WO2000059890A1 - Tetrahydropyridazine derivatives - Google Patents

Tetrahydropyridazine derivatives Download PDF

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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
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WIPO (PCT)
Prior art keywords
benzoyl
tetrahydro
pyridazine
methoxyphenyl
ethoxy
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PCT/EP2000/002275
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German (de)
French (fr)
Inventor
Jonas Rochus
Michael Wolf
Norbert Beier
Franz-Werner Kluxen
Claus Fittschen
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Merck Patent Gmbh
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Priority to AU32897/00A priority Critical patent/AU3289700A/en
Publication of WO2000059890A1 publication Critical patent/WO2000059890A1/en

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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
    • A61K31/50—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.

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Abstract

The invention relates to tetrahydropyridazine derivatives selected from the following group: 1-(4-ureido-benzoyl) -3-(3-ethoxy- 4-methoxy-phenyl) -1,4,5,6-tetrahydro- pyridazine, 1-(4-nicotinoylamino- benzoyl)-3- (3-propoxy-4- methoxyphenyl) -1,4,5,6-tetrahydro- pyridazine, 1-(4-trifluoracetamido- benzoyl)-3- (3-ethoxy-4- methoxyphenyl) -1,4,5,6-tetrahydro- pyridazine, 1-(4-ethoxycarbonylamino- benzoyl)-3- (3-propoxy-4- methoxyphenyl) -1,4,5,6-tetrahydro- pyridazine, 1-(4-isopropoxycarbonylamino- benzoyl)-3- (3-ethoxy-4- methoxyphenyl) -1,4,5,6-tetrahydro- pyridazine, 1-(4-propoxycarbonylamino- benzoyl)-3- (3-ethoxy-4- methoxyphenyl) -1,4,5,6-tetrahydro- pyridazine, 1-(4-nicotinoylamino- benzoyl)-3- (3,4-dimethoxyphenyl) -4-ethyl-1,4,5,6- tetrahydro- pyridazin, 1-(4-ethoxycarbonylamino- benzoyl)-3- (3,4-dimethoxyphenyl)- 4-ethyl-1,4,5,6- tetrahydro- pyridazine and 1-(4-acetamido- benzoyl)-3- (3,4-dimethoxyphenyl)- 4-ethyl-1,4,5,6- tetrahydro- pyridazine and their salts and solvates. Said tetrahydropyridazine derivatives present an inhibiting effect on phosphodiesterase IV and can be used for treating osteoporosis, tumours, arteriosclerosis, rheumatoid arthritis, multiple sclerosis, diabetes mellitus, inflammatory processes, allergies, asthma, autoimmune diseases and AIDS, atopic dermatitis, psoriasis and transplant rejection reactions.

Description

Tetrahydropyridazin-Derivate Tetrahydropyridazine derivatives
Die Erfindung betrifft Tetrahydropyridazinderivate ausgewählt aus derThe invention relates to tetrahydropyridazine derivatives selected from the
Gruppegroup
1-(4-Ureido-benzoyl)-3-(3-ethoxy-4-methoxy-phenyl)-1 ,4,5,6-tetrahydro- pyridazin,1- (4-ureido-benzoyl) -3- (3-ethoxy-4-methoxy-phenyl) -1, 4,5,6-tetrahydropyridazine,
1-(4-Nicotinoylamino-benzoyl)-3-(3-propoxy-4-methoxyphenyl)-1 , 4,5,6- tetrahydro-pyridazin, 1-(4-Trifluoracetamido-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1 , 4,5,6- tetrahydro-pyridazin,1- (4-Nicotinoylamino-benzoyl) -3- (3-propoxy-4-methoxyphenyl) -1, 4,5,6-tetrahydro-pyridazine, 1- (4-trifluoroacetamido-benzoyl) -3- (3-ethoxy -4-methoxyphenyl) -1, 4,5,6-tetrahydro-pyridazine,
1-(4-Ethoxycarbonylamino-benzoyi)-3-(3-propoxy-4-methoxyphenyl)-1- (4-ethoxycarbonylamino-benzoyi) -3- (3-propoxy-4-methoxyphenyl) -
1 ,4,5,6-tetrahydro-pyridazin,1, 4,5,6-tetrahydro-pyridazine,
1-(4-lsopropoxycarbonylamino-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)- 1 ,4,5,6-tetrahydro-pyridazin,1- (4-isopropoxycarbonylamino-benzoyl) -3- (3-ethoxy-4-methoxyphenyl) - 1, 4,5,6-tetrahydro-pyridazine,
1-(4-Propoxycarbonylamino-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1- (4-propoxycarbonylamino-benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -
1 ,4,5,6-tetrahydro-pyridazin,1, 4,5,6-tetrahydro-pyridazine,
1-(4-Nicotinoylamino-benzoyl)-3-(3,4-dimethoxyphenyl)-4-ethyl-1 , 4,5,6- tetrahydro-pyridazin, 1-(4-Ethoxycarbonylamino-benzoyl)-3-(3,4-dimethoxyphenyl)-4-ethyl-1- (4-Nicotinoylamino-benzoyl) -3- (3,4-dimethoxyphenyl) -4-ethyl-1, 4,5,6-tetrahydro-pyridazine, 1- (4-ethoxycarbonylamino-benzoyl) -3- (3rd , 4-dimethoxyphenyl) -4-ethyl-
1 ,4,5,6-tetrahydro-pyridazin und1, 4,5,6-tetrahydro-pyridazine and
1-(4-Acetamido-benzoyl)-3-(3,4-dimethoxyphenyl)-4-ethyl-1 ,4,5,6-tetra- hydro-pyridazin,1- (4-acetamido-benzoyl) -3- (3,4-dimethoxyphenyl) -4-ethyl-1, 4,5,6-tetra-hydro-pyridazine,
sowie deren Salze und Solvate.and their salts and solvates.
Verbindungen der Formel ICompounds of formula I.
Figure imgf000003_0001
worin B A, OA, NH2, NHA, NAA' oder einen ungesättigten Hetero- cyclus mit 1 bis 4 N-, O- und/oder S-Atomen, der unsubstitu- iert oder ein-, zwei- oder dreifach durch Hai, A und/oder OA substituiert sein kann,
Figure imgf000003_0001
wherein BA, OA, NH 2 , NHA, NAA 'or an unsaturated heterocycle with 1 to 4 N, O and / or S atoms, which is unsubstituted or one, two or three times by shark, A and / or OA can be substituted,
Q fehlt oder Alkylen mit 1-6 C-Atomen,Q is absent or alkylene with 1-6 C atoms,
R1, R2 jeweils unabhängig voneinander -OH, OR5, -S-R5,R 1 , R 2 each independently of one another -OH, OR 5 , -SR 5 ,
-SO-R5, -SO2-R5, Hai, -NO2, -NH2, -NHR5 oder -NR5R6,-SO-R 5 , -SO 2 -R 5 , shark, -NO 2 , -NH 2 , -NHR 5 or -NR 5 R 6 ,
R1 und R2 zusammen auch -O-CH2-O-,R 1 and R 2 together also -O-CH 2 -O-,
R5 und R jeweils unabhängig voneinander A, Cycloalkyl mit 3-7R 5 and R are each independently A, cycloalkyl with 3-7
C-Atomen, Methylencycloalkyl mit 4-8 C-Atomen oder Alkenyl mit 2-8 C-Atomen,C atoms, methylene cycloalkyl with 4-8 C atoms or alkenyl with 2-8 C atoms,
A, A' jeweils unabhängig voneinander Alkyl mit 1 bis 10 C-Atomen, das durch 1 bis 5 F- und/oder Cl-Atome substituiert sein kann undA, A 'each independently of one another alkyl having 1 to 10 C atoms, which can be substituted by 1 to 5 F and / or Cl atoms and
Hai F, Cl, Br oder IShark F, Cl, Br or I
bedeuten,mean,
sowie deren physiologisch unbedenklichen Salze sind bekannt aus der WO 98/06704.and their physiologically acceptable salts are known from WO 98/06704.
Die erfindungsgemäßen Verbindungen sind zum Teil als Auswahlerfindung in bezug auf die dort beschriebenen Strukturen zu betrachten.The compounds according to the invention are to be regarded in part as selection inventions with regard to the structures described there.
Der Erfindung lag die Aufgabe zugrunde, neue Verbindungen mit wertvollen Eigenschaften aufzufinden, insbesondere solche, die zur Herstellung von Arzneimitteln verwendet werden können. Es wurde gefunden, daß die erfindungsgemäßen Verbindungen und ihre Salze bei guter Verträglichkeit sehr wertvolle pharmakologische Eigenschaften besitzen.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.
Insbesondere zeigen sie eine selektive Phosphodiesterase IV-Hemmung, die mit einer intrazellulären Erhöhung von cAMP verbunden ist (N. Sommer et al., Nature Medicine, 1, 244-248 (1995)).In particular, they show selective phosphodiesterase IV inhibition, which is associated with an intracellular increase in cAMP (N. Sommer et al., Nature Medicine, 1, 244-248 (1995)).
Die PDE IV-Hemmung kann z.B. analog C.W. Davis in Biochim. biophys. Acta 797, 354-362 (1984) nachgewiesen werden.PDE IV inhibition can e.g. analogous to C.W. Davis in Biochim. biophys. Acta 797, 354-362 (1984).
Die erfindungsgemäßen Verbindungen können zur Behandlung von asthmatischen Erkrankungen eingesetzt werden. Die antiasthmatische Wirkung der PDE IV-Hemmer ist z.B. von TJ. Torphy et al. in Thorax, 46, 512-523 (1991) beschrieben und kann z. B. nach der Methode von T. Ols- son, Acta allergologica 26, 438-447 (1971), bestimmt werden.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.
Da cAMP knochenabbauende Zellen hemmt und knochenaufbauende Zellen stimuliert (S. Kasugai et al., M681 und K. Miyamoto, M 682, in Ab- stract der American Society for Bone and Mineral Research 18lh annual meeting, 1996), können die erfindungsgemäßen Verbindungen zur Behandlung von Osteoporose eingesetzt werden.Since cAMP inhibits bone-degrading cells and stimulates bone-building cells (S. Kasugai et al., M681 and K. Miyamoto, M 682, in abstract from the American Society for Bone and Mineral Research 18 lh annual meeting, 1996), the compounds according to the invention can used to treat osteoporosis.
Die Verbindungen zeigen außerdem eine hemmende Wirkung auf die Bildung von TNF (Tumor Nekrose Faktor) und eignen sich daher zur Behand- lung von allergischen und entzündlichen Krankheiten, Autoimmunkrankheiten und Transplantatabstoßungsreaktionen. Sie können zur Behandlung von Gedächtnisstörungen, Tumoren, Atherosklerose, rheumatoide Arthritis, multiple Sklerose, Morbus Crohn, atopi- sche Dermatitis, Diabetes mellitus, Ulzerative Kolitis und AIDS eingesetzt werden.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.
Die Wirkung von PDE IV-Hemmem bei der Behandlung von Asthma, entzündlichen Erkrankungen, Diabetes mellitus, atopischer Dermatitis, Psoriasis, AIDS, Tumorwachstum oder Tumormetastasen ist z.B. in der EP 77 92 91 beschrieben. Die antiinflammatorische Wirkung der erfindungsgemäßen Substanzen und ihre Wirksamkeit zur Behandlung von z.B. Autoimmunerkrankungen, Multiplesklerose oder rheumatoider Arthritis kann analog den Methoden von N. Sommer et al., Nature Medicine, 1, 244-248 (1995) oder L. Sekut et al., Clin. Exp. Immunol., 100, 126-132 (1995) bestimmt werden.The effect of 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).
Die Wirkung von PDE IV-Hemmem bei der Tumorbehandlung ist z.B. in der WO 95 35 281 , WO 95 17 399 oder WO 96 00 215 beschrieben.The effect of PDE IV inhibitors in tumor treatment is e.g. described in WO 95 35 281, WO 95 17 399 or WO 96 00 215.
Die erfindungsgemäßen Verbindungen können als Arzneimittelwirkstoffe in der Human- und Veterinärmedizin eingesetzt werden. Ferner können sie als Zwischenprodukte zur Herstellung weiterer Arzneimittelwirkstoffe eingesetzt werden.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.
Die erfindungsgemäßen Verbindungen können analog folgender Verfahren hergestellt werden, dadurch gekennzeichnet, daß man eine Verbindung der Formel IIThe compounds according to the invention can be prepared analogously to the following processes, characterized in that a compound of the formula II
Figure imgf000006_0001
Figure imgf000006_0001
worinwherein
R1 und R2 die bei Formel I angegebenen Bedeutungen haben undR 1 and R 2 have the meanings given for formula I and
R und R jeweils unabhängig voneinander H oder Alkyl bedeuten,R and R each independently of one another denote H or alkyl,
mit einer Verbindung der Formel IIIwith a compound of formula III
Figure imgf000006_0002
Figure imgf000006_0002
worin B und Q die angegebenen Bedeutungen haben, und L Cl, Br, OH oder eine reaktionsfähige veresterte OH-Gruppe bedeutet,wherein B and Q have the meanings given and L is Cl, Br, OH or a reactive esterified OH group,
umsetzt,implements
oderor
daß man eine Verbindung der Formel IVthat a compound of formula IV
Figure imgf000007_0001
Figure imgf000007_0001
worinwherein
R1, R2, R3, R4 und Q die angegebenen Bedeutungen haben, mit einer Verbindung der Formel VR 1 , R 2 , R 3 , R 4 and Q have the meanings given, with a compound of the formula V.
B-CO-L VB-CO-L V
worinwherein
B die angegebene Bedeutung hat, und L Cl, Br, OH oder eine reaktionsfähige veresterte OH-Gruppe bedeutet,B has the meaning given and L is Cl, Br, OH or a reactive esterified OH group,
umsetzt,implements
und/oder daß man eine basische Verbindung der Formel I durch Behandeln mit einer Säure in eines ihrer Salze überführt. Vor- und nachstehend haben die Reste R1, R2, R3, R4, B,_Q und L die bei den Formeln I, II, III, IV und V angegebenen Bedeutungen, sofern nicht ausdrücklich etwas anderes angegeben ist.and / or that a basic compound of formula I is converted into one of its salts by treatment with an acid. Above and below, the radicals R 1 , R 2 , R 3 , R 4 , B, _Q and L have the meanings given in the formulas I, II, III, IV and V, unless expressly stated otherwise.
Die Verbindungen der Formel I können ein chirales Zentrum aufweisen und können daher in mehreren stereoisomeren Formen auftreten. Alle diese Formen (z. B. R- und S-Formen) und deren Gemische (z. B. die R,S- Formen) sind in der Formel I eingeschlossen.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.
Unter Solvate versteht man Hydrate oder z.B. Alkoholate, wie die Additionsverbindungen mit Methanol, Ethanol oder Isopropanol.Solvates are hydrates or e.g. Alcoholates, such as the addition compounds with methanol, ethanol or isopropanol.
A und A' bedeutet vorzugsweise Alkyl, weiter bevorzugt durch 1 bis 5 Fluor- und/oder Chloratome substituiertes Alkyl.A and A 'is preferably alkyl, more preferably alkyl substituted by 1 to 5 fluorine and / or chlorine atoms.
In den vorstehenden Formeln ist Alkyl vorzugsweise unverzweigt und hat 1 , 2, 3, 4, 5, 6, 7, 8, 9 oder 10 C-Atome, vorzugsweise 1 , 2, 3, 4 oder 5 C-Atome und bedeutet vorzugsweise Methyl, Ethyl, Trifluormethyl, Pen- tafluorethyl oder Propyl, weiterhin bevorzugt Isopropyl, Butyi, Isobutyl, sek.-Butyi oder tert.-Butyl, aber auch n-Pentyl, neo-Pentyl oder Isopentyl.In the above formulas, 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 hat vorzugsweise 3-7 C-Atome und steht bevorzugt für Cyclo- propyl und Cyclobutyl, weiterhin bevorzugt für Cyclopentyl oder Cyclo- hexyl, ferner auch für Cycloheptyl.Cycloalkyl preferably has 3-7 C atoms and is preferably cyclopropyl and cyclobutyl, further preferably cyclopentyl or cyclohexyl, and also cycloheptyl.
Methyiencycloalkyl hat vorzugsweise 4-8 C-Atome und steht bevorzugt für Methylencyclopropyl und Methylencyclobutyl, weiterhin bevorzugt für Me- thylencyclopentyl und Methylencyclohexyl, ferner auch für Methylen- 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 steht vorzugsweise für Vinyl, 1- oder 2-Propenyl, 1 -Butenyl, Iso- butenyl, sek.-Butenyl, ferner bevorzugt ist 1-Pentenyl, iso-Pentenyl oder 1- Hexenyl.Alkenyl preferably stands for vinyl, 1- or 2-propenyl, 1-butenyl, isobutenyl, sec-butenyl, further preferred is 1-pentenyl, isopentyl or 1-hexenyl.
Alkylen ist vorzugsweise unverzweigt und bedeutet bevorzugt Methylen oder Ethylen, ferner bevorzugt Propylen oder Butylen. Von den Resten R3 und R4 steht einer vorzugsweise für H, während der andere bevorzugt Propyl oder Butyl, besonders bevorzugt aber Ethyl oder Methyl bedeutet. Ferner bedeuten R3 und R4 auch zusammen bevorzugt jeweils Wasserstoff.Alkylene is preferably unbranched and is preferably methylene or ethylene, more preferably propylene or butylene. Of the radicals R 3 and R 4 , one is preferably H, while the other is preferably propyl or butyl, but particularly preferably ethyl or methyl. Furthermore, R 3 and R 4 together preferably each represent hydrogen.
Hai bedeutet vorzugsweise F, Cl oder Br, aber auch I.Shark preferably means F, Cl or Br, but also I.
Die Reste R1 und R2 können gleich oder verschieden sein und stehen in der 3- oder 4-Position des Phenylrings. Sie bedeuten beispielsweise unabhängig voneinander Hydroxy, -S-CH3, -SO-CH3, -SO2CH3, F, Cl, Br oder I oder zusammen Methylendioxy. Besonders bevorzugt stehen sie aber jeweils für Methoxy, Ethoxy, Propoxy, Cyclopentoxy, oder aber für Fluor-, Difluor-, Trifluormethoxy, 1 -Fluor-, 2-Fluor-, 1 ,2-Difluor-, 2,2-Difluor-, 1 ,2,2- Trifluor- oder 2,2,2-Trifluorethoxy.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.
Der Rest B ist vorzugsweise 2- oder 3-Furyl, 2- oder 3-Thienyl, 1-, 2- oder 3-Pyrrolyl, 1-, 2-, 4- oder 5-lmidazolyl, 1-, 3-, 4- oder 5-Pyrazolyl, 2-, 4- oder 5-Oxazolyl, 3-, 4- oder 5-lsoxazolyl, 2-, 4- oder 5-Thiazolyl, 3-, 4- oder 5-lsothiazolyl, 2-, 3- oder 4-Pyridyl, 2-, 4-, 5- oder 6-Pyrimidinyl, weiterhin bevorzugt 1,2,3-TriazoM-, -4- oder -5-yI, 1 ,2,4-TriazoM-, -3- oder 5-yl, 1- oder 5-Tetrazolyl, 1 ,2,3-Oxadiazol-4- oder -5-yl, 1 ,2,4-Oxadiazol-3- oder - 5-yl, 1 ,3,4-Thiadiazol-2- oder -5-yl, 1 ,2,4-Thiadiazol-3- oder -5-yl, 1 ,2,3- Thiadiazol-4- oder -5-yl, 3- oder 4-Pyridazinyl, Pyrazinyl, 2-, 3-, 4-, 5- 6- oder 7-Benzofuryl, 2-, 3-, 4-, 5-, 6- oder 7-Benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- oder 7-lndolyl, 1-, 2-, 4- oder 5-Benzimidazolyl, 1-, 3-, 4-, 5-, 6- oder 7- Benzopyrazolyl, 2-, 4-, 5-, 6- oder 7-Benzoxazolyl, 3-, 4-, 5-, 6- oder 7- Benzisoxazolyl, 2-, 4-, 5-, 6- oder 7-Benzthiazolyl, 2-, 4-, 5-, 6- oder 7- Benzisothiazolyl, 4-, 5-, 6- oder 7-Benz-2,1 ,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- oder 8-Chinolyl, 1-, 3-, 4-, 5-, 6-, 7- oder 8-lsochinolyl, 3-, 4-, 5-, 6-, 7- oder 8-Cinnoiinyl, 2-, 4-, 5-, 6-, 7- oder 8-Chinazolinyl. Der Rest B bedeutet vorzugsweise weiterhin Methyl, Ethyl, Propyl, n-Butyl, Methoxy, Ethoxy, Propoxy, N-Methylamino, N,N-Dimethylamino, N-Ethyl- amino oder N,N-Diethylamino. Für die gesamte Erfindung gilt, daß sämtliche Reste, die mehrfach auftreten, gleich oder verschieden sein können, d.h. unabhängig voneinander sind.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-yl, 3- or 4-pyridazinyl, pyrazinyl , 2-, 3-, 4-, 5- 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5- , 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6 - or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1, 3-oxadiazolyl, 2- , 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5- , 6-, 7- or 8-cinnoiinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl. 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.
Die erfindungsgemäßen Verbindungen und auch die Ausgangsstoffe zu ihrer Herstellung werden im übrigen nach an sich bekannten Methoden hergestellt, wie sie in der Literatur (z.B. in den Standardwerken wie Houben- Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart), beschrieben sind, und zwar unter Reaktionsbedingungen, die für die genannten Umsetzungen bekannt und geeignet sind. Dabei kann man auch von an sich bekannten, hier nicht näher erwähnten Varianten Gebrauch machen.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.
In den Verbindungen der Formeln II und IV haben R1, R2, R3, R4 und Q die angegebenen Bedeutungen, insbesondere die angegebenen bevorzugten Bedeutungen.In the compounds of the formulas II and IV, R 1 , R 2 , R 3 , R 4 and Q have the meanings indicated, in particular the preferred meanings indicated.
In den Verbindungen der Formeln III und IV steht Q vorzugsweise für Methylen oder Ethylen, ferner bevorzugt für Propylen oder Butylen.In the compounds of the formulas III and IV, Q is preferably methylene or ethylene, more preferably propylene or butylene.
B hat in den Verbindungen der Formeln III und V die angegebenen bevorzugten Bedeutungen, während L Cl, Br, OH oder eine reaktionsfähige veresterte OH-Gruppe bedeutet.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.
Falls L eine reaktionsfähige veresterte OH-Gruppe bedeutet, so ist diese vorzugsweise Alkylsulfonyloxy mit 1-6 C-Atomen (bevorzugt Methyl- sulfonyloxy) oder Arylsulfonyioxy mit 6-10 C-Atomen (bevorzugt Phenyl- oder p-Tolylsulfonyloxy, ferner auch 2-Naphthalinsulfonyloxy).If 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).
Die Ausgangsstoffe können, falls erwünscht, auch in situ gebildet werden, so daß man sie aus dem Reaktionsgemisch nicht isoliert, sondern sofort weiter zu den erfindungsgemäßen Verbindungen umsetzt. Andererseits ist es möglich, die Reaktion stufenweise durchzuführen. Die erfindungsgemäßen Verbindungen können vorzugsweise erhalten werden, indem man Verbindungen der Formel II mit Verbindungen der Formel III umsetzt.If desired, 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.
Die Ausgangsstoffe der Formeln II und III sind teilweise bekannt. Sofern sie nicht bekannt sind, können sie nach an sich bekannten Methoden hergestellt werden.Some of the starting materials of formulas II and III are known. If they are not known, they can be produced by methods known per se.
Im einzelnen erfolgt die Umsetzung der Verbindungen der Formel II mit den Verbindungen der Formel III in Gegenwart oder Abwesenheit eines inerten Lösungsmittels bei Temperaturen zwischen etwa -20 und etwa 150°, vorzugsweise zwischen 20 und 100°.In particular, 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 °.
Als inerte Lösungsmittel eignen sich z.B. Kohlenwasserstoffe wie Hexan, Petrolether, Benzol, Toluol oder Xylol; chlorierte Kohlenwassertoffe wie Trichlorethylen, 1 ,2-Dichlorethan,Tetrachlorkohlenstoff, Chloroform oder Dichlormethan; Alkohole wie Methanol, Ethanol, Isopropanol, n-Propanol, n-Butanol oder tert.-Butanol; Ether wie Diethylether, Diisopropylether, Te- trahydrofuran (THF) oder Dioxan; Glykolether wie Ethylenglykolmono- methyl- oder -monoethylether (Methylglykol oder Ethylglykol), Ethylen- glykoldimethylether (Diglyme); Ketone wie Aceton oder Butanon; Amide wie Acetamid, Dimethylacetamid oder Dimethylformamid (DMF); Nitrile wie Acetonitril; Sulfoxide wie Dimethylsulfoxid (DMSO); Schwefelkohlenstoff; Carbonsäuren wie Ameisensäure oder Essigsäure; Nitroverbindungen wie Nitromethan oder Nitrobenzol; Ester wie Ethylacetat oder Gemische der genannten Lösungsmittel.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); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulfide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned.
Die erfindungsgemäßen Verbindungen können weiterhin erhalten werden, indem man Verbindungen der Formel IV mit Verbindungen der Formel V umsetzt.The compounds according to the invention can furthermore be obtained by reacting compounds of the formula IV with compounds of the formula V.
Die Ausgangsverbindungen der Formeln IV und V sind in der Regel bekannt. Sind sie nicht bekannt, so können sie nach an sich bekannten Methoden hergestellt werden. So ist z.B. die Herstellung von 1-Benzoyl-tetrahydropyridazin in J. Med. Chem. 38, 4878 (1995) beschrieben. ln den Verbindungen der Formel V bedeutet der Rest -CO-L eine voraktivierte Carbonsäure, vorzugsweise ein Carbonsäurehalogenid.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). In the compounds of the formula V, the radical -CO-L denotes a preactivated carboxylic acid, preferably a carboxylic acid halide.
Die Umsetzung der Verbindungen der Formel IV mit Verbindungen der Formel V erfolgt unter den gleichen Bedingungen, betreffend die Reaktionszeit, Temperatur und Lösungsmittel, wie dies für die Umsetzung der Verbindungen der Formel II mit Verbindungen der Formel III beschrieben ist.The 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.
Eine Base der erfindungsgemäßen Verbindungen kann mit einer Säure in das zugehörige Säureadditionssalz übergeführt werden, beispielsweise durch Umsetzung äquivalenter Mengen der Base und der Säure in einem inerten Lösungsmittel wie Ethanoi und anschließendes Eindampfen. Für diese Umsetzung kommen insbesondere Säuren in Frage, die physiolo- gisch unbedenkliche Salze liefern. So können anorganische Säuren verwendet werden, z.B. Schwefelsäure, Salpetersäure, Halogenwasserstoffsäuren wie Chlorwasserstoffsäure oder Bromwasserstoffsäure, Phosphorsäuren wie Orthophosphorsäure, Sulfaminsäure, ferner organische Säuren, insbesondere aliphatische, alicyclische, araliphatische, aromati- sehe oder heteroeyclische ein- oder mehrbasige Carbon-, Sulfon- oder Schwefelsäuren, z.B. Ameisensäure, Essigsäure, Propionsäure, Pivalin- säure, Diethylessigsäure, Malonsäure, Bernsteinsäure, Pimelinsäure, Fu- marsäure, Maleinsäure, Milchsäure, Weinsäure, Äpfelsäure, Citronensäu- re, Gluconsäure, Ascorbinsäure, Nicotinsäure, Isonicotinsäure, Methan- oder Ethansulfonsäure, Ethandisulfonsäure, 2-Hydroxyethansulfonsäure, Benzolsulfonsäure, p-Toluolsulfonsäure, Naphthalin-mono- und disulfon- säuren, Laurylschwefelsäure. Salze mit physiologisch nicht unbedenklichen Säuren, z.B. Pikrate, können zur Isolierung und /oder Aufreinigung der Verbindungen der Formel I verwendet werden.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. In particular, 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.
Gegenstand der Erfindung ist ferner die Verwendung der erfindungsgemäßen Verbindungen und/oder ihrer physiologisch unbedenklichen Salze zur Herstellung pharmazeutischer Zubereitungen, insbesondere auf nichtchemischem Wege. Hierbei können sie zusammen mit mindestens einem festen, flüssigen und/oder halbflüssigen Träger- oder Hilfsstoff und gege- benenfalls in Kombination mit einem oder mehreren weiteren Wirkstoffen in eine geeignete Dosierungsform gebracht werden.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. Here, 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.
Gegenstand der Erfindung sind auch Arzneimittel der erfindungsgemäßen Verbindungen ausgewählt aus der GruppeThe invention also relates to medicaments of the compounds according to the invention selected from the group
1-(4-Ureido-benzoyl)-3-(3-ethoxy-4-methoxy-phenyl)-1 ,4,5,6-tetrahydro- pyridazin,1- (4-ureido-benzoyl) -3- (3-ethoxy-4-methoxy-phenyl) -1, 4,5,6-tetrahydropyridazine,
1-(4-Nicotinoylamino-benzoyl)-3-(3-propoxy-4-methoxyphenyl)-1 , 4,5,6- tetrahydro-pyridazin,1- (4-nicotinoylamino-benzoyl) -3- (3-propoxy-4-methoxyphenyl) -1, 4,5,6-tetrahydro-pyridazine,
1-(4-Trifluoracetamido-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1 , 4,5,6- tetrahydro-pyridazin,1- (4-trifluoroacetamido-benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1, 4,5,6-tetrahydro-pyridazine,
1-(4-Ethoxycarbonylamino-benzoyl)-3-(3-propoxy-4-methoxyphenyl)-1- (4-ethoxycarbonylamino-benzoyl) -3- (3-propoxy-4-methoxyphenyl) -
1 ,4,5,6-tetrahydro-pyridazin, 1 -(4-lsopropoxycarbonylamino-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1, 4,5,6-tetrahydro-pyridazine, 1 - (4-isopropoxycarbonylamino-benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -
1 ,4,5,6-tetrahydro-pyridazin,1, 4,5,6-tetrahydro-pyridazine,
1-(4-Propoxycarbonylamino-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1- (4-propoxycarbonylamino-benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -
1 ,4,5,6-tetrahydro-pyridazin,1, 4,5,6-tetrahydro-pyridazine,
1-(4-Nicotinoylamino-benzoyl)-3-(3,4-dimethoxyphenyl)-4-ethyl-1 , 4,5,6- tetrahydro-pyridazin,1- (4-nicotinoylamino-benzoyl) -3- (3,4-dimethoxyphenyl) -4-ethyl-1, 4,5,6-tetrahydro-pyridazine,
1-(4-Ethoxycarbonylamino-benzoyl)-3-(3,4-dimethoxyphenyl)-4-ethyl-1- (4-ethoxycarbonylamino-benzoyl) -3- (3,4-dimethoxyphenyl) -4-ethyl-
1 ,4,5,6-tetrahydro-pyridazin und1, 4,5,6-tetrahydro-pyridazine and
1-(4-Acetamido-benzoyl)-3-(3,4-dimethoxyphenyi)-4-ethyl-1 ,4,5,6-tetra- hydro-pyridaziπ,1- (4-acetamido-benzoyl) -3- (3,4-dimethoxyphenyi) -4-ethyl-1, 4,5,6-tetra-hydro-pyridaziπ,
und/oder ihre physiologisch unbedenklichen Salze und Solvate als Phosphodiesterase IV-Hemmer.and / or their physiologically acceptable salts and solvates as phosphodiesterase IV inhibitors.
Gegenstand der Erfindung sind ferner pharmazeutische Zubereitungen, enthaltend mindestens eine erfindungsgemäße Verbindung und/oder eines ihrer physiologisch unbedenklichen Salze oder Solvate.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.
Diese Zubereitungen können als Arzneimittel in der Human- oder Veterinärmedizin verwendet werden. Als Trägerstoffe kommen organische oder anorganische Substanzen in Frage, die sich für die enterale (z.B. orale), parenterale oder topische Applikation eignen und mit den neuen Verbin- dungen nicht reagieren, beispielsweise Wasser, pflanzliche Öle, Benzylal- kohole, Alkylenglykole, Polyethylenglykole, Glycerintriacetat, Gelatine, Kohlehydrate wie Lactose oder Stärke, Magnesiumstearat, Talk, Vaseline. Zur oralen Anwendung dienen insbesondere Tabletten, Pillen, Dragees, Kapseln, Pulver, Granulate, Sirupe, Säfte oder Tropfen, zur rektalen Anwendung Suppositorien, zur parenteralen Anwendung Lösungen, vorzugsweise ölige oder wässrige Lösungen, ferner Suspensionen, Emulsionen oder Implantate, für die topische Anwendung Salben, Cremes oder Puder. Die neuen Verbindungen können auch lyophilisiert und die erhalte- nen Lyophilisate z.B. zur Herstellung von Injektionspräparaten verwendet werden. Die angegebenen Zubereitungen können sterilisiert sein und/oder Hilfsstoffe wie Gleit-, Konservierungs-, Stabilisierungs- und/oder Netzmittel, Emulgatoren, Salze zur Beeinflussung des osmotischen Druckes, Puffersubstanzen, Färb-, Geschmacks- und /oder ein oder mehrere weite- re Wirkstoffe enthalten, z.B. ein oder mehrere Vitamine.These preparations can be used as medicinal products in human or veterinary medicine. 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.
Die erfindungsgemäßen Verbindungen und ihre physiologisch unbedenklichen Salze können bei der Bekämpfung von Krankheiten, bei denen eine Erhöhung des cAMP(cyclo-Adenosin-monophosphat)-Spiegels zu Entzün- dungshemmung oder -Verhinderung und Muskelentspannung führt, eingesetzt werden. Besondere Verwendung können die erfindungsgemäßen Verbindungen bei der Behandlung von Allergien, Asthma, chronischer Bronchitis, atopischer Dermatitis, Psoriasis und anderer Hautkrankheiten und Autoimmunerkrankungen finden.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.
Dabei werden die erfindungsgemäßen Substanzen in der Regel vorzugsweise in Dosierungen zwischen etwa 1 und 500 mg, insbesondere zwischen 5 und 100 mg pro Dosierungseinheit verabreicht. Die tägliche Dosierung liegt vorzugsweise zwischen etwa 0,02 und 10 mg/kg Körperge- wicht. Die spezielle Dosis für jeden Patienten hängt jedoch von den verschiedensten Faktoren ab, beispielsweise von der Wirksamkeit der eingesetzten speziellen Verbindung, vom Alter, Körpergewicht, allgemeinen Gesundheitszustand, Geschlecht, von der Kost, vom Verabreichungszeitpunkt und -weg, von der Ausscheidungsgeschwindigkeit, Arzneistoffkom- bination und Schwere der jeweiligen Erkrankung, welcher die Therapie gilt. Die orale Applikation ist bevorzugt. Die erfindungsgemäßen Verbindungen können ein oder mehrere Asymmetriezentren enthalten. In diesem Fall liegen sie gewöhnlich in racemi- scher Form vor. Erhaltene Racemate können nach an sich bekannten Methoden mechanisch oder chemisch in ihre Enantiomeren getrennt werden. Vorzugsweise werden aus dem racemischen Gemisch durch Umsetzung mit einem optisch-aktiven Trennmittel Diastereomere gebildet.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. However, 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.
Natürlich ist es auch möglich, optisch aktive Verbindungen nach den oben beschriebenen Methoden zu erhalten, indem man Ausgangsstoffe verwendet, die bereits optisch aktiv sind.Of course, it is also possible to obtain optically active compounds by the methods described above by using starting materials that are already optically active.
Vor- und nachstehend sind alle Temperaturen in °C angegeben. In den nachfolgenden Beispielen bedeutet "übliche Aufarbeitung": Man gibt, falls erforderlich, Wasser hinzu, stellt, falls erforderlich, je nach Konstitution des Endprodukts auf pH-Werte zwischen 2 und 10 ein, extrahiert mit Ethyla- cetat oder Dichlormethan, trennt ab, trocknet die organische Phase über Natriumsulfat, dampft ein und reinigt durch Chromatographie an Kieselgel und /oder durch Kristallisation.All temperatures above and below are given in ° C. In the examples below, "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.
Massenspektrometrie (MS): El (Elektronenstoß-Ionisation) M+ Mass spectrometry (MS): El (electron impact ionization) M +
FAB (Fast Atom Bombardment) (M+H)+ FAB (Fast Atom Bombardment) (M + H) +
Beispiel 1example 1
Eine Suspension von 4,70 g 3-(3,4-Dimethoxyphenyl)-1 ,4,5,6-tetrahydro- pyridazin ("A") in 150 ml THF wird mit 2,24 g Kalium-tert.-butylat versetzt und 30 Minuten gerührt. Man gibt 7,3 g 4-Nicotinoylaminobenzoylchlorid dazu und rührt 10 Stunden bei Raumtemperatur nach. Das Lösungsmittel wird entfernt und wie üblich aufgearbeitet. Man erhält 1-(4-Nicotinoyl- amino-benzoyl)-3-(3,4-dimethoxyphenyl)-1 ,4,5,6-tetrahydro-pyridazin, Hy- drochlorid, F. 239° (Zersetzung).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. 1- (4-Nicotinoylamino-benzoyl) -3- (3,4-dimethoxyphenyl) -1, 4,5,6-tetrahydro-pyridazine, hydrochloride, mp 239 ° (decomposition) is obtained.
Analog erhält man durch Umsetzung von "A"Analogously, by converting "A"
mit 4-lsonicotinoylamino-benzoylchlorid: 1-(4-lsonicotinoylamino-benzoyl)-3-(3,4-dimethoxyphenyl)-1 ,4,5,6- tetrahydro-pyridazin, Hydrochlorid , F. 247° (Zersetzung).with 4-isonicotinoylamino-benzoyl chloride: 1- (4-isonicotinoylamino-benzoyl) -3- (3,4-dimethoxyphenyl) -1, 4,5,6-tetrahydro-pyridazine, hydrochloride, mp 247 ° (decomposition).
Beispiel 2Example 2
Eine Lösung von 2,0 g 1-(4-Aminobenzoyl)-3-(3,4-dimethoxyphenyl)- 1 ,4,5,6-tetrahydro-pyridazin, F. 197° [erhältlich durch katalytische Hydrierung von 1-(4-Nitrobenzoyl)-3-(3,4-dimethoxyphenyl)-1 ,4,5,6-tetrahydro- pyridazin, F. 203°, in 150 ml Tetrahydrofuran in Gegenwart von 3,5 g Ra- ney-Nickel bei Raumtemperatur] und 1 ,6 ml Pyridin in 150 ml Acetonitril wird mit 1 ,2 g Nicotinoylchlorid-Hydrochlorid versetzt und zwei Stunden nachgerührt. Man entfernt das Lösungsmittel und arbeitet wie üblich auf. Nach Umkristallisation erhält man 1-(4-Nicotinoylamino-benzoyl)-3-(3,4- dimethoxyphenyl)-1 ,4,5,6-tetrahydro-pyridazin, Hydrochlorid, F. 239° (Zer- setzung).A solution of 2.0 g of 1- (4-aminobenzoyl) -3- (3,4-dimethoxyphenyl) -1, 4,5,6-tetrahydro-pyridazine, mp 197 ° [obtainable by catalytic hydrogenation of 1- ( 4-nitrobenzoyl) -3- (3,4-dimethoxyphenyl) -1, 4,5,6-tetrahydropyridazine, mp 203 °, in 150 ml of tetrahydrofuran in the presence of 3.5 g of french nickel at room temperature ] and 1.6 ml of pyridine in 150 ml of acetonitrile are mixed with 1.2 g of nicotinoyl chloride hydrochloride and stirred for two hours. The solvent is removed and the mixture is worked up in the customary manner. After recrystallization, 1- (4-nicotinoylamino-benzoyl) -3- (3,4-dimethoxyphenyl) -1, 4,5,6-tetrahydropyridazine, hydrochloride, mp 239 ° (decomposition) is obtained.
Beispiel 3Example 3
Eine Lösung von 2,0 g 1-(4-Aminobenzoyl)-3-(3,4-dimethoxyphenyl)- 1 ,4,5,6-tetrahydro-pyridazin, F. 197° und 0,8 ml Pyridin in 160 ml Dichlor- methan wird mit 0,6 ml Chlorameisensäureethylester ("B") versetzt und zwei Stunden nachgerührt. Man entfernt das Lösungsmittel und arbeitet wie üblich auf. Nach Umkristallisation aus Isopropanol/Petrolether erhält man 2,2 g 1-(4-Ethoxycarbonylamino-benzoyl)-3-(3,4-dimethoxyphenyl)- 1 ,4,5,6-tetrahydro-pyridazin, F. 165°.A solution of 2.0 g of 1- (4-aminobenzoyl) -3- (3,4-dimethoxyphenyl) -1, 4,5,6-tetrahydropyridazine, mp 197 ° and 0.8 ml of pyridine in 160 ml Dichloromethane is mixed with 0.6 ml of ethyl chloroformate ("B") and stirred for two hours. The solvent is removed and the mixture is worked up in the customary manner. After recrystallization from isopropanol / petroleum ether, 2.2 g of 1- (4-ethoxycarbonylamino-benzoyl) -3- (3,4-dimethoxyphenyl) -1, 4,5,6-tetrahydro-pyridazine, mp 165 °.
Beispiel 4Example 4
Eine Lösung aus 2,0 g 1-(4-Aminobenzoyl)-3-(3,4-dimethoxyphenyl)- 1 ,4,5,6-tetrahydro-pyridazin und 0,8 ml N-Ethylisocyanat in 160 mlA solution of 2.0 g of 1- (4-aminobenzoyl) -3- (3,4-dimethoxyphenyl) -1, 4,5,6-tetrahydro-pyridazine and 0.8 ml of N-ethyl isocyanate in 160 ml
Dichlormethan wird zwei Stunden bei Raumtemeratur gerührt. Man entfernt das Lösungsmittel und arbeitet wie üblich auf. Nach Umkristallisation aus Isopropanol/Petrolether erhält man 2,1 g 1-(4-Ethyiureido-benzoyl)-3- (3,4-dimethoxyphenyl)-1 ,4,5,6-tetrahydro-pyridazin.Dichloromethane is stirred for two hours at room temperature. The solvent is removed and the mixture is worked up in the customary manner. After recrystallization from isopropanol / petroleum ether, 2.1 g of 1- (4-ethyureido-benzoyl) -3- (3,4-dimethoxyphenyl) -1, 4,5,6-tetrahydro-pyridazine are obtained.
Analog erhält man durch Umsetzung mit Kaliumcyanat die Verbindung 1 -(4-Ureido-benzoyl)-3-(3-ethoxy-4-methoxy-phenyl)-1 ,4,5,6- tetrahydro-pyridazin, F. 251°.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 °.
Beispiel 5Example 5
Analog den Beispielen 2 und 3 erhält man nachstehende VerbindungenThe following compounds are obtained analogously to Examples 2 and 3
1-(4-Nicotinoylamino-benzoyl)-3-(3-propoxy-4-methoxyphenyl)- 1 ,4,5,6-tetrahydro-pyridazin, F. 239°;1- (4-Nicotinoylamino-benzoyl) -3- (3-propoxy-4-methoxyphenyl) - 1, 4,5,6-tetrahydropyridazine, mp 239 °;
1-(4-Trifluoracetamido-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)- 1 ,4,5,6-tetrahydro-pyridazin, F. 211°;1- (4-Trifluoroacetamido-benzoyl) -3- (3-ethoxy-4-methoxyphenyl) - 1, 4,5,6-tetrahydropyridazine, mp 211 °;
1-(4-Ethoxycarbonylamino-benzoyl)-3-(3-propoxy-4-methoxyphenyl)- 1 ,4,5,6-tetrahydro-pyridazin, F. 154°;1- (4-Ethoxycarbonylamino-benzoyl) -3- (3-propoxy-4-methoxyphenyl) -1, 4,5,6-tetrahydropyridazine, mp 154 °;
1-(4-lsopropoxycarbonylamino-benzoyl)-3-(3-ethoxy-4- methoxyphenyl)-1 ,4,5,6-tetrahydro-pyridazin, F. 147°;1- (4-isopropoxycarbonylamino-benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1, 4,5,6-tetrahydropyridazine, mp 147 °;
1 -(4-Propoxycarbonylamino-benzoyl)-3-(3-ethoxy-4- methoxyphenyl)-1 ,4,5,6-tetrahydro-pyridazin, F. 113°.1 - (4-Propoxycarbonylamino-benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1, 4,5,6-tetrahydro-pyridazine, mp 113 °.
Beispiel 6Example 6
Analog den Beispielen 2 und 3 erhält man, ausgehend von 1-(4-Amino- benzoyl)-3-(3,4-dimethoxyphenyl)-4-ethyl-1 ,4,5,6-tetrahydro-pyridazin, durch UmsetzungAnalogously to Examples 2 and 3, starting from 1- (4-aminobenzoyl) -3- (3,4-dimethoxyphenyl) -4-ethyl-1, 4,5,6-tetrahydro-pyridazine, is obtained by reaction
mit Nicotinoylchlorid 1-(4-Nicotinoylamino-benzoyl)-3-(3,4-dimethoxyphenyl)-4-ethyl-with nicotinoyl chloride 1- (4-nicotinoylamino-benzoyl) -3- (3,4-dimethoxyphenyl) -4-ethyl-
1 ,4,5,6-tetrahydro-pyridazin, F. 190°;1, 4,5,6-tetrahydro-pyridazine, mp 190 °;
mit "B"with "B"
1-(4-Ethoxycarbonylamino-benzoyl)-3-(3,4-dimethoxyphenyl)-4- ethyl-1 ,4,5,6-tetrahydro-pyridazin, F. 141° und it Acetylchlorid1- (4-ethoxycarbonylamino-benzoyl) -3- (3,4-dimethoxyphenyl) -4-ethyl-1, 4,5,6-tetrahydro-pyridazine, mp 141 ° and it acetyl chloride
1-(4-Acetamido-benzoyl)-3-(3,4-dimethoxyphenyl)-4-ethyl-1 , 4,5,6- tetrahydro-pyridazin, F. 223°.1- (4-Acetamido-benzoyl) -3- (3,4-dimethoxyphenyl) -4-ethyl-1, 4,5,6-tetrahydro-pyridazine, mp 223 °.
Die nachfolgenden Beispiele betreffen pharmazeutische Zubereitungen:The following examples relate to pharmaceutical preparations:
Beispiel A: InjektionsgläserExample A: Injection glasses
Eine Lösung von 100 g eines Wirkstoffes der Formel I und 5 g Dinatrium- hydrogenphosphat wird in 3 I zweifach destilliertem Wasser mit 2 n Salzsäure auf pH 6,5 eingestellt, steril filtriert, in Injektionsgläser abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jedes Injektionsglas enthält 5 mg Wirkstoff.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.
Beispiel B: SuppositorienExample B: Suppositories
Man schmilzt ein Gemisch von 20 g eines Wirkstoffes der Formel I mit 100 g Sojalecithin und 1400 g Kakaobutter, gießt in Formen und läßt er- kalten. Jedes Suppositorium enthält 20 mg Wirkstoff.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.
Beispiel C: LösungExample C: solution
Man bereitet eine Lösung aus 1 g eines Wirkstoffes der Formel I, 9,38 g NaH2PO4 ■ 2 H2O, 28,48 g Na2HPO4 • 12 H2O und 0,1 g Benzalkonium- chlorid in 940 ml zweifach destilliertem Wasser. Man stellt auf pH 6,8 ein, füllt auf 1 I auf und sterilisiert durch Bestrahlung. Diese Lösung kann in Form von Augentropfen verwendet werden.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.
Beispiel D: SalbeExample D: ointment
Man mischt 500 mg eines Wirkstoffes der Formel I mit 99,5 g Vaseline unter aseptischen Bedingungen.500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
Beispiel E: Tabletten Ein Gemisch von 1 kg Wirkstoff der Formel I, 4 kg Lactose, 1,2 kg Kartoffelstärke, 0,2 kg Talk und 0,1 kg Magnesiumstearat wird in üblicher Weise zu Tabletten verpreßt, derart, daß jede Tablette 10 mg Wirkstoff enthält.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.
Beispiel F: DrageesExample F: coated tablets
Analog Beispiel E werden Tabletten gepreßt, die anschließend in üblicher Weise mit einem Überzug aus Saccharose, Kartoffelstärke, Talk, Tragant und Farbstoff überzogen werden.Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
Beispiel G: KapselnExample G: capsules
2 kg Wirkstoff der Formel I werden in üblicher Weise in Hartgelatine- kapseln gefüllt, so daß jede Kapsel 20 mg des Wirkstoffs enthält.2 kg of active ingredient of the formula I are filled into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of the active ingredient.
Beispiel H: AmpullenExample H: ampoules
Eine Lösung von 1 kg Wirkstoff der Formel I in 60 I zweifach destilliertem Wasser wird steril filtriert, in Ampullen abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jede Ampulle enthält 10 mg Wirkstoff.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.
Beispiel I: Inhalations-SprayExample I: Inhalation spray
Man löst 14 g Wirkstoff der Formel I in 10 I isotonischer NaCI-Lösung und füllt die Lösung in handelsübliche Sprühgefäße mit Pump-Mechanismus. Die Lösung kann in Mund oder Nase gesprüht werden. Ein Sprühstoß (etwa 0,1 ml) entspricht einer Dosis von etwa 0,14 mg. 14 g of active ingredient of the formula I are dissolved in 10 I of isotonic NaCI solution and the solution is filled into commercially available spray vessels with a pump mechanism. The solution can be sprayed into the mouth or nose. One spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg.

Claims

Patentansprüche claims
1. Tetrahydropyridazinderivate ausgewählt aus der Gruppe1. Tetrahydropyridazine derivatives selected from the group
1 -(4-Ureido-benzoyl)-3-(3-ethoxy-4-methoxy-phenyl)-1 ,4,5,6- tetrahydro-pyridazin,1 - (4-ureido-benzoyl) -3- (3-ethoxy-4-methoxy-phenyl) -1, 4,5,6-tetrahydro-pyridazine,
1-(4-Nicotinoylamino-benzoyl)-3-(3-propoxy-4-methoxyphenyl)-1- (4-nicotinoylamino-benzoyl) -3- (3-propoxy-4-methoxyphenyl) -
1 ,4,5,6-tetrahydro-pyridazin,1, 4,5,6-tetrahydro-pyridazine,
1-(4-Trifluoracetamido-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)- 1 ,4,5,6-tetrahydro-pyridazin,1- (4-trifluoroacetamido-benzoyl) -3- (3-ethoxy-4-methoxyphenyl) - 1, 4,5,6-tetrahydro-pyridazine,
1-(4-Ethoxycarbonylamino-benzoyl)-3-(3-propoxy-4-methoxyphenyl)-1- (4-ethoxycarbonylamino-benzoyl) -3- (3-propoxy-4-methoxyphenyl) -
1 ,4,5,6-tetrahydro-pyridazin,1, 4,5,6-tetrahydro-pyridazine,
1-(4-lsopropoxycarbonylamino-benzoyl)-3-(3-ethoxy-4- methoxyphenyl)-1 ,4,5,6-tetrahydro-pyridazin, 1 -(4-Propoxycarbonylamino-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1- (4-Isopropoxycarbonylamino-benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1, 4,5,6-tetrahydro-pyridazine, 1 - (4-propoxycarbonylamino-benzoyl) -3- (3-ethoxy -4-methoxyphenyl) -
1 ,4,5,6-tetrahydro-pyridazin,1, 4,5,6-tetrahydro-pyridazine,
1-(4-Nicotinoylamino-benzoyl)-3-(3,4-dimethoxyphenyl)-4-ethyl-1- (4-nicotinoylamino-benzoyl) -3- (3,4-dimethoxyphenyl) -4-ethyl-
1 ,4,5,6-tetrahydro-pyridazin,1, 4,5,6-tetrahydro-pyridazine,
1-(4-Ethoxycarbonylamino-benzoyl)-3-(3,4-dimethoxyphenyl)-4-ethyl- 1,4,5,6-tetrahydro-pyridazin und1- (4-ethoxycarbonylamino-benzoyl) -3- (3,4-dimethoxyphenyl) -4-ethyl-1,4,5,6-tetrahydro-pyridazine and
1-(4-Acetamido-benzoyl)-3-(3,4-dimethoxyphenyl)-4-ethyl-1 ,4,5,6- tetrahydro-pyridazin,1- (4-acetamido-benzoyl) -3- (3,4-dimethoxyphenyl) -4-ethyl-1, 4,5,6-tetrahydro-pyridazine,
sowie deren Salze und Solvate.and their salts and solvates.
2. Pharmazeutische Zubereitung, gekennzeichnet durch einen Gehalt an mindestens einer Verbindung ausgewählt aus der Gruppe2. Pharmaceutical preparation, characterized by a content of at least one compound selected from the group
1 -(4-Ureido-benzoyl)-3-(3-ethoxy-4-methoxy-phenyl)-1 ,4,5,6- tetrahydro-pyridazin,1 - (4-ureido-benzoyl) -3- (3-ethoxy-4-methoxy-phenyl) -1, 4,5,6-tetrahydro-pyridazine,
1-(4-Nicotinoylamino-benzoyl)-3-(3-propoxy-4-methoxyphenyl)-1- (4-nicotinoylamino-benzoyl) -3- (3-propoxy-4-methoxyphenyl) -
1 ,4,5,6-tetrahydro-pyridazin,1, 4,5,6-tetrahydro-pyridazine,
1-(4-Trifluoracetamido-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1- (4-trifluoroacetamido-benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -
1 ,4τ5,6-tetrahydro-pyridazin, 1-(4-Ethoxycarbonylamino-benzoyl)-3-(3-propoxy-4-methoxyphenyl)-1, 4 τ 5,6-tetrahydro-pyridazine, 1- (4-ethoxycarbonylamino-benzoyl) -3- (3-propoxy-4-methoxyphenyl) -
1 ,4,5,6-tetrahydro-pyridazin, 1-(4-lsopropoxycarbonylamino-benzoyl)-3-(3-ethoxy-4- methoxypheny -I Aδ.e-tetrahydro-pyridazin,1, 4,5,6-tetrahydro-pyridazine, 1- (4-isopropoxycarbonylamino-benzoyl) -3- (3-ethoxy-4-methoxypheny -I Aδ.e-tetrahydro-pyridazine,
1-(4-Propoxycarbonylamino-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1- (4-propoxycarbonylamino-benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -
1 ,4,5,6-tetrahydro-pyridazin, 1-(4-Nicotinoylamino-benzoyl)-3-(3,4-dimethoxyphenyl)-4-ethyl-1, 4,5,6-tetrahydro-pyridazine, 1- (4-nicotinoylamino-benzoyl) -3- (3,4-dimethoxyphenyl) -4-ethyl-
1 ,4,5,6-tetrahydro-pyridazin,1, 4,5,6-tetrahydro-pyridazine,
1-(4-Ethoxycarbonylamino-benzoyl)-3-(3,4-dimethoxyphenyl)-4-ethyl-1- (4-ethoxycarbonylamino-benzoyl) -3- (3,4-dimethoxyphenyl) -4-ethyl-
1 ,4,5,6-tetrahydro-pyridazin und1, 4,5,6-tetrahydro-pyridazine and
1-(4-Acetamido-benzoyl)-3-(3,4-dimethoxyphenyl)-4-ethyl-1 , 4,5,6- tetrahydro-pyridazin,1- (4-acetamido-benzoyl) -3- (3,4-dimethoxyphenyl) -4-ethyl-1, 4,5,6-tetrahydro-pyridazine,
und/oder einem ihrer physiologisch unbedenklichen Salze oder Solvate.and / or one of their physiologically acceptable salts or solvates.
Arzneimittel ausgewählt aus der GruppeMedicines selected from the group
1-(4-Ureido-benzoyl)-3-(3-ethoxy-4-methoxy-phenyl)-1 ,4,5,6- tetrahyd ro-pyridazin ,1- (4-ureido-benzoyl) -3- (3-ethoxy-4-methoxy-phenyl) -1, 4,5,6-tetrahydro-pyridazine,
1-(4-Nicotinoyiamino-benzoyl)-3-(3-propoxy-4-methoxyphenyl)- 1 ,4,5,6-tetrahydro-pyridazin,1- (4-nicotinoyiamino-benzoyl) -3- (3-propoxy-4-methoxyphenyl) - 1, 4,5,6-tetrahydro-pyridazine,
1-(4-Trifluoracetamido-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1- (4-trifluoroacetamido-benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -
1 ,4,5,6-tetrahydro-pyridazin,1, 4,5,6-tetrahydro-pyridazine,
1-(4-Ethoxycarbonylamino-benzoyl)-3-(3-propoxy-4-methoxyphenyl)-1- (4-ethoxycarbonylamino-benzoyl) -3- (3-propoxy-4-methoxyphenyl) -
1 ,4,5,6-tetrahydro-pyridazin, 1 -(4-lsopropoxycarbonylamino-benzoyl)-3-(3-ethoxy-4- methoxyphenyl)-1 ,4,5,6-tetrahydro-pyridazin,1, 4,5,6-tetrahydro-pyridazine, 1 - (4-isopropoxycarbonylamino-benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1, 4,5,6-tetrahydro-pyridazine,
1-(4-Propoxycarbonylamino-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1- (4-propoxycarbonylamino-benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -
1 ,4,5,6-tetrahydro-pyridazin,1, 4,5,6-tetrahydro-pyridazine,
1-(4-Nicotinoylamino-benzoyl)-3-(3,4-dimethoxyphenyl)-4-ethyl- 1 ,4,5,6-tetrahydro-pyridazin,1- (4-nicotinoylamino-benzoyl) -3- (3,4-dimethoxyphenyl) -4-ethyl-1, 4,5,6-tetrahydro-pyridazine,
1-(4-Ethoxycarbonylamino-benzoyl)-3-(3,4-dimethoxyphenyl)-4-ethyl-1- (4-ethoxycarbonylamino-benzoyl) -3- (3,4-dimethoxyphenyl) -4-ethyl-
1 ,4,5,6-tetrahydro-pyridazin und1, 4,5,6-tetrahydro-pyridazine and
1-(4-Acetamido-benzoyl)-3-(3,4-dimethoxyphenyl)-4-ethyl-1 , 4,5,6- tetrahydro-pyridazin, und/oder einem ihrer physiologisch unbedenklichen Salze oder Solvate als Phosphodiesterase IV-Hemmer.1- (4-acetamido-benzoyl) -3- (3,4-dimethoxyphenyl) -4-ethyl-1, 4,5,6-tetrahydro-pyridazine, and / or one of their physiologically acceptable salts or solvates as phosphodiesterase IV inhibitors.
4. Verwendung von Verbindungen ausgewählt aus der Gruppe4. Use of compounds selected from the group
1 -(4-Ureido-benzoyl)-3-(3-ethoxy-4-methoxy-phenyl)-1 ,4,5,6- tetrahydro-pyridazin,1 - (4-ureido-benzoyl) -3- (3-ethoxy-4-methoxy-phenyl) -1, 4,5,6-tetrahydro-pyridazine,
1-(4-Nicotinoylamino-benzoyl)-3-(3-propoxy-4-methoxyphenyl)-1- (4-nicotinoylamino-benzoyl) -3- (3-propoxy-4-methoxyphenyl) -
1 ,4,5,6-tetrahydro-pyridazin, 1 -(4-Trifluoracetamido-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1, 4,5,6-tetrahydro-pyridazine, 1 - (4-trifluoroacetamido-benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -
1 ,4,5,6-tetrahydro-pyridazin,1, 4,5,6-tetrahydro-pyridazine,
1-(4-Ethoxycarbonylamino-benzoyl)-3-(3-propoxy-4-methoxyphenyl)-1- (4-ethoxycarbonylamino-benzoyl) -3- (3-propoxy-4-methoxyphenyl) -
1 ,4,5,6-tetrahydro-pyridazin,1, 4,5,6-tetrahydro-pyridazine,
1-(4-lsopropoxycarbonylamino-benzoyl)-3-(3-ethoxy-4- methoxyphenyl)-1 ,4,5,6-tetrahydro-pyridazin,1- (4-isopropoxycarbonylamino-benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1, 4,5,6-tetrahydropyridazine,
1-(4-Propoxycarbonylamino-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1- (4-propoxycarbonylamino-benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -
1 ,4,5,6-tetrahydro-pyridazin,1, 4,5,6-tetrahydro-pyridazine,
1-(4-Nicotinoylamino-benzoyl)-3-(3,4-dimethoxyphenyl)-4-ethyl-1- (4-nicotinoylamino-benzoyl) -3- (3,4-dimethoxyphenyl) -4-ethyl-
1 ,4,5,6-tetrahydro-pyridazin, 1-(4-Ethoxycarbonyiamino-benzoyl)-3-(3,4-dimethoxyphenyl)-4-ethyl-1, 4,5,6-tetrahydro-pyridazine, 1- (4-ethoxycarbonyiamino-benzoyl) -3- (3,4-dimethoxyphenyl) -4-ethyl-
1 ,4,5,6-tetrahydro-pyridazin und1, 4,5,6-tetrahydro-pyridazine and
1-(4-Acetamido-benzoyl)-3-(3,4-dimethoxyphenyl)-4-ethyl-1 ,4,5,6- tetrahydro-pyridazin, und/oder ihrer physiologisch unbedenklichen Salze oder Solvate1- (4-Acetamido-benzoyl) -3- (3,4-dimethoxyphenyl) -4-ethyl-1, 4,5,6-tetrahydro-pyridazine, and / or their physiologically acceptable salts or solvates
zur Herstellung eines Arzneimittels zur Behandlung von Osteoporose,for the manufacture of a medicament for the treatment of osteoporosis,
Tumoren, Atherosklerose, rheumatoide Arthritis, multiple Sklerose,Tumors, atherosclerosis, rheumatoid arthritis, multiple sclerosis,
Diabetes mellitus, ulzerative Kolitis, entzündlichen Krankheiten, Allergien, Asthma, Autoimmunerkrankungen, AIDS, atopischer Dermatitis, Psoriasis und Transplantatabstoßungsreaktionen. Diabetes mellitus, ulcerative colitis, inflammatory diseases, allergies, asthma, autoimmune diseases, AIDS, atopic dermatitis, psoriasis and graft rejection reactions.
PCT/EP2000/002275 1999-04-06 2000-03-15 Tetrahydropyridazine derivatives WO2000059890A1 (en)

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WO2003037349A1 (en) * 2001-10-31 2003-05-08 Merck Patent Gmbh Type 4 phosphodiesterase inhibitors and uses thereof
WO2010099217A1 (en) 2009-02-25 2010-09-02 Braincells, Inc. Modulation of neurogenesis using d-cycloserine combinations
EP2258359A2 (en) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenesis by muscarinic receptor modulation with sabcomelin
EP2275095A2 (en) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenesis by muscarinic receptor modulation
EP2314289A1 (en) 2005-10-31 2011-04-27 Braincells, Inc. Gaba receptor mediated modulation of neurogenesis
WO2011063115A1 (en) 2009-11-19 2011-05-26 Braincells Inc. Combination of nootropic agent with one or more neurogenic or neurogenic sensitizing agents for stimulating or increasing neurogenesis
US7985756B2 (en) 2005-10-21 2011-07-26 Braincells Inc. Modulation of neurogenesis by PDE inhibition
WO2011091033A1 (en) 2010-01-20 2011-07-28 Braincells, Inc. Modulation of neurogenesis by ppar agents
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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000059484A2 (en) * 1999-04-06 2000-10-12 Merck Patent Gmbh Use of arylalkanoylpyridazines
WO2000059484A3 (en) * 1999-04-06 2001-08-23 Merck Patent Gmbh Use of arylalkanoylpyridazines
WO2003037349A1 (en) * 2001-10-31 2003-05-08 Merck Patent Gmbh Type 4 phosphodiesterase inhibitors and uses thereof
EP2275096A2 (en) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenesis via modulation of the muscarinic receptors
EP2258358A2 (en) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenesis with acetylcholinesterase inhibitor
EP2258357A2 (en) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenesis with acetylcholinesterase inhibitor
EP2275095A2 (en) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenesis by muscarinic receptor modulation
EP2258359A2 (en) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenesis by muscarinic receptor modulation with sabcomelin
US7985756B2 (en) 2005-10-21 2011-07-26 Braincells Inc. Modulation of neurogenesis by PDE inhibition
EP2377530A2 (en) 2005-10-21 2011-10-19 Braincells, Inc. Modulation of neurogenesis by PDE inhibition
EP2314289A1 (en) 2005-10-31 2011-04-27 Braincells, Inc. Gaba receptor mediated modulation of neurogenesis
EP2377531A2 (en) 2006-05-09 2011-10-19 Braincells, Inc. Neurogenesis by modulating angiotensin
EP2382975A2 (en) 2006-05-09 2011-11-02 Braincells, Inc. Neurogenesis by modulating angiotensin
WO2010099217A1 (en) 2009-02-25 2010-09-02 Braincells, Inc. Modulation of neurogenesis using d-cycloserine combinations
WO2011063115A1 (en) 2009-11-19 2011-05-26 Braincells Inc. Combination of nootropic agent with one or more neurogenic or neurogenic sensitizing agents for stimulating or increasing neurogenesis
WO2011091033A1 (en) 2010-01-20 2011-07-28 Braincells, Inc. Modulation of neurogenesis by ppar agents
WO2013106547A1 (en) 2012-01-10 2013-07-18 President And Fellows Of Harvard College Beta-cell replication promoting compounds and methods of their use

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