EP1663205A1 - Verwendung von 4,5-dihydro-1h-pyrazol-derivaten mit cb1-antagonistischer wirkung - Google Patents

Verwendung von 4,5-dihydro-1h-pyrazol-derivaten mit cb1-antagonistischer wirkung

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Publication number
EP1663205A1
EP1663205A1 EP04766644A EP04766644A EP1663205A1 EP 1663205 A1 EP1663205 A1 EP 1663205A1 EP 04766644 A EP04766644 A EP 04766644A EP 04766644 A EP04766644 A EP 04766644A EP 1663205 A1 EP1663205 A1 EP 1663205A1
Authority
EP
European Patent Office
Prior art keywords
treatment
prophylaxis
juvenile
phenyl
chlorophenyl
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Withdrawn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
EP04766644A
Other languages
English (en)
French (fr)
Inventor
Jochen Antel
Günter Krause
Josephus Hubertus Maria Lange
Cornelis Gerrit Kruse
Peter-Colin Gregory
Cathaline Den Besten
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Products GmbH
Original Assignee
Solvay Pharmaceuticals GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Solvay Pharmaceuticals GmbH filed Critical Solvay Pharmaceuticals GmbH
Priority to EP04766644A priority Critical patent/EP1663205A1/de
Publication of EP1663205A1 publication Critical patent/EP1663205A1/de
Withdrawn legal-status Critical Current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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic 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
    • A61K31/4164—1,3-Diazoles
    • 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
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
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    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P3/04—Anorexiants; Antiobesity 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a group of novel therapeutic and/or prophylactic uses of 4,5-dihydro-1 H-pyrazole derivatives and to pharmaceutical compositions containing one or more of these compounds as an active component for the novel uses.
  • the 4,5-dihydro-1 H-pyrazoles are potent Cannabis-1 (CBi) receptor antagonists with outstanding utility for the novel medical uses provided by the present invention.
  • Cannabinoids are present in the Indian hemp Cannabis Sativa L. and have been used as medicinal agents for centuries ( echoulam, R.; Feigenbaum, J.J. Prog. Med. Chem. 1987, 24, 159). However, only within the past ten years the research in the cannabinoid area has revealed pivotal information on cannabinoid receptors and their (endogenous) agonists and antagonists. The discovery and the subsequent cloning of two different subtypes of Cannabinoid receptors (CBi and CB 2 ) stimulated the search for novel cannabinoid receptor antagonists (Munro, S.; Thomas, K.L.; Abu-Shaar, M. Nature 1993, 365, 61.
  • AM-630 lodopravadoline
  • a representative example is lodopravadoline (AM-630), which was introduced in 1995.
  • AM-630 is a CBi receptor antagonist, but sometimes behaves as a weak partial agonist (Hosohata, K.; Quock, R.M.; Hosohata, Y.; Burkey, T.H.; Makriyannis, A.; Consroe, P.; Roeske, W.R.; Yamamura, H.I. Life Sc. 1997, 61,
  • aryl-aroyl substituted benzofurans as selective CB ! receptor antagonists (e.g. LY -320135) (Felder, CO; Joyce, K.E.; Briley, E.J.; Glass, M.; Mackie, K.P.; Fahey, K.J.; Cullinan, G.J.; Hunden, D.C.; Johnson, D.W.; Chaney, M.O.; Koppel, G.A.; Brownstein, M. J. Pharmacol. Exp. Ther. 1998, 284, 291 ).
  • 5-dihydro-1 H-pyrazole compounds which exhibit potent and selective cannabis CB receptor antagonistic activity.
  • These compounds have the formula (I) defined below, and have been suggested for use in the treatment of psychiatric disorders such as psychosis, anxiety, depression, attention deficits, memory disorders and appetite disorders, obesity, neurological disorders such as dementia, distonia, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischaemia, as well as for the treatment of pain disorders and other CNS-diseases involving cannabinoid neurotransmission, and in the treatment of gastrointestinal disorders and cardiovascular disorders.
  • - R and Ri are the same or different and represent phenyl, thienyl or pyridyl which groups may be substituted with 1 , 2 or 3 substituents Y, which can be the same or different, from the group C 1-3 -alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C 1-2 )-amino, mono- or dialkyl (C ⁇ -2 )-amido, (d -3 )-alkyl sulfonyl, dimethylsulfamido, C ⁇ -3 -alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R and/or R represent naphtyl, - R 2 represents hydrogen, hydroxy, d- 3 -alkoxy
  • R 4 and R 5 independently of each other represent hydrogen or C 1 - 8 branched or unbranched alkyl or C 3-8 cycloalkyl or R 4 represents acetamido or dimethylamino or 2,2,2-trifluoroethyl or phenyl or pyridyl with the proviso that R 5 represents hydrogen - R 6 represents hydrogen or C 1-3 unbranched alkyl
  • - Bb represents sulfonyl or carbonyl
  • R 3 represents benzyl, phenyl, thienyl or pyridyl which may be substituted with 1 , 2 or 3 substituents Y, which can be the same or different, or R 3 represents d -8 branched or unbranched alkyl or C 3-8 cycloalkyl, or R 3 represents naphtyl
  • the outstanding unique pharmacological profile of compounds of formula (I) includes particularly high safety and tolerability which make the compounds particularly suitable in patient groups with enhanced need of safety and tolerability, in particular such as juvenile patients and/or patients subject to long term treatment, e.g. in drug induced obesity.
  • the compounds used according to the invention are suitable for use in the paediatric treatment and/or prophylaxis of psychiatric disorders such as psychosis, anxiety, depression, attention deficits, memory disorders and appetite disorders, obesity, neurological disorders such as dementia, distonia, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischaemia, as well as for the treatment of pain disorders and other CNS-diseases involving cannabinoid neurotransmission, and in the treatment of gastrointestinal disorders and cardiovascular disorders, in young patients .
  • psychiatric disorders such as psychosis, anxiety, depression, attention deficits, memory disorders and appetite disorders, obesity, neurological disorders such as dementia, distonia, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischaemia, as well as for the treatment of pain disorders and other CNS-diseases involving cannabinoid neurotransmission, and in the treatment of gastrointestinal disorders and cardiovascular disorders, in
  • the affinity of the compounds of formula (I) for cannabinoid CBi receptors is described in the WO 01/70700, e.g. it was determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabis CBi receptor is stably transfected in conjunction with [3H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [3H]-ligand, with or without addition of compounds of the invention, separation of bound and free ligand was performed by filtration over glassfiber filters. Radioactivity on the filter was measured by liquid scintillation counting.
  • the cannabinoid CBi antagonistic activity of compounds of formula (I) is also described in the WO 01/70700, and was determined by functional studies using CHO cells in which human cannabinoid CB receptors are stably expressed.
  • Adenylyl cyclase was stimulated using forskolin and measured by quantifying the amount of accumulated cyclic AMP.
  • Concomitant activation of CB ! receptors by CBi receptor agonists e.g. CP -55,940 or (R)-WIN-55,212-2
  • CBi receptor agonists e.g. CP -55,940 or (R)-WIN-55,212-2
  • This CBi receptor-mediated response can be antagonized by CBi receptor antagonists such as the compounds used in the present invention.
  • At least one centre of chirality is present (at the C 4 position of the 4,5-dihydro-1 H- pyrazole moiety) in the compounds of the formula (I).
  • the invention relates both to the novel use of racemates, mixtures of diastereomers and the individual stereoisomers of the compounds having formula (I).
  • the invention also relates both to the novel use of the E isomer, Z isomer and E/Z mixtures of compounds having formula (I) wherein Aa has the meaning (i) or (ii) as described herein above.
  • compound having formula (I) are used, wherein R is the group 4-chlorophenyl, Ri is phenyl, R 2 is hydrogen, Aa is the group (i) wherein R 4 is hydrogen and R 5 is methyl, Bb is sulfonyl, and R 3 represents 4-chlorophenyl, and salts thereof.
  • the compound having formula (I) used according to the invention may be a levorotatory enantiomer.
  • the compounds used in the present the invention can be obtained according to known methods.
  • a suitable synthesis for the compounds used according to the present invention is described for compounds of formula (I) in the international patent application WO 01/70700.
  • compounds having formula (III) (vide infra), wherein R 2 represents hydrogen can be also obtained according to methods known, for example: a) EP 0021506; b) DE 2529689.
  • Example compounds having been prepared according to WO 01/70700 and being investigated include the e.g. the following compounds:
  • N-Dimethylamino-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5- dihydro-4-phenyl-1 H-pyrazole-1 -carboxamidine N-Methyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-3-(4-chlorophenyl)-4,5- dihydro-4-phenyl-1 H-pyrazole-1 -carboxamidine
  • the compounds used according to the invention can be brought into forms suitable for paediatric administration, as well as for the administration in treating drug induced obesity by means of usual processes using auxiliary substances and/or liquid or solid carrier materials.
  • the invention also pertains to a pharmaceutical composition containing at least one compound of formula (I) as an active component for the treatment and/or prophylaxis of CBi receptor related diseases in juvenile patients and/or for the treatment and/or prophylaxis of drug induced obesity in juvenile as well as adolescent patients, and at least one auxiliary excipient.
  • the compound of formula (I) is preferably present in an amount effectively suited for the treatment and/or prophylaxis of a psychiatric disorder, a gastrointestinal disorder, a cardiovascular disorder, or a combination of said disorders, in a juvenile patient in need of such treating.
  • the compound of formula (I) in the pharmaceutical composition is present in an amount effectively suited for the treatment and/or prophylaxis of drug induced obesity in juvenile as well as adolescent patients in need of such treating.
  • the invention also includes a method of treatment and/or prophylaxis of
  • CBi receptor related diseases in juvenile patients and/or for the treatment and/or prophylaxis of drug induced obesity in juvenile as well as adolescent patients characterized in that a compound of formula (I) is administered to said patient in need of such treating.
  • the method of treatment and/or prophylaxis according to the invention may be further characterized in that the treating is directed to psychiatric disorders such as psychosis, anxiety, depression, attention deficits, memory disorders and appetite disorders, obesity, including drug induced obesity, neurological disorders such as Parkinson's disease, dementia, distonia, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, ischemia, pain and other CNS-diseases involving cannabinoid neurotransmission.
  • the method of treatment and/or prophylaxis is directed to the treating of obesity in juvenile patients.
  • the method of treatment and/or prophylaxis is directed to the treating of drug induced obesity in juvenile or adolescent patients. This drug induced obesity may be in particular caused by drugs like atypical antipsychotics.
  • the method of treatment and/or prophylaxis is directed to the treating of obesity in juvenile patients.
  • Cannabinoid antagonists are suitable for the treatment of Childhood Obesity and related Comorbidities as for example Type 2 Diabetes.
  • Childhood Obesity and related Comorbidities as for example Type 2 Diabetes.
  • the prevalence of overweight in children grew from 5% to 11 % (Sorof and Daniels 2002).
  • Obesity in childhood causes a wide range of serious complications, and increases the risk of premature illness and death later in life, raising public-health concerns (Ebbeling,
  • Type-2-diabetes was in the past considered a disease of adults and older individuals, not a paediatric condition (Arslanian 2002).
  • One of the main risk factor of paediatric type 2 diabetes is obesity.
  • Type 2 diabetes in children is part of the insulin resistance syndrome (Rosenbloom 2002) that includes hypertension, dyslipidemia and other atherosclerosis risk factors, and hyperandrogenism seen as premature adrenarche and polycystic ovary syndrome.
  • Other outcomes related to childhood obesity include left ventricular hypertrophy, nonalcoholic steatohepatitis, obstructive sleep apnea, orthopedic problems, and severe psychosocial problems.
  • CBi antagonists used according to the present invention offer a unique opportunity for the treatment of obesity by interacting with these "driving forces".
  • CBi antagonists in childhood are a medical condition that is likely to require long-term management.
  • the safety profile of CBi antagonists according to the present invention are suggested to be superior to current standard medications, and these CBi antagonists will be especially suited for the treatment and prevention of childhood obesity and related co-morbidities.
  • the method of treatment and/or prophylaxis is directed to the treating of drug induced obesity in juvenile or adolescent patients.
  • Drug induced weight gain is also of major concern and subject to high medical need of improved treatments.
  • the CBi antagonists according to the present invention are suggested to be superior to current standard medications, and these CB ! antagonists will be especially suited for the treatment and prevention of drug induced obesity in juvenile as well as in adolescent patients.

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EP04766644A 2003-09-02 2004-08-31 Verwendung von 4,5-dihydro-1h-pyrazol-derivaten mit cb1-antagonistischer wirkung Withdrawn EP1663205A1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP04766644A EP1663205A1 (de) 2003-09-02 2004-08-31 Verwendung von 4,5-dihydro-1h-pyrazol-derivaten mit cb1-antagonistischer wirkung

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP03019939 2003-09-02
EP04766644A EP1663205A1 (de) 2003-09-02 2004-08-31 Verwendung von 4,5-dihydro-1h-pyrazol-derivaten mit cb1-antagonistischer wirkung
PCT/EP2004/051961 WO2005020988A1 (en) 2003-09-02 2004-08-31 Use of 4,5-dihydro-1h-pyrazole derivatives having cb1-antagonistic activity

Publications (1)

Publication Number Publication Date
EP1663205A1 true EP1663205A1 (de) 2006-06-07

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EP04766644A Withdrawn EP1663205A1 (de) 2003-09-02 2004-08-31 Verwendung von 4,5-dihydro-1h-pyrazol-derivaten mit cb1-antagonistischer wirkung

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Country Link
EP (1) EP1663205A1 (de)
JP (1) JP2007504200A (de)
CN (2) CN1845735A (de)
AR (1) AR045533A1 (de)
AU (1) AU2004268388A1 (de)
BR (1) BRPI0413980A (de)
CA (1) CA2537090A1 (de)
MX (1) MXPA06002365A (de)
RU (1) RU2006110543A (de)
TW (1) TW200511990A (de)
WO (1) WO2005020988A1 (de)

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AU2003300967B2 (en) 2002-12-19 2009-05-28 Merck Sharp & Dohme Corp. Substituted amides
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MXPA06002365A (es) 2006-06-20
CA2537090A1 (en) 2005-03-10
RU2006110543A (ru) 2007-10-10
CN1845735A (zh) 2006-10-11
CN1835747A (zh) 2006-09-20
AU2004268388A1 (en) 2005-03-10
WO2005020988A1 (en) 2005-03-10
JP2007504200A (ja) 2007-03-01

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