CA2068238A1 - Indole derivatives - Google Patents
Indole derivativesInfo
- Publication number
- CA2068238A1 CA2068238A1 CA002068238A CA2068238A CA2068238A1 CA 2068238 A1 CA2068238 A1 CA 2068238A1 CA 002068238 A CA002068238 A CA 002068238A CA 2068238 A CA2068238 A CA 2068238A CA 2068238 A1 CA2068238 A1 CA 2068238A1
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- Prior art keywords
- quinuclidin
- formula
- carboxamide
- compound
- ind
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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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
-
- 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
-
- 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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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Addiction (AREA)
- Pain & Pain Management (AREA)
- Anesthesiology (AREA)
- Otolaryngology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Abstract 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, 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-alkyl-sulfonyloxy, 6-10 C-arylsulfonyloxy, carboxyl and/or methylenedioxy and R is 3-quinuclidinyl and their physiologically accep-table salts which show a selective serotonin-antagonistic effect and can be used as psychophar-maceuticals.
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-alkyl-sulfonyloxy, 6-10 C-arylsulfonyloxy, carboxyl and/or methylenedioxy and R is 3-quinuclidinyl and their physiologically accep-table salts which show a selective serotonin-antagonistic effect and can be used as psychophar-maceuticals.
Description
20~2~
Merck Patent Ge~ellschaft mit be~chrankter ~aftung 6100 Darm~tadt Indole d~rivatives The invention relate~ to novel 3-(indole-2-carboxamido)quinuclidine derivative~ of the formula I
Ind-CO-NHR
in which Ind i~ a 2-indolyl group which is unsubstituted or mono~ubstituted to tri~ubstituted by alkyl, alkoxy, alkoxycarbonyl and/or alkylthio with in each ca~e 1-4 C atom~, 7-11 C-aralkyloxy, 1-5 C acyloxy, 6-10 C-aroyloxy, 6-10 C-aryloxy, trifluoromethyl, cyano, fluorine, chlorine, hydroxyl, 1-4 C-alkyl-sulfonyloxy, 6-10 C-arylsulfonyloxy, carboxyl, and/or methylenedioxy and R i~ 3-quinuclidinyl, and their salts.
The invention i~ based on the object of finding novel compounds which can be u~ed for the preparation of medicaments.
It ha~ been found that the ~aid subqtanceY have useful pharmacological propertie~ combined with good tolerability. These effectq make it possible to employ the~e substances for the treatment of di~orders which are characterised by an exce~c o circulating ~erotonin or by a ~erotonergic hyperactivity. The~e include, in parti-cular, the treatment of psychoses, of naueea and YOmiting (as occur~, for example, in the chemotherapeutic or radiotherapeutic treatment of carcinose~), of dementia or other cognitive di~order~, of migraine and o~ addictive disorders. Thece furthermore include u~e a3 an axiolytic, as an anti.-aggres~ive, as an anti-depre~sive and a~ an 6823~
analgesic. In particular, the compound~ antagonise the effect of ge~otonin on 5-HT3 receptors, quch a8~ for example, the von Bezold-Jarisch reflex caused by ~ero-tonin (for method see J. Pharm. Pharmacol. 40 (1980), 301-302 and Nature 316 (1985), 126-131). Additionally, the novel compound~ di~place the substance 3H-GR65630, which is known aq a selective 5-HT3 ligand, from homogen-ised tiqsue from the endorhiDal ~ortex of the rat (~ee Europ. J. Pharmacol. 159 (1989), 157-164).
The compounds I and their phy~iologically accept-able acid addition salt~ can therefore be used as medica-ment active compound3 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 i~ preferably methyl, additionally also ethyl, n-propyl, isopropyl, n-butyl, is~obutyl, 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 prefer-ably phenyloxy, 7-11-C-aralkyloxy is preferably benzyloxy and 6-10-C-aroyloxy i~ 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 sub-stituted in the 4-, 5- and/or 6-po3ition and/or alkylated in the l-position. In particular, Ind i8 preferably 2-indolyl, 5-methoxy-2-indolyl, 1- or 5-methyl-2-indolyl or 4-chloro- or 4-fluoro-2-indolyl. The radical R i~
Merck Patent Ge~ellschaft mit be~chrankter ~aftung 6100 Darm~tadt Indole d~rivatives The invention relate~ to novel 3-(indole-2-carboxamido)quinuclidine derivative~ of the formula I
Ind-CO-NHR
in which Ind i~ a 2-indolyl group which is unsubstituted or mono~ubstituted to tri~ubstituted by alkyl, alkoxy, alkoxycarbonyl and/or alkylthio with in each ca~e 1-4 C atom~, 7-11 C-aralkyloxy, 1-5 C acyloxy, 6-10 C-aroyloxy, 6-10 C-aryloxy, trifluoromethyl, cyano, fluorine, chlorine, hydroxyl, 1-4 C-alkyl-sulfonyloxy, 6-10 C-arylsulfonyloxy, carboxyl, and/or methylenedioxy and R i~ 3-quinuclidinyl, and their salts.
The invention i~ based on the object of finding novel compounds which can be u~ed for the preparation of medicaments.
It ha~ been found that the ~aid subqtanceY have useful pharmacological propertie~ combined with good tolerability. These effectq make it possible to employ the~e substances for the treatment of di~orders which are characterised by an exce~c o circulating ~erotonin or by a ~erotonergic hyperactivity. The~e include, in parti-cular, the treatment of psychoses, of naueea and YOmiting (as occur~, for example, in the chemotherapeutic or radiotherapeutic treatment of carcinose~), of dementia or other cognitive di~order~, of migraine and o~ addictive disorders. Thece furthermore include u~e a3 an axiolytic, as an anti.-aggres~ive, as an anti-depre~sive and a~ an 6823~
analgesic. In particular, the compound~ antagonise the effect of ge~otonin on 5-HT3 receptors, quch a8~ for example, the von Bezold-Jarisch reflex caused by ~ero-tonin (for method see J. Pharm. Pharmacol. 40 (1980), 301-302 and Nature 316 (1985), 126-131). Additionally, the novel compound~ di~place the substance 3H-GR65630, which is known aq a selective 5-HT3 ligand, from homogen-ised tiqsue from the endorhiDal ~ortex of the rat (~ee Europ. J. Pharmacol. 159 (1989), 157-164).
The compounds I and their phy~iologically accept-able acid addition salt~ can therefore be used as medica-ment active compound3 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 i~ preferably methyl, additionally also ethyl, n-propyl, isopropyl, n-butyl, is~obutyl, 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 prefer-ably phenyloxy, 7-11-C-aralkyloxy is preferably benzyloxy and 6-10-C-aroyloxy i~ 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 sub-stituted in the 4-, 5- and/or 6-po3ition and/or alkylated in the l-position. In particular, Ind i8 preferably 2-indolyl, 5-methoxy-2-indolyl, 1- or 5-methyl-2-indolyl or 4-chloro- or 4-fluoro-2-indolyl. The radical R i~
3-quinuclidinyl.
The invention further relatesl to a process for the preparation o~ compoun~ of the formula I and of their ~alts~, characterised in that compounds of the ~ _ 3 _ 2~823~
formula II
Ind-CO-X II
where Ind has the meaning indicated, and X is chlorine, bromine, acy:loxy, preferably pivaloyloxy, furthermore acetyloxy, propionyloxy or butanoyloxy, 1-6 C-alkoxy, preferably methoxy or ethoxy, 7-11 C-aralkyl-oxy, preferably benzyloxy or 6-10 C-aroyloxy, preferably benzoyloxy, or hydroxyl, are reacted with 3-quinucliciine, 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 i~ converted into another radical Ind and~or a base of the fo~mula 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 ex~mple J. March, Advanced Organic Chemistry, 3rd Edition, John Wiley &
Sons, New York; F.M. Finn et al., ~he Proteinc 3rd Ed.
Vol. II Chap. 2 or Houben-Weyl, Methoden der Organi~chen Chemie (Method~ of Organic Chemi3try~, Georg-Thieme-Verlag, Stuttgart), and in particular under reaction conditions which are known and suitable for the said reactions. Use can al~o be made in this connection o variants which are known per se but which are not men-tioned here in greater detail.
If de3ired, the ~tarting material3 for the claimed proces~ can al80 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 iB prepared in accordance with method~ kn~wn per se, as are u~ed in 2~6g2~3~
general for preparing amidea or in peptide chemi~try, preferably by reacting a compound of the formula II with 3-aminoquinuclidine or one of its salts in a ~uitable solvent, ~uch a~, for example, tetrahydrofuran (THF), S dimethylformamide (DMF), 1,4-dioxane, alcoholq, such as, for example, methanol or ethanol, further ethexs, su~h as, for example, diethyl ether, dichloromethane, or al~o mixtures of the solvents mentioned, at temperatureq between 10 and the relevant boiling point of the ~olvent 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 racemate~ if several asymmetric carbon atoms are present, and also as mixtures of several racemates and in various optically active formq. 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 t~rtaric acid, diben~oyltartaric 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 cry~tallisation, 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 eaqily be prepared analogou~ly to the known compound~. Thus, Por example, N- or 0-acylated compound~ can be prepared from the 2 ~ 3 ~
nonacylated precurqors by reaction with acid anhydrides, for example acetic anhydride, in basic organic solvents, for example pyridine.
~qually it i8 al90 po~ible to u~e the m~thod~
S known per se for derivatising carboxylic acids to prepare compounds of the formula II.
The protecting group can furthermore be removed from compound3 which otherwise correspond to the formula I, but in tead 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 hydroqenation, 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 ~ulfonyl (for example methane-sulfonyl or toluenesulfonyl), can be solvolysed to give compounds of the formula I, in particular hydrolysed.
The starting materials for the ~olvolysis are obtainable, for example, by reactions of 1-Z-Ind-COX with 3-aminoquinuclidine or one of its salts, Ind having the meaning ind-cated and Z being a group which can be removed by solvolysis. Thus, compounds of the formula I
where the radical Ind in the l-po~ition of the indole contains an acyl group, preferably an alkanoyl, alkyl-sulfonyl or arylsulfonyl group in each case having up to 10 C atoms, such as methane-, benzene- or p-toluene-sulfonyl, can in particular be hydrolysed to give the correspondinq compounds which are unsubstituted in the 1-po~ition, for example in acidic, or better, neutral or alkaline medium, at temperature~ between 0 and 200C.
Bases used are advanta~eously sodium hydroxide, potassium hydroxide or calcium hydroxide, sodium carbonate or pota~sium carbonate or ammonia, under conditions in which the acid amide bond is not cleaved. The cho~en solvent is preferably water, lower alcohols such as methanol or ethanol, ether~ such as T~F or dioxane, sulfones ~uch as tetramethylene sulfone or their mixtures, particularly 2 ~
the mixtures containin~ water. Hydrolysis can even ~e carried out while treating with wat~r alone, in parti-cular at boiling h~at.
A radical Ind in a compound of the formula I can S be converted into another radical Ind, if the chosen reaction condition~ do not destroy the acid amide bond, by cleaving, for example, an ether group, the correspond-ing 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 sulfide-boron tribromide complex, for example in toluene, ethers such as THF or dime~hyl sulfoxide, or by fusing with pyridine or aniline hydrohalides, preferably pyridine hydrochloride, at about 150-250C, or by treating with diisobutylaluminium hydride in toluene at about 0-110C, or by catalytic hydrogenation, for example in the pre-sence of palladium-carbon in one of the abovementioned inert solvents, for example methanol, at, for example, 0 to 50C 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. Decarboxylation~ are advantageously carried out in alkaline medium, for example in N,N-dimethylaniline at temperatures between 40 and 190C, preferably between 160 and 190C.
A resulting base of the fo~nula I can be con-verted into the respective acid addition salts using an acid. Acids which give physiologically acceptable salt~
are preferred for thi~ reaction. Thus, inorganic acids can be used, for example ~ulfuric acid, hydrohalic acids ~uch as hydrochloric acid or hydrobromic acid, phosphoric acids 3uch as orthophoYphoric acid, nitric acid, sulfa-minic acid, and al80 organic acid~, in particular 2 ~ 3 ~
aliphatic, alicyclic, araliphatic, aromatic or hetero-cyclic mono- or polyba3ic carboxylic, sulfonic or sulfuric acids, such a~ 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, ~alicylic 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 lauryl-~ulfuric acid. Acid addition ~alts which are not physio-logically acceptable (for example picrate~) can be used for the isolation and purification o~ the bases of the formula I.
If de~ired, a base of the formula I can be liberated ~rom one of its salts using strong base~ ~uch as sodium hydroxidP or potassium hydroxide, or sodium carbonate or potas~ium carbonate.
The invention further relates to the use of compollndR 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).
~he invention further relate~ to compositions, in particular pharmaceutical preparations, containing one or more compounds of the formula I and~or their physio-logically acceptable salts. The~e 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 alcohol~, polyethylene glycols, gelatine, carbohydrate~ such as lactose or starch, magne~ium stearate, talc or petroleum jelly. Tablets, coated 2~ 2~
tablets, capsules, syrups, elixirs, drop~ or supposi-torie~ are used in particular for enteral admini~tration, solution3, preferably oily or aqueou~ solution~, and al~o su~pensions, emulsions or implants are used for par-enteral admini3tration, and ointments, creams, plastersor powders are used for topical administration. The novel compounds can al o be lyophilised and the resulting lyophilisate~ used, for example, for the production of injection preparations.
The preparations indicated can be sterilised and/or contain auxiliaries such a~ lubricant~, preservative~, stabilisers and/or wetting agent~, emulsi-fiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavourings and/or aromatisers. If d~sired, they can also contain one or more other active compounds, for example one or more vitamills.
Compound~ of the formula I and their physiologi-cally acceptable salt~ can be used in the therapeutic treatment of the human or animal body and in controlling diseases, in particular disease~ which are characterised by an excess of circulating serotonin or by a seroto-nergic hyperactivityO These diseases in particular include psychoses, nausea and vomiting, which arise a~
accompanying symptoms in the chemotherapeutic and radio-therapeutic treatment of tumours, dementia and othercognitive disorders, migraine and addictive disorder Thi~ area of application furthermore includes anxiolytic, analgesic and anti-aggressive action.
The substances according to the invention are in this case as a rule administersd in analogy to known commercially availa~le preparations (thioridazine, haloperidol), preferably in dosage~ between about 0.2 and 1000 mg, in particular between 0.2 and 100 mg per dosage unit. The daily dosage i preferably between about 0.003 and 20 mq/kg of body weight. Howev~r, the specific do~e for each individual patient depends on the most diver~e factor~, for example on the activity of the ~pecific compound employed, on the age, body weight, general state of heal~h, ~ex, on the diet, on the tLme and route of 2 ~
admini~tration, and on the excretion rate, medicament combination and ~everity of the particular disorder to which the therapy applies. Oral admini~tration i~
preferred.
Example~
In the example~ below, ~customary working upl~
means: water is added, if neces~ary, the mixture iq extracted with ethyl acetate or ether and separated, the organic phase is dried over ~;odium 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 i3 boiled for 3 hours.
Customary working up give~ N-(quinuclidin-3-yl)-indole-2-carboxamide, m.p. 178-80~. ¦
The following are obtained analogously by reac- ¦
tion 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-yl)-5-methoxyindole-2-carboxamide, m.p. 250-52, with 4-fluoroindole-2-carboxylic acid N-(quinuclidin-3-yl)-4-fluoroindole-2-carboxamlde, m.p~ 255-257, 20~2t,S~
with 5-fluoroindole-2-carboxylic acid N-(quinuclidin-3-yl)-5-fluoroindole-2-carboxamid~, m.p. 316-318, with l-ethylindole-2-carboxylic acid N-(quinuclidin-3-yl~ ethylindole-2-carboxamlde, 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)-~-cyanoindol~-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-dimethoxyindolP-2-carboxylic acid N-(quinuclidin-3-yl)-5,6-dimethoxyindole-2-car-boxamide, with 5,6-methylenedioxyindole-2-carboxylic acid N,(quinuclidin-3-yl)-5,6-methylenedioxyindole-2-carboxamide, 2 ~
with 4,5,6-trimethoxyindole-2-carboxylic acid N-(quinuclidin-3-yl)-4,5,6-trimethoxyindole-2-carboxamide, with 5-trifluoromethylindole-2-carboxylic acid N- ( quinuclidin-3-yl)-5-trifluoromethylindole-2-carboxamide, with 6-trifluoromethylindolle-2-carboxylic acid N-(quinuclidin-3-yl)-6-trifluoromethylindole-2-carboxamide, with 5-benzylindole-2-carboxylic acid N-(guinuclidin-3-yl)-5-benzylindole-2-carboxamide, with 6-benzylindole-2-carbox~lic acid N-(quinuclidin-3-yl)-6-benzylindole-2-carboxamide, with 6-benzyl-1-methylindole-2-carboxylic acid N-(quinuclidin-3-yl)-6-benzyl-l-methylindole-2-carboxamide, with 6-chloro-l-methylindole-2-carboxylic acid N-(quinuclidin-3-yl)-6-chloro-1-methylindole-2-carboxamide, with 6-cyano-1-methylindol~-L-carboxylic acid N-(quinuclidin-3-yl)-6-cyano-1-methylindole-2-carboxamide, with l-methylindole-2-carboxylic acid N-(quinuclidin-3-yl)-1-methylindole-2-carboxamide m.p. 182-84, with 7-benzylindole-2-carboxylic acid N-(quinuclidin-3-yl)-7-benzylindole-2-carboxamide, with 6-ethoxy-1-methylindole-2-carboxylic acid N-(quinuclidin-3-yl)-6-ethoxy-1-methylindole-2-carboxamide, with 5-cyan-1-methylindole-2-carboxylic acid N-(quinuclidin-3-yl)-5-cyan-1-methylindole-2-carboxamide, with 6-propoxyindole-2-carboxylic acid N-(qui~uclidin-3-yl)-6-propoxyindole-2-carboxamide, 2~2 ~3~
_ 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-2-carboxamide, with S-ethylindole-2-carboxylic acid N-(quinuclidin-3-yl)-5~-ethylindole-2-carbox~mide, with ~-tert.-butylindole-2-carboxylic acid N-(quinuclidin-3-yl)--~-tert.-butylindole-2-car-~oxamide and with 6-acetoxy-1-methylindole-2-carboxylic acid M-(quinuclidin-3-yl)-6-acetoxy-1-methylindole-2-carboxamide.
with 4-benzyloxy-indole-2-carboxylic acid 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-hydroxyindole-2-carboxamide are dissolved in 20 ml of pyridine and treated with 8 ml of acetic anhydride with cooling. ~he mixture i9 then ~tirred for 1 hour at room temperature and worked up in the cu~tomary manner. N-(quinuclidin-3-yl)-5-acetoxyindole-2-carboxamide i~ obtained.
The following are obtained analogously by reac-tion of 4-, 5- or 6-hydroxyindole-2-carboxylic acid~ with the appropriate carboxylic anhydrides N-(quinuclidin-3-yl~-S-piva:Loyloxyindole-2-carboxamide, N-(quinuclidin-3-yl)-6-piva]Loyloxyindole~2-carboxamide, N-(quinuclidin-3-yl)-6-butanoyloxyindole-2-carboxamide, N-(quinuclidin-3-yl)-5-butanoyloxyloxyindole-2-carbox-amide, N-(quinuclidin-3-yl)-4-propanoyloxyindole-2-carboxamide, N-(quinuclidin-3-yl)-S-propanoyloxyindole-2-carboxamide, N-(quinuclidin-3-yl)-6-propanoyloxyindole-2-carboxamide, N-(quinuclidin-3-yl)-4-methanesulfonyloxyindole-2-car-boxamide, N-(quinuclidin-3-yl)-5-methanesulfonyloxyindole~2-car-boxamide, N-(quinuclidin-3-yl)-6-methanesulfonyloxyindole-~-carbox-amide, ~0 N-(quinuclidin-3-yl)-5-propanoyloxy-1-methylindole-2-carboxamide, N-(quinuclidin-3-yl)-4-methane~ulfonyloxy-1-methylindole-2-carboxamide, N-(quinuclidin-3-yl)-5-methanesulfonyloxy-1-methylindole-2-carboxamide and N-(quinuclidin-3-yl)-5-acetoxy-1-methylindole-2-car~oxamide.
Example 3 0.5 g of N-(quinuclidin-3-yl)-7-kenzyloxyindole-2-car~oxamide (m.p.268-269)i~ 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 hydrogenat:ion solution i8 then concentrated and worked up in the cust:omary manner. N-(quinuclidin-3-yl)-7-hydroxy-indole-2-carboxamide is obtained.
The following are obtained analagously by hydrogenation , - 14 - 2~$$~s3~
f rom N- (quinuclidin-3-yl ) -5-benzyloxyindol.e-2~arboxamide ( m . p . 283-284 ) N-~quinuclidin-3-yl)-5-hydroxyindole-2-carboxamide, from N-(quinuclidin-3-yl)-6-benzyloxyindole-2-carbox~nide N-(quinuclidin-3-yl~-6-hyroxyindole-2-carboxantide 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 in 100 ml of T~F at room temperature with the a~dition of 3.0 g of dicyclohexylcarbodiimide (DCC) and treated with 3.2 g of 3-antinoquinuclidine suspended in 20 ml of TH~.
The mixture i~ then stirred for 6 hours at 40 and worked up in the customary manner. N-(quinuclidin-3-yl)-5-methylindole-2-carboxamide is obtained.
The ex~ttple~ below relate to pharmaceutical preparations which contain substanceR of the formula I
or one of their acid addition salts:
~xample A: tablets A mixture of 1 kg of N-(quinuclidin-3-yl)-4-chloroindole-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 ea~h tablet contains 10 mg of active compound.
Example B: coated tablets Analogou31y to ~xample A, tablets are pressed and are then coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth and colorant ~ample C: cap~ule-~
~ard gelatine cap~ules are filled with 2 kg of N-(quinucl:idin-3-yl)-5-methoxyindole-2-carboxamide in a cu~tomary manner such that each capsule contain3 20 mg of active compound.
Rxample D: ampoules A solution of 1 kg of N-(quinuclidin-3-yl~-indole-2-carboxamide in 60 l of double-distilled water is sterile filtered, poured into ampoules, lyophilised under sterile conditions and sterile ~ealed. Each ampoule contains 10 mg of active compound.
Tablats, coated tablets, capsules and ampoules which contain another compound of the formula I and/or one or more phy~iologically acceptable acid addition salts of a compound of the formula I can be obtained analogously.
The invention further relatesl to a process for the preparation o~ compoun~ of the formula I and of their ~alts~, characterised in that compounds of the ~ _ 3 _ 2~823~
formula II
Ind-CO-X II
where Ind has the meaning indicated, and X is chlorine, bromine, acy:loxy, preferably pivaloyloxy, furthermore acetyloxy, propionyloxy or butanoyloxy, 1-6 C-alkoxy, preferably methoxy or ethoxy, 7-11 C-aralkyl-oxy, preferably benzyloxy or 6-10 C-aroyloxy, preferably benzoyloxy, or hydroxyl, are reacted with 3-quinucliciine, 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 i~ converted into another radical Ind and~or a base of the fo~mula 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 ex~mple J. March, Advanced Organic Chemistry, 3rd Edition, John Wiley &
Sons, New York; F.M. Finn et al., ~he Proteinc 3rd Ed.
Vol. II Chap. 2 or Houben-Weyl, Methoden der Organi~chen Chemie (Method~ of Organic Chemi3try~, Georg-Thieme-Verlag, Stuttgart), and in particular under reaction conditions which are known and suitable for the said reactions. Use can al~o be made in this connection o variants which are known per se but which are not men-tioned here in greater detail.
If de3ired, the ~tarting material3 for the claimed proces~ can al80 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 iB prepared in accordance with method~ kn~wn per se, as are u~ed in 2~6g2~3~
general for preparing amidea or in peptide chemi~try, preferably by reacting a compound of the formula II with 3-aminoquinuclidine or one of its salts in a ~uitable solvent, ~uch a~, for example, tetrahydrofuran (THF), S dimethylformamide (DMF), 1,4-dioxane, alcoholq, such as, for example, methanol or ethanol, further ethexs, su~h as, for example, diethyl ether, dichloromethane, or al~o mixtures of the solvents mentioned, at temperatureq between 10 and the relevant boiling point of the ~olvent 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 racemate~ if several asymmetric carbon atoms are present, and also as mixtures of several racemates and in various optically active formq. 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 t~rtaric acid, diben~oyltartaric 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 cry~tallisation, 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 eaqily be prepared analogou~ly to the known compound~. Thus, Por example, N- or 0-acylated compound~ can be prepared from the 2 ~ 3 ~
nonacylated precurqors by reaction with acid anhydrides, for example acetic anhydride, in basic organic solvents, for example pyridine.
~qually it i8 al90 po~ible to u~e the m~thod~
S known per se for derivatising carboxylic acids to prepare compounds of the formula II.
The protecting group can furthermore be removed from compound3 which otherwise correspond to the formula I, but in tead 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 hydroqenation, 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 ~ulfonyl (for example methane-sulfonyl or toluenesulfonyl), can be solvolysed to give compounds of the formula I, in particular hydrolysed.
The starting materials for the ~olvolysis are obtainable, for example, by reactions of 1-Z-Ind-COX with 3-aminoquinuclidine or one of its salts, Ind having the meaning ind-cated and Z being a group which can be removed by solvolysis. Thus, compounds of the formula I
where the radical Ind in the l-po~ition of the indole contains an acyl group, preferably an alkanoyl, alkyl-sulfonyl or arylsulfonyl group in each case having up to 10 C atoms, such as methane-, benzene- or p-toluene-sulfonyl, can in particular be hydrolysed to give the correspondinq compounds which are unsubstituted in the 1-po~ition, for example in acidic, or better, neutral or alkaline medium, at temperature~ between 0 and 200C.
Bases used are advanta~eously sodium hydroxide, potassium hydroxide or calcium hydroxide, sodium carbonate or pota~sium carbonate or ammonia, under conditions in which the acid amide bond is not cleaved. The cho~en solvent is preferably water, lower alcohols such as methanol or ethanol, ether~ such as T~F or dioxane, sulfones ~uch as tetramethylene sulfone or their mixtures, particularly 2 ~
the mixtures containin~ water. Hydrolysis can even ~e carried out while treating with wat~r alone, in parti-cular at boiling h~at.
A radical Ind in a compound of the formula I can S be converted into another radical Ind, if the chosen reaction condition~ do not destroy the acid amide bond, by cleaving, for example, an ether group, the correspond-ing 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 sulfide-boron tribromide complex, for example in toluene, ethers such as THF or dime~hyl sulfoxide, or by fusing with pyridine or aniline hydrohalides, preferably pyridine hydrochloride, at about 150-250C, or by treating with diisobutylaluminium hydride in toluene at about 0-110C, or by catalytic hydrogenation, for example in the pre-sence of palladium-carbon in one of the abovementioned inert solvents, for example methanol, at, for example, 0 to 50C 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. Decarboxylation~ are advantageously carried out in alkaline medium, for example in N,N-dimethylaniline at temperatures between 40 and 190C, preferably between 160 and 190C.
A resulting base of the fo~nula I can be con-verted into the respective acid addition salts using an acid. Acids which give physiologically acceptable salt~
are preferred for thi~ reaction. Thus, inorganic acids can be used, for example ~ulfuric acid, hydrohalic acids ~uch as hydrochloric acid or hydrobromic acid, phosphoric acids 3uch as orthophoYphoric acid, nitric acid, sulfa-minic acid, and al80 organic acid~, in particular 2 ~ 3 ~
aliphatic, alicyclic, araliphatic, aromatic or hetero-cyclic mono- or polyba3ic carboxylic, sulfonic or sulfuric acids, such a~ 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, ~alicylic 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 lauryl-~ulfuric acid. Acid addition ~alts which are not physio-logically acceptable (for example picrate~) can be used for the isolation and purification o~ the bases of the formula I.
If de~ired, a base of the formula I can be liberated ~rom one of its salts using strong base~ ~uch as sodium hydroxidP or potassium hydroxide, or sodium carbonate or potas~ium carbonate.
The invention further relates to the use of compollndR 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).
~he invention further relate~ to compositions, in particular pharmaceutical preparations, containing one or more compounds of the formula I and~or their physio-logically acceptable salts. The~e 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 alcohol~, polyethylene glycols, gelatine, carbohydrate~ such as lactose or starch, magne~ium stearate, talc or petroleum jelly. Tablets, coated 2~ 2~
tablets, capsules, syrups, elixirs, drop~ or supposi-torie~ are used in particular for enteral admini~tration, solution3, preferably oily or aqueou~ solution~, and al~o su~pensions, emulsions or implants are used for par-enteral admini3tration, and ointments, creams, plastersor powders are used for topical administration. The novel compounds can al o be lyophilised and the resulting lyophilisate~ used, for example, for the production of injection preparations.
The preparations indicated can be sterilised and/or contain auxiliaries such a~ lubricant~, preservative~, stabilisers and/or wetting agent~, emulsi-fiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavourings and/or aromatisers. If d~sired, they can also contain one or more other active compounds, for example one or more vitamills.
Compound~ of the formula I and their physiologi-cally acceptable salt~ can be used in the therapeutic treatment of the human or animal body and in controlling diseases, in particular disease~ which are characterised by an excess of circulating serotonin or by a seroto-nergic hyperactivityO These diseases in particular include psychoses, nausea and vomiting, which arise a~
accompanying symptoms in the chemotherapeutic and radio-therapeutic treatment of tumours, dementia and othercognitive disorders, migraine and addictive disorder Thi~ area of application furthermore includes anxiolytic, analgesic and anti-aggressive action.
The substances according to the invention are in this case as a rule administersd in analogy to known commercially availa~le preparations (thioridazine, haloperidol), preferably in dosage~ between about 0.2 and 1000 mg, in particular between 0.2 and 100 mg per dosage unit. The daily dosage i preferably between about 0.003 and 20 mq/kg of body weight. Howev~r, the specific do~e for each individual patient depends on the most diver~e factor~, for example on the activity of the ~pecific compound employed, on the age, body weight, general state of heal~h, ~ex, on the diet, on the tLme and route of 2 ~
admini~tration, and on the excretion rate, medicament combination and ~everity of the particular disorder to which the therapy applies. Oral admini~tration i~
preferred.
Example~
In the example~ below, ~customary working upl~
means: water is added, if neces~ary, the mixture iq extracted with ethyl acetate or ether and separated, the organic phase is dried over ~;odium 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 i3 boiled for 3 hours.
Customary working up give~ N-(quinuclidin-3-yl)-indole-2-carboxamide, m.p. 178-80~. ¦
The following are obtained analogously by reac- ¦
tion 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-yl)-5-methoxyindole-2-carboxamide, m.p. 250-52, with 4-fluoroindole-2-carboxylic acid N-(quinuclidin-3-yl)-4-fluoroindole-2-carboxamlde, m.p~ 255-257, 20~2t,S~
with 5-fluoroindole-2-carboxylic acid N-(quinuclidin-3-yl)-5-fluoroindole-2-carboxamid~, m.p. 316-318, with l-ethylindole-2-carboxylic acid N-(quinuclidin-3-yl~ ethylindole-2-carboxamlde, 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)-~-cyanoindol~-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-dimethoxyindolP-2-carboxylic acid N-(quinuclidin-3-yl)-5,6-dimethoxyindole-2-car-boxamide, with 5,6-methylenedioxyindole-2-carboxylic acid N,(quinuclidin-3-yl)-5,6-methylenedioxyindole-2-carboxamide, 2 ~
with 4,5,6-trimethoxyindole-2-carboxylic acid N-(quinuclidin-3-yl)-4,5,6-trimethoxyindole-2-carboxamide, with 5-trifluoromethylindole-2-carboxylic acid N- ( quinuclidin-3-yl)-5-trifluoromethylindole-2-carboxamide, with 6-trifluoromethylindolle-2-carboxylic acid N-(quinuclidin-3-yl)-6-trifluoromethylindole-2-carboxamide, with 5-benzylindole-2-carboxylic acid N-(guinuclidin-3-yl)-5-benzylindole-2-carboxamide, with 6-benzylindole-2-carbox~lic acid N-(quinuclidin-3-yl)-6-benzylindole-2-carboxamide, with 6-benzyl-1-methylindole-2-carboxylic acid N-(quinuclidin-3-yl)-6-benzyl-l-methylindole-2-carboxamide, with 6-chloro-l-methylindole-2-carboxylic acid N-(quinuclidin-3-yl)-6-chloro-1-methylindole-2-carboxamide, with 6-cyano-1-methylindol~-L-carboxylic acid N-(quinuclidin-3-yl)-6-cyano-1-methylindole-2-carboxamide, with l-methylindole-2-carboxylic acid N-(quinuclidin-3-yl)-1-methylindole-2-carboxamide m.p. 182-84, with 7-benzylindole-2-carboxylic acid N-(quinuclidin-3-yl)-7-benzylindole-2-carboxamide, with 6-ethoxy-1-methylindole-2-carboxylic acid N-(quinuclidin-3-yl)-6-ethoxy-1-methylindole-2-carboxamide, with 5-cyan-1-methylindole-2-carboxylic acid N-(quinuclidin-3-yl)-5-cyan-1-methylindole-2-carboxamide, with 6-propoxyindole-2-carboxylic acid N-(qui~uclidin-3-yl)-6-propoxyindole-2-carboxamide, 2~2 ~3~
_ 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-2-carboxamide, with S-ethylindole-2-carboxylic acid N-(quinuclidin-3-yl)-5~-ethylindole-2-carbox~mide, with ~-tert.-butylindole-2-carboxylic acid N-(quinuclidin-3-yl)--~-tert.-butylindole-2-car-~oxamide and with 6-acetoxy-1-methylindole-2-carboxylic acid M-(quinuclidin-3-yl)-6-acetoxy-1-methylindole-2-carboxamide.
with 4-benzyloxy-indole-2-carboxylic acid 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-hydroxyindole-2-carboxamide are dissolved in 20 ml of pyridine and treated with 8 ml of acetic anhydride with cooling. ~he mixture i9 then ~tirred for 1 hour at room temperature and worked up in the cu~tomary manner. N-(quinuclidin-3-yl)-5-acetoxyindole-2-carboxamide i~ obtained.
The following are obtained analogously by reac-tion of 4-, 5- or 6-hydroxyindole-2-carboxylic acid~ with the appropriate carboxylic anhydrides N-(quinuclidin-3-yl~-S-piva:Loyloxyindole-2-carboxamide, N-(quinuclidin-3-yl)-6-piva]Loyloxyindole~2-carboxamide, N-(quinuclidin-3-yl)-6-butanoyloxyindole-2-carboxamide, N-(quinuclidin-3-yl)-5-butanoyloxyloxyindole-2-carbox-amide, N-(quinuclidin-3-yl)-4-propanoyloxyindole-2-carboxamide, N-(quinuclidin-3-yl)-S-propanoyloxyindole-2-carboxamide, N-(quinuclidin-3-yl)-6-propanoyloxyindole-2-carboxamide, N-(quinuclidin-3-yl)-4-methanesulfonyloxyindole-2-car-boxamide, N-(quinuclidin-3-yl)-5-methanesulfonyloxyindole~2-car-boxamide, N-(quinuclidin-3-yl)-6-methanesulfonyloxyindole-~-carbox-amide, ~0 N-(quinuclidin-3-yl)-5-propanoyloxy-1-methylindole-2-carboxamide, N-(quinuclidin-3-yl)-4-methane~ulfonyloxy-1-methylindole-2-carboxamide, N-(quinuclidin-3-yl)-5-methanesulfonyloxy-1-methylindole-2-carboxamide and N-(quinuclidin-3-yl)-5-acetoxy-1-methylindole-2-car~oxamide.
Example 3 0.5 g of N-(quinuclidin-3-yl)-7-kenzyloxyindole-2-car~oxamide (m.p.268-269)i~ 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 hydrogenat:ion solution i8 then concentrated and worked up in the cust:omary manner. N-(quinuclidin-3-yl)-7-hydroxy-indole-2-carboxamide is obtained.
The following are obtained analagously by hydrogenation , - 14 - 2~$$~s3~
f rom N- (quinuclidin-3-yl ) -5-benzyloxyindol.e-2~arboxamide ( m . p . 283-284 ) N-~quinuclidin-3-yl)-5-hydroxyindole-2-carboxamide, from N-(quinuclidin-3-yl)-6-benzyloxyindole-2-carbox~nide N-(quinuclidin-3-yl~-6-hyroxyindole-2-carboxantide 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 in 100 ml of T~F at room temperature with the a~dition of 3.0 g of dicyclohexylcarbodiimide (DCC) and treated with 3.2 g of 3-antinoquinuclidine suspended in 20 ml of TH~.
The mixture i~ then stirred for 6 hours at 40 and worked up in the customary manner. N-(quinuclidin-3-yl)-5-methylindole-2-carboxamide is obtained.
The ex~ttple~ below relate to pharmaceutical preparations which contain substanceR of the formula I
or one of their acid addition salts:
~xample A: tablets A mixture of 1 kg of N-(quinuclidin-3-yl)-4-chloroindole-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 ea~h tablet contains 10 mg of active compound.
Example B: coated tablets Analogou31y to ~xample A, tablets are pressed and are then coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth and colorant ~ample C: cap~ule-~
~ard gelatine cap~ules are filled with 2 kg of N-(quinucl:idin-3-yl)-5-methoxyindole-2-carboxamide in a cu~tomary manner such that each capsule contain3 20 mg of active compound.
Rxample D: ampoules A solution of 1 kg of N-(quinuclidin-3-yl~-indole-2-carboxamide in 60 l of double-distilled water is sterile filtered, poured into ampoules, lyophilised under sterile conditions and sterile ~ealed. Each ampoule contains 10 mg of active compound.
Tablats, coated tablets, capsules and ampoules which contain another compound of the formula I and/or one or more phy~iologically acceptable acid addition salts of a compound of the formula I can be obtained analogously.
Claims (7)
1. 3-(Indole-2-carboxamido)quinuclidines of the formula I
Ind-CO-NHR
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-alkylsul-fonyloxy, 6-10 C-arylsulfonyloxy, carboxyl and/or methylenedioxy and R is 3-quinuclidinyl, and their salts.
Ind-CO-NHR
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-alkylsul-fonyloxy, 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)-1-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 l, and X is Cl, Br, acyloxy, alkoxy with in each case 1-6 C-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 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.
Ind-CO-X II
where the radical Ind has the meaning given in Claim l, and X is Cl, Br, acyloxy, alkoxy with in each case 1-6 C-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 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.
4. Process for the production of a pharmaceutical preparation, characterized 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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4115215A DE4115215A1 (en) | 1991-05-10 | 1991-05-10 | INDOLDER DERIVATIVES |
| DEP4115215.8 | 1991-05-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2068238A1 true CA2068238A1 (en) | 1992-11-11 |
Family
ID=6431344
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002068238A Abandoned CA2068238A1 (en) | 1991-05-10 | 1992-05-08 | 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 |
|---|---|---|---|---|
| WO1992004347A1 (en) * | 1990-08-31 | 1992-03-19 | Nippon Shinyaku Co., Ltd. | Indole derivative and medicine |
| IT1255467B (en) * | 1992-07-29 | 1995-11-02 | Dompe Farmaceutici Spa | PHARMACOLOGICALLY ACTIVE ACRYLIC STARCHES |
| US6486172B2 (en) | 2000-08-18 | 2002-11-26 | Pharmacia & Upjohn Company | Quinuclidine-substituted aryl compounds for treatment of disease |
| EP1381603A2 (en) | 2000-08-18 | 2004-01-21 | PHARMACIA & UPJOHN COMPANY | Quinuclidine-substituedaryl 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 |
| WO2002017358A2 (en) | 2000-08-21 | 2002-02-28 | Pharmacia & Upjohn Company | Quinuclidine-substituted heteroaryl moieties for treatment of disease (nicotinic acetylcholine receptor antagonists) |
| WO2002015662A2 (en) | 2000-08-21 | 2002-02-28 | Pharmacia & Upjohn Company | Quinuclidine-substituted heteroaryl moieties for treatment of disease (nicotinic acetylcholine receptor antagonists |
| 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 |
| EA007429B1 (en) | 2001-10-02 | 2006-10-27 | Фармация Энд Апджон Компани | Azabicyclic-substituted fused-heteroaryl compounds |
| 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 |
| AU2003219690A1 (en) | 2002-02-19 | 2003-09-09 | Pharmacia And Upjohn Company | Fused bicyclic-n-bridged-heteroaromatic carboxamides for the treatment of disease |
| EP1476448A2 (en) | 2002-02-19 | 2004-11-17 | PHARMACIA & UPJOHN COMPANY | Azabicyclic compounds for the treatment of disease |
| WO2004013137A1 (en) | 2002-08-01 | 2004-02-12 | 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 |
| EP2355822B1 (en) | 2008-11-19 | 2012-10-10 | Envivo Pharmaceuticals, Inc. | Treatment of cognitive disorders with (r)-7-chloro-n-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and pharmaceutically acceptable salts thereof |
| PE20170923A1 (en) | 2010-05-17 | 2017-07-12 | Forum Pharmaceuticals Inc | A CRYSTALLINE FORM OF (R) -7-CHLORO-N- (QUINUCLIDIN-3-IL) BENZO [B] THIOPHENE-2-CARBOXAMIDE MONOHYDRATED HYDROCHLORIDE |
| RU2017136693A (en) | 2012-05-08 | 2019-02-08 | Форум Фармасьютикалз, Инк. | METHODS FOR MAINTAINING, TREATING OR IMPROVING COGNITIVE FUNCTION |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL8701682A (en) * | 1986-07-30 | 1988-02-16 | Sandoz Ag | METHOD FOR THE THERAPEUTIC USE OF SEROTONIN ANTAGONISTS, ACTIVE COMPOUNDS AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS |
| DE3881950T2 (en) * | 1987-04-25 | 1993-09-30 | Beecham Group Plc | Azabicyclic compounds, processes for their preparation and pharmaceutical preparations 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 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
- 1992-05-08 KR KR1019920007824A patent/KR920021507A/en not_active Withdrawn
- 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 |
|---|---|
| HUT61541A (en) | 1993-01-28 |
| AU1604492A (en) | 1992-11-12 |
| MX9202152A (en) | 1992-11-01 |
| EP0512350A3 (en) | 1992-12-16 |
| HU208136B (en) | 1993-08-30 |
| EP0512350A2 (en) | 1992-11-11 |
| ZA923351B (en) | 1993-01-27 |
| CS130592A3 (en) | 1992-11-18 |
| DE4115215A1 (en) | 1992-11-12 |
| JPH05155886A (en) | 1993-06-22 |
| NO921831L (en) | 1992-11-11 |
| IE921488A1 (en) | 1992-11-18 |
| NO921831D0 (en) | 1992-05-08 |
| KR920021507A (en) | 1992-12-18 |
| TW221807B (en) | 1994-03-21 |
| PL294457A2 (en) | 1992-11-16 |
| HU9201550D0 (en) | 1992-07-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |