EP1210080A2 - Use of monoamine oxidase inhibitors for the manufacture of drugs intended for the treatment of obesity - Google Patents

Use of monoamine oxidase inhibitors for the manufacture of drugs intended for the treatment of obesity

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Publication number
EP1210080A2
EP1210080A2 EP00951508A EP00951508A EP1210080A2 EP 1210080 A2 EP1210080 A2 EP 1210080A2 EP 00951508 A EP00951508 A EP 00951508A EP 00951508 A EP00951508 A EP 00951508A EP 1210080 A2 EP1210080 A2 EP 1210080A2
Authority
EP
European Patent Office
Prior art keywords
monoamine oxidase
reversible
inhibitor
befloxatone
mao
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Withdrawn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
EP00951508A
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German (de)
French (fr)
Inventor
Pierre Rosenzweig
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Sanofi Aventis France
Original Assignee
Sanofi Synthelabo SA
Sanofi Aventis France
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Priority to EP00951508A priority Critical patent/EP1210080A2/en
Publication of EP1210080A2 publication Critical patent/EP1210080A2/en
Withdrawn legal-status Critical Current

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/39—Heterocyclic compounds having sulfur as a ring hetero atom having oxygen in the same ring
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4465—Non condensed piperidines, e.g. piperocaine only substituted in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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

Definitions

  • the present invention relates to the use of monoamine oxidase inhibitors in the manufacture of drugs intended for the treatment of obesity.
  • Obesity is a major health problem in western societies and its prevalence is increasing. As described in Cheryl P. Kordik and Allen B. Reitz, J. Med. Chem. (1999), 42(2), 181-201 , reviewing the various known strategies to treat obesity, obesity is a "chronic condition characterized by overabundance of adipose tissue" which "correlates with risks such as high blood pressure, coronary heart disease, diabetes, altered steroid metabolism, gallstones and certain forms of cancer".
  • Obesity is a muitifactorial disease and its treatment requires multidisciplinary approaches.
  • the treatment includes diet, exercise, behavior change, pharmacotherapy, and surgery.
  • Drugs may decrease energy intake (central or peripheral action), decrease energy storage, increase energy expenditure, or have a combination of different actions.
  • a few compounds are currently available in some countries. These include sibutramine (a serotonin and norepinephrine reuptake inhibitor) and orlistat (a pancreatic lipase inhibitor).
  • disorders linked to disturbances of eating behavior include bulimia nervosa and anorexia nervosa.
  • Bulimia nervosa is characterized by compulsive overeating binges followed by inappropriate compensatory behaviors such as vomiting, fasting, excessive exercise, and misuse of diuretics or laxatives to maintain a desired weight.
  • This eating behavior is associated with comorbid psychopathology, and can result in serious medical complications (e.g., dental erosion, esophagitis, gastrointestinal irritation, electrolyte imbalances).
  • bulimia nervosa differs from the treatment of common forms of obesity. It may include cognitive-behavioral therapy, group therapy, family therapy, individual psychotherapy, and pharmacotherapy (e.g., antidepressants). Since bulimia nervosa is associated with marked alteration in monoaminergic systems (Benedetti M.S. et al.: "monamine oxidase: from physiologicology to the design and clinical application of reversible inhibitors", Advances in drug research (1992), 23, 65-125), a number of monoamine oxidase inhibitors have been tried in bulimia nervosa as reported in Liebowitz M.R.
  • the present invention relates to the use of reversible selective inhibitors of MAO-A, reversible selective inhibitors of MAO-B or reversible mixed inhibitors of MAO-A and MAO-B for the manufacture of drugs intended for the treatment of obesity.
  • the invention therefore further relates to a method of treating obesity by administering to a patient in need of such treatment a therapeutically effective amount of a reversible selective inhibitor of MAO-A, a reversible selective inhibitor of MAO-B or a reversible mixed inhibitor of MAO-A and MAO-B.
  • candidates for treatment may be men and women suffering from obesity or overweight.
  • MAO-A inhibitors befloxatone, moclobemide, brofaromine, phenoxathine, esuprone, befol, RS 8359 (Sankyo), T794 (Tanabe), KP 9 (Krenitsky, USA), E 201 1 (Eisei), toloxatone, pirlindole, amiflamine, sercloremine and apelinaprine may be cited.
  • reversible selective inhibitors of MAO-A reversible selective inhibitors of MAO-B or reversible mixed inhibitors of MAO-A and MAO-B
  • the following compounds may also be cited: - compounds disclosed in patent application EP 699680, i.e.
  • reversible MAO-A inhibitor Befloxatone or 3-[4-(4,4,4-trifluoro-3(R)-hydroxybutoxy)phenyl]5(F?)- methoxymethyl-2-oxazolidinone, which is known for its antidepressive and mild anxiolytic activity is particularly prefered as reversible MAO-A inhibitor. It is a reversible monamine oxidase inhibitor with both a very high affinity for the A isoform (MAO-A) and great selectivity versus the B isoform (MAO-B), which does not affect reuptake of noradrenaline (NA), serotonine (5-HT) or dopamine (DA). Its chemical synthesis is described in EP 424244. As reversible MAO-B inhibitor (S)-5-methoxymethyl-3-
  • the active substance according to the invention can be administred to patients in a variety of pharmaceutical forms well-known in the art and particularly in the form of compositions formulated for administration by the oral, injectable, transdermal or rectal route.
  • compositions can take the form of tablets, dragees or capsules prepared by the conventional techniques using known carriers and excipients, such as binding agents, fillers, lubricants and desintegration agents; they can also be in form of solutions, syrups or suspensions.
  • the compositions according to the invention may be in the form of injectable solutions, suspensions or emulsions containing an acceptable oily or aqueous liquid carrier.
  • the composition can take the form of a patch wherein the drug can be encompassed in a gel, solution, ointment or cream.
  • compositions may be in the form of suppositories containing the conventional bases for suppositories.
  • the percentage of active compound in such compositions may be varied so that a suitable dosage is obtained.
  • the dosage administered to a particular patient is determined by the clinician according to the mode of administration, the age and weight of the patient and the patients response.
  • Unit dosage forms may be administered in a single dose or in multiple divided doses to provide the appropriate daily dosage.
  • the daily dosage for example of befloxatone can range from about 2.5 to 40 mg, preferably from about 10 to 20 mg.
  • Rats Male Wistar rats (Iffa-Credo) were individually housed in polycarbonate cages (48x26.5x21.5 cm) in a temperature- and humidity-controlled animal colony room (20 ⁇ 2°C) with a 12-hour light dark cycle (7 a.m. - 7 p.m.). At least 1 week before the experiment, every animal was often handled and administered saline by oral route in order to avoid stress. Food and water were available ad libitum, and all testing was done in the home cage. Rats were fasted for 24 hour before testing and allowed free access to water. In the morning of the test day, rats were first assigned to either a treatment or a control group then weighed and administered drug or vehicle p.o.
  • mice Male Wistar rats (Iffa-Credo) were individually housed into a temperature- and humidity-controlled animal room (20 ⁇ 2°C) with a 12-hour light dark cycle (4.30 a.m. - 4.30 p.m.). in polycarbonate special cages with transducers connected to MacLab system. This enables to record the food consumption at every moment of day (light/dark phase). A measured quantity of food (RMM, Harlan Iberica) is placed on the cage just before dark onset. In order to avoid any kind of stress that could have an effect on their behaviour, every rat is administered saline and put in the cage at least 1 or 2 days before the test. The food consumption is recorded, without interruption, during these days. Once the animal is used to the cage, the test compound or vehicle are administered, by oral route.
  • RMM Harlan Iberica
  • Grams of food consumed by the animals during the first 4 hours after drug administration was compared to food consumed by the control animals over the same period of time, using one-way analysis of variance with a Newman-Keuls' test.
  • Befloxatone was studied in obese (fa/fa) Zucker rats, a genetic animal model of obesity.
  • mice were individually housed in polycarbonate cages (45 x 30 x 20 cm), with food (A04 standard diet, UAR, France) and water ad libitum, in a room with controlled temperature (23°C ⁇ 1 °C), in a reversed light-dark cycle (lights off at 9 h 00, on at 21 h 00) and total refresh air (12-15 times per hour).
  • Obese and lean rats were 13 weeks old when used and weighed 380-430 g and 280-330 g respectively.
  • Befloxatone was suspended in an aqueous solution with 0.5 % Tween 80, and administered orally in a volume of 5 ml/kg.
  • Results are expressed as mean ⁇ SEM for each treatment group.
  • a two-way ANOVA with repeated measures on time factor was conducted on food intake and cumulative body weight gain across weeks of befloxatone administration.
  • a 5-week chronic treatment with befloxatone induced a dose related reduction of body weight gain in obese rats. This effect was significant from the first week of treatment for the dose of 10 mg/kg/day. In lean rats befloxatone (10mg/kg/day) also induced a similar and significant reduction of body weight gain. At the end of the treatment, weight gain was reduced by 26% (p ⁇ 0.05) and 24% (p ⁇ 0.01) in obese and lean rats respectively.

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  • Animal Behavior & Ethology (AREA)
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Abstract

The present invention relates to the use of reversible selective inhibitors of monoamine oxidase A (MAO-A), reversible selective inhibitors of monoamine oxidase B (MAO-B) or reversible mixed inhibitors of MAO-A and MAO-B in the manufacture of drugs intended for the treatment of obesity.

Description

USE OF MONOAMINE OXIDASE INHIBITORS FOR THE MANUFACTURE OF DRUGS INTENDED FOR THE TREATMENT OF OBESITY
The present invention relates to the use of monoamine oxidase inhibitors in the manufacture of drugs intended for the treatment of obesity.
Obesity is a major health problem in western societies and its prevalence is increasing. As described in Cheryl P. Kordik and Allen B. Reitz, J. Med. Chem. (1999), 42(2), 181-201 , reviewing the various known strategies to treat obesity, obesity is a "chronic condition characterized by overabundance of adipose tissue" which "correlates with risks such as high blood pressure, coronary heart disease, diabetes, altered steroid metabolism, gallstones and certain forms of cancer".
Obesity is a muitifactorial disease and its treatment requires multidisciplinary approaches. The treatment includes diet, exercise, behavior change, pharmacotherapy, and surgery. In the medical treatment of obesity, different approaches may be considered. Drugs may decrease energy intake (central or peripheral action), decrease energy storage, increase energy expenditure, or have a combination of different actions. A few compounds are currently available in some countries. These include sibutramine (a serotonin and norepinephrine reuptake inhibitor) and orlistat (a pancreatic lipase inhibitor). Disorders linked to disturbances of eating behavior include bulimia nervosa and anorexia nervosa. Bulimia nervosa is characterized by compulsive overeating binges followed by inappropriate compensatory behaviors such as vomiting, fasting, excessive exercise, and misuse of diuretics or laxatives to maintain a desired weight. This eating behavior is associated with comorbid psychopathology, and can result in serious medical complications (e.g., dental erosion, esophagitis, gastrointestinal irritation, electrolyte imbalances).
The treatment of bulimia nervosa differs from the treatment of common forms of obesity. It may include cognitive-behavioral therapy, group therapy, family therapy, individual psychotherapy, and pharmacotherapy (e.g., antidepressants). Since bulimia nervosa is associated with marked alteration in monoaminergic systems (Benedetti M.S. et al.: "monamine oxidase: from physiologicology to the design and clinical application of reversible inhibitors", Advances in drug research (1992), 23, 65-125), a number of monoamine oxidase inhibitors have been tried in bulimia nervosa as reported in Liebowitz M.R. et al.: "reversible and irreversible monamine oxidase inhibitors in other psychiatric disorders", Ada Psychiatrica Scandinavica supplementum (1990), 360, 29-34; Kennedy S.H. et al.: "is there a role for selective monoamine oxidase inhibitor therapy in blimia nervosa ? A placebo-controlled trial of brofaromine", Journal of clinical psyche-pharmacology (1993), 13(6), 415-22; Priest R.G. et al.: "reversible and selective inhibitors of monoamine oxidase A in mental and other disorders", Ada Psychatrica Scandinavica (1995), 91 , Suppl. 386, 40-43; Wittal M.C. et al.: "Boulimia nervosa: A meta-analysis of phsychosocial and pharmacological treatments", Behaviour therapy (1999), 30, 117-135. It has now been found that reversible selective inhibitors of monoamine oxidase A (MAO-A), reversible selective inhibitors of monoamine oxidase B (MAO-B) or reversible mixed inhibitors of MAO-A and MAO-B have activity in decreasing body weight of obese patients. They may act by decreasing energy intake and/or increasing energy expenditure. Accordingly, the present invention relates to the use of reversible selective inhibitors of MAO-A, reversible selective inhibitors of MAO-B or reversible mixed inhibitors of MAO-A and MAO-B for the manufacture of drugs intended for the treatment of obesity.
The invention therefore further relates to a method of treating obesity by administering to a patient in need of such treatment a therapeutically effective amount of a reversible selective inhibitor of MAO-A, a reversible selective inhibitor of MAO-B or a reversible mixed inhibitor of MAO-A and MAO-B.
In fact, candidates for treatment may be men and women suffering from obesity or overweight. Among reversible MAO-A inhibitors, befloxatone, moclobemide, brofaromine, phenoxathine, esuprone, befol, RS 8359 (Sankyo), T794 (Tanabe), KP 9 (Krenitsky, USA), E 201 1 (Eisei), toloxatone, pirlindole, amiflamine, sercloremine and bazinaprine may be cited.
These compounds are known and their preparation are described in the art. Among reversible selective inhibitors of MAO-B, lazabemide, milacemide, caroxazone and IFO may be cited.
Among reversible selective inhibitors of MAO-A, reversible selective inhibitors of MAO-B or reversible mixed inhibitors of MAO-A and MAO-B the following compounds may also be cited: - compounds disclosed in patent application EP 699680, i.e. 3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one derivatives and particularly [3(S),3a(S)]-3-methoxymethyl-7-(4,4,4-trifluoro-3(R)-hydroxybutoxy)-3,3a,4,5- tetrahydro-1 H-oxazolo[3,4-a]quinolin-1 -one and [3(S),3a(S)]-3-methoxymethyl-7- [4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one,
- compounds disclosed in patent application WO 96/38444, i.e. oxazolidin-2-one derivatives and particularly (S)-5-methoxymethyl-3- [6-(4,4,4-trifluorobutoxy)-1 ,2-benzisoxazol-3-yl]oxazolidin-2-one,
- compounds disclosed in patent application WO 97/13768, i.e. oxazolidin-2- one derivatives and particularly (R)-5-(methoxymethyl)-3-[6-(4,4,4- trifluorobutoxy)benzofuran-3-yl]oxazolidin-2-one and (R)-5-methoxymethyl-3-(6- cyclopropylmethoxybenzofuran-3-yl)oxazolidin-2-one.
Befloxatone or 3-[4-(4,4,4-trifluoro-3(R)-hydroxybutoxy)phenyl]5(F?)- methoxymethyl-2-oxazolidinone, which is known for its antidepressive and mild anxiolytic activity is particularly prefered as reversible MAO-A inhibitor. It is a reversible monamine oxidase inhibitor with both a very high affinity for the A isoform (MAO-A) and great selectivity versus the B isoform (MAO-B), which does not affect reuptake of noradrenaline (NA), serotonine (5-HT) or dopamine (DA). Its chemical synthesis is described in EP 424244. As reversible MAO-B inhibitor (S)-5-methoxymethyl-3-
[6-(4,4,4-trifluorobutoxy)-1 ,2-benzisoxazol-3-yl]oxazolidin-2-one is preferred.
As reversible mixed inhibitor of MAO-A and MAO-B [3(S),3a(S)]-3- methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1/-/-oxazolo[3,4- a]quinolin-1-one, (f?)-5-(methoxymethyl)-3-[6-(4,4,4-trifluorobutoxy)benzofuran-3- yl]oxazolidin-2-one and (R)-5-methoxymethyl-3-(6-cyclopropylmethoxybenzofuran- 3-yl)oxazolidin-2-one are preferred.
The active substance according to the invention can be administred to patients in a variety of pharmaceutical forms well-known in the art and particularly in the form of compositions formulated for administration by the oral, injectable, transdermal or rectal route.
For oral administration, said compositions can take the form of tablets, dragees or capsules prepared by the conventional techniques using known carriers and excipients, such as binding agents, fillers, lubricants and desintegration agents; they can also be in form of solutions, syrups or suspensions. For administration by the injectable route, the compositions according to the invention may be in the form of injectable solutions, suspensions or emulsions containing an acceptable oily or aqueous liquid carrier.
For transdermal administration, the composition can take the form of a patch wherein the drug can be encompassed in a gel, solution, ointment or cream.
For rectal administration, the compositions may be in the form of suppositories containing the conventional bases for suppositories.
The percentage of active compound in such compositions may be varied so that a suitable dosage is obtained. The dosage administered to a particular patient is determined by the clinician according to the mode of administration, the age and weight of the patient and the patients response. Unit dosage forms may be administered in a single dose or in multiple divided doses to provide the appropriate daily dosage.
The daily dosage for example of befloxatone can range from about 2.5 to 40 mg, preferably from about 10 to 20 mg.
The following examples relating to pharmacological data and a galenic formulation illustrate the present invention.
Example 1
FEEDING BEHAVIOUR IN FASTED RATS
Male Wistar rats (Iffa-Credo) were individually housed in polycarbonate cages (48x26.5x21.5 cm) in a temperature- and humidity-controlled animal colony room (20±2°C) with a 12-hour light dark cycle (7 a.m. - 7 p.m.). At least 1 week before the experiment, every animal was often handled and administered saline by oral route in order to avoid stress. Food and water were available ad libitum, and all testing was done in the home cage. Rats were fasted for 24 hour before testing and allowed free access to water. In the morning of the test day, rats were first assigned to either a treatment or a control group then weighed and administered drug or vehicle p.o. (10.30 a.m.) and returned to their home cage. Thirty minutes later, a measured quantity of food (RMM, Harlan Iberica) was made available to the animals. The food intake is calculated every hour until 6 hours after the drug administration. (W095/11894, Gehlert et al., J. Pharmacol. Exp. Ther. (1998), 287, 122-127).
Grams of food consumed by the treated animals every hour was compared to food consumed by the control animals using one-way analysis of variance with a Newman-Keuls' test.
Table
Effect of befloxatone on food consumption during light period (7 a.m.-7 p.m.) in fasted rats (24 hours). Recording and access to food 1 1 a.m. -2 p.m.
"p< 0.05 vs control (ANOVA test)
Example 2
FEEDING BEHAVIOUR IN FED RATS
Male Wistar rats (Iffa-Credo) were individually housed into a temperature- and humidity-controlled animal room (20±2°C) with a 12-hour light dark cycle (4.30 a.m. - 4.30 p.m.). in polycarbonate special cages with transducers connected to MacLab system. This enables to record the food consumption at every moment of day (light/dark phase). A measured quantity of food (RMM, Harlan Iberica) is placed on the cage just before dark onset. In order to avoid any kind of stress that could have an effect on their behaviour, every rat is administered saline and put in the cage at least 1 or 2 days before the test. The food consumption is recorded, without interruption, during these days. Once the animal is used to the cage, the test compound or vehicle are administered, by oral route.
Grams of food consumed by the animals during the first 4 hours after drug administration was compared to food consumed by the control animals over the same period of time, using one-way analysis of variance with a Newman-Keuls' test.
Table
Effect of 7 days treatment with befloxatone (10 mg/kg/day, p.o.) on food consumption during dark period (4.30 p.m. - 4.30 a.m.) in fed male Wistar rats
'p< 0.05 vs control (ANOVA test)
These results show that in the model using fasted rats, befloxatone
(3 mg/kg p.o.) inhibits food intake by about 25% during the first hour after administration of the drug, and in the model of fed rats with recording of food consumption in the dark, befloxatone (10 mg/kg p.o.), once a day for 7 days, inhibits as from the third day, food intake during the first four hours after drug administration. Exemple 3
BODY WEIGHT GAIN STUDY IN OBESE ZUCKER RATS
Befloxatone was studied in obese (fa/fa) Zucker rats, a genetic animal model of obesity.
Experimental procedure
Animals
Genetically obese Zucker (fa/fa) male rats and lean (+/?) male littermates were purchased from IFFA CREDO (France).
One week before the start of the experiment, animals were individually housed in polycarbonate cages (45 x 30 x 20 cm), with food (A04 standard diet, UAR, France) and water ad libitum, in a room with controlled temperature (23°C ± 1 °C), in a reversed light-dark cycle (lights off at 9 h 00, on at 21 h 00) and total refresh air (12-15 times per hour). Obese and lean rats were 13 weeks old when used and weighed 380-430 g and 280-330 g respectively.
Drug
Befloxatone was suspended in an aqueous solution with 0.5 % Tween 80, and administered orally in a volume of 5 ml/kg.
Protocol
• Animals were treated p.o., once daily (at 9 h 00) for 5 weeks.
Four groups of obese (fa/fa) rats were administered vehicle or befloxatone at the doses of 1 , 3 and 10 mg/kg/day.
Two groups of lean rats were administered vehicle or befloxatone (10 mg/kg/day).
• Daily food intake and body weight were recorded (at 8 h 00).
Results
Results are expressed as mean ± SEM for each treatment group. A two-way ANOVA with repeated measures on time factor was conducted on food intake and cumulative body weight gain across weeks of befloxatone administration.
In obese rats, befloxatone induced a decrease (but non significant) of food intake over the treatment period. In lean rats this effect was more pronounced as food intake was significantly decreased on weeks 1 and 4.
A 5-week chronic treatment with befloxatone induced a dose related reduction of body weight gain in obese rats. This effect was significant from the first week of treatment for the dose of 10 mg/kg/day. In lean rats befloxatone (10mg/kg/day) also induced a similar and significant reduction of body weight gain. At the end of the treatment, weight gain was reduced by 26% (p<0.05) and 24% (p<0.01) in obese and lean rats respectively.
Example 4
ORAL FORMULATION
Befloxatone 2.5 mg 0.125 kg
Maize starch 5 mg 0.250 kg Lactose monohydrate 83 mg 4.150 kg
Povidone K29/32 5 mg 0.250 kg
Crospovidone 4 mg 0.200 kg
Magnesium stearate 0.5 % 0.025 kg size 3 gelatine capsule
The befloxatone and approximately 10% of the lactose (415 g), were premixed for 10 minutes using a Turbula mixer. The mixture was then transferred to a Diosna mixer-granulator. The remainder of the lactose, the maize starch, the povidone, and half the crospovidone were added and mixed for 3 minutes. A sufficient quantity of water was added (13%) and the mixture granulated for 3 minutes. The granulate was dried in a ventilated oven and calibrated at 0.63 mm. The rest of the crospovidone, plus the magnesium stearate was added to the resulting granulate, and the whole was mixed using a Turbula mixer for 10 minutes, and then filled into size 3 capsules to a unit mass of 100 mg.

Claims

Claims
1. Use of a reversible selective inhibitor of monoamine oxidase A, reversible selective inhibitor of monoamine oxidase B or a reversible mixed inhibitor of monoamine oxidase A and B for the manufacture of drugs intended for the treatment of obesity.
2. Use of a reversible mixed inhibitor of monoamine oxidase A and B according to claim 1.
3. The use according to claim 2 wherein the reversible mixed inhibitor of monoamine oxidase A and B is chosen among [3(S),3a(S)]-3-methoxymethyl-7- [4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1 r-/-oxazolo[3,4-a]quinolin-1 -one, (R)-5- (methoxymethyl)-3-[6-(4,4,4-trifluorobutoxy)benzofuran-3-yl]oxazolidin-2-one and (f?)-5-methoxymethyl-3-(6-cyclopropylmethoxybenzofuran-3-yl)oxazolidin-2-one.
4. Use of a reversible selective inhibitor of monoamine oxidase B according to claim 1.
5. The use according to claim 4 wherein the reversible selective monoamine oxidase B is chosen among lazabemide, milacemide, caroxazone and IFO.
6. The use according to claim 4 wherein the reversible selective monoamine oxidase B is (S)-5-methoxymethyl-3-[6-(4,4,4-trifluorobutoxy)-1 ,2- benzisoxazol-3-yl]oxazolidin-2-one.
7. Use of a reversible selective inihibtor of monoamine oxidase A according to claim 1.
8. The use according to claim 7 wherein the reversible selective inhibitor of monoamine oxidase A is chosen among befloxatone, moclobemide, brofaromine, phenoxathine, esuprone, befol, RS 8359 (Sankyo), T794 (Tanabe), KP 9 (Krenitsky, USA), E 2011 (Eisei), toloxatone, pirlindole, amiflamine, sercloremine and bazinaprine.
9. The use according to claim 7 wherein the reversible selective inhibitor of monoamine oxidase A is befloxatone.
10. The use according to claim 9 wherein the dosage amount of befloxatone is from about 2.5 to 40 mg per day.
11. The use according to claim 10 wherein the amount of befloxatone to be administered is from 10 to 20 mg.
12. The use according to any of claims 1 to 11 wherein the inhibitor of monoamine oxidase is intended for administration by the oral, injectable, transdermal or rectal route.
EP00951508A 1999-08-16 2000-08-08 Use of monoamine oxidase inhibitors for the manufacture of drugs intended for the treatment of obesity Withdrawn EP1210080A2 (en)

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Families Citing this family (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1307182B1 (en) * 2000-08-01 2005-03-30 Sanofi-Aventis Pharmaceutical composition for transdermal delivery of befloxatone
US6982251B2 (en) 2000-12-20 2006-01-03 Schering Corporation Substituted 2-azetidinones useful as hypocholesterolemic agents
US7071181B2 (en) 2001-01-26 2006-07-04 Schering Corporation Methods and therapeutic combinations for the treatment of diabetes using sterol absorption inhibitors
HU230253B1 (en) 2001-01-26 2015-11-30 Merck Sharp & Dohme Corp Combinations of peroxisome proliferator-activated receptor (ppar) activator(s) and sterol absorption inhibitor(s) and their use in the treatment of vascular indications
DK1355644T3 (en) 2001-01-26 2006-10-23 Schering Corp Use of substituted azetidinone compounds for the treatment of sitosterolemia
DE10142660A1 (en) 2001-08-31 2003-03-20 Aventis Pharma Gmbh Use of derivatives of C2-substituted indan-1-ol systems for the preparation of medicaments for the prophylaxis or treatment of obesity
AU2002331064B2 (en) 2001-08-10 2007-08-23 Palatin Technologies, Inc. Peptidomimetics of biologically active metallopeptides
US7456184B2 (en) 2003-05-01 2008-11-25 Palatin Technologies Inc. Melanocortin receptor-specific compounds
US7354923B2 (en) 2001-08-10 2008-04-08 Palatin Technologies, Inc. Piperazine melanocortin-specific compounds
DE10142659A1 (en) 2001-08-31 2003-03-20 Aventis Pharma Gmbh Use of multiply substituted indan-1-ol. Systems for the preparation of medicaments for the prophylaxis or treatment of obesity
DE10142667B4 (en) 2001-08-31 2004-06-09 Aventis Pharma Deutschland Gmbh C2-substituted indan-1-oles and their derivatives and their use as medicines
DE10142722A1 (en) 2001-08-31 2003-03-27 Aventis Pharma Deutschland GmbH, 65929 Frankfurt C2-substituted indan-1-ones and their derivatives, processes for their preparation and their use as medicaments
DE10142668A1 (en) 2001-08-31 2003-03-20 Aventis Pharma Gmbh Use of C2-substituted indan-1-one systems for the preparation of medicaments for the prophylaxis or treatment of obesity
DE10142662B4 (en) 2001-08-31 2004-07-08 Aventis Pharma Deutschland Gmbh Derivatives of C2-substituted indan-1-ol systems and their use as pharmaceuticals
DE10142666A1 (en) 2001-08-31 2003-03-20 Aventis Pharma Gmbh Use of C2-substituted indan-1-ol systems for the preparation of medicaments for the prophylaxis or treatment of obesity
DE10142663B4 (en) 2001-08-31 2004-08-19 Aventis Pharma Deutschland Gmbh C2-Disubstituted indan-1-ol systems
DE10142665B4 (en) 2001-08-31 2004-05-06 Aventis Pharma Deutschland Gmbh C2-Disubstituted indan-1-ones and their derivatives
DE10142661B4 (en) 2001-08-31 2004-06-09 Aventis Pharma Deutschland Gmbh Poly-substituted indan-1-ol systems and their use as pharmaceuticals
US7053080B2 (en) 2001-09-21 2006-05-30 Schering Corporation Methods and therapeutic combinations for the treatment of obesity using sterol absorption inhibitors
JP2005504091A (en) 2001-09-21 2005-02-10 シェーリング　コーポレイション Treatment of xanthomas with azetidinone as a sterol absorption inhibitor
US7056906B2 (en) 2001-09-21 2006-06-06 Schering Corporation Combinations of hormone replacement therapy composition(s) and sterol absorption inhibitor(s) and treatments for vascular conditions in post-menopausal women
CA2487849A1 (en) 2002-07-18 2004-01-29 Cytos Biotechnology Ag Hapten-carrier conjugates comprising virus like particles and uses thereof
WO2004043457A1 (en) 2002-11-06 2004-05-27 Schering Corporation Cholesterol absorptions inhibitors for the treatment of autoimmune disorders
CA2517571C (en) 2003-03-07 2011-07-05 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
US7459442B2 (en) 2003-03-07 2008-12-02 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
JP4589919B2 (en) 2003-03-07 2010-12-01 シェーリング コーポレイション Substituted azetidinone compounds, their formulations and uses for the treatment of hypercholesterolemia
JP2006519869A (en) 2003-03-07 2006-08-31 シェーリング　コーポレイション Substituted azetidinone compounds, processes for preparing substituted azetidinone compounds, their formulations and uses
US7732162B2 (en) 2003-05-05 2010-06-08 Probiodrug Ag Inhibitors of glutaminyl cyclase for treating neurodegenerative diseases
DE10342672A1 (en) * 2003-09-16 2005-04-21 Bayer Chemicals Ag Chiral phosphines for use in asymmetric syntheses
CN101300006B (en) 2005-06-02 2012-07-25 叶林发现公司 MAO-B inhibitors useful for treating obesity
WO2006138475A2 (en) * 2005-06-16 2006-12-28 Jenrin Discovery Mao-b inhibitors useful for treating obesity
US8278345B2 (en) 2006-11-09 2012-10-02 Probiodrug Ag Inhibitors of glutaminyl cyclase
ATE554085T1 (en) 2006-11-30 2012-05-15 Probiodrug Ag NEW INHIBITORS OF GLUTAMINYL CYCLASE
JP5930573B2 (en) 2007-03-01 2016-06-15 プロビオドルグ エージー New use of glutaminyl cyclase inhibitors
EP2142514B1 (en) 2007-04-18 2014-12-24 Probiodrug AG Thiourea derivatives as glutaminyl cyclase inhibitors
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
WO2009070533A1 (en) * 2007-11-29 2009-06-04 Complegen, Inc. Methods of inhibiting steroyl coa desaturase
ES2522968T3 (en) 2008-06-04 2014-11-19 Synergy Pharmaceuticals Inc. Guanylate cyclase agonists useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
AU2009270833B2 (en) 2008-07-16 2015-02-19 Bausch Health Ireland Limited Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
JP5934645B2 (en) 2009-09-11 2016-06-15 プロビオドルグ エージー Heterocyclic derivatives as glutaminyl cyclase inhibitors
JP6026284B2 (en) 2010-03-03 2016-11-16 プロビオドルグ エージー Inhibitors of glutaminyl cyclase
NZ602312A (en) 2010-03-10 2014-02-28 Probiodrug Ag Heterocyclic inhibitors of glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (en) 2010-04-21 2011-10-27 Probiodrug Ag Novel inhibitors
US9133123B2 (en) 2010-04-23 2015-09-15 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
AR081331A1 (en) 2010-04-23 2012-08-08 Cytokinetics Inc AMINO- PYRIMIDINES COMPOSITIONS OF THE SAME AND METHODS FOR THE USE OF THE SAME
AR081626A1 (en) 2010-04-23 2012-10-10 Cytokinetics Inc AMINO-PYRIDAZINIC COMPOUNDS, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND USE OF THE SAME TO TREAT CARDIAC AND SKELETIC MUSCULAR DISORDERS
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
EP2686313B1 (en) 2011-03-16 2016-02-03 Probiodrug AG Benzimidazole derivatives as inhibitors of glutaminyl cyclase
CN102267990B (en) * 2011-06-03 2013-11-13 浙江工业大学 2,3-dihydrobenzofuran derivatives as well as preparation method and application thereof
AU2014235215A1 (en) 2013-03-15 2015-10-01 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
AU2014235209B2 (en) 2013-03-15 2018-06-14 Bausch Health Ireland Limited Guanylate cyclase receptor agonists combined with other drugs
BR112015030326A2 (en) 2013-06-05 2017-08-29 Synergy Pharmaceuticals Inc ULTRAPURE GUANYLATE CYCLASE C AGONISTS, METHOD OF MANUFACTURING AND USING THEM
ES2812698T3 (en) 2017-09-29 2021-03-18 Probiodrug Ag Glutaminyl cyclase inhibitors
CN110511208B (en) * 2019-08-02 2020-08-25 浙江工业大学 N-2-pyridyl-2, 3-diazido indoline compound and preparation and application thereof
KR20230075912A (en) 2021-11-23 2023-05-31 서제표 Foldable glasses

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3153092A (en) * 1961-07-17 1964-10-13 Smith Kline French Lab 1-methyl-2-phenylcyclopropylamine derivatives
US3466236A (en) * 1965-11-09 1969-09-09 Eastman Kodak Co Irradiation of aminocyclobutanones
AU5550780A (en) * 1979-04-26 1980-10-30 Merrell Toraude Et Compagnie Alpha-halomethyl amines
FR2724171B1 (en) * 1994-09-05 1997-01-03 Synthelabo DERIVATIVES OF 3.3A, 4,5-TETRAHYDRO-1H-OXAZOLO (3,4-A) QUINOLEIN-1-ONE, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
KR100457502B1 (en) * 1995-06-02 2005-09-05 사노피-신델라보 Oxazolidinone derivatives, their preparation and therapeutical use
US5969146A (en) * 1995-10-11 1999-10-19 Synthelabo Oxazolidin-2-one derivatives, preparation method therefor and therapeutical use thereof
US5955471A (en) * 1998-01-13 1999-09-21 Sk Corporation Tetrahydroisoquinolinealkanol derivatives and pharmaceutical compositions containing same
US6303617B1 (en) * 1998-05-04 2001-10-16 Neotherapeutics, Inc. Serotonin-like 9-substituted hypoxanthine and methods of use
AU5330599A (en) * 1998-07-31 2000-02-21 Vela Pharmaceuticals Inc. Methods and compositions for treating and preventing certain psychiatric and medical disorders using moclobemide

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0112176A2 *

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