WO2018015862A1 - Sels de 1-méthylnicotinamide destinés à être utilisés pour augmenter les taux sanguins d'adiponectine. - Google Patents

Sels de 1-méthylnicotinamide destinés à être utilisés pour augmenter les taux sanguins d'adiponectine. Download PDF

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WO2018015862A1
WO2018015862A1 PCT/IB2017/054294 IB2017054294W WO2018015862A1 WO 2018015862 A1 WO2018015862 A1 WO 2018015862A1 IB 2017054294 W IB2017054294 W IB 2017054294W WO 2018015862 A1 WO2018015862 A1 WO 2018015862A1
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disorder
disease
subject
obesity
adiponectin
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PCT/IB2017/054294
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English (en)
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Konrad PALKA
Jerzy Gebicki
Marzena WIECZORKOWSKA
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Pharmena S.A.
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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
    • A61K31/435—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
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

  • the present invention relates to new use of 1-methylnicotinamide for raising circulating adiponectin levels in a human subject.
  • the invention is useful for treating diseases and disorders that are mediated by insufficient production of adiponectin in a human subject.
  • Adiponectin a 30 kDa protein, is a main and most abundantly produced hormone from the group of adipokinines that is expressed predominantly by adipocytes in adipose tissue. It is involved in the regulation of body fat accumulation, tissue development, energy metabolism and control of food intake. Adiponectin plays important role in metabolic and cardiovascular homeostasis. Circulating adiponectin levels are inversely related to inflammatory process, oxidative stress and metabolic dysregulation. Adiponectin activity is strongly associated with metabolic disorders. Reduced adiponectin levels seem to be not just a mere biomarker of ailment, but play a causal role in the development of many metabolic ailments.
  • Decreased levels of circulating adiponectin may act as a mediator for the pathophysiology in type 2 diabetes, metabolic syndrome, obesity, and atherosclerosis (S. Lim et al., Atherosclerosis 233 (2014), 721-728; Fisham et al., Cardiovascular Diabetology 2014, 13: 103-11).
  • Adiponectin was found to be decreased in disorders such as obesity, diabetes, and metabolic syndrome (M. Iwabu et al., Aging and Mechanisms of Disease (2015) 15013); Renaldi O, Pramono B, Sinorita H, Purnomo LB, Asdie RH, Asdie AH (2009). "Hypoadiponectinemia: a risk factor for metabolic syndrome”. Acta Med Indones 41(1): 20-4; and Diez JJ, Iglesias P (2003). "The role of the novel adipocyte-derived hormone adiponectin in human disease”. Eur. J. Endocrinol. 148 (3): 293-300).
  • Adiponectin may couple regulation of insulin sensitivity with energy metabolism and serve to link obesity with insulin resistance.
  • Obesity-related disorders including metabolic syndrome, diabetes, atherosclerosis, hypertension, and coronary artery disease are associated with decreased plasma levels of adiponectin, insulin resistance, and endothelial dysfunction. (Han et al, Journal of the American College of Cardiology, Vo. 49, No 5, 2007, 531-8).
  • Agents that raise adiponectin levels are believed to be potential therapy for the treatment pf disroders such as obesity, diabetes and metabolic syndrome.
  • Adiponectin appears to play an important role in the development and progression of several obesity-related malignancies.
  • Obese subjects have not only an increased risk of developing cancer, but their mortality is also increased with increasing BMI, especially when the BMI is > 40 kgm "2 .
  • BMI is > 40 kgm "2 .
  • obesity has been identified as a risk factor for several cancers, especially in women, including endometrial cancer and breast cancer (especially after menopause), colon and rectal, oesophageal, kidney, pancreatic, biliary, ovarian, cervical and liver cancer (I. Kelesidis et al, British Journal of Cancer (2006) 94, 1221 - 1225).
  • Adiponectin normally circulates in blood plasma at high concentrations (5-30 ⁇ g/mL) and is typically found at levels 35% lower in men than in women. However, adiponectin concentrations are lower in women under certain conditions. Data on adiponectin concentrations in obese women have consistently been found to be abnormally low. Similarly, low adiponectin levels have also been found in women with endometriosis. Adiponectin levels have been shown to increase with weight loss. Thus, adiponectin is strongly associated with obesity and is a potentially important hormone in the link between obesity and women's cancers. (G.P. Nagaraju, et al, The role of adiponectin in obesity- associated female-specific carcinogenesis, Cytokine Growth Factor Rev (2016)).
  • Reduced adiponectin levels are also implicated in the pathology of various mental disorders such as mood disorders, including depression and major depression, neuropsychiatric disorders, including anxiety disorders, panic disorders, schizophrenia, eating disorders, severe sleep disorders, and neurodegenerative disorders such as Alzheimer disease.
  • Adiponectin also plays an important role in depression-related behaviors. Circulating adiponectin levels were decreased in a chronic social defeat stress model of depression; they were also inversely correlated with the social interaction ratio. Adiponectin insufficiency increased susceptibility to stress-induced depressive behaviors and impaired function of hypothalamic-pituitary-adrenal axis.
  • Circulating adiponectin level can be raised by non-pharmacological treatments (e.g. life-style modification, weight-loss diet, physical activity) as well as treatments using therapeutic agents such as thiazolidinediones, fibrates, ACE inhibitors, statins, nicotinic acid, calcium channel blockers, beta-blockers, and some natural compounds, like resveratrol (S. Lim et al., Atherosclerosis 233 (2014), 721-728).
  • non-pharmacological treatments e.g. life-style modification, weight-loss diet, physical activity
  • therapeutic agents such as thiazolidinediones, fibrates, ACE inhibitors, statins, nicotinic acid, calcium channel blockers, beta-blockers, and some natural compounds, like resveratrol (S. Lim et al., Atherosclerosis 233 (2014), 721-728).
  • 1-Methylnicotinamide (1-MNA) is known nicotinic acid metabolite, a quaternary pyridinium compound existing in the form of salts with anions of various acids.
  • Activity of 1-MNA in dyslipidemia has been disclosed in WO2005067927.
  • 1- MNA triglyceride level lowering and HDL-cholesterol level raising activities as well its prostacyclin raising have been disclosed.
  • EP1147086 discloses the use of 1-MNA in the treatment of anti-inflammatory skin diseases and cosmetic treatment of the skin.
  • the primary basis for this invention is the finding that 1-MNA has the ability to raise adiponectin blood level in mammals such as human.
  • 1-MNA or a pharmaceutically acceptable salt thereof can be useful for raising circulating adiponectin levels in a subject and for the treatment of diseases and disorders mediated by insufficient production of adiponectin.
  • a method for raising circulating adiponectin levels in a subject including human which comprises administration to said subject 1-MNA or a pharmaceutically acceptable salt thereof in an amount effective to raise adiponectin level in the blood.
  • said subject is a subject suffering from mental disease.
  • Said mental disease includes in particular depression, depression-related behavior, mood disorder or post-traumatic stress disorder.
  • said subject is a subject suffering from neuropsychiatric disease.
  • Said neuropsychiatric disease includes anxiety disorder, panic disorder, schizophrenia, eating disorder, or severe sleep disorder.
  • Said neuropsychiatric disease include also neurodegenerative disease, such as Alzheimer disease.
  • said subject is a subject suffering from obesity, especially central obesity. In one aspect, the subject has BMI index > 40 kgm "2 .
  • the treatment of the invention may therefore lower the risk of or prevent obesity-related disorder.
  • obesity-related disorder includes metabolic syndrome and diabetes.
  • obesity-related disorder is obesity-related cancer such as endometrial cancer and breast cancer (especially after menopause), colon, rectal, esophageal, kidney, pancreatic, biliary, ovarian, cervical and liver cancer.
  • obesity-related cancer such as endometrial cancer and breast cancer (especially after menopause), colon, rectal, esophageal, kidney, pancreatic, biliary, ovarian, cervical and liver cancer.
  • said disease is a mental disease.
  • Said mental disease includes in particular depression, depression-related behavior, mood disorder and post-traumatic stress disorder.
  • said disease is a neuropsychiatric disease.
  • Said neuropsychiatric disease includes anxiety disorder, panic disorder, schizophrenia, eating disorder, and severe sleep disorder.
  • the neuropsychiatric disease includes also neurodegenerative disease, such as Alzheimer disease.
  • the disease is obesity and the subject is a person suffering from obesity, especially central obesity, and for example having BMI index > 40 kgm "2 .
  • the terms “treat,” “treatment,” or “treatment of” refers to (i) reducing the potential for a disease or disorder (e.g., a cardiovascular disease such as CHD or other diseases disclosed herein), (ii) reducing the occurrence of a disease or disorder, (iii) reducing the severity of a disease or disorder, preferably, to an extent that the subject suffers less or no longer suffers discomfort and/or altered function due to it, (iv) reducing an indication or marker of a disease or disorder such as reducing the blood or serum CRP level, or (v) a combination thereof.
  • a disease or disorder e.g., a cardiovascular disease such as CHD or other diseases disclosed herein
  • reducing the occurrence of a disease or disorder e.g., a cardiovascular disease such as CHD or other diseases disclosed herein
  • reducing the severity of a disease or disorder preferably, to an extent that the subject suffers less or no longer suffers discomfort and/or altered function due to it
  • subject refers to any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy of a disease or disorder (e.g., a cardiovascular disease such as CHD or other diseases disclosed herein) is desired.
  • a disease or disorder e.g., a cardiovascular disease such as CHD or other diseases disclosed herein
  • subject include any human or nonhuman animal.
  • nonhuman animal includes all vertebrates, e.g., mammals and non-mammals, such as mice, nonhuman primates, sheep, dogs, cats, horses, cows, bears, chickens, amphibians, reptiles, etc.
  • a subject is a human.
  • administration includes delivering, applying, or giving the therapy or drug to a subject including self-administering by the subject.
  • terapéuticaally effective amount refers to an amount of a drug effective to "treat” a disease or disorder in a subject or reduce the risk, potential, possibility or occurrence of a disease or disorder (e.g., diabetes or other disease disclosed herein).
  • a “therapeutically effective amount” includes an amount of a drug or a therapeutic agent that provides some improvement or benefit to a subject having or at risk of having a disease or disorder (e.g., diabetes or other disease disclosed herein).
  • a “therapeutically effective” amount is an amount that reduces the risk, potential, possibility or occurrence of a disease or provides disorder or some alleviation, mitigation, and/or decrease in at least one clinical symptom of a disease or disorder (e.g., diabetes or other disease disclosed herein).
  • blood adiponectin level refers to blood, plasma, or serum adiponectin level unless otherwise clear from the context.
  • blood adiponectin level refers to blood, plasma, or serum adiponectin level unless otherwise clear from the context.
  • plasma adiponectin level refers to blood, plasma, or serum adiponectin level unless otherwise clear from the context.
  • serum adiponectin level refers to blood, plasma, or serum adiponectin level unless otherwise clear from the context.
  • 1-methylnicotinamide also known as 1-MNA
  • 1-MNA is a quaternary pyridinium compound and has the structural formula of
  • pharmaceutically acceptable salt refers to a salt of an acidic or basic group of a base compound that is generally safe, non-toxic, neither biologically nor otherwise undesirable, and useful for either or both veterinary use and/or human pharmaceutical use.
  • the disclosure herein discloses 1-MNA, which is capable of forming a wide variety of salts with anions of various inorganic and organic acids.
  • the primary basis for this invention is the finding that 1-MNA or a pharmaceutically acceptable salt thereof has the ability to raise adiponectin blood level in mammals, especially human subjects.
  • 1-MNA or a pharmaceutically acceptable salt thereof can be useful inter alia for the treatment of diseases and disorders mediated by or that are caused or worsened by, insufficient production of adiponectin.
  • Diseases and disorders mediated or caused or worsened by insufficient production of adiponectin include mental disorders, including mood disorders, such as depression and major depression, neuropsychiatric disorders, including anxiety disorders, panic disorders, schizophrenia, eating disorders, severe sleep disorders, and neurodegenerative disorders such as Alzheimer disease.
  • Diseases and disorders mediated or caused or worsened by insufficient production of adiponectin include metabolic disorders such as obesity and metabolic syndrome.
  • Diseases and disorders mediated or caused or worsened by insufficient production of adiponectin include depression-related behavior and post-traumatic stress disorder.
  • the preferred form of 1-MNA is as a salt, especially pharmaceutically acceptable salt (1-MNA + X " , wherein X " is a pharmaceutically acceptable anion) and includes salts with any pharmaceutically acceptable acid, both organic and inorganic.
  • Suitable salts with inorganic acids are for example chloride, bromide, iodide and carbonate; suitable salts with organic acids may be salts with mono-, di- and tricarboxylic acids, for example acetate, benzoate, salicylate, hydroxyacetate, lactate, malonate and citrate.
  • Preferred salts are chloride, benzoate, salicylate, acetate, citrate and lactate; especially advantageous is chloride salt (also known as TRIA-662).
  • 1-MNA pharmaceutically salts are known as such. Some are commercially available, for example 1-methylnicotinamide chloride (from Sigma). Alternatively, 1- MNA pharmaceutically salts the compounds can be readily prepared from nicotinamide by synthetic methods well-known to the person skilled in the art. Salts wherein X- represents halogen anion can be prepared starting from nicotinamide by direct methylation with methyl halogenide in a manner known per se, analogously as described for direct methylation with methyl chloride in AT131118, GB348345, US3614408, and US4115390.
  • Salts with a non-halogen anion can be prepared by substitution of a halogen anion to another anion, for example by treatment with a salt of such another anion, such as for example sodium or silver salt of another anion.
  • lactate and acetate can be prepared by the treatment of a halogenide, preferably chloride, with silver lactate or acetate, respectively.
  • Salicylate can be prepared by the treatment of a halogenide, preferably chloride, with sodium salicylate.
  • the therapeutically effective amount of 1-MNA or a pharmaceutically acceptable salt thereof includes an amount effective to increase the subject's blood or serum adiponectin level as compared to that before the treatment.
  • the therapeutically effective amount of 1-MNA or a pharmaceutically acceptable salt thereof is from 1000 to about 8000 mg, from about 1000 mg to about 7000 mg, from about 1000 mg to about 6000 mg, from about 1000 mg to about 5000 mg, from about 1000 mg to about 4000 mg, from about 1000 mg to about 3000 mg, from about 1000 mg to about 2000 mg, from about 2000 mg to about 8000 mg, from about 2000 mg to about 7000 mg, from about 2000 mg to about 6000 mg, from about 2000 mg to about 5000 mg, from about 2000 mg to about 4000 mg, from about 2000 mg to about 3000 mg, from about 3000 mg to about 8000 mg, from about 3000 mg to about 7000 mg, from about 3000 mg to about 6000 mg, from about 3000 mg to about 5000 mg, from about 3000 mg, from about 3000 mg to about 8000 mg,
  • the therapeutically effective 1-MNA or a pharmaceutically acceptable salt thereof is about 1000 mg, about 2000 mg, about 3000 mg, about 4000, about 5000 mg, about 6000 mg, about 7000 mg, or about 8000 mg, per day. In some embodiments, the therapeutically effective amount of 1-MNA or a pharmaceutically acceptable salt thereof is about 1000 mg, about 3000 mg, or about 6000 mg, per day.
  • the preferred dose of 1-MNA chloride is in the range of 1000 - 6000 mg per day, in a single dose or in divided doses, such as 1000 mg per day, 3000 mg per day, or 6000 mg per day, for example 1000 mg three times a day or 2000 mg three times a day.
  • the therapeutically effective amount of 1-MNA or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, or three times a day. In some embodiments, the therapeutically effective amount of 1-MNA or a pharmaceutically acceptable salt thereof is administered more than three times a day.
  • a therapeutically effective amount can be administered in one dose or divided into multiple doses, as long as the dose is sufficiently high that the subject benefits from the dose or treatment.
  • the therapeutically effective amount of 1-MNA or a pharmaceutically acceptable salt thereof can be administered by the subject or by one other than the subject systemically (e.g., orally, transmucosally, and via injections) or locally (e.g., topically and via suppositories) via various routes known in the art.
  • routes of administration include oral, topical (e.g., transdermal), transmucosal (e.g., buccal and sublingual), injectable (e.g., intravenous, intramuscular, and subcutaneous), and inhalation (e.g., aerosol).
  • the therapeutically effective amount of 1-MNA or a pharmaceutically acceptable salt thereof is administered orally.
  • the therapeutically effective amount of 1-MNA or a pharmaceutically acceptable salt thereof is administered transmucosally. In some embodiments, the therapeutically effective amount of 1-MNA or a pharmaceutically acceptable salt thereof is administered via injection. In some embodiments, the treatment does not cause flushing, hepatotoxicity, gout, or a combination thereof in the subject. In some embodiments, the therapeutically effective amount of the 1-MNA or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, or three times a day, preferably in an oral dosage form.
  • 1-MNA or a pharmaceutically acceptable salt thereof is administered as long as the subject benefits from the administration (e.g., blood or serum adiponectin level is increased or maintained at an increased level as compared to that before the treatment).
  • the 1-MNA or a pharmaceutically acceptable salt thereof is administered for at least one month, at least three months, at least six months, at least one year, at least three years, or at least five years.
  • 1-MNA or a pharmaceutically acceptable salt thereof is preferably be administered by administration routes such as oral, parenteral, intranasal or inhalation route, either as a medicinal product or dietary supplement.
  • a highly preferred manner of administration is oral administration.
  • 1-MNA or a pharmaceutically acceptable salt thereof can be formulated in various pharmaceutically compositions for administration.
  • Non-limiting exemplary pharmaceutical compositions include solutions, suspensions, emulsions, tablets, pills, pellets, powders, multi-particulates, capsules, capsules containing liquids, capsules containing powders, capsules containing multi-particulates, lozenges, controlled- or sustained-release formulations, suppositories, transdermal patches, transmucosal films, sublingual tablets or films, aerosols, sprays, injections, or any other form suitable for use.
  • compositions and methods for making the compositions are known in art, e.g., as described in described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995), incorporated herein by reference in its entirety.
  • the 1-MNA or a pharmaceutically acceptable salt thereof is formulated as a solid formulation.
  • Solid formulations include conventional tablets, capsules, troches, powders or granulates for direct ingestion or for reconstitution in liquids, such as water or juices. Any suitable conventional excipients can be used for the preparation of such solid forms.
  • the formulation can be a controlled- or sustained-release formulation that releases 1-MNA or a pharmaceutically acceptable salt thereof at a desired location in the digestive tract. Alternatively or in addition to release the 1-MNA or a pharmaceutically acceptable salt thereof over an extended period in the blood or a specific tissue or organ.
  • Preferred pharmaceutically acceptable salt is 1-MNA chloride.
  • the study was a randomized, double-blind, placebo controlled, forced escalation, multicenter study.
  • 164 patients received 1000 mg placebo three times daily with meals in a single-blind manner for a dietary-controlled baseline period of 6 to 8 weeks. From the sample of eligible subjects who completed the 6 to 8 week dietary-controlled baseline period, 66 subjects (22 to placebo and 44 to 1-MNA) meeting all inclusion and no exclusion criteria were randomized in a double-blind manner (3 : 1 ratio) to the treatment arm. The treatment periods were: weeks 1 and 2 two 500 mg tablets administered three times daily with meals (total daily dose 3000 mg); weeks 3 to 14 two 1000 mg tablets administered three times daily with meals (total daily dose 6000 mg).
  • Adiponectin blood level was evaluated during the baseline period, upon randomization and throughout the active treatment period. All blood samples were to be collected following a 12-hour fast. Throughout the study, subject were required to adhere to a heart-healthy diet and abstain from/minimize ethyl alcohol intake. Safety and tolerability were assessed throughout the trial through the evaluation of physical exams, electrocardiograms, routine hematology ad blood chemistry testing, vital signs and adverse events. [00055] Changes of the laboratory parameters of adiponectin levels were expressed as changes from baselines. Parameters were analyzed using analysis of covariance (ANCOVA) models adjusting for baseline value of the response variable
  • the adjusted mean changes in adiponectin were -0.06 ⁇ g/mL (95% CI (-0.53 ⁇ g/mL, 0.42 ⁇ .)) for placebo and 0.55 ⁇ g/mL (95% CI (0.23 ⁇ g/mL, 0.86 ⁇ .)) for 1-MNA.

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Abstract

L'invention concerne un procédé d'augmentation du taux d'adiponectine circulant, ou pour traiter des maladies causées par une production insuffisante d'adiponectine. Le traitement consisterait à administrer de 1-MNA, ou d'un sel de celui-ci, en une quantité suffisante pour augmenter le taux d'adiponectine dans le sang du sujet.
PCT/IB2017/054294 2016-07-18 2017-07-16 Sels de 1-méthylnicotinamide destinés à être utilisés pour augmenter les taux sanguins d'adiponectine. WO2018015862A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2020115765A1 (fr) * 2018-12-05 2020-06-11 Celagenex Research (India) Pvt. Ltd. Nouvelle composition synergique comprenant des activateurs de sirt1 et d'ampk pour le traitement du syndrome métabolique
WO2021205341A1 (fr) 2020-04-07 2021-10-14 Pharmena S.A. 1-méthylnicotinamide destiné à la prévention/le traitement de maladies inflammatoires des voies respiratoires

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WO2007074406A2 (fr) * 2005-07-11 2007-07-05 Pharmena North America Inc. Derives et formulations de methylnicotinamide pour le traitement d'anomalies de lipoproteine
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AT131118B (de) 1929-04-19 1933-01-10 Ig Farbenindustrie Ag Verfahren zur Darstellung von N-Methylpyridiniumchlorid.
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WO2020115765A1 (fr) * 2018-12-05 2020-06-11 Celagenex Research (India) Pvt. Ltd. Nouvelle composition synergique comprenant des activateurs de sirt1 et d'ampk pour le traitement du syndrome métabolique
WO2021205341A1 (fr) 2020-04-07 2021-10-14 Pharmena S.A. 1-méthylnicotinamide destiné à la prévention/le traitement de maladies inflammatoires des voies respiratoires

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