Classifications

• • 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
  • C07D401/14—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 three or more hetero 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

• the invention relates to new 1-pyrazol-3-yl-ethyl-4-indol-3-yl-piperidine derivatives of the formula I.
• R 2 H single to triple through Hal, N0 2 , CON (R 4 ) 2 , S0 2 N (R 4 ) 2 ,
• the invention was therefore based on the object of making available new compounds which, as medicaments, selectively act nerve system, but at the same time have few side effects and have no or only a very low dependency potential.
• the invention further relates to a process for the preparation of compounds of the given formula I and of their salts r, characterized in that a compound of the formula II
• n ⁇ dr R-, 5 have the meanings given above and Z Hal, 0-S0 2 CH 3 , 0-S0 2 CF 3 , OS ⁇ 2-C 6 H 4 or O-SOrCeHs
• R 3 and R 4 have the meanings given above,
• R 1 and R 2 have the meanings given above, converted into an activated form, then reacted with a compound of the formula III under conditions known for the formation of peptide bonds and from the compound thus obtained forms the desired compound of the formula I by means of a reduction reaction,
• Corresponding compounds of the formula I can occur in several enantiomeric forms. All of these forms (e.g. D and L forms) and their mixtures (e.g. the DL forms) are included in Formula 1.
• radicals or parameters R 1 to R 5 , A and Hal have the meanings given in the formulas I to III, unless expressly stated otherwise. If there are several groups of the same name in the molecule, they can assume different definitions independently of one another.
• group A has 1 to 6, preferably 1, 2, 3 or 4, carbon atoms.
• A is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and also also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl.
• Group A furthermore represents a straight-chain or branched alkylene group having 1 to 6, in particular having 1 to 4, carbon atoms, preferably methylene or ethylene, but also, for. B. for ethylidene, trimethylene, -CH (CH 3 ) CH 2 -, -CH2CH (CH 3 ) -, -C (CH 3 ) 2 -,
• the group R 4 -0- when R 4 is A, in particular a straight-chain or branched alkylene group bonded via an oxygen atom and having 1 to 6, in particular 1 to 4, carbon atoms.
• AO is preferably methoxy, ethoxy, 1- or 2-propoxy, 1-butoxy, isobutoxy, sec-butoxy, tert-butoxy.
• a group denoted by phenyl is preferably an unsubstituted phenyl.
• a substituted phenyl group is preferably monosubstituted. However, such a phenyl group can also be substituted twice or three times, where the substituents can be identical or different.
• Preferred substituents are F, Cl, methoxy or OH.
• N0 2 , cyano, A or AO are also suitable as substituents, where A and AO- can have the meanings mentioned above.
• a phenyl group is preferably o-, m-, p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, 2 , 3- 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyl, 3-hydroxy-4-methoxyphenyl, 3-methoxy-4-hydroxyphenyl, 2,3- , 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dihydroxyphenyl, 2,3- or 3,4-methylenedioxyphenyl.
• Hal corresponds to a halogen radical and can be fluorine, chlorine, bromine or iodine. It is particularly preferably fluorine or chlorine.
• R 1 is preferably a hydrogen or has the meanings of A.
• R 2 preferably represents hydrogen or one, two or three times by one Hal, A or R 4 -0-, where R 4 preferably has the meaning of A, but in particular also one, two or three phenyl substituted three times by C0N (R 4 ) 2 or S0 2 N (R 4 ) 2 .
• R 3 is preferably a hydrogen, a radical with the meaning of A, in particular methyl or ethyl, or with the meaning of
• R 4 -0 preferably methoxy or ethoxy. It particularly preferably has the meaning of a cyano, carboxamido or nitro group. In particular, it can also be an optionally substituted sulfonyl group. Possible substituents of this sulfonyl group are Hal, A, A substituted one to three times by Hal.
• R 4 is preferably hydrogen, but may also have the meanings of A, in particular it is a methyl or ethyl radical.
• R 5 is preferably hydrogen, but may also have the meanings of A if appropriate, in particular it is a methyl or ethyl radical.
• R 1 is hydrogen or methyl
• R 2 is hydrogen or a phenyl which is mono- to trisubstituted by Hal
• R 3 denotes hydrogen, fluorine, hydroxy, cyan, carboxamide, ethyl, methoxy or a trifluoromethylsulfonyloxy
• R 4 represents hydrogen or methyl.
• the compounds of the formula I and also their starting compounds are prepared by methods known per se to the person skilled in the art, as are also described in the literature (for example in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag Stuttgart ), produced, under reaction conditions that are known and suitable for the reactions mentioned. In this case, use can also be made of variants which are known per se and are not mentioned here.
• the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I.
• Starting compounds for the preparation of compounds of the formula I can be obtained by liberating them from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis.
• Compounds of the formula I are preferably obtained by coupling reactions of the compounds of the formulas II or IIa known to those skilled in the art with those of the formula III, if appropriate after selective hydrogenation. If possible, the synthesis of compounds of the formula I is carried out in such a way that solvolysis to release the desired compound of the Formula I is superfluous, especially since compounds of this structure often behave unstably under such conditions.
• Preferred starting materials for solvolysis or hydrogenolysis are those which otherwise correspond to the formulas mentioned above, but instead of free amino and / or hydroxyl groups contain corresponding protected amino and or hydroxyl groups, preferably those which instead of an H atom , which is connected to an N atom, carry an amino protective group, in particular those which, instead of an HN group, carry an R'-N group, in which R 'is an amino protective group, and / or those which replace the H atoms of a hydroxy group carry a hydroxy protecting group, e.g. B. those who instead of a group -COOH a group -COOR "gene, wherein R" is a hydroxy protecting group.
• amino protecting group is generally known and refers to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which are easily removable after the desired chemical reaction at another point in the Unsubstituted or substituted acyl, aryl (e.g. dinitrophenyl (DNP), aralkoxymethyl (e.g. benzoxymethyl (BOM)) or aralkyl groups (e.g. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their type and size is otherwise not critical, but those with 1-20, in particular 1-8, are preferred.
• acyl group is to be understood in the broadest sense in connection with the present process.
• acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenacetyl; Aroyl such as benzoyl or tolyl; Aryloxyalkanoyl such as phenoxyacetyl; Alkoxycarbonyl such as methoxycarbonyl,
• Ethoxycarbonyl 2,2,2-trichloroethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl (BOC), 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as benzyloxycarbonyl (CBZ), 4-methoxybenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC).
• Preferred amino protecting groups are BOC, DNP and BOM, furthermore CBZ, benzyl and acetyl.
• hydroxyl protecting group is also generally known and refers to groups which are suitable for protecting a hydroxyl group against chemical reactions, but which are easily removable after the desired chemical reaction has been carried out elsewhere in the molecule. Typical for such groups are unsubstituted or substituted aryl, aralkyl or acyl groups, furthermore also alkyl groups.
• the nature and size of the hydroxy protecting groups is not critical since they are removed again after the desired chemical reaction or reaction sequence; groups with 1-20, in particular, are preferred 1-10 carbon atoms, examples of hydroxy protecting groups include tert-butyl, benzyl, p-nitrobenzoyl, p-toluenesulfonyl protecting groups and acetyl, with benzyl and acetyl being particularly preferred.
• Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran (THF) or dioxane, amides such as dimethylformamide (DMF), and also alcohols such as methanol, ethanol or isopropanol and water. Mixtures of the abovementioned solvents are also suitable. Trifluoroacetic acid is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1.
• the reaction temperatures for the elimination of protective groups are advantageously between about 0 and 50 ° C .; preferably one works between 15 and 30 ° C (room temperature).
• the BOC group can e.g. B. preferably with 40% trifluoroacetic acid in dichloromethane or with about 3 to 5N HCl in dioxane at 15 to 60 ° C, the FMOC group with an about 5 to 20% solution of dimethylamine, diethylamine or piperidine in DMF at 15 to 50 ° C.
• the DNP group can be split off, e.g. B. also with an approximately 3 to 10% solution of 2-mercaptoethanol in DMF / water at 15 to 30 ° C.
• Hydrogenolytically removable protective groups can e.g. B. by treatment with hydrogen in the presence of a catalyst (z. B. a noble metal catalyst such as palladium, advantageously on a support such as coal).
• a catalyst z. B. a noble metal catalyst such as palladium, advantageously on a support such as coal.
• Suitable solvents are the above, in particular z. B. alcohols such as methanol or ethanol or amides such as DMF.
• the hydrogenolysis is generally carried out at temperatures between 0 and about 100 ° C. and pressures between about 1 and 200 bar, preferably at 20 to 30 ° C. and 1 to 10 bar.
• a hydrogeno- CBZ group lysis is successful, for example. B. good at 5 to 10% Pd-C in methanol at 20 to 30 ° C.
• Compounds of the formula I can preferably be obtained by reacting a pyrazole derivative of the formula II with a compound of the formula III.
• the methods known per se for N-alkylation of amines are expediently used.
• the leaving group Z of the formula II is preferably Cl, Br, J, Cr to Ce-alkylsulfonyloxy, such as methane or ethanesulfonyloxy, Ci- to C ⁇ -fluoroalkylsulfonyloxy, such as trifluoromethanesulfonyloxy or Ce-Cio-arylsulfonyloxy such as benzene, p-toluene or 1- or 2-naphthalene sulfonyloxy.
• the reaction succeeds in an inert solvent e.g. B. a halogenated hydrocarbon such as dichloromethane, trichloromethane or carbon tetrachloride, an ether such as THF or dioxane, an amide such as DMF or dimethylacetamide, a nitrile such as acetonitrile.
• an inert solvent e.g. B. a halogenated hydrocarbon such as dichloromethane, trichloromethane or carbon tetrachloride, an ether such as THF or dioxane, an amide such as DMF or dimethylacetamide, a nitrile such as acetonitrile.
• Dimethyl sulfoxide, toluene or benzene are also suitable as solvents. However, mixtures of these solvents can also be used.
• This reaction can be carried out at temperatures between about -10 and 200 ° C., preferably between 0 and 120 ° C
• an alkali or alkaline earth metal hydroxide or carbonate such as sodium, potassium or calcium hydroxide, sodium, potassium or calcium carbonate. If the escape group Z is different from I, the addition of an iodide such as potassium iodide is recommended.
• the starting materials of the formula II can be prepared by methods known from the literature.
• the starting materials of the formula III can be prepared by methods generally known to the person skilled in the art, as are described in manuals on indole chemistry.
• Benzyl and BOC are preferred as protective groups of the piperidine nitrogen.
• These protective groups are added in order to introduce a substituent called R 4 , which is not equal to hydrogen, on the indole nitrogen.
• R 4 substituent which is not equal to hydrogen
• the latter reaction is particularly successful in the presence of a strong base, preferably from the group NaH, KH, KOC (CH 3 ) 3 or n-, sec- or tert-butyl lithium.
• the “amino protecting group” is then cleaved off using one of the methods described above.
• Coupling reactions of compounds of the general formula IIa with compounds of the general formula III can be carried out under conditions known for the formation of peptide bonds.
• Corresponding methods are described, for example, in “Amino acids, peptides, proteins”, Jakubke, Hans-Dieter; Jeschkeit, Hans; Verlag Chemie, Weinheim (1982), but also in Wünsch E. (1974).
• “Synthesis of peptides” in: Houben-Weyl, “Methods of Organic Chemistry", Vol. 15, 1/2, (Ed., Müller, E.) Georg Thieme Verlag, Stuttgart.
• These methods include the azide method, the mixed anhydride method with carbonic acid half-ester Chlorides as anhydride formers, various methods of the activated esters and the carbodiimide method, and their modified form, the DCC additive method, from which the carbonyl compound obtained by the linkage reaction can be reduced by reducing the desired compound of the formula I. release suitable conditions.
• This reaction is preferably carried out in a solvent from the ether group.
• Tetrahydrofuran is particularly preferably used as the solvent.
• this reduction takes place under mild conditions at temperatures from -78 to + 66 ° C., preferably at room temperature.
• this reduction can also be carried out with sodium bis (2-methoxyethoxy) aluminum hydride (e.g. Vitride®). ren. For this purpose, this is used in excess.
• suitable ethers are preferred as solvents.
• a base of the formula I can be converted into the associated acid addition salt using an acid.
• acids that provide physiologically acceptable salts are suitable for this reaction.
• So inorganic acids can be used, e.g. B. sulfuric acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, sulfamic acid, also organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. b.
• Formic acid Acetic acid, trifluoroacetic 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, ethandisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-mono- and disulfonic acids, lauryl-sulfuric acid. Salts with physiologically unacceptable acids, e.g. B. picrates, can be used for the isolation and / or purification of the compounds of formula I.
• physiologically unacceptable acids e.g. B. picrates
• the free bases of the formula I can be liberated from their salts by treatment with strong bases, such as sodium or potassium hydroxide, sodium or potassium carbonate.
• the compounds of the formula I can contain one or more chiral centers and can therefore be present in racemic or in optically active form. Racemates obtained can be separated mechanically or chemically into the enantiomers by methods known per se. Diastereomers are preferably formed from the racemic mixture by reaction with an optically active release agent. Suitable release agents are, for. B. optically active acids, such as the D and L forms of tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, Malic acid, lactic acid or the various optically active camphorsulfonic acids such as ß-camphorsulfonic acid.
• optically active acids such as the D and L forms of tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, Malic acid, lactic acid or the various optically active camphorsulfonic acids such as ß-camphorsulfonic acid.
• Enantiomer separation using a column filled with an optically active separating agent is also advantageous.
• an optically active separating agent eg dinitrobenzoyl-phenylglycine
• a solvent is suitable for.
• optically active compounds of the formula I by the methods described above by using starting materials (for example those of the formula II) which are already optically active.
• the new compounds of formula I and their physiologically harmless salts can therefore be used as active pharmaceutical ingredients for anxiety agents, antidepressants, neuroleptics, anti-Parkinson agents and / or antihypertensives. They are useful for the treatment and prophylaxis of anxiety, for the treatment of panic attacks, schizophrenia, delusional obsessions, Alzheimer's disease, migraines, anorexia, bulimia, sleep disorders and drug abuse or for combating the consequences of cerebral infarction, but also for treatment extrapyramidal motor side effects of neuroleptics are suitable.
• Active pharmaceutical ingredients are used.
• the compounds of the general formula I and their physiologically acceptable salts can therefore be used for the production of pharmaceutical preparations by combining them with the appropriate dose together with at least one carrier or auxiliary and, if desired, with one or more further active ingredients ⁇ rungsform brings.
• the preparations thus obtained can be used as medicaments in human or veterinary medicine.
• Suitable carrier substances are organic or inorganic substances which are suitable for enteral (eg oral or rectal) or parenteral application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, poly- ethylene glycols, glycerol triacetate and other fatty acid glycerides, gelatin, soy lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc or cellulose.
• Capsules, syrups, juices or drops are coated tablets and capsules with enteric coatings or capsule shells. Suppositories are used for rectal application, solutions are used for parenteral application, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants.
• the active compounds claimed according to the invention can also be lyophilized and the lyophilizates obtained, for. B. be used for the production of Injek ⁇ tion preparations.
• the specified preparations can be sterilized and / or
• auxiliaries such as preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants and / or flavorings. If desired, they can also contain one or more other active ingredients, e.g. B. one or more vitamins, diuretics, anti-inflammatory drugs.
• the compounds of the formula I according to the invention are generally administered in analogy to other known preparations which are commercially available for the claimed indications, preferably in doses between about 1 mg and 50 mg, in particular between 5 and 30 mg, per dosage unit.
• the daily dosage is preferably between about 0.02 and 20 mg / kg, in particular 0.2 and 0.4 mg / kg body weight.
• the specific dose for each individual patient depends, however, on a wide variety of factors, for example on the effectiveness of the special compound used, on the age, body weight, general state of health, gender, on the diet, on the time and route of administration, on the Elimination rate, drug combination and severity of each Disease to which the therapy applies. Oral application is preferred.
• the 7-ethyl-3- (1-benzyl-1, 2,3,6-tetrahydro-4-pyridyl) indole obtained from Example 1 is dissolved in a solvent mixture consisting of 2 l of methanol and 0.5 l of glacial acetic acid and dissolved in Presence of a palla third.
• the catalyst is then filtered off and the solvent is distilled off in vacuo.
• the residue obtained is codistilled with toluene and dissolved in 1 liter of water.
• the pH of the solution is made alkaline by adding sodium hydroxide solution (32%). The crystals which precipitate out are separated off and dried.
• Example A Injection glasses
• a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate are adjusted to pH 6.5 in 3 l of double-distilled water with 2 N 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 P0 4 -2H 2 ⁇ , 28.48 g of Na 2 HP0 4 12H 2 0 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.
• 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 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 under sterile conditions. Each ampoule contains 10 mg of active ingredient.

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Citations (5)

• 1996
  • 1996-01-25 DE DE19602505A patent/DE19602505A1/de not_active Withdrawn
• 1997
  • 1997-01-17 CA CA002244136A patent/CA2244136A1/en not_active Abandoned
  • 1997-01-17 EP EP97901049A patent/EP0879234A1/de not_active Withdrawn
  • 1997-01-17 AU AU14432/97A patent/AU715785B2/en not_active Ceased
  • 1997-01-17 PL PL97328228A patent/PL328228A1/xx unknown
  • 1997-01-17 SK SK992-98A patent/SK99298A3/sk unknown
  • 1997-01-17 WO PCT/EP1997/000187 patent/WO1997027186A1/de not_active Application Discontinuation
  • 1997-01-17 CZ CZ982318A patent/CZ231898A3/cs unknown
  • 1997-01-17 KR KR1019980705688A patent/KR19990081970A/ko not_active Application Discontinuation
  • 1997-01-17 BR BR9707467A patent/BR9707467A/pt unknown
  • 1997-01-17 JP JP9526493A patent/JP2000503972A/ja active Pending
  • 1997-01-17 HU HU9900980A patent/HUP9900980A2/hu unknown
  • 1997-01-17 CN CN97191852A patent/CN1209807A/zh active Pending
  • 1997-01-23 ZA ZA9700572A patent/ZA97572B/xx unknown
  • 1997-01-24 AR ARP970100297A patent/AR005549A1/es unknown
• 1998
  • 1998-07-24 NO NO983439A patent/NO983439L/no unknown

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