched saturated hydrocarbon chain group which preferably contains not more than 8 carbon atoms, more preferred not more than 4 carbon atoms.
  • Especially preferred alkyl groups are methyl, ethyl, propyl and isopropyl.
  • halogen refers to chloro, bromo or fluoro, preferably fluoro.
  • N-alkylamino is N-methylamino.
  • N,N-dialkylamino is N,N-dimethyl-amino.
  • acyl refers to carbonyl substituted with hydrogen, alkyl or phenyl.
  • cycloalkyl preferably contains 3-7 carbon atoms, more prefered 3-6 carbon atoms.
  • Alkoxy preferably is methoxy or ethoxy.
  • Alkoxycarbonyl preferably is methoxycarbonyl or ethoxycarbonyl.
  • Aralkyl preferably is benzyl.
  • Trifluoroalkyl preferably is trifluoromethyl or 2,2,2-trifluoroethyl.
  • Alkene preferably contains not more than 8 carbon atoms and preferably is allyl.
  • the term "one or more" substituents preferably is 1-3 substituents, most preferred 1.
  • compound of formula (I) contains at least 2 hydroxy groups in another embodiment formula (I) contains at least 3 hydroxy goups.
  • a subgroup of compounds to be used according to this invention are compounds of formula wherein the two substituent designated by the symbols R3 and R5 are situated at the same side of the plane formed by the 5 membered nitrogen containing ring, and R4 is situated at the opposite side of the plane formed by the 5 membered nitrogen containing ring.
  • Examples of compounds to be used according to this invention are compounds of formula I wherein R1 is alkyl which optionally is substituted with one or more of the following groups: hydroxy, alkoxy, amino, N-alkylamino, N,N-dialkylamino, alkoxycarbonyl, cycloalkyl or optionally substituted phenyl.
  • R1 is hydrogen
  • R1 is phenylalkyl wherein the phenyl moiety optionally is substituted with one or more of the following groups: halogen, hydroxy, alkoxy, trifluoromethyl or cyano.
  • R3 and R4 are both hydroxy.
  • R5 is hydroxyalkyl, such as hydroxy methyl.
  • Another subgroup of compounds to be used according to this invention are compounds of formula I wherein R3 and R4 each are hydroxy, and R5 is hydroxymethyl.
  • the compounds of formula I may be presented as a mixture of isomers which, if desired, may be resolved into the individual pure enantiomers. This resolution may conveniently be performed by fractional crystallisation from various solvents, of the salts of compounds of the formula I with optical active acids or by other methods known per se, for example, chiral column chromatography. This invention includes all isomers, whether resolved or mixtures thereof.
  • Examples of compounds to be used according to this invention are 3,4-dihydroxy-2- hydroxymethylpyrrolidine, 3,4-dihydroxy-2-hydroxymethyl-1-methylpyrrolidine, 1- cyclopropylmethyl-3,4-dihydroxy-2-hydroxymethyl-pyrrolidine, 3,4-dihydroxy-2- hydroxymethyl-1 -propylpyrrolidine, 1 -butyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine, 3,4- dihydroxy-2-hydroxymethyl-1 -(2,2,2-trifluoroethyl)pyrrolidine, 1 -benzyl-3,4-dihydroxy-2- hydroxymethylpyrrolidine, 3,4-dihydroxy-2-hydroxymethyl-1 -(2-hydroxyethyl)pyrrolidine, 3,4- dihydroxy-2-hydroxymethyl-1-(1 ,3-dihydroxyprop-2-yl)pyrrolidine, 3,4-dihydroxy-2- hydroxymethyl-1 -(2, 3-dihydroxyprop-1 -yl)pyrrolidine, 1 -(2-amino
  • the compound of general formula (I) is (2R,3R,4R)-3,4-dihydroxy-2- hydroxymethylpyrrolidine, hydrochloride or (2R,3R,4R)-3,4-dihydroxy-2- hydroxymethylpyrrolidine, hydrobromide.
  • the present invention relates to (2R,3R,4R)-3,4-dihydroxy-2- hydroxymethylpyrrolidine, hydrobromide.
  • the present invention relates to the use of a compound of formula (I) for the manufacture of a medicament for lowering of food intake.
  • the present invention relates to the use of (2R,3R,4R)-3,4-dihydroxy-2- hydroxymethylpyrrolidine for the manufacture of a medicament for lowering of food intake.
  • the present invention relates to the use of a glycogen phosphorylase inhibitor for the manufacture of a medicament for lowering of food intake.
  • the present invention relates to the use of a compound of formula (I) for the manufacture of a medicament for lowering of food intake of food with a high fat content.
  • the present invention relates to the use of (2R,3R,4R)-3,4-dihydroxy-2- hydroxymethylpyrrolidine for the manufacture of a medicament for lowering of food intake of food with a high fat content.
  • the present invention relates to the use of a glycogen phosphorylase inhibitor for the manufacture of a medicament for lowering of food intake of food with a high fat content.
  • the present invention relates to the use of a compound of formula (I) for the manufacture of a medicament for changing the preference of food with a high fat content to food with a low fat content.
  • the present invention relates to the use of (2R,3R,4R)-3,4-dihydroxy-2- hydroxymethylpyrrolidine for the manufacture of a medicament for changing the preference of food with a high fat content to food with a low fat content.
  • the present invention relates to the use of a glycogen phosphorylase inhibitor for the manufacture of a medicament for changing the preference of food with a high fat content to food with a low fat content.
  • the present invention relates to the use of a glycogen phosphorylase inhibitor for the manufacture of a medicament for the treatment or prophylaxis of obesity or appetite regulation.
  • the present invention relates to the use of a glycogen phosphorylase inhibitor with an IC50 value less than 10 ⁇ M.
  • the present invention relates to a method for the treatment or prophylaxis of obesity or appetite regulation which method comprises administering an effective amount of a compound of formula I defined in anyone of the preceding claims to a patient in need of such a treatment.
  • the present invention relates to a method for the treatment or prophylaxis of obesity or appetite regulation which method comprises administering an effective amount of a glycogen phosphorylase inhibitor to a patient in need of such a treatment.
  • the compounds of formula I are prepared by methods known per se by the skilled art worker, for example as described in the following.
  • the compounds of formula I can be prepared by joining the C-1 and C-4 of xylose together with nitrogen to form the pyrrolidine ring as described in Tetrahedron 42 (1986), 5685 et seq, hereby incorporated by reference.
  • a variety of functional groups can be introduced in the compounds prepared as out-lined above by methods well known to those skilled in the art.
  • R2, R3, R4, and R5 are as defined in the claims below, with an aldehyde in presence of a reducing agent among which sodium cyanoborohydride is preferred, to form a compound of formula I.
  • the leaving group, Y may be any suitable leaving group as for example halogen.
  • R1 either is as defined in the claims below or is a readily removable protection group, i.e. benzyl
  • R2 is as defined in the claims below and R3 and R4 are protected hy- droxy, i.e. benzyloxy, with a halogenating agent such as thionyl chloride, thionyl bromide, or diethylaminosulfur trifluoride (DAST) and subsequent removal of the protection groups to form a compound of formula I, wherein R1 , R3, and R4 are as defined in the claims below, and R5 is methyl substituted with halogen.
  • a halogenating agent such as thionyl chloride, thionyl bromide, or diethylaminosulfur trifluoride (DAST)
  • R1 either is as defined in the claims below or is a readily removable protection group, i.e. benzyl
  • R2 is as defined in the claims below
  • R3 and R4 are protected hydroxy, i.e. benzyloxy
  • X is a leaving group, with a compound of the general formula NHR6R7, wherein the two substituents R6 and R7 may both be alkyl, or one is alkyl and the other is hydrogen or together with NH R6 and R7 form phthalimide, and subsequent removal of the protection groups to form the compounds of formula I, wherein R1 , R2, R3, and R4 are as defined in the claims below, and R5 is methyl substituted with amino, N-alkylamino, or N,N- dialkyiamino.
  • the leaving group, X may be any suitable leaving group as for example halogen.
  • R1 and R2 are as defined in the claims below, and one or two of the groups R3 and R4 is hydroxy and the remaining is protected hydroxy, i.e. benzyl, R5 is as defined in the claims below or is a corresponding protected group, with a halogenating agent such as thionyl chloride, thionyl bromide or diethylaminosulfur trifluoride (DAST) and subsequent removal of the protection groups to form a compound of the formula I, wherein R1 , R2 and R5 are as defined in the claims below, and R3 and R4 are hydroxy or halogen, but not more than one of R3 and R4 is hydroxy.
  • a halogenating agent such as thionyl chloride, thionyl bromide or diethylaminosulfur trifluoride (DAST)
  • Examples of pharmaceutically acceptable salts are acid addition salts with non-toxic acids, either inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid, or organic acids such as formic acid, acetic acid, propionic acid, succinic acid, gluconic acid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid, methanesulphonic acid and malonic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid
  • organic acids such as formic acid, acetic acid, propionic acid, succinic acid, gluconic acid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid, methanesulphonic acid and malonic acid.
  • 2-alkyl-pyrrolidines of formula I and their salts are useful within human and veterinary medicine, for example, in the treatment of patients suffering from obesity.
  • 2-alkyl-pyrrolidines of formula I and their pharmaceutically acceptable salts are formulated with a pharmaceutically acceptable carrier to provide a medicament for par- enteral, oral, nasal, rectal, subdermal or intradermal or transdermal, pulmonal, buccal administration according to conventional methods.
  • Formulations may further include one or more diluents, fillers, emulsifiers, preservatives, buffers, excipients, etc.
  • the active compound of formula I is prepared in a form suitable for oral administration, such as a tablet or capsule.
  • a pharmaceutically ac- ceptable salt of the compound of formula I is combined with a carrier and moulded into a tablet.
  • Suitable carriers include 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 compound 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 that provides a clinically significant effect against obesity or appetite regulation. 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 convenient daily dosage can be less than about 1g, preferably in the range around 50-1000mg.
  • Test 2 Twenty-eight genetically obese male Zucker fatty (fa/fa) rates are bought from Charles River, Germany. The animals are housed in metal hanging cages in groups of 3 or 4 per cage and have ad libitum access to food and water for one week of acclimation. Room temperature is maintained at 21+ 0.5°C with a relative humidity of 40%. The photope od in the room is 12 hours light and 12 hours dark.
  • test compounds After a one week acclimation period dosing with the test compounds is initiated.
  • the amount of compound administered is from 0.001 to 100 mg/day and the period of administration is 1 month.
  • the compound is given by gavage twice daily.
  • the food consumption is measured daily and the animals are weighed two times per week during the treatment period.
  • Test 4 The same procedure is used as in Test 2, except the period of administration is 3 months. Test 4
  • Test 5 Between 3 and 20 obese (according to the criteria mentioned above) women are administered a compound of the present invention.
  • the amount of compound administered is from 0.1 to 4000 mg/day, and the period of treatment is 6 months.
  • the women are observed during the period of administration, and up to 3 months after discon- tinuance of administration, for effects on their obesity.
  • Twenty male Sprague-Dawley rats are allocated into two groups and are presented with a high-fat diet ad libitum. After a two week acclimation period, the animals are presented with an isocaloric, high-carbohydrate diet as well as. During the following two baseline weeks, the consumption of the two types of foods is measured on a daily basis. Hereafter, one group is injected intraperitoneally twice daily for seven days with 85 mg/kg/dose compound 1 , the other group is injected intraperitoneally twice daily with vehicle. The consumption of the two types of foods and the change in body weight is measured and compared between the groups and between treatment and baseline periods. Based on the results in the previous example, treatment with compound 1 will cause the animals to eat less high fat food, rela- tively more high carbohydrate food, fewer total calories as well as a reduction in body weight, all relative to the vehicle treated group.

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
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  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Obesity (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Child & Adolescent Psychology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne l'utilisation des composés représentés par la formule générale (I) pour le traitement ou la prévention de l'obésité ou pour la régulation de l'appétit. L'invention concerne également l'utilisation d'inhibiteurs de la phosophorylase du glycogène pour le traitement ou la prévention de l'obésité ou la régulation de l'appétit, ainsi que les utilisations de ces composés et des compositions pharmaceutiques les contenant.
PCT/DK2000/000055 1999-02-12 2000-02-10 Utilisation de derives de pyrrolidine pour la preparation d'une composition pharmaceutique destinee au traitement ou a la prevention de l'obesite ou a la regulation de l'appetit WO2000047206A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2000598158A JP2002536410A (ja) 1999-02-12 2000-02-10 肥満の治療又は予防もしくは食欲の調節を目的とした薬学的組成物の製造におけるピロリジン誘導体の使用
EP00903558A EP1150674A1 (fr) 1999-02-12 2000-02-10 Utilisation de derives de pyrrolidine pour la preparation d'une composition pharmaceutique destinee au traitement ou a la prevention de l'obesite ou a la regulation de l'appetit
AU25357/00A AU2535700A (en) 1999-02-12 2000-02-10 Use of pyrrolidine derivatives for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of obesity or appetite regulation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DKPA199900188 1999-02-12
DKPA199900188 1999-02-12

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WO2000047206A1 true WO2000047206A1 (fr) 2000-08-17

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Cited By (21)

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Publication number Priority date Publication date Assignee Title
WO2004037233A2 (fr) * 2002-10-28 2004-05-06 Novo Nordisk A/S Utilisation d'inhibiteurs de la glycogene phosphorylase pour le traitement de maladies cardio-vasculaires
WO2005041972A1 (fr) * 2003-10-31 2005-05-12 Pfizer Products Inc. Inhibition de la phosphodiesterase 9 comme traitement d'etats associes a l'obesite
EP1559710A2 (fr) 2000-03-10 2005-08-03 Bristol-Myers Squibb Company Inhibiteurs de la dipeptidyl-peptidase IV, à base de pyrrolidine, fusionnée à du cyclopropyle, procédé pour leur préparation et leur utilisation
US6960610B2 (en) 2002-10-28 2005-11-01 Novo Nordick, A/S Use of glycogen phosphorylase inhibitors for treatment of cardiovascular diseases
US7057046B2 (en) 2002-05-20 2006-06-06 Bristol-Myers Squibb Company Lactam glycogen phosphorylase inhibitors and method of use
US7115648B2 (en) 2002-03-06 2006-10-03 Astrazeneca Ab Indole-amide derivatives and their use as glycogen phosphorylase inhibitors
US7122567B2 (en) 2002-03-06 2006-10-17 Astrazeneca Ab Heterocyclic amide derivatives having glycogen phosphorylase inhibitory activity
US7129249B2 (en) 2002-03-06 2006-10-31 Astrazeneca Ab Heterocyclic amide derivatives as inhibitors of glycogen phoshorylase
US7138415B2 (en) 2002-03-06 2006-11-21 Astrazeneca Ab Indolamid derivatives which possess glycogenphosphorylase inhibitory activity
US7166636B2 (en) 2002-03-06 2007-01-23 Astrazeneca Ab Indole-amid derivatives which possess glycogen phosphorylase inhibitory activity
US7169927B2 (en) 2002-03-06 2007-01-30 Astrazeneca Ab Indole-amide derivatives and their use as glycogen phosphorylase inhibitors
US7214704B2 (en) 2004-11-15 2007-05-08 Bristol-Myers Squibb Company 2-Amino-1-functionalized tetralin derivatives and related glycogen phosphorylase inhibitors
US7223786B2 (en) 2004-11-15 2007-05-29 Bristol-Myers Squibb Company 2-aminonaphthalene derivatives and related glycogen phosphorylase inhibitors
US7226942B2 (en) 2004-11-15 2007-06-05 Bristol-Myers Squibb Company 2-amino-4-functionalized tetralin derivatives and related glycogen phosphorylase inhibitors
US7317109B2 (en) 2003-11-12 2008-01-08 Phenomix Corporation Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
US7365061B2 (en) 2004-11-15 2008-04-29 Bristol-Myers Squibb Company 2-Amino-3-functionalized tetralin derivatives and related glycogen phosphorylase inhibitors
WO2008062739A1 (fr) * 2006-11-20 2008-05-29 Japan Tobacco Inc. Pyrazoles et leur utilisation en tant que médicaments
EP1997533A1 (fr) 2003-11-12 2008-12-03 Phenomix Corporation Composés hétérocycliques d'acide boronique, inhibiteurs de dipeptidyl peptidase IV
US7576121B2 (en) 2003-11-12 2009-08-18 Phenomix Corporation Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
US7786163B2 (en) 2004-07-12 2010-08-31 Forest Laboratories Holdings Limited (BM) Constrained cyano compounds
US7825139B2 (en) 2005-05-25 2010-11-02 Forest Laboratories Holdings Limited (BM) Compounds and methods for selective inhibition of dipeptidyl peptidase-IV

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JPH09295966A (ja) * 1996-03-04 1997-11-18 Suntory Ltd ピロリジンアルカロイド化合物
WO1999026659A1 (fr) * 1997-11-21 1999-06-03 Pfizer Products Inc. Combinaison d'un inhibiteur de reductase d'aldose et d'un inhibiteur de phosphorylase de glycogene

Patent Citations (5)

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US7057046B2 (en) 2002-05-20 2006-06-06 Bristol-Myers Squibb Company Lactam glycogen phosphorylase inhibitors and method of use
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US6960610B2 (en) 2002-10-28 2005-11-01 Novo Nordick, A/S Use of glycogen phosphorylase inhibitors for treatment of cardiovascular diseases
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WO2005041972A1 (fr) * 2003-10-31 2005-05-12 Pfizer Products Inc. Inhibition de la phosphodiesterase 9 comme traitement d'etats associes a l'obesite
US7576121B2 (en) 2003-11-12 2009-08-18 Phenomix Corporation Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
US7884217B2 (en) 2003-11-12 2011-02-08 Phenomix Corporation Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
US7317109B2 (en) 2003-11-12 2008-01-08 Phenomix Corporation Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
EP1997533A1 (fr) 2003-11-12 2008-12-03 Phenomix Corporation Composés hétérocycliques d'acide boronique, inhibiteurs de dipeptidyl peptidase IV
US7786163B2 (en) 2004-07-12 2010-08-31 Forest Laboratories Holdings Limited (BM) Constrained cyano compounds
US7214704B2 (en) 2004-11-15 2007-05-08 Bristol-Myers Squibb Company 2-Amino-1-functionalized tetralin derivatives and related glycogen phosphorylase inhibitors
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US7825139B2 (en) 2005-05-25 2010-11-02 Forest Laboratories Holdings Limited (BM) Compounds and methods for selective inhibition of dipeptidyl peptidase-IV
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