IE921488A1 - Indole derivatives - Google Patents
Indole derivativesInfo
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- IE921488A1 IE921488A1 IE148892A IE921488A IE921488A1 IE 921488 A1 IE921488 A1 IE 921488A1 IE 148892 A IE148892 A IE 148892A IE 921488 A IE921488 A IE 921488A IE 921488 A1 IE921488 A1 IE 921488A1
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- quinuclidin
- carboxamide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- 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
- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
3-(Indole-2-carboxamido)quinuclidines of the formula 1 Ind-CO-NHR in which Ind denotes a 2-indolyl group which is unsubstituted or mono- to trisubstituted by alkyl, alkoxy, alkoxycarbonyl and/or alkylthio each having 1-4 C atoms, 7-11 C-aralkyloxy, 1-5 C-acyloxy, 6-10 C-aroyloxy, 6-10 C-aryloxy, trifluoromethyl, cyano, fluorine, chlorine, hydroxyl, 1-4 C-alkylsulphonyloxy, 6-10 C-arylsulphonyloxy, carboxyl and/or methylenedioxy and R denotes 3-quinuclidinyl and their physiologically acceptable salts, which show selective serotonin-antagonistic action and can be used as psychopharmaceuticals.
Description
MERCK PATENT GESELLSCHAFT MIT BESCHRANKTER HAFTUNG, a body corporate organised under the laws of Germany, of Postfach 41 19, D-6100 Darmstadt 1, Frankfurter Strasse 250, Federal Republic of Germany.
- lfrMerck Patent Gesellschaft mit beschrankter Haftung
6100 Darmstadt
Indole derivatives
The invention relates to novel 3-(indole-2carboxamido)quinuclidine derivatives of the formula I
Ind-CO-NHR I in which
Ind is a 2-indolyl group which is unsubstituted or monosubstituted to trisubstituted by alkyl, alkoxy, alkoxycarbonyl and/or alkylthio with in each case 1-4 C atoms, 7-11 C-aralkyloxy, 1-5 C-acyloxy, 6-10 C-aroyloxy, 6-10 C-aryloxy, trifluoromethyl, cyano, fluorine, chlorine, hydroxyl, 1-4 C-alkylsulfonyloxy, 6-10 C-arylsulfonyloxy, carboxyl, and/or methylenedioxy and
R is 3-quinuclidinyl, and their salts.
The invention is based on the object of finding novel compounds which can be used for the preparation of medicaments.
It has been found that the said substances have useful pharmacological properties combined with good tolerability. These effects make it possible to employ these substances for the treatment of disorders which are characterised by an excess of circulating serotonin or by a serotonergic hyperactivity. These include, in particular, the treatment of psychoses, of nausea and vomiting (as occurs, for example, in the chemotherapeutic or radiotherapeutic treatment of carcinoses), of dementia or other cognitive disorders, of migraine and of addictive disorders. These furthermore include use as an axiolytic, as an anti-aggressive, as an anti-depressive and as an analgesic. In particular, the compounds antagonise the effect of serotonin on 5-HT·, receptors, such as, for example, the von Bezold-Jarisch reflex caused by serotonin (for method see J. Pharm. Pharmacol. 40 (1980), 301-302 and Nature 316 (1985), 126-131). Additionally, the novel compounds displace the substance 3H-GR65630, which is known as a selective 5-HT3 ligand, from homogenised tissue from the endorhinal cortex of the rat (see Europ. J. Pharmacol. 159 (1989), 157-164).
The compounds I and their physiologically acceptable acid addition salts can therefore be used as medicament active compounds and also as intermediates for the preparation of other medicament active compounds.
Similar compounds are described in J.Org. Chem. 40, 2525-2529 (1975), in J.Org.Chem. 38, 3004-3011 (1973) and in J.Org.Chem. 33. 487-490 (1968). However, in all these cases no pharmacological effects are indicated.
In the radical Ind, 1-4-C-alkyl is preferably methyl, additionally also ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl.
1- 4-C-alkoxy is preferably methoxy, additionally also ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.butoxy or tert.-butoxy and 1-5-C-acyloxy is preferably formyloxy or acetyloxy, propanoyloxy, n-butanoyloxy, isobutanoyloxy or pivaloyloxy. 1-4-C-alkylsulfonyloxy is preferably methanesulfonyloxy. 6-10-C-aryloxy is preferably phenyloxy, 7-11-C-aralkyloxy is preferably benzyloxy and 6-10-C-aroyloxy is preferably benzoyloxy.
The radical Ind is preferably an unsubstituted, monosubstituted or disubstituted 2-indolyl group. If Ind is a substituted 2-indolyl group, it is preferably substituted in the 4-, 5- and/or 6-position and/or alkylated in the 1-position. In particular, Ind is preferably
2- indolyl, 5-methoxy-2-indolyl, 1- or 5-methyl-2-indolyl or 4-chloro- or 4-fluoro-2-indolyl. The radical R is
3- quinuclidinyl.
The invention further relates to a process for the preparation of compounds of the formula I and of their salts, characterised in that compounds of the formula II
Ind-CO-X II where Ind has the meaning indicated, and
X is chlorine, bromine, acyloxy, preferably pivaloyloxy, furthermore acetyloxy, propionyloxy or butanoyloxy, 1-6 C-alkoxy, preferably methoxy or ethoxy, 7-11 C-aralkyloxy, preferably benzyloxy or 6-10 C-aroyloxy, preferably benzoyloxy, or hydroxyl, are reacted with 3-quinuclidine, and/or a compound which otherwise corresponds to the formula I, but contains a removable protecting group instead of one or more H atoms, is converted into a compound of the formula I by removing this protecting group and/or a radical Ind in a compound of the formula I is converted into another radical Ind and/or a base of the formula I is converted into one of its salts by treating with an acid and/or a base of the formula I is liberated from a salt by means of a strong base.
The compound of the formula I is otherwise prepared by methods which are known per se, as are described in the literature (for example J. March, Advanced Organic Chemistry, 3rd Edition, John Wiley & Sons, New York; F.M. Finn et al., The Proteins 3rd Ed.
Vol. II Chap. 2 or Houben-Weyl, Methoden der Organischen
Chemie (Methods of Organic Chemistry), Georg-ThiemeVerlag, Stuttgart), and in particular under reaction conditions which are known and suitable for the said reactions. Use can also be made in this connection of variants which are known per se but which are not mentioned here in greater detail.
If desired, the starting materials for the claimed process can also be formed in situ such that they are not isolated from the reaction mixture, but directly reacted further to give a compound of the formula I.
A compound of the formula I is prepared in accordance with methods known per se, as are used in general for preparing amides or in peptide chemistry, preferably by reacting a compound of the formula II with 3-aminoquinuclidine or one of its salts in a suitable solvent, such as, for example, tetrahydrofuran (THF), dimethylformamide (DMF), 1,4-dioxane, alcohols, such as, for example, methanol or ethanol, further ethers, such as, for example, diethyl ether, dichloromethane, or also mixtures of the solvents mentioned, at temperatures between 10® and the relevant boiling point of the solvent used, if appropriate with the addition of an activator or a catalyst, such as, for example, 4-(dimethylamino)pyridine or N,N'-dicyclohexylcarbodiimide, but also pivaloyl chloride, over a period of 0.5 to 72 hours.
The compounds of the formula I contain at least one asymmetric carbon atom. They can therefore exist as racemates if several asymmetric carbon atoms are present, and also as mixtures of several racemates and in various optically active forms. If the compounds have two or more centres of asymmetry, then they are in general obtained in the synthesis as a mixture of racemates, from which the individual racemates can be isolated in pure form, for example by recrystallisation from inert solvents. If desired, the racemates obtained can be resolved into their optical antipodes mechanically or chemically by methods known per se. Preferably, diastereomers are formed from the racemate by reaction with an optically active resolving agent. Suitable resolving agents are, for example, optically active acids, such as the D- and L- forms of tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, camphorsulfonic acids, mandelic acid, malic acid or lactic acid. The various forms of the diastereomers can be separated in a manner known per se, for example by fractional crystallisation, and the optically active compounds of the formula I can be set free from the diastereomers in a known manner.
The compounds of the formula II are known in some cases; the unknown compounds can easily be prepared analogously to the known compounds. Thus, for example, N- or O-acylated compounds can be prepared from the nonacylated precursors by reaction with acid anhydrides, for example acetic anhydride, in basic organic solvents, for example pyridine.
Equally it is also possible to use the methods 5 known per se for derivatising carboxylic acids to prepare compounds of the formula II.
The protecting group can furthermore be removed from compounds which otherwise correspond to the formula I, but instead of one or more H atoms contain a removable protecting group, in particular a protecting group which can be removed by hydrogenolysis, such as benzyloxy, by means of catalytic hydrogenation, compounds of the formula I being obtained. Furthermore, particular compounds which otherwise correspond to the formula I, but instead of one or more H atoms contain a protecting group which can be removed by solvolysis, such as acyl (for example acetyl) or sulfonyl (for example methanesulfonyl or toluenesulfonyl), can be solvolysed to give compounds of the formula I, in particular hydrolysed.
The starting materials for the solvolysis are obtainable, for example, by reactions of 1-Z-Ind-COX with 3-aminoquinuclidine or one of its salts, Ind having the meaning indicated and Z being a group which can be removed by solvolysis. Thus, compounds of the formula I where the radical Ind in the 1-position of the indole contains an acyl group, preferably an alkanoyl, alkylsulfonyl or arylsulfonyl group in each case having up to 10 C atoms, such as methane-, benzene- or p-toluenesulfonyl, can in particular be hydrolysed to give the corresponding compounds which are unsubstituted in the
1-position, for example in acidic, or better, neutral or alkaline medium, at temperatures between 0 and 200°C. Bases used are advantageously sodium hydroxide, potassium hydroxide or calcium hydroxide, sodium carbonate or potassium carbonate or ammonia, under conditions in which the acid amide bond is not cleaved. The chosen solvent is preferably water, lower alcohols such as methanol or ethanol, ethers such as THF or dioxane, sulfones such as tetramethylene sulfone or their mixtures, particularly the mixtures containing water. Hydrolysis can even be carried out while treating with water alone, in particular at boiling heat.
A radical Ind in a compound of the formula I can 5 be converted into another radical Ind, if the chosen reaction conditions do not destroy the acid amide bond, by cleaving, for example, an ether group, the corresponding hydroxy derivative being formed, and/or esterifying a carboxyl group and/or saponifying an ester group and/or removing a carboxyl group by decarboxylation. Thus, the ether can be cleaved by treating with dimethyl sulfideboron tribromide complex, for example in toluene, ethers such as THF or dimethyl sulfoxide, or by fusing with pyridine or aniline hydrohalides, preferably pyridine hydrochloride, at about 150-250eC, or by treating with diisobutylaluminium hydride in toluene at about 0-110°C, or by catalytic hydrogenation, for example in the presence of palladium-carbon in one of the abovementioned inert solvents, for example methanol, at, for example, 0 to 50°C and at, for example, 1 to 10 bar. The said esterifications are carried out, for example, by the treatment of a solution of the carboxylic acid with an alcohol while adding SOC12 or a dehydrating agent, an excess of the alcohol preferably being used as solvent.
Carboxylic acid esters are hydrolysed, for example, by means of acidic or basic catalysis in an aqueous solution which can additionally contain an inert water-miscible organic solvent, such as dioxane. Decarboxylations are advantageously carried out in alkaline medium, for example in Ν,Ν-dimethylaniline at temperatures between 40 and 190°C, preferably between 160 and 190eC.
A resulting base of the formula I can be converted into the respective acid addition salts using an acid. Acids which give physiologically acceptable salts are preferred for this reaction. Thus, inorganic acids can be used, for example sulfuric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, nitric acid, sulfaminic acid, and also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- and ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids, and laurylsulfuric acid. Acid addition salts which are not physiologically acceptable (for example picrates) can be used for the isolation and purification of the bases of the formula I.
If desired, a base of the formula I can be liberated from one of its salts using strong bases such as sodium hydroxide or potassium hydroxide, or sodium carbonate or potassium carbonate.
The invention further relates to the use of compounds of the formula I and/or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by non-chemical routes. In this connection, they can be brought into a suitable administration form together with at least one excipient or auxiliary and, if appropriate, in combination with one or more other active compound(s).
The invention further relates to compositions, in particular pharmaceutical preparations, containing one or more compounds of the formula I and/or their physiologically acceptable salts. These preparations can be employed as medicaments in human and veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatine, carbohydrates such as lactose or starch, magnesium stearate, talc or petroleum jelly. Tablets, coated tablets, capsules, syrups, elixirs, drops or suppositories are used in particular for enteral administration, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants are used for par5 enteral administration, and ointments, creams, plasters or powders are used for topical administration. The novel compounds can also be lyophilised and the resulting lyophilisates used, for example, for the production of injection preparations.
The preparations indicated can be sterilised and/or contain auxiliaries such as lubricants, preservatives, stabilisers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavourings and/or aromatisers. If desired, they can also contain one or more other active compounds, for example one or more vitamins.
Compounds of the formula I and their physiologically acceptable salts can be used in the therapeutic treatment of the human or animal body and in controlling diseases, in particular diseases which are characterised by an excess of circulating serotonin or by a serotonergic hyperactivity. These diseases in particular include psychoses, nausea and vomiting, which arise as accompanying symptoms in the chemotherapeutic and radio25 therapeutic treatment of tumours, dementia and other cognitive disorders, migraine and addictive disorders. This area of application furthermore includes anxiolytic, analgesic and anti-aggressive action.
The substances according to the invention are in this case as a rule administered in analogy to known commercially available preparations (thioridazine, haloperidol), preferably in dosages between about 0.2 and 1000 mg, in particular between 0.2 and 100 mg per dosage unit. The daily dosage is preferably between about 0.003 and 20 mg/kg of body weight. However, the specific dose for each individual patient depends on the most diverse factors, for example on the activity of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and route of administration, and on the excretion rate, medicament combination and severity of the particular disorder to which the therapy applies. Oral administration is preferred.
Examples
In the examples below, customary working up means: water is added, if necessary, the mixture is extracted with ethyl acetate or ether and separated, the organic phase is dried over sodium sulfate and filtered, and the filtrate is evaporated and purified by chromatography on silica gel and/or by crystallisation. Temperatures are indicated in degrees Celsius.
The solidification points refer to the free bases, if not stated otherwise.
Example 1
A solution of 2.4 g of indole-2-carboxylic acid in 70 ml of THF is treated with the equimolar amount of pivaloyl chloride and 2 ml of pyridine. 3.1 g of 3-aminoquinuclidine in 10 ml of THF are then added at room temperature and the mixture is boiled for 3 hours. Customary working up gives N-(quinuclidin-3-yl)indole-2-carboxamide, m.p. 178-80°.
The following are obtained analogously by reaction of 3-aminoquinuclidine with 5-methylindole-2-carboxylic acid
N- (quinuclidin-3-yl) -5-methylindole-2-carboxamide, m.p. 163-165°;
with 6-methoxyindole-2-carboxylic acid
N- (quinuclidin-3-yl)-6-methoxyindole-2-carboxamide, with 5-methoxyindole-2-carboxylic acid
N-(quinuclidin-3-y1)-5-methoxyindole-2-carboxamide, m.p. 250-52°, with 4-fluoroindole-2-carboxylic acid
N-(quinuc1idin-3-y1)-4-fluoroindole-2-carboxamide,
m.p. 255-257°,
- 10 15 with 5-fluoroindole-2-carboxylic acid
N-(quinuclidin-3-yl)-5-fluoroindole-2-carboxamide,
m.p. 316-318°, with l-ethylindole-2-carboxylic acid
N-(quinuclidin-3-yl)-l-ethylindole-2-carboxamide, with 5-ethoxyindole-2-carboxylic acid
N-(quinuclidin-3-yl)-5-ethoxyindole-2-carboxamide, with 6-ethoxyindole-2-carboxylic acid
N-(quinuclidin-3-yl)-6-ethoxyindole-2-carboxamide, with 7-ethoxyindole-2-carboxylic acid
N-(quinuclidin-3-yl)-7-ethoxyindole-2-carboxamide, with 5-cyanoindole-2-carboxylic acid
N-(quinuclidin-3-yl)-5-cyanoindole-2-carboxamide, with 6-cyanoindole-2-carboxylic acid
N-(quinuclidin-3-yl)-6-cyanoindole-2-carboxamide, with 7-cyanoindole-2-carboxylic acid
N-(quinuclidin-3-yl)-7-cyanoindole-2-carboxamide, with 4-chloroindole-2-carboxylic acid
N-(quinuclidin-3-yl)-4-chloroindole-2-carboxamide, m.p. 240-42’, with 5-chloroindole-2-carboxylic acid
N-(quinuclidin-3-yl)-4-chloroindole-2-carboxamide, with 6-chloroindole-2-carboxylic acid
N-(quinuclidin-3-yl)-6-chloroindole-2-carboxamide, with 5,6-dimethoxyindole-2-carboxylic acid
N- (quinuclidin-3-yl )-5,6-dimethoxyindole-2-carboxamide, with 5,6-methylenedioxyindole-2-carboxylic acid
Ny(quinuclidin-3-yl)-5,6-methylenedioxyindole-2carboxamide,
-1115 with 4,5,6-trimethoxyindole-2-carboxylic acid
N-(quinuclidin-3-yl)-4,5,6-trimethoxyindole-2carboxamide, with 5-trifluoromethylindole-2-carboxylic acid
N- (quinuclidin-3-yl) -5-trifluoromethylindole-2carboxamide, with 6-trifluoromethylindole-2-carboxylic acid
N- (quinuclidin-3-yl) -6-trifluoromethylindole-2carboxamide, with 5-benzylindole-2-carboxylic acid
N- (quinuclidin-3-y1) -5-benzy lindole-2-carboxamide, with 6-benzylindole-2-carboxylic acid
N-(quinuclidin-3-yl)-6-benzylindole-2-carboxamide, with 6-benzyl-l-methylindole-2-carboxylic acid
N- (quinuclidin-3-yl) -6-benzyl-l-methy 1 indole-2carboxamide, with 6-chloro-l-methylindole-2-carboxylic acid
N- (quinuclidin-3-yl) -6-chloro-l-methylindole-2carboxamide, with 6-cyano-l-methylindole-2-carboxylic acid
N-(quinuclidin-3-yl) -6-cyano-l-methy1indole-2carboxamide, with l-methylindole-2-carboxylic acid
N-(quinuclidin-3-yl)-l-methylindole-2-carboxamide m.p. 182-84°, with 7-benzylindole-2-carboxylic acid
N-(quinuclidin-3-yl)-7-benzylindole-2-carboxamide, with 6-ethoxy-l-methylindole-2-carboxylic acid
N- (quinuclidin-3-yl) -6-ethoxy-1-methylindole-2carboxamide, with 5-cyan-l-methylindole-2-carboxylic acid
N-(quinuclidin-3-yl) -5-cyan-l-methy1indole-2carboxamide, with 6-propoxyindole-2-carboxylic acid
N- (quinuclidin-3-yl) -6-propoxyindole-2-carboxamide,
- 12 with 7-fluoroindole-2-carboxylic acid
N-(quinuclidin-3-yl)-7-fluoroindole-2-carboxamide, with 4-trifluoromethylindole-2-carboxylic acid
N- (quinuclidin-3-yl) -4-trifluoromethylindole-25 carboxamide, with 5-ethylindole-2-carboxylic acid
N-(quinuclidin-3-yl)-5-ethylindole-2-carboxamide, with 6-tert.-butylindole-2-carboxylic acid
N- (quinuclidin-3-yl)-6-tert.-butylindole-2-car1 0 boxamide and with 6-acetoxy-l-methylindole-2-carboxylic acid
N-(quinuclidin-3-yl)-6-acetoxy-l-methylindole-2carboxamide.
with 4-benzyloxy-indole-2-carboxylic acid 1 5 N-(quinuclidin-3-yl)-4-benzyloxy-indole-2-carboxamide, with 5-benzyloxy-indole-2-carboxylic acid
N-(quinuclidin-3-yl)-5-benzyloxy-indole-2-carboxamide, m.p. 283-284* with 6-benzyloxy-indole-2-carboxylic acid
N-(quinuclidin-3-yl)-6-benzyloxy-indole-2-carboxamide , with 7-benzyloxy-indole-2-carboxylic acid
N-(quinuclidin-3-yl)-7-benzyloxy-indole-2-carboxamide , m.p. 268-269.*
Example 2
300 mg of N-(quinuclidin-3-yl)-5-hydroxyindole2-carboxamide are dissolved in 20 ml of pyridine and treated with 8 ml of acetic anhydride with cooling. The mixture is then stirred for 1 hour at room temperature and worked up in the customary manner. N-(quinuclidin-3yl)-5-acetoxyindole-2-carboxamide is obtained.
The following are obtained analogously by reaction of 4-, 5- or 6-hydroxyindole-2-carboxylic acids with the appropriate carboxylic anhydrides
N-(quinuclidin-3-yl)-5-pivaloyIoxyindole-2-carboxamide, N-(quinuclidin-3-yl)-6-pivaloyloxyindole-2-carboxamide, N-(quinuclidin-3-yl)-6-butanoyloxyindole-2-carboxamide, N-(quinuclidin-3-yl)-5-butanoyloxyloxyindole-2-carbox10 amide,
N-(quinuclidin-3-y1)-4-propanoyloxyindole-2-carboxamide, N-(quinuclidin-3-yl)-5-propanoyloxyindole-2-carboxamide, N-(quinuclidin-3-yl) -6-propanoyloxyindole-2-carboxamide, N-(quinuclidin-3-yl)-4-methanesulfonyloxyindole-2-car15 boxamide,
N-(quinuclidin-3-yl)-5-methanesulfonyloxyindole-2-carboxamide,
N- (quinuclidin-3-yl)-6-methanesulfonyloxyindole-2-carboxamide,
N-(quinuclidin-3-yl)-5-propanoyloxy-l-methylindole-2carboxamide,
N- (quinuclidin-3-yl) -4-methanesulfonyloxy-1-methylindole2-carboxamide,
N- (quinuclidin-3-yl) -5-methanesulf onyloxy-1-methylindole25 2-carboxamide and
N-(quinuclidin-3-yl)-5-acetoxy-1-methylindole-2 carboxamide.
Example 3
0.5 g of N-(quinuclidin-3-yl)-7-benzyloxyindole-2-carboxamide 30 (m.p.268-269°) is dissolved in 40 ml of methanol and, after addition of 0.2 g of palladium-carbon (5%), hydrogenated at room temperature over a period of 1 hour. The hydrogenation solution is then concentrated and worked up in the customary manner. N-(quinuclidin-3-yl)-7-hydroxy35 indole-2-carboxamide is obtained.
The following are obtained analagously by hydrogenation from N-(quinuclidin-3-yl)-5-benzyloxyindole-2-carboxamide (m.p.283-284°) N-(quinuclidin-3-yl)-5-hydroxyindole-2-carboxamide, from N- (quinuclidin-3-yl)-6-benzyloxyindole-2-carboxamide N-(quinuclidin-3-yl)-6-hyroxyindole-2-carboxamide and from N-(quinuclidin-3-yl)-4-benzyloxyindole-2-carboxamide N-(quinuclidin-3-yl)-4-hydroxyindole-2-carboxamide
Example 4
2.7 g of 5-methylindole-2-carboxylic acid are dissolved 10 in 100 ml of THF at room temperature with the addition of
3.0 g of dicyclohexylcarbodiimide (DCC) and treated with
3.2 g of 3-aminoquinuclidine suspended in 20 ml of THF.
The mixture is then stirred for 6 hours at 40° and worked up in the customary manner. N-(quinuclidin-3-yl)-515 methylindole-2-carboxamide is obtained.
The examples below relate to pharmaceutical preparations which contain substances of the formula I or one of their acid addition salts:
Example A: tablets
A mixture of 1 kg of N-(quinuclidin-3-yl)-4chloroindole-2-carboxamide, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in a customary manner to give tablets such that each tablet contains 10 mg of active
compound.
Example B: coated tablets
Analogously to Example A, tablets are pressed and are then coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
Example C: capsules
Hard gelatine capsules are filled with 2 kg of N-(quinuclidin-3-yl)-5-methoxyindole-2-carboxamide in a customary manner such that each capsule contains 20 mg of active compound.
Example D: ampoules
A solution of 1 kg of N-(quinuclidin-3-yl)IE 921488 indole-2-carboxamide in 60 1 of double-distilled water is sterile filtered, poured into ampoules, lyophilised under sterile conditions and sterile sealed. Each ampoule contains 10 mg of active compound.
Tablets, coated tablets, capsules and ampoules which contain another compound of the formula I and/or one or more physiologically acceptable acid addition salts of a compound of the formula I can be obtained analogously.
- 16 Merck Patent Gesellschaft mit beschrankter Haftung
Claims (13)
1. Patent Claims 5 1. 3-(Indole-2-carboxamido)quinuclidines of the formula I Ind-CO-NHR I in which Ind is a 2-indolyl group which is unsubstituted or monosubstituted to trisubstituted by alkyl, alkoxy, alkoxycarboxyl and/or alkylthio with in each case 1-4 C-atoms, 7-11 C-aralkyloxy, 1-5 C-acyloxy, 6-10 C-aroyloxy, 6-10 C-aryloxy, trifluoromethyl, cyano, fluorine, chlorine, hydroxyl, 1-4 C-alkylsulfonyloxy, 6-10 C-arylsulfonyloxy, carboxyl and/or methylenedioxy and R is 3-quinuclidinyl, and their salts.
2. a) N-(Quinuclidin-3-yl)-4-chloroindole-2-carboxamide b) N-(Quinuclidin-3-yl)-5-methoxyindole-2-carboxamide c) N-(Quinuclidin-3-yl)-indole-2-carboxamide d) N-(Quinuclidin-3-yl)-l-methylindole-2-carboxamide e) N-(Quinuclidin-3-yl)-5-methylindole-2-carboxamide f) N-(Quinuclidin-3-yl)-4-fluoroindole-2-carboxamide
3. Process for the preparation of compounds of the formula I according to Claim 1 and of their salts, characterised in that compounds of the formula II Ind-CO-X II where the radical Ind has the meaning given in Claim 1, and X is Cl, Br, acyloxy, alkoxy with in each case 1-6 C30 atoms, aralkyloxy with 7-11 C-atoms, aroyloxy with in each case 6-10 C-atoms or hydroxyl, are reacted with 3-aminoquinuclidine and/or a compound which otherwise 17 10 corresponds to the formula I, but contains a removable protecting group instead of one or more B atoms, ie converted into a compound of the formula I by removing thia protecting group and/or a radical Ind in a compound of the formula I is converted into another radical Ind and/or a base of the formula I is converted into one of its salts by treating with an acid.
4. Process for the production of a pharmaceutical preparation, characterised in that a compound of the formula I according to Claim 1 and/or one of its physiologically acceptable salts is brought into a suitable administration form together with at least one solid, liquid or semi-liquid excipient or auxiliary.
5. Pharmaceutical preparation which contains at least one compound of the formula I according to Claim 1 and/or one of its physiologically acceptable salts.
6. Use of a compound of the formula I according to Claim 1 and/or one of its physiologically acceptable salts in the control of diseases.
7. Use of a compound of the formula I according to Claim 1 and/or one of its physiologically acceptable salts for the production of medicaments.
8. A 3-(indole-2-carboxamido)quinuclidine of the formula I given and defined in Claim 1 or a salt thereof, substantially as hereinbefore described and exemplified.
9. A process for the preparation of a 3-(indole-2carboxamido)quinuclidine of the formula I given and defined in Claim 1 or a salt thereof, substantially as hereinbefore described and exemplified.
10. A 3-(indole-2-carboxamido)quinuclidine of the formula I given and defined in Claim 1 or a salt thereof, whenever prepared by a process claimed in Claim 3 or 9.
11. A pharmaceutical preparation according to Claim 5, substantially as hereinbefore described and exemplified.
12. Use according to Claim 6, substantially as hereinbefore described.
13. Use according to Claim 7, substantially as hereinbefore described and exemplified.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4115215A DE4115215A1 (en) | 1991-05-10 | 1991-05-10 | INDOLDER DERIVATIVES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE921488A1 true IE921488A1 (en) | 1992-11-18 |
Family
ID=6431344
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE148892A IE921488A1 (en) | 1991-05-10 | 1992-07-01 | Indole derivatives |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0512350A3 (en) |
| JP (1) | JPH05155886A (en) |
| KR (1) | KR920021507A (en) |
| AU (1) | AU1604492A (en) |
| CA (1) | CA2068238A1 (en) |
| CS (1) | CS130592A3 (en) |
| DE (1) | DE4115215A1 (en) |
| HU (1) | HU208136B (en) |
| IE (1) | IE921488A1 (en) |
| MX (1) | MX9202152A (en) |
| NO (1) | NO921831L (en) |
| PL (1) | PL294457A2 (en) |
| TW (1) | TW221807B (en) |
| ZA (1) | ZA923351B (en) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0546181B1 (en) * | 1990-08-31 | 1995-08-02 | Nippon Shinyaku Company, Limited | Indole derivatives and their use as serotonin antagonists |
| IT1255467B (en) * | 1992-07-29 | 1995-11-02 | Dompe Farmaceutici Spa | PHARMACOLOGICALLY ACTIVE ACRYLIC STARCHES |
| AU2001282874A1 (en) | 2000-08-18 | 2002-03-04 | Pharmacia And Upjohn Company | Quinuclidine-substituted aryl moieties for treatment of disease (nicotinic acetylcholine receptor ligands) |
| US6492385B2 (en) | 2000-08-18 | 2002-12-10 | Pharmacia & Upjohn Company | Quinuclidine-substituted heteroaryl moieties for treatment of disease |
| WO2002016357A2 (en) | 2000-08-18 | 2002-02-28 | Pharmacia & Upjohn Company | Quinuclidine-substituted aryl moieties for treatment of disease (nicotinic acetylcholine receptor ligands) |
| WO2002015662A2 (en) | 2000-08-21 | 2002-02-28 | Pharmacia & Upjohn Company | Quinuclidine-substituted heteroaryl moieties for treatment of disease (nicotinic acetylcholine receptor antagonists |
| AU2001282875A1 (en) | 2000-08-21 | 2002-03-04 | Pharmacia And Upjohn Company | Quinuclidine-substituted heteroaryl moieties for treatment of disease |
| DE10045112A1 (en) * | 2000-09-11 | 2002-03-21 | Merck Patent Gmbh | Use of indole derivatives for the treatment of diseases of the central nervous system |
| AR036040A1 (en) | 2001-06-12 | 2004-08-04 | Upjohn Co | MULTICICLIC HETEROARYL COMPOUNDS REPLACED WITH QUINUCLIDINES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| AR036041A1 (en) | 2001-06-12 | 2004-08-04 | Upjohn Co | HETEROCICLIC AROMATIC COMPOUNDS REPLACED WITH QUINUCLIDINE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| IL160884A0 (en) | 2001-10-02 | 2004-08-31 | Upjohn Co | Azabicyclic-substituted fused-heteroaryl compounds for the treatment of disease |
| US6849620B2 (en) | 2001-10-26 | 2005-02-01 | Pfizer Inc | N-(azabicyclo moieties)-substituted hetero-bicyclic aromatic compounds for the treatment of disease |
| DE10164139A1 (en) * | 2001-12-27 | 2003-07-10 | Bayer Ag | 2-heteroaryl carboxamides |
| BR0307782A (en) | 2002-02-19 | 2005-01-04 | Upjohn Co | Azabicycle compounds for the treatment of disease |
| US6858613B2 (en) | 2002-02-19 | 2005-02-22 | Pfizer Inc. | Fused bicyclic-N-bridged-heteroaromatic carboxamides for the treatment of disease |
| AU2003253686A1 (en) | 2002-08-01 | 2004-02-23 | Pharmacia & Upjohn Company Llc | 1h-pyrazole and 1h-pyrrole-azabicyclic compounds with alfa-7 nachr activity |
| WO2009158375A1 (en) * | 2008-06-25 | 2009-12-30 | Abbott Laboratories | Aza-cylic indole- 2 -carboxamides and methods of use thereof |
| ES2541528T3 (en) | 2008-11-19 | 2015-07-21 | Forum Pharmaceuticals Inc. | Treatment of cognitive disorders with (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide and pharmaceutically acceptable salts thereof |
| MX357676B (en) | 2010-05-17 | 2018-07-18 | Forum Pharmaceuticals Inc | A crystalline form of (r)-7-chloro-n-(quinuclidin-3-yl)benzo[b]th iophene-2-carboxamide hydrochloride monohydrate. |
| RU2635522C2 (en) | 2012-05-08 | 2017-11-13 | Форум Фармасьютикалз, Инк. | Methods for cognitive function support, treatment or improvement |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU202108B (en) * | 1986-07-30 | 1991-02-28 | Sandoz Ag | Process for producing pharmaceutical compositions containing serotonine antqgonistic derivatives of indol-carboxylic acid or imidazolyl-methyl-carbazol |
| EP0289170B1 (en) * | 1987-04-25 | 1993-06-23 | Beecham Group Plc | Azabicyclic compounds, process for their preparation and pharmaceutical compositions containing them |
| NZ227841A (en) * | 1988-02-12 | 1991-08-27 | Merck Sharp & Dohme | Heterocyclic compounds with at least two non-condensed five membered rings and pharmaceutical compositions |
| DE3810552A1 (en) * | 1988-03-29 | 1989-10-19 | Sandoz Ag | Esters and amides of indole-, benzo[b]thiophene or benzo[b]furancarboxylic acids or 4-amino-2-methoxybenzoic acids with N-heterocyclic or N-heterobicyclic alcohols or amines, processes for their preparation, pharmaceutical compositions containing them and applicator for administration thereof |
-
1991
- 1991-05-10 DE DE4115215A patent/DE4115215A1/en not_active Withdrawn
-
1992
- 1992-04-27 EP EP19920107132 patent/EP0512350A3/en not_active Withdrawn
- 1992-04-29 CS CS921305A patent/CS130592A3/en unknown
- 1992-05-05 AU AU16044/92A patent/AU1604492A/en not_active Abandoned
- 1992-05-07 PL PL29445792A patent/PL294457A2/en unknown
- 1992-05-07 TW TW081103571A patent/TW221807B/zh active
- 1992-05-08 KR KR1019920007824A patent/KR920021507A/en not_active Application Discontinuation
- 1992-05-08 MX MX9202152A patent/MX9202152A/en unknown
- 1992-05-08 ZA ZA923351A patent/ZA923351B/en unknown
- 1992-05-08 NO NO92921831A patent/NO921831L/en unknown
- 1992-05-08 HU HU9201550A patent/HU208136B/en not_active IP Right Cessation
- 1992-05-08 CA CA002068238A patent/CA2068238A1/en not_active Abandoned
- 1992-05-11 JP JP4143642A patent/JPH05155886A/en active Pending
- 1992-07-01 IE IE148892A patent/IE921488A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| HU9201550D0 (en) | 1992-07-28 |
| HUT61541A (en) | 1993-01-28 |
| JPH05155886A (en) | 1993-06-22 |
| HU208136B (en) | 1993-08-30 |
| AU1604492A (en) | 1992-11-12 |
| KR920021507A (en) | 1992-12-18 |
| NO921831L (en) | 1992-11-11 |
| DE4115215A1 (en) | 1992-11-12 |
| ZA923351B (en) | 1993-01-27 |
| CS130592A3 (en) | 1992-11-18 |
| MX9202152A (en) | 1992-11-01 |
| TW221807B (en) | 1994-03-21 |
| NO921831D0 (en) | 1992-05-08 |
| PL294457A2 (en) | 1992-11-16 |
| CA2068238A1 (en) | 1992-11-11 |
| EP0512350A3 (en) | 1992-12-16 |
| EP0512350A2 (en) | 1992-11-11 |
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| FC9A | Application refused sect. 31(1) |