WO1996026925A1 - Derives de l'arylthioacetamide - Google Patents

Derives de l'arylthioacetamide Download PDF

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Publication number
WO1996026925A1
WO1996026925A1 PCT/JP1996/000412 JP9600412W WO9626925A1 WO 1996026925 A1 WO1996026925 A1 WO 1996026925A1 JP 9600412 W JP9600412 W JP 9600412W WO 9626925 A1 WO9626925 A1 WO 9626925A1
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group
formula
silica gel
methyl
nmr
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PCT/JP1996/000412
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English (en)
Japanese (ja)
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Kiyofumi Ishikawa
Takashi Hayama
Toshio Kamei
Yasufumi Nagata
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Banyu Pharmaceutical Co., Ltd.
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Publication of WO1996026925A1 publication Critical patent/WO1996026925A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/58—Two sulfur atoms

Definitions

  • the present invention relates to novel arylthioacetamide derivatives, and more particularly to arylthioacetamides which are useful in the field of medicine, particularly in the field of treatment and prevention of hypercholesterolemia, hyperlipidemia and arteriosclerosis. It relates to derivatives and their uses.
  • arteriosclerosis and the accompanying frequency of various coronary and cerebral artery diseases have increased.
  • a variety of factors are thought to contribute to the occurrence of arteriosclerosis, and elevated blood cholesterol in particular is considered to be one of the major causes. Therefore, many attempts have been made to develop cholesterol-lowering agents for the purpose of preventing and treating arteriosclerosis, and some of them have already been used clinically.
  • ACAT acyltransferase
  • the present invention provides a novel anti-hypercholesterolemic agent, an anti-hyperlipidemic agent, and a therapeutic and / or prophylactic agent for arteriosclerosis having ACAT inhibitory activity useful in the field of medicine. Disclosure of the invention
  • Ar represents a phenyl group, a naphthyl group or a pyridyl group which may have 1 to 4 substituents selected from the group consisting of a lower alkyl group, a lower alkoxy group, and a halogen atom.
  • R ′ represents a hydrogen atom or a lower alkyl group
  • R 2 and R 3 may be the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a mono-lower alkylamino group or a di-lower alkylamino group
  • any hydrogen atom of the lower alkyl group, lower alkoxy group, lower alkylthio group, mono-lower alkylamino group or di-lower alkylamino group is a morpholino group, a thiomorpholino group, an imidazolyl group, an amino group, Lower alkylamino group, di-lower alkylamino group, 1-piperazinyl group, 4-1-benzyloxycarbonyl—1-piperazinyl N, 0 and 1 may be substituted with a group selected from the group consisting of a group, a hydroxyl group, a lower alkoxy group,
  • lower is used to mean that the group or compound to which it is attached has at most 6, preferably at most 5, carbon atoms.
  • a lower alkyl group is a straight or straight chain having 1-6, preferably 1-5, carbon atoms.
  • the lower alkoxy group means a linear or branched alkoxy group having 1 to 6, preferably 1 to 5 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butkin, sec-butoxy group, tert-butoxy group, pentoxy group and the like.
  • the halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the lower alkylthio group means a linear or branched lower alkylthio group having 1 to 6 carbon atoms, preferably 1 to 5 carbon atoms, such as a methylthio group, an ethylthio group, a propylthio group, and an isopropylthio group.
  • a methylthio group such as a methylthio group, an ethylthio group, a propylthio group, and an isopropylthio group.
  • a mono-lower alkylamino group has 1 to 6 carbon atoms, preferably 1 to 6 carbon atoms.
  • the di-lower alkylamino group means a dialkylamino group having 1 to 6 carbon atoms, preferably 2 linear or branched lower alkyl groups having 1 to 5 carbon atoms, such as a dimethylamino group. , Acetylamino, methylethylamino, methylpropylamino, ethylisopropylamino, butylmethylamino, sec-butylethylamino, tert-butylmethylamino, ethylpentylamino, And an isopentylmethylamino group and a hexylmethylamino group.
  • a lower alkoxy group is a linear or branched lower alkoxycarbonyl group having 1 to 5 carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, or an isocarbonyl group.
  • Propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxy Examples include a carbonyl group, a tert-butoxycarbonyl group, a pentyloxycarbonyl group, an isopentyloxycarbonyl group, a hexyloxycarbonyl group, and the like.
  • Ar represents a phenyl group, a naphthyl group or a pyridyl group which may have 1 to 4 substituents selected from the group consisting of a lower alkyl group, a lower alkoxy group and a halogen atom, and specifically, , Phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-propylphenyl, 2-isopropylphenyl, 3-isopropylphenyl Phenyl group, 4-isopropylphenyl group, 2-butylphenyl group, 3-butylphenyl group, 2-pentylphenyl group, 2-hexylphenyl group, 3-hexylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl, 2-ethoxyquinyl, 3-ethoxy
  • R ′ represents a hydrogen atom or a lower alkyl group.
  • the lower alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, a pentyl group, Examples include an isopentyl group and a hexyl group.
  • R 2 and R 3 are the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a mono-lower alkylamino group or a di-lower alkylamino group (provided that the lower alkyl group, lower alkoxy group, Any hydrogen atom of a lower alkylthio group, a mono-lower alkylamino group or a di-lower alkylamino group is a pyrrolidino group, a morpholino group, a thiomorpholino group, an imidazolyl group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, 1 1 piperazinyl group, 4 benzyloxycarbonyl 1 1 piperazinyl group, hydroxyl group, lower alkoxy group, lower alkoxycarbonyl group, carboxyl group, rubamoyl group and hydroxy
  • lower alkylthio groups include methylthio, ethylthio, propylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, and the like.
  • Examples include a pentylthio group, an isopentylthio group, and a hexylthio group.
  • the mono-lower alkylamino group means a linear or branched lower alkylthio group having 1 to 6 carbon atoms, preferably 1 to 5 carbon atoms, such as a methylamino group, an ethylamino group, and a propylamino group. Isopropylamino group, butylamino group, sec-butylamino group, tert-butylamino group, pentylamino group, isopentylamino group, hexylamino group and the like.
  • the di-lower alkylamino group means a dialkylamino group having 1 to 6 carbon atoms, preferably 2 linear or branched lower alkyl groups having 1 to 5 carbon atoms, such as a dimethylamino group. , Acetylamino, ethylmethylamino, methylpropylamino, ethylisopropylamino, butylmethylamino, sec-butylethylamino, tert-butylmethylamino, ethylpentylamino, And an isopentylmethylamino group and a hexylmethylamino group.
  • the arylthioacetamide derivative of the above formula [I] may optionally be present in the form of an acid addition salt, and examples of such an acid addition salt include hydrochloride, hydrobromide, and iodine.
  • Inorganic salts such as hydrides, sulfates, nitrates, perchlorates or phosphates; or, for example, p-toluenesulfonate, benzenesulfonate, methanesulfonate, oxalate, succinate
  • organic acid salts such as tartrate, citrate, fumarate and maleate, and particularly preferably pharmaceutically acceptable non-toxic salts.
  • the compound of the formula [I] of the present invention can be produced, for example, by the following production methods 1 to 3. Release 1
  • Y examples include, for example, a chlorine atom, a halogen atom such as a bromine atom or an iodine atom, a methanesulfonyloquine group or a P-toluenesulfonyloquine group.
  • Organic sulfonyloxy group and the like can be mentioned.
  • the above Production Methods 1 to 3 are all application examples of reactions well-known in the field of organic synthetic chemistry, and they are capable of selecting various reaction conditions in consideration of the physical properties of raw material compounds and the like.
  • Production method 1 is a conventional amidation reaction in which a carboxylic acid compound [II] is condensed with a pyridylamine or pyrimidinylamine compound [III], and is the most general method that can be used for the synthesis of almost all the compounds of the present invention. is there.
  • This reaction is usually carried out in a suitable solvent in an aromatic hydrocarbon such as benzene, toluene or xylene; ethers such as ethyl ether, tetrahydrofuran or dioxane: halogens such as methylene chloride, chloroform or dichloroethane.
  • Hydrocarbon pyridine, dimethylformamide, case Using an aprotic polar solvent such as tonitrile or dimethyl sulfoxide; or a mixture thereof, usually using a carboxylic acid compound represented by the general formula [II] with a suitable condensation auxiliary, In an equimolar or excess mole, preferably in the range of 1 to 2 moles, and 0.5 to 2 moles or an excess, preferably 0.5 to 2 moles, of the amine compound represented by the general formula [III]. It can be produced by reacting in a molar range.
  • the reaction temperature is generally about -7 (from TC to the boiling point of the solvent, preferably from about 120 ° C to about 150 ° C, and the reaction time is Usually, the reaction time can be from 5 minutes to 10 days, preferably from 1 to 24 hours
  • the condensing aid include dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimid.
  • Carbodimids such as chlorinated hydrochloride (EDCI) and diisopropyl carbodiimide: carbodildimidazole; organic acid chlorides such as chlorocarbonate carbonate, isopropyl chlorocarbonate, p-toluenesulfonic acid chloride and benzenesulfonic acid chloride; chloride Inorganic halogenating reagents such as thionyl, oxyphosphorus chloride, phosphorous pentachloride, phosphorous trichloride, phosphorous tribromide and the like. In order to proceed smoothly, the reaction can be carried out in the presence of a base.
  • organic acid chlorides such as chlorocarbonate carbonate, isopropyl chlorocarbonate, p-toluenesulfonic acid chloride and benzenesulfonic acid chloride
  • chloride Inorganic halogenating reagents such as thionyl, oxyphosphorus chloride, phosphorous pen
  • the base used is, for example, a hydrogenated metal such as sodium hydride, hydrogenated hydride or lithium hydride.
  • a hydrogenated metal such as sodium hydride, hydrogenated hydride or lithium hydride.
  • alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or calcium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate or sodium hydrogen carbonate Salts: or, for example, organic amines such as triethylamine or pyridine etc.
  • These bases are generally used in an equimolar amount to the starting compounds [II] and [III] or Excess moles, preferably in the range of 1 to 5 moles.
  • Production method 2 is a well-known thiol alkylation reaction in the field of synthetic organic chemistry.
  • the target compound of the above formula [la] can be prepared in a solvent that does not affect the reaction, for example, in an aromatic hydrocarbon such as benzene, toluene or xylene: for example, an ether such as ethyl ether, tetrahydrofuran or dioxane.
  • aromatic hydrocarbon such as benzene, toluene or xylene
  • an ether such as ethyl ether, tetrahydrofuran or dioxane.
  • Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; e.g.
  • An aprotic polar solvent such as dimethylformamide, acetonitrile or dimethyl sulfoxide; or a mixture thereof, is usually used to prepare a thiol compound represented by the general formula [IV], V] can be produced by reacting the alkylating agent with the amines in an equimolar amount or a small excess amount, preferably in a range of 1 to 2 mol.
  • the reaction temperature is generally in a range from about ⁇ 70 ° C. to the boiling point of the solvent, preferably from about 120 ° C. to about 150 ° C.
  • the reaction time may be generally from 5 minutes to 10 days, preferably from 1 to 24 hours.
  • a base for example, sodium hydride, lithium hydride or Alkali metal hydrides such as potassium hydride; Alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, lium hydroxide or hydroxide hydroxide; For example, sodium carbonate, carbonate Metal salts such as potassium carbonate and sodium bicarbonate; and organic amines such as triethylamine or pyridine.
  • the amount of the base to be used is generally equimolar or excess, preferably in the range of 1 to 5 mol, based on the raw material compound of the formula [IV].
  • Production method 3 is a sulfide oxidation reaction well known in the field of synthetic organic chemistry.
  • the target compound of the above formula [ Ib ] is used in a solvent that does not affect the reaction, for example, a halogenated hydrocarbon such as methylene chloride, chloroform or dichloroethane, or an aprotic solvent such as ethyl acetate.
  • It can be produced by reacting in a range of 0.5 to 10 mol, preferably 0.5 to 3 mol.
  • the reaction temperature is generally in the range of ⁇ 70 ° C. to the boiling point of the solvent, preferably in the range of about 120 ° C. to about 150 ° C.
  • the reaction time can be from 5 minutes to 10 days, preferably 0.524 hours.
  • the compound [I] of the present invention obtained in the above steps can be isolated and purified by a conventional separation means such as column chromatography, solvent extraction or recrystallization alone or in an appropriate combination. It is.
  • the compounds represented by the general formulas [II] and [V] used in the above production methods 1 to 3 are produced and obtained by various production methods known in organic synthetic chemistry. For example, there are the following methods.
  • Ra represents a lower alkyl group
  • Ar XYR ′ R 2 R 3 and n have the above-mentioned meanings.
  • the compounds of the formulas [III], [IV] and [VI] used in the above-mentioned production method 13 and production method AB may be purchased as a commercial product or disclosed in JP-A-62-174011. No. 268676 or JP-A-3- No. 120243, Production method (compound [111]), Journal, Ob american 'Chemical Society, J. Am. Chem. Soc., Vol. 100, p. 2149 (1978) (Compound [IV]) or a method analogous thereto, and further, can be produced by the production method described in Examples below.
  • the compound of the present invention of the formula [I] extremely strongly inhibits ACAT in mammals, and is expected to be used as an anti-hypercholesterolemic agent, an anti-hyperlipidemic agent, and furthermore as an anti-atherosclerotic agent It is a useful compound.
  • Enzyme specimen A CAT was derived from human liver according to the method described in Clinica Chimica Acta, Smith et al., 158, 271 (11986). Cell line
  • the compound of the present invention potently inhibits ACAT, and is therefore effective for treating and preventing diseases such as hypercholesterolemia, hyperlipidemia, and arteriosclerosis.
  • the compound of the formula [I] of the present invention can be administered orally or parenterally, and when formulated into a form suitable for such administration, it can be used to produce hypercholesterolemia, hyperlipidemia and arterial hyperlipidemia. It can be used for treatment and prevention of sclerosis. When the compound of the present invention is used clinically, it can be administered after formulating various preparations by adding pharmaceutically acceptable additives according to the dosage form.
  • additives commonly used in the field of pharmaceutical preparations can be used, such as gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropyl methylcellulose, carboxymethyl Chilled cellulose, corn starch, microcrystalline wax, white petrolatum, magnesium aluminate metasilicate, calcium phosphate anhydrous, cunic acid, trisodium citrate, hydroquinine propylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, Sugar fatty acid ester, polyoxyethylene hydrogenated castor oil, polyvinylpyrrolidone, magnesium stearate, light gay anhydride, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol Le, polyalkylene glycols, Ru include cyclo dextrin or hydroxypropyl cyclodextrin and the like.
  • Dosage forms formulated as a mixture with these additives include solid preparations such as tablets, capsules, granules, powders or suppositories; or syrups, for example.
  • elixirs and liquid preparations such as injections, which can be prepared according to a usual method in the field of preparations.
  • liquid preparations they may be dissolved or suspended in water or another appropriate medium before use.
  • an injection it may be dissolved or suspended in a physiological saline solution or a glucose solution as necessary, and a buffer or a preservative may be added.
  • These preparations can contain the compound of the present invention in a proportion of 1.0 to 100% by weight, preferably 1.0 to 60% by weight in the total preparation. These formulations may also contain other therapeutically effective compounds.
  • the dose and frequency of administration depend on the sex, age, weight, degree of symptoms and purpose of the patient. In general, for oral administration, 0.01 to 20 mg of Zkg per adult per day is divided into 1 to several doses, and for parenteral administration, 0.001 l It is preferred to administer 22 mgZkg in one or several divided doses.
  • the present invention will be described more specifically with reference to Examples, but the present invention is not limited to these Examples.
  • Example 26 The compound of Example 26 was produced in the same manner as in Example 8.
  • Example 1 2-Chloro-3-nitro-6-methyl-4-methyl-0-thiopyridine (60. Omg, 0.274 mmol), 4- (3-aminopropyl) morpholine (59.3 mg) obtained in Example 1 (2) , 0.411 mmo 1) and triethylamine (48/1, 0.343 mmol) in EtOH (5 ml) were stirred at 80 ° C. for 2 hours under a nitrogen atmosphere.
  • Example 11 2-chloro-3-nitro-6-methyl-4-monomethylthiopyridine (21.9 mg, 0.10 Ommo 1) and 4-propargyl morpholine (18.8 mg, 0 .15 Ommo l), KOAc (1 4.7 mg, 0.15 Ommo 1) and Pd (O) (PP h 3 ) 4 (5.8 mg, 0.005 mmo 1) to DMF (1.Oml) Add 70. The mixture was stirred at C for 12 hours. The mixture was concentrated under reduced pressure, AcOEt was added to the residue, and the mixture was filtered using celite. The filtrate was washed with saturated NaHCO 3 water, and then dried down pressure concentrated Na 2 S0 4.
  • Example 1 2-Chloro-3-nitro-6-methyl-4-monomethylthiopyridine (50 Omg, 2.29 mmol I) and 2-tert-butyldimethylsilyloxyethanethiol (46 Omg, 2) obtained in (2) Under a nitrogen atmosphere, 2 MNaOH (1.20 ml) was added to a solution of .39 mmol) in MeOH (50 ml), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, the residue A c OE t - distributed by H 2 0, the organic layer was dried over N a 2 S 0 4. The residue obtained after concentration under reduced pressure was subjected to column chromatography (manufactured by Merck, silica gel 60).
  • Noxane: AcOEt 9: Purified by 1), and 2- (2-tert-butyldimethylsilyloxhexylthio) -16-methyl-4-methylthio-13-nitropyridine (690 mg) was obtained as a yellow oil. Obtained as a product.
  • Example 7- (1) Using 2- (2-tert-butyldimethylsilyloxyshethylthio) —6-methyl-4-methylthio-13-2-nitropyridine obtained in (1), Example 7- (1) and Example 11 ( It was synthesized in the same manner as in 5).
  • Example 34 Of the compound obtained in Example 34 (4 Omg, 0. 088mmo l ) in DMF (lml) solution of, 0 ° C nitrogen ⁇ air under, NH C l (5. 6mg) , NE t 3 (29. 4 1) , 1-hydroxyl 1 H-benzotriazole (16.2 mg) and EDC I (20.2 mg) were added, and the mixture was stirred at room temperature overnight. The residue of the reaction solution was concentrated under reduced pressure to give Ac OE t - distributed by H 2 0, the organic layer was dried over Na 2 S0 4.
  • Example 44 to prepare the compound of Example 44 45 in the same manner as
  • Example 48 to 50 were prepared in the same manner as in Example 29. c
  • Example 48
  • Example 30 c Example compounds were prepared Example 5 1 61 in the same manner as 51
  • Example 62 The compound was prepared in Example 62, 63 by a method similar to Example 3 [delta]
  • the compound of the present invention by inhibiting ACAT, suppresses the production of cholesterol ester, inhibits the absorption of cholesterol, lowers the blood cholesterol concentration, and further suppresses the accumulation of cholesterol ester in the blood vessel wall. . Therefore, it is expected to be effective as a therapeutic or preventive drug for hypercholesterolemia, hyperlipidemia, arteriosclerosis, and associated heart diseases.

Abstract

Dérivés de l'arylthioacétamide représentés par la formule générale (I) ou ses sels, compatibles sur le plan pharmaceutique. Dans cette formule, Ar correspond à phényle, naphtyle ou pyridyle ayant éventuellement un à quatre substituts choisis dans le groupe constitué d'alkyle inférieur, alcoxy inférieur et d'halogéno; R1 correspond à hydrogène ou à alkyle inférieur; R2 et R3 peuvent être les mêmes ou être différents et chacun correspond à hydrogène, alkyle inférieur, alcoxy inférieur, alkylthio, mono(alkyle inférieur)amino ou di(alkyle inférieur)amino, à condition qu'alkyle inférieur, alcoxy inférieur, alkylthio inférieur, mono(alkyle inférieur)amino ou di(alkyle inférieur)amino puissent être substitués par pyrrolidino, etc. sur n'importe quel atome d'hydrogène; n correspond à 0, 1 ou 2; et X correspond à CH ou N. Les composés, qui inhibent l'ACAT afin de supprimer la formation d'esters de cholesterol, devraient pouvoir être utilisés comme agent thérapeutique ou prophylactique dans l'hypercholestérolémie, l'hyperlipémie, l'artériosclérose et les maladies cardiovasculaires associées.
PCT/JP1996/000412 1995-03-01 1996-02-23 Derives de l'arylthioacetamide WO1996026925A1 (fr)

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US8247573B2 (en) 2009-03-12 2012-08-21 Gruenenthal Gmbh Substituted N-(2-mercaptopyridin-3-yl)amides as KCNQ2/3 modulators
US8299103B2 (en) 2009-06-15 2012-10-30 Boehringer Ingelheim International Gmbh Compounds which selectively modulate the CB2 receptor
US8329735B2 (en) 2010-03-05 2012-12-11 Boehringer Ingelheim International Gmbh Tetrazole compounds which selectively modulate the CB2 receptor
US8383615B2 (en) 2009-06-16 2013-02-26 Boehringer Ingelheim International Gmbh Azetidine 2-carboxamide derivatives which modulate the CB2 receptor
US8383651B2 (en) 2009-09-22 2013-02-26 Boehringer Ingelheim International Gmbh Compounds which selectively modulate the CB2 receptor
US8399673B2 (en) 2009-03-12 2013-03-19 Gruenenthal Gmbh Substituted 2-mercaptoquinoline-3-carboxamides as KCNQ2/3 modulators
US8470852B2 (en) 2010-08-27 2013-06-25 Gruenenthal Gmbh Substituted 2-amino-quinoline-3-carboxamides as KCNQ2/3 modulators
US8546563B2 (en) 2007-11-07 2013-10-01 Boehringer Ingelheim International Gmbh Compounds which modulate the CB2 receptor
US8618129B2 (en) 2010-09-01 2013-12-31 Gruenenthal Gmbh Substituted 1-oxo-dihydroisoquinoline-3-carboxamides as KCNQ2/3 modulators
US8653102B2 (en) 2010-08-27 2014-02-18 Gruenenthal Gmbh Substituted 2-oxo- and 2-thioxo-dihydroquinoline-3-carboxamides as KCNQ2/3 modulators
US8653101B2 (en) 2010-08-27 2014-02-18 Gruenenthal Gmbh Substituted 2-oxy-quinoline-3-carboxamides as KCNQ2/3 modulators
US8846936B2 (en) 2010-07-22 2014-09-30 Boehringer Ingelheim International Gmbh Sulfonyl compounds which modulate the CB2 receptor
US8865744B1 (en) 2013-05-17 2014-10-21 Boehringer Ingelheim International Gmbh (Cyano-dimethyl-methyl)-isoxazoles and -[1,3,4]thiadiazoles
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