WO2000059890A1 - Derives de tetrahydropyridazine - Google Patents

Derives de tetrahydropyridazine Download PDF

Info

Publication number
WO2000059890A1
WO2000059890A1 PCT/EP2000/002275 EP0002275W WO0059890A1 WO 2000059890 A1 WO2000059890 A1 WO 2000059890A1 EP 0002275 W EP0002275 W EP 0002275W WO 0059890 A1 WO0059890 A1 WO 0059890A1
Authority
WO
WIPO (PCT)
Prior art keywords
benzoyl
tetrahydro
pyridazine
methoxyphenyl
ethoxy
Prior art date
Application number
PCT/EP2000/002275
Other languages
German (de)
English (en)
Inventor
Jonas Rochus
Michael Wolf
Norbert Beier
Franz-Werner Kluxen
Claus Fittschen
Original Assignee
Merck Patent 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 Merck Patent Gmbh filed Critical Merck Patent Gmbh
Priority to AU32897/00A priority Critical patent/AU3289700A/en
Publication of WO2000059890A1 publication Critical patent/WO2000059890A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not 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
    • A61K31/495—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to tetrahydropyridazine derivatives selected from the
  • Q is absent or alkylene with 1-6 C atoms
  • R 1 , R 2 each independently of one another -OH, OR 5 , -SR 5 ,
  • R 1 and R 2 together also -O-CH 2 -O-,
  • R 5 and R are each independently A, cycloalkyl with 3-7
  • the invention was based on the task of finding new compounds with valuable properties, in particular those which can be used for the production of medicaments. It has been found that the compounds according to the invention and their salts have very valuable pharmacological properties with good tolerability.
  • PDE IV inhibition can e.g. analogous to C.W. Davis in Biochim. biophys. Acta 797, 354-362 (1984).
  • the compounds according to the invention can be used for the treatment of asthmatic diseases.
  • the anti-asthmatic effect of the PDE IV inhibitors is e.g. by TJ. Torphy et al. in Thorax, 46, 512-523 (1991) and can e.g. B. by the method of T. Olson, Acta allergologica 26, 438-447 (1971) can be determined.
  • the compounds according to the invention can used to treat osteoporosis.
  • the compounds also show an inhibitory effect on the formation of TNF (tumor necrosis factor) and are therefore suitable for the treatment of allergic and inflammatory diseases, autoimmune diseases and graft rejection reactions. They can be used to treat memory disorders, tumors, atherosclerosis, rheumatoid arthritis, multiple sclerosis, Crohn's disease, atopic dermatitis, diabetes mellitus, ulcerative colitis and AIDS.
  • TNF tumor necrosis factor
  • PDE IV inhibitors in the treatment of asthma, inflammatory diseases, diabetes mellitus, atopic dermatitis, psoriasis, AIDS, tumor growth or tumor metastases is described, for example, in EP 77 92 91.
  • the anti-inflammatory effect of the substances according to the invention and their effectiveness for the treatment of, for example, autoimmune diseases, multiplesclerosis or rheumatoid arthritis can be analogous to the methods of N. Sommer et al., Nature Medicine, 1, 244-248 (1995) or L. Sekut et al., Clin. Exp. Immunol., 100, 126-132 (1995).
  • the compounds according to the invention can be used as active pharmaceutical ingredients in human and veterinary medicine. They can also be used as intermediates for the production of further active pharmaceutical ingredients.
  • R 1 and R 2 have the meanings given for formula I and
  • R and R each independently of one another denote H or alkyl
  • R 1 , R 2 , R 3 , R 4 and Q have the meanings given, with a compound of the formula V.
  • L is Cl, Br, OH or a reactive esterified OH group
  • the compounds of formula I can have a chiral center and can therefore occur in several stereoisomeric forms. All of these forms (e.g. R and S forms) and their mixtures (e.g. the R, S forms) are included in Formula I.
  • Solvates are hydrates or e.g. Alcoholates, such as the addition compounds with methanol, ethanol or isopropanol.
  • a and A ' is preferably alkyl, more preferably alkyl substituted by 1 to 5 fluorine and / or chlorine atoms.
  • alkyl is preferably unbranched and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably 1, 2, 3, 4 or 5 carbon atoms and is preferably methyl , Ethyl, trifluoromethyl, pentafluoroethyl or propyl, further preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl or isopentyl.
  • Cycloalkyl preferably has 3-7 C atoms and is preferably cyclopropyl and cyclobutyl, further preferably cyclopentyl or cyclohexyl, and also cycloheptyl.
  • Methyl cycloalkyl preferably has 4-8 C atoms and preferably represents methylene cyclopropyl and methylene cyclobutyl, further preferably methylene cyclopentyl and methylene cyclohexyl, and also methylene cycloheptyl.
  • Alkenyl preferably stands for vinyl, 1- or 2-propenyl, 1-butenyl, isobutenyl, sec-butenyl, further preferred is 1-pentenyl, isopentyl or 1-hexenyl.
  • Alkylene is preferably unbranched and is preferably methylene or ethylene, more preferably propylene or butylene.
  • R 3 and R 4 one is preferably H, while the other is preferably propyl or butyl, but particularly preferably ethyl or methyl.
  • the radicals R 1 and R 2 can be the same or different and are in the 3- or 4-position of the phenyl ring. They mean, for example, independently of one another hydroxy, -S-CH 3 , -SO-CH 3 , -SO 2 CH 3 , F, Cl, Br or I or together methylenedioxy. However, they are particularly preferably each methoxy, ethoxy, propoxy, cyclopentoxy, or else fluorine, difluoro, trifluoromethoxy, 1-fluorine, 2-fluorine, 1, 2-difluoro, 2,2-difluoro, 1, 2,2-trifluoro or 2,2,2-trifluoroethoxy.
  • the radical B is preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further preferably 1,2,3-triazoM-, -4- or -5-yI, 1, 2,4-triazoM-, -3- or 5-yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4- or -5-yl, 1, 2,4-oxadiazol-3- or - 5-yl, 1, 3,4- Thiadiazol-2- or -5-yl, 1, 2,4-thiadiazol-3- or -5-yl, 1, 2,3-thiadiazol-4- or -5-y
  • the radical B is preferably also methyl, ethyl, propyl, n-butyl, methoxy, ethoxy, propoxy, N-methylamino, N, N-dimethylamino, N-ethylamino or N, N-diethylamino. It applies to the entire invention that all radicals which occur more than once can be the same or different, ie are independent of one another.
  • the compounds of the invention and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart) are, under reaction conditions that are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.
  • R 1 , R 2 , R 3 , R 4 and Q have the meanings indicated, in particular the preferred meanings indicated.
  • Q is preferably methylene or ethylene, more preferably propylene or butylene.
  • B has the preferred meanings indicated in the compounds of the formulas III and V, while L denotes Cl, Br, OH or a reactive esterified OH group.
  • L is a reactive esterified OH group, this is preferably alkylsulfonyloxy with 1-6 C atoms (preferably methylsulfonyloxy) or arylsulfonyioxy with 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy, further also 2- Naphthalenesulfonyloxy).
  • the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately converted further into the compounds according to the invention. On the other hand, it is possible to carry out the reaction in stages.
  • the compounds according to the invention can preferably be obtained by reacting compounds of the formula II with compounds of the formula III.
  • the compounds of the formula II are reacted with the compounds of the formula III in the presence or absence of an inert solvent at temperatures between about -20 and about 150 °, preferably between 20 and 100 °.
  • Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF);
  • the compounds according to the invention can furthermore be obtained by reacting compounds of the formula IV with compounds of the formula V.
  • the starting compounds of the formulas IV and V are generally known. If they are not known, they can be produced by methods known per se. For example, the production of 1-benzoyl-tetrahydropyridazine is described in J. Med. Chem. 38, 4878 (1995).
  • the radical -CO-L denotes a preactivated carboxylic acid, preferably a carboxylic acid halide.
  • reaction of the compounds of the formula IV with compounds of the formula V takes place under the same conditions, with regard to the reaction time, temperature and solvent, as is described for the reaction of the compounds of the formula II with compounds of the formula III.
  • a base of the compounds according to the invention can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanoi and subsequent evaporation.
  • acids that provide physiologically acceptable salts are suitable for this implementation.
  • So inorganic acids can be used, e.g. Sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heteroeyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g.
  • Formic acid acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid -Hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfuric acid. Salts with physiologically unacceptable acids, e.g. Picrates can be used for the isolation and / or purification of the compounds of the formula I.
  • Picrates can be used for the isolation and / or purification of the compounds of the formula I.
  • the invention further relates to the use of the compounds according to the invention and / or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non-chemical route.
  • they can be combined with at least one solid, liquid and / or semi-liquid carrier or auxiliary and if necessary, in combination with one or more other active ingredients are brought into a suitable dosage form.
  • the invention also relates to medicaments of the compounds according to the invention selected from the group
  • the invention further relates to pharmaceutical preparations containing at least one compound according to the invention and / or one of its physiologically acceptable salts or solvates.
  • Suitable carrier substances are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical application and with the new compounds not react, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly.
  • Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for topical use for parenteral use Ointments, creams or powder.
  • the new compounds can also be lyophilized and the lyophilisates obtained used, for example, for the production of injection preparations.
  • the specified preparations can be sterilized and / or auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colors, flavors and / or one or more other active substances contain, for example, one or more vitamins.
  • auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colors, flavors and / or one or more other active substances contain, for example, one or more vitamins.
  • the compounds according to the invention and their physiologically acceptable salts can be used in the control of diseases in which an increase in the cAMP (cyclo-adenosine monophosphate) level leads to inhibition or prevention of inflammation and muscle relaxation.
  • the compounds according to the invention can be used particularly in the treatment of allergies, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin diseases and autoimmune diseases.
  • the substances according to the invention are generally preferably administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit.
  • the daily dosage is preferably between about 0.02 and 10 mg / kg body weight.
  • the specific dose for each patient depends on a wide variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of elimination and combination of drugs and severity of the disease to which the therapy applies. Oral application is preferred.
  • the compounds according to the invention can contain one or more centers of asymmetry. In this case, they are usually in racemic form. Racemates obtained can be separated into their enantiomers mechanically or chemically by methods known per se. Diastereomers are preferably formed from the racemic mixture by reaction with an optically active release agent.
  • optically active compounds by the methods described above by using starting materials that are already optically active.
  • customary work-up means: if necessary, water is added, if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, and the mixture is separated off, dries the organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization.
  • a suspension of 4.70 g of 3- (3,4-dimethoxyphenyl) -1, 4,5,6-tetrahydropyridazine ("A") in 150 ml of THF is mixed with 2.24 g of potassium tert-butoxide and stirred for 30 minutes.
  • 7.3 g of 4-nicotinoylaminobenzoyl chloride are added and the mixture is subsequently stirred at room temperature for 10 hours. The solvent is removed and worked up as usual.
  • the compound is obtained analogously by reaction with potassium cyanate 1 - (4-ureido-benzoyl) -3- (3-ethoxy-4-methoxy-phenyl) -1, 4,5,6-tetrahydro-pyridazine, mp 251 °.
  • Example A Injection glasses
  • a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.
  • a mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
  • a solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH 2 PO 4 .2H 2 O, 28.48 g of Na 2 HPO 4 .12H 2 O and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.
  • Example D ointment
  • 500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • Example E tablets A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient.
  • Example F coated tablets
  • Example E tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
  • Example G capsules
  • each capsule contains 20 mg of the active ingredient.
  • a solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne des dérivés de tétrahydropyridazine faisant partie du groupe: 1-(4-ureido-benzoyl) -3-(3-éthoxy-4- méthoxy-phényl) -1,4,5,6-tétrahydro- pyridazine; 1-(4-nicotinoylamino- benzoyl)-3- (3-propoxy-4- méthoxyphényl) -1,4,5,6-tétrahydro- pyridazine; 1-(4-trifluoracétamido- benzoyl)-3- (3-éthoxy-4- méthoxyphényl) -1,4,5,6-tétrahydro- pyridazine; 1-(4-éthoxycarbonylamino- benzoyl) -3-(3-propoxy- 4-méthoxyphényl) -1,4,5,6-tétrahydro- pyridazine; 1-(4-isopropoxycarbonylamino- benzoyl)-3- (3-éthoxy-4- méthoxyphényl) -1,4,5,6-tétrahydro- pyridazine, 1-(4-propoxycarbonylamino- benzoyl)-3- (3-éthoxy-4- méthoxyphényl) -1,4,5,6-tétrahydro- pyridazine; 1-(4-nicotinoylamino- benzoyl)-3- (3,4-diméthoxyphényl) -4-éthyl-1,4,5,6- tétrahydro- pyridazine; 1-(4-éthoxycarbonylamino- benzoyl) -3-(3,4-diméthoxyphényl) -4-éthyl-1,4,5,6- tétrahydro- pyridazine; 1-(4-acétamido- benzoyl)-3- (3,4-diméthoxyphényl) -4-éthyl-1,4,5,6- tétrahydro- pyridazine; leurs sels et solvates. Ces composés exercent une action inhibitrice sur la phosphodiestérase IV et peuvent servir au traitement de l'ostéoporose, de tumeurs, de l'athérosclérose, de l'arthrite rhumatoïde, de la sclérose en plaques, du diabète sucré, de réactions inflammatoires, d'allergies, de l'asthme, de maladies auto-immunes, du SIDA, de la dermatite atopique, du psoriasis et des réactions de rejet post-transplantation.
PCT/EP2000/002275 1999-04-06 2000-03-15 Derives de tetrahydropyridazine WO2000059890A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU32897/00A AU3289700A (en) 1999-04-06 2000-03-15 Tetrahydropyridazine derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19915365.5 1999-04-06
DE19915365A DE19915365A1 (de) 1999-04-06 1999-04-06 Tetrahydropyridazin-Derivate

Publications (1)

Publication Number Publication Date
WO2000059890A1 true WO2000059890A1 (fr) 2000-10-12

Family

ID=7903584

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2000/002275 WO2000059890A1 (fr) 1999-04-06 2000-03-15 Derives de tetrahydropyridazine

Country Status (4)

Country Link
AR (1) AR023262A1 (fr)
AU (1) AU3289700A (fr)
DE (1) DE19915365A1 (fr)
WO (1) WO2000059890A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000059484A2 (fr) * 1999-04-06 2000-10-12 Merck Patent Gmbh Utilisation d'arylalcanoylpyridazines
WO2003037349A1 (fr) * 2001-10-31 2003-05-08 Merck Patent Gmbh Inhibiteurs de la phosphodiesterase de type 4 et leurs utilisations
WO2010099217A1 (fr) 2009-02-25 2010-09-02 Braincells, Inc. Modulation de neurogenèse à l'aide de combinaisons de d-cyclosérine
EP2258357A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse avec inhibiteur de l'acetylcholinestérase
EP2275095A2 (fr) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese par modulation des recepteurs muscariniques
EP2314289A1 (fr) 2005-10-31 2011-04-27 Braincells, Inc. Modulation de la neurogenese dont la médiation est assurée par récepteur gaba
WO2011063115A1 (fr) 2009-11-19 2011-05-26 Braincells Inc. Combinaison d'un agent nootropique avec un ou plusieurs agents neurogènes ou à effet neurogène par synergie pour stimuler ou intensifier la neurogenèse
US7985756B2 (en) 2005-10-21 2011-07-26 Braincells Inc. Modulation of neurogenesis by PDE inhibition
WO2011091033A1 (fr) 2010-01-20 2011-07-28 Braincells, Inc. Modulation de la neurogenèse par des agents ppar
EP2377531A2 (fr) 2006-05-09 2011-10-19 Braincells, Inc. Neurogénèse par modulation de l'angiotensine
WO2013106547A1 (fr) 2012-01-10 2013-07-18 President And Fellows Of Harvard College Composés promoteurs de réplication des cellules bêta et leurs procédés d'utilisation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1235589C (zh) * 2001-02-12 2006-01-11 默克专利股份公司 4型磷酸二酯酶抑制剂在制备治疗心肌疾病药物中的应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19632549A1 (de) * 1996-08-13 1998-02-19 Merck Patent Gmbh Arylalkanoylpyridazine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19632549A1 (de) * 1996-08-13 1998-02-19 Merck Patent Gmbh Arylalkanoylpyridazine
WO1998006704A1 (fr) * 1996-08-13 1998-02-19 Merck Patent Gmbh Arylalcanoylpyridazines

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000059484A2 (fr) * 1999-04-06 2000-10-12 Merck Patent Gmbh Utilisation d'arylalcanoylpyridazines
WO2000059484A3 (fr) * 1999-04-06 2001-08-23 Merck Patent Gmbh Utilisation d'arylalcanoylpyridazines
WO2003037349A1 (fr) * 2001-10-31 2003-05-08 Merck Patent Gmbh Inhibiteurs de la phosphodiesterase de type 4 et leurs utilisations
EP2275096A2 (fr) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese par modulation des recepteurs muscariniques
EP2258358A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse avec un inhibiteur de l'acetylcholinestérase
EP2258359A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse par modulation des récepteurs muscariniques avec sabcomeline
EP2275095A2 (fr) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese par modulation des recepteurs muscariniques
EP2258357A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse avec inhibiteur de l'acetylcholinestérase
US7985756B2 (en) 2005-10-21 2011-07-26 Braincells Inc. Modulation of neurogenesis by PDE inhibition
EP2377530A2 (fr) 2005-10-21 2011-10-19 Braincells, Inc. Modulation de neurogénèse par inhibition PDE
EP2314289A1 (fr) 2005-10-31 2011-04-27 Braincells, Inc. Modulation de la neurogenese dont la médiation est assurée par récepteur gaba
EP2377531A2 (fr) 2006-05-09 2011-10-19 Braincells, Inc. Neurogénèse par modulation de l'angiotensine
EP2382975A2 (fr) 2006-05-09 2011-11-02 Braincells, Inc. Neurogénèse par modulation d'angiotensine
WO2010099217A1 (fr) 2009-02-25 2010-09-02 Braincells, Inc. Modulation de neurogenèse à l'aide de combinaisons de d-cyclosérine
WO2011063115A1 (fr) 2009-11-19 2011-05-26 Braincells Inc. Combinaison d'un agent nootropique avec un ou plusieurs agents neurogènes ou à effet neurogène par synergie pour stimuler ou intensifier la neurogenèse
WO2011091033A1 (fr) 2010-01-20 2011-07-28 Braincells, Inc. Modulation de la neurogenèse par des agents ppar
WO2013106547A1 (fr) 2012-01-10 2013-07-18 President And Fellows Of Harvard College Composés promoteurs de réplication des cellules bêta et leurs procédés d'utilisation

Also Published As

Publication number Publication date
DE19915365A1 (de) 2000-10-12
AU3289700A (en) 2000-10-23
AR023262A1 (es) 2002-09-04

Similar Documents

Publication Publication Date Title
EP0922036B1 (fr) Arylalcanoylpyridazines
EP0763534B1 (fr) Dérivés d'arylalkyl-diazinone en tant qu'inhibiteurs de la phosphodiestérase de type IV
EP1226143B1 (fr) Derives d'imidazopyridine comme inhibiteurs de phosphodiesterase vii
EP1087946B1 (fr) Arylalcanoylpyridazines
EP0934301A1 (fr) Amides d'acide carboxylique d'aminothiophene et leur utilisation comme inhibiteurs de phosphodiesterase
EP1124809B1 (fr) Benzoylpyridazines
EP0738715B1 (fr) Arylalkyl-pyridazinones
EP1228073B1 (fr) Composes imidazole utilises comme inhibiteurs de la phosphodiesterase vii
WO2000059890A1 (fr) Derives de tetrahydropyridazine
DE19604388A1 (de) Arylalkyl-diazinone
EP0723962B1 (fr) Arylalkyl-thiadiazinones
EP1225896A1 (fr) Derives d'isoxazol utilises comme inhibiteurs vii de phosphodiesterase
DE10064997A1 (de) Benzoylpyridazine
EP1143944A3 (fr) Utilisation d'arylalcanoylpyridazines
EP1194411B1 (fr) Benzolpyridazines
EP1406878A1 (fr) Derives de 4-(benzylidene-amino)-3-(methylsulfanyle)-4h-(1, 2, 4) triazin-5-one a effet inhibiteur de pde-iv et antagoniste de tnf pour le traitement des maladies cardiaques et des allergies
WO2003008373A1 (fr) Hydrazides de tyrosine
DE19653024A1 (de) Endothelin-Rezeptor-Antagonisten
DE10156230A1 (de) Tyrosinhydrazide
DE10156229A1 (de) Triazinderivate
DE10135009A1 (de) Triazinderivate
DE10135248A1 (de) Tyrosinhydrazide
EP0647627A1 (fr) Dihydro-1,2 oxo-2 méthylsulfonylaminométhyl-3 pyridines comme antagonistes d'angiotensine II

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642