EP0746549A1 - Acetic acid amide derivatives and process for the preparation thereof - Google Patents

Acetic acid amide derivatives and process for the preparation thereof

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Publication number
EP0746549A1
EP0746549A1 EP95909911A EP95909911A EP0746549A1 EP 0746549 A1 EP0746549 A1 EP 0746549A1 EP 95909911 A EP95909911 A EP 95909911A EP 95909911 A EP95909911 A EP 95909911A EP 0746549 A1 EP0746549 A1 EP 0746549A1
Authority
EP
European Patent Office
Prior art keywords
general formula
acetamide
tetrahydroacridin
piperazin
pharmaceutically acceptable
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.)
Withdrawn
Application number
EP95909911A
Other languages
German (de)
French (fr)
Inventor
Józsefné REITER
Zoltán Budai
Gáborné TAKATS
Tibor Mezei
Gábor Blasko
Gyula Simig
András Egyed
E. Szilveszter Vizi
Márton Fekete
Katalin Szemeredi
István GYERTYAN
István GACSALYI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals PLC
Original Assignee
Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals PLC
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Egyt Gyogyszervegyeszeti Gyar, Egis Pharmaceuticals PLC filed Critical Egyt Gyogyszervegyeszeti Gyar
Publication of EP0746549A1 publication Critical patent/EP0746549A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C07D219/08—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C07D219/08—Nitrogen atoms
    • C07D219/10—Nitrogen atoms attached in position 9
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates to new acetic acid derivatives, a process for the preparation thereof, pharmaceutical compositions comprising the same, to the use of the said acetic acid amide derivatives for the treatment of diseases and for the preparation of pharmaceutical compositions suitable for the treatment of diseases.
  • B represents piperazino, 8-azaspiro[4,5]decane-7,9-dion- -8-yl or 2-(l,2,4-triazolo[4,3-a]pyridyl-3(2H)-on-2-yl) optionally carrying an aryl, aralkyl or heteroaryl substituent.
  • the invention encompasses the pharmaceutically acceptable acid-addition salts of the compounds of general formula (I) , too.
  • the new compounds according to the invention posses valuable pharmaceutical properties, more specifically they are suitable for the treatment of Alzheimer's disease. At the same time they exert only a few side-effects.
  • Senile dementia is a common diagnosis characterized by the deterioration of cognitive functions and of adjustment to situations in everyday life.
  • 80966-62-PT-tm thereof is constituted by the plaques decreasing cerebral activity described by Alois Alzheimer in 1906. These symptoms are called Alzheimer's disease.
  • Alzheimer's disease As the average age is increasing and the urbanization is spreading, the disease becomes more and more widespread. At present about 15 % and 20 % of the population over 65 and 80 years, respectively, suffer from some form of dementia. In the United States 10 billion dollars were spent in 1982 (Terry and Katzman, 1983) , 34 billion in 1985 and 40 billion in 1987 for the treatment of patients suffering from the different forms of dementia. In 1985 2.5 million people were stricken by this disease. According to Szilagyi (1985) , taking ratios into account the situation was similar in Hungary, too. The Alzheimer's disease is, to our knowledge, incurable.
  • tacrine l,2,3,4-tetrahydro-9-acridinamine
  • the aim of the present invention is to eliminate the above-mentioned drawbacks of tacrine and to provide new compounds which possess the reversible cholinesterase- inhibiting effect of tacrine but are devoid of its undesirable side-effects.
  • aryl group used throughout the specification relates to the phenyl and naphthyl groups that may optionally carry substituents such as lower alkyl, lower alkoxy, hydroxy, nitro, amino or halogen.
  • lower covers groups having 1 to 7, preferably 1 to 4, carbon at ⁇ -n(s) .
  • lower alkyl or “lower alkoxy” refers to straight or branched chained alkyl or alkoxy groups (e.g. methyl, ethyl, propyl, ethoxy, methoxy, isopropoxy, etc.).
  • halogen atom encompasses the fluorine, chlorine, bromine and iodine atoms.
  • aralkyl covers lower alkyl groups carrying one or two aryl substituent(s) (e.g. benzyl, beta-phenylethyl, ⁇ , ⁇ -diphenylethyl, etc.).
  • heteroaryl relates to heteroaromatic groups comprising one or two ring(s) and containing one or two nitrogen, oxygen and/or sulfur atom(s) (e.g. pyridyl, pyrimidinyl, thiazolyl, oxazolyl, i idazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, etc.).
  • the aralkyl and heteroaryl groups may carry one or two substituent(s) enumerated in connection with the aryl group.
  • Preferred representatives of the compounds of general formula (I) are those wherein B stands for piperazino optionally carrying a phenyl or benzyl substituent optionally substituted by halogen, pyridyl or pyrimidinyl, and pharmaceutically acceptable acid-addition salts thereof.
  • Particularly preferred representatives of the compounds of general formula (I) are the following derivatives: N-(l,2,3,4-tetrahydroacridin-9-yl)-2-[ (3-chlorophenyl)- piperazin-1-y1]-acetamide, N-(1,2,3,4-tetrahydroacridin-9-yl)-2-[ (N-benzyl)-piperazin- 1-yl]-acetamide,
  • the pharmaceutically acceptable acid-addition salts of the compounds of general formula (I) can be formed with inorganic or organic acids (e.g. hydrohalides such as hydrochlorides or hydrobromides; sulfates, nitrates, phosphates, acetates, propionates, maleates, fumarates, lactates, succinates, ascorbinates, tartrates, etc.) or with sulfonic acids (e.g. benzenesulfonates, methanesulfonates, p-toluenesulfonates) .
  • inorganic or organic acids e.g. hydrohalides such as hydrochlorides or hydrobromides
  • sulfonic acids e.g. benzenesul
  • Hlg stands for chlorine, bromine or iodine, with a compound of general formula (V) ,
  • reaction of the compounds of general formulae (II) and (V) is carried out in a known manner.
  • the reaction is preferably performed in an inert organic solvent.
  • organic solvents particularly aliphatic alcohols (e.g. ethanol or isopropanol) , aromatic hydrocarbons (e.g. benzene, toluene or xylene) or ethers (e.g. diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane) can be used.
  • the reaction is carried out in the presence of a basic condensing agent.
  • organic bases e.g.
  • reaction is carried out at a temperature between 0 °C and 130 °C, preferably at a temperature between 40 °C and 90 °C.
  • an amino compound of formula (III) is reacted with a compound of general formula (IV) by methods known per se .
  • the compounds of general formula (IV) used as starting substances may be, depending on the meaning of X, free carboxylic acids, acid halides, esters, acid anhydrides or mixed anhydrides.
  • carboxylic acids of general formula (IV) wherein X represents hydroxy, acid halides (X stands for chlorine or bromine) or esters (X stands for lower alkoxy such as methoxy or ethoxy) .
  • the reaction of the compounds of general formulae (III) and (IV) can be carried out in an inert solvent.
  • reaction medium the solvents mentioned in connection with process variant a) can be used.
  • the reaction is preferably performed under heating.
  • the compounds of general formula (I) can be converted into pharmaceutically acceptable acid-addition salts with the appropriate acids by methods known per se , or can be liberated from their salts in a known manner.
  • the 9-amino-l,2,3,4-tetrahydroacridine of general formula (III) used as starting substance for the process according to the invention can be prepared as specified in J. Soc. Chem. Ind. 64, 16972 (1945) .
  • the acetamide derivatives of general formula (II) can be produced as specified in Chem. Listy 5_1, 1906-8 (1957) and the substituted acetic acid derivatives of general formula (IV) can be prepared as described e.g. in Acta Univ. Szegediensis, Acta Phys. et Chem. 6_, 80-6, 1960 or Acta Pharm. Hung. 3.1, 113-21 (1961) or in the U.S. patent specification No. 2,568,141.
  • compositions comprising as active ingreident a compound of general formula (I) or a pharmaceutically acceptable acid-addition salt thereof in admixture with suitable inert solid or liquid pharmaceutical carriers.
  • compositions of the present invention can be prepared by methods known per se by admixing the active ingredient with suitable inert solid or liquid carriers and bringing the mixture to galenic form.
  • compositions of the present invention may be suitable for oral (e.g. tablet, pill, coated pill, dragee, capsule, drop, solution or suspension) , parenteral (e.g. injection solution) or rectal (e.g. suppository) administration.
  • oral e.g. tablet, pill, coated pill, dragee, capsule, drop, solution or suspension
  • parenteral e.g. injection solution
  • rectal e.g. suppository
  • the solid pharmaceutical compositions may comprise usual additives (such as lubricants, stabilizers, emulsifiers, disintegrating agents, salts or buffers causing the change of osmotic pressure) .
  • the capsules may be soft or hard gelatin capsules.
  • the suppositories may contain usual synthetic or natural base materials (e.g. cocoa butter, fatty acid triglycerides, Witepsol, etc.).
  • the injections are usually aqueous solutions which can be isotonized with sodium chloride.
  • the daily dose of the compounds of general formula (I) can vary within wide ranges depending on several factors, e.g. on the activity of the active ingredient, the patient's condition and age, the severity of the disease, etc.
  • the oral dose is generally 1 to 1000 mg/day, while the parenteral dose is generally 0.1 to 100 mg/day, preferably 0.1 to 50 mg/day.
  • the daily dose of the compounds of the present invention may be administered at once or in several (e.g. three) portions with appropriate intervals. Determination of the proper dosage for a particular situation is within the skill of the art.
  • a process for the preparation of pharmaceutical compositions which comprises admixing a compound of general formula (I) or a pharmaceutically acceptable acid-addition salt thereof with suitable inert solid or liquid therapeutical carriers.
  • the use of the compounds of general formula (I) or pharmaceutically acceptable acid-addition salts thereof for the preparation of pharmaceutical compositions useful for the treatment of Alzheimer's disease comprises administering to a patient an effective amount of a compound of general formula (I) or a pharmaceutically acceptable acid-addition salt thereof.
  • the new compounds of general formula (I) are remarkable for their low toxicity and selective cholinesterase- inhibiting effect.
  • the ratio of the inhibitions exerted on the two kinds of enzyme provides information on the specificity of the inhibition. These enzymes are much more liable to split thiocholine esters than the physiological substrates thereof. Thiocholine formed as a consequence of the enzyme activity can be determined by photometry when reacted with dithio-bis-nitrobenzoic acid (DTNB) .
  • DTNB dithio-bis-nitrobenzoic acid
  • Tacrine wa ⁇ used as reference substance.
  • the inhibitory activity of the test compounds at a concentration of 10 ⁇ 5 M (inhibition %) and ID5 0 values are shown in the following Tables.
  • Example 1 One proceeds as specified in Example 1 except that 1- (2-pyrimidinyl) -piperazine (7.22 g, 0.044 mole) is used as amine.
  • Tablet comprising 25 mg of active ingredient Composition of one tablet is as follows :
  • Active ingredient 25 0 mg
  • the tablet is prepared as follows:
  • the active ingredient and the corn starch are admixed, then wetted with 10-15 % by weight of aqueous polyvinyl ⁇ pyrrolidone solution and the mixture is granulated, then dried at a temperature of 40 to 50 °C.
  • the dry granules are rubbed through a sieve, mixed with talc and magnesium stearate and tablets are prepared from the mixture.
  • the weight of one tablet is 300 mg.
  • Composition of one tablet is as follows :
  • Active ingredient 250 0 mg
  • the tablet is prepared as follows:
  • the active ingredient, the lactose and the corn starch are wetted and mixed, granulated and dried at a temperature of 40 to 50 °C.
  • the dry granules are rubbed through a sieve, mixed with magnesium stearate and tablets are formed.
  • the weight of one tablet is 600.0 mg.
  • Example 10 Dragee comprising 25 mg of active ingredient
  • the composition of one dragee core is as follows:
  • the dragee is prepared as follows: The active ingredient and the corn starch are mixed, wetted with 10 % by weight aqueous gelatin solution, granules are formed from the wet mixture and the granules are dried at a temperature of 40 to 50 °C. The dry granules are rubbed through a sieve, homogenized with talc and magnesium stearate and dragee cores of 300.0 mg are compressed from the mixture.
  • composition of one dragee core is as follows:
  • the granules are prepared as described in Example 10.
  • the weight of one dragee core is 150.0 mg.
  • the dragee cores are coated with a layer containing sugar and talc in a manner known per se .
  • the dragee thus obtained is painted with non-toxic food paint to the desired colour and polished with bee-wax.
  • Gelatin capsule comprising 5.0 mg og active ingredient
  • the composition of one gelatine capsule is as follows:
  • Aerosil 3.0 mg Magnesium stearate 2.0 a ⁇
  • the components are homogenized and filled into gelatin capsules of suitable size.
  • Gelatine capsule comprising 25.0 mg of active ingredient
  • composition of one gelatin capsule is as follows: Active ingredient 25.0 mg
  • the ingredients are homogenized and filled into gelatin capsules of suitable size.
  • Gelatine capsule comprising 50 mg of active ingredient
  • composition of one gelatin capsule is as follows:
  • Example 15 The ingredients are homogenized and filled into gelatin capsules of suitable size.
  • Example 15 The ingredients are homogenized and filled into gelatin capsules of suitable size.
  • Gelatine capsule comprising 250 mg of active ingredient
  • composition of one gelatin capsule is as follows : Active ingredient 250. 0 mg
  • the ingredients are homogenized and filled into gelatine capsules of suitable size .
  • composition of one ampoule is as follows: Active ingredient 25.0 mg
  • the active ingredient and sodium chloride are dissolved in the necessary amount of twice-distilled water suitable for making injections .
  • the solution is filtered, filled into ampoules and sterilized.
  • composition of one ampoule is as follows : Active ingredient 50.0 mg
  • Suppository comprising 250.0 mg of active ingredient
  • composition of one suppository is as follows: Active ingredient 250.0 mg
  • the fatty acid glyceride is melted, the active ingredient is homogenized, then poured into a mould.
  • Example 19 Drop comprising 10 % of active ingredient
  • the sorbitol, the active ingredient, the citric acid and the sodium citrate are dissolved in the aqueous solution of propylene glycol, then after dissolution of the solid materials the flavourant is added.
  • the solution is filtered and filled into flasks supplied with a drop-dispenser.

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Abstract

The invention relates to new acetic acid derivatives, a process for the preparation thereof, pharmaceutical compositions comprising the same, to the use of the said acetic acid amide derivatives for the treatment of diseases and for the preparation of pharmaceutical compositions suitable for the treatment of diseases. The new compounds according to the invention can be characterized by general formula (I), wherein R stands for hydrogen and B represents piperazino, 8-azaspiro[4,5]decane-7,9-dion-8-yl or 2-(1,2,4-triazolo[4,3-a]pyridyl-3(2H)-on-2-yl) optionally carrying an aryl, aralkyl or heteroaryl substituent, and possess valuable pharmaceutical properties, they are suitable for the treatment of Alzheimer's disease.

Description

ACETIC ACID AMIDE DERIVATIVES AND PROCESS FOR THE
PREPARATION THEREOF
This invention relates to new acetic acid derivatives, a process for the preparation thereof, pharmaceutical compositions comprising the same, to the use of the said acetic acid amide derivatives for the treatment of diseases and for the preparation of pharmaceutical compositions suitable for the treatment of diseases.
According to an aspect of the present invention there are provided new acetic acid amide derivatives of general formula (I) ,
wherein
R stands for hydrogen and
B represents piperazino, 8-azaspiro[4,5]decane-7,9-dion- -8-yl or 2-(l,2,4-triazolo[4,3-a]pyridyl-3(2H)-on-2-yl) optionally carrying an aryl, aralkyl or heteroaryl substituent.
The invention encompasses the pharmaceutically acceptable acid-addition salts of the compounds of general formula (I) , too. The new compounds according to the invention posses valuable pharmaceutical properties, more specifically they are suitable for the treatment of Alzheimer's disease. At the same time they exert only a few side-effects.
Senile dementia is a common diagnosis characterized by the deterioration of cognitive functions and of adjustment to situations in everyday life. The neuropathological basis
80966-62-PT-tm thereof is constituted by the plaques decreasing cerebral activity described by Alois Alzheimer in 1906. These symptoms are called Alzheimer's disease.
As the average age is increasing and the urbanization is spreading, the disease becomes more and more widespread. At present about 15 % and 20 % of the population over 65 and 80 years, respectively, suffer from some form of dementia. In the United States 10 billion dollars were spent in 1982 (Terry and Katzman, 1983) , 34 billion in 1985 and 40 billion in 1987 for the treatment of patients suffering from the different forms of dementia. In 1985 2.5 million people were stricken by this disease. According to Szilagyi (1985) , taking ratios into account the situation was similar in Hungary, too. The Alzheimer's disease is, to our knowledge, incurable. So far the following methods have been used for the treatment thereof: a) In order to compensate the insufficient activity of the cholinergic system, high doses of choline, the precursor of acetylcholine, were administered to the patients. In most of the cases this method was ineffective (John et al. , 1983) . b) The rate of the decomposition of acetylcholine in the synaptic slit was reduced, therefore the effect of the liberated acetylcholine was enhanced. A remission was observed in patients suffering from Alzheimer's disease after treatment with acetylcholine esterase inhibitors (Doris et al. 11982, 1983). The inhibition of the non-central nervous choline esterases, however, increases the amount of acetyl¬ choline in the viscera, too. The hypotension, the intestinal hyperactivity, and the retardation of cardiac frequency, that are developing due to the increased acetylcholine level, cause unpleasant side- effects when applying these drugs. Our aim was to develop pharmaceuticals inhibiting the decomposition -3-
of the cerebral acetylcholine at such low doses wherein they effect the peripheral serum choline esterase not at all or only very slightly.
As choline esterase inhibitor physostig ine has been used, which possesses considerable side-effects (vomiting, nausea, epileptiform spasms etc.). Due to these side-effects the application of this drug is restricted.
Another reversible choline esterase inhibitor is the l,2,3,4-tetrahydro-9-acridinamine (tacrine) [Koopmans Summers et al.: Engl. J. Med. , 315, 1241-45 (1986)].
The multicentric trials carried out with tacrine in the United States [Javlik, L.F.: Alzheimer's Disease and Associated Disorders 1 , 123-127 (1987] were suspended due to the serious hepatotoxic side-effects of the drug. Later the FDA suggested [Pharm. Ind. 5_3, (12) 277-78 (1991)] a so- called "extended availability" programme for 2-3000 patients. This programme enables physicians to prescribe tacrine for those patients who fail to react to any other drug. At present about 15,000 patients are treated with tacrine under the sponsorship of the manufacturer.
Several attempts have been made to modify the structure of tacrine, and a great number of tacrine derivatives have been described in the literature. The published European patent applications Nos. 411,534, 427,636 and 319,429 provide tacrine derivatives acylated at the amino group.
These acridine derivatives are reported to be useful for the treatment of Alzheimer's disease. The substituted tetra- hydroacridines described in Khim-Pharm. Zh. .23., (12) 1441-2
(1989) exert antidepressant activity and are comparable with amitriptyline
The aim of the present invention is to eliminate the above-mentioned drawbacks of tacrine and to provide new compounds which possess the reversible cholinesterase- inhibiting effect of tacrine but are devoid of its undesirable side-effects.
The new compounds according to the invention meet the above requirements.
The term "aryl group" used throughout the specification relates to the phenyl and naphthyl groups that may optionally carry substituents such as lower alkyl, lower alkoxy, hydroxy, nitro, amino or halogen. The term "lower" covers groups having 1 to 7, preferably 1 to 4, carbon atθ-n(s) . The term "lower alkyl" or "lower alkoxy" refers to straight or branched chained alkyl or alkoxy groups (e.g. methyl, ethyl, propyl, ethoxy, methoxy, isopropoxy, etc.). The term "halogen atom" encompasses the fluorine, chlorine, bromine and iodine atoms. The term "aralkyl" covers lower alkyl groups carrying one or two aryl substituent(s) (e.g. benzyl, beta-phenylethyl, β,β-diphenylethyl, etc.). The term "heteroaryl" relates to heteroaromatic groups comprising one or two ring(s) and containing one or two nitrogen, oxygen and/or sulfur atom(s) (e.g. pyridyl, pyrimidinyl, thiazolyl, oxazolyl, i idazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, etc.). The aralkyl and heteroaryl groups may carry one or two substituent(s) enumerated in connection with the aryl group.
Preferred representatives of the compounds of general formula (I) are those wherein B stands for piperazino optionally carrying a phenyl or benzyl substituent optionally substituted by halogen, pyridyl or pyrimidinyl, and pharmaceutically acceptable acid-addition salts thereof. Particularly preferred representatives of the compounds of general formula (I) are the following derivatives: N-(l,2,3,4-tetrahydroacridin-9-yl)-2-[ (3-chlorophenyl)- piperazin-1-y1]-acetamide, N-(1,2,3,4-tetrahydroacridin-9-yl)-2-[ (N-benzyl)-piperazin- 1-yl]-acetamide,
N-(1,2,3,4-tetrahydroacridin-9-yl)-2-[ (4-fluorobenzyl)- piperazin-1-yl]-acetamide, N-(1,2,3,4-tetrahydroacridin-9-yl)-2-[1-(2-pyridiyl)- piperazin-1-yl]-acetamide,
N-(1,2,3,4-tetrahydroacridin-9-y1)-2-[4-(2-pyrimidyl)- piperazin-l- 1]-acetamide, and pharmaceutically acceptable acid-addition salts thereof.
The pharmaceutically acceptable acid-addition salts of the compounds of general formula (I) can be formed with inorganic or organic acids (e.g. hydrohalides such as hydrochlorides or hydrobromides; sulfates, nitrates, phosphates, acetates, propionates, maleates, fumarates, lactates, succinates, ascorbinates, tartrates, etc.) or with sulfonic acids (e.g. benzenesulfonates, methanesulfonates, p-toluenesulfonates) .
According to a further aspect of the present invention there is provided a process for the preparation of compounds of general formula (I) and pharmaceutically accceptable acid-addition salts thereof, which comprises a) reacting a haloacetamide derivative of general formula (ID,
wherein Hlg stands for chlorine, bromine or iodine, with a compound of general formula (V) ,
HB (v)
wherein B is as stated above; or b) reacting an amino compound of formula (III )
(III ) with a reactive acetic acid derivative of general formula (IV),
B-CH2-C0 -X (iv)
wherein X is a reactive group and Hlg is as stated above, and, if desired, converting the thus-obtained compound of general formula (I) into a pharmaceutically acceptable acid- addition salt or setting free a base of general formula (I) from an acid-addition salt.
According to process variant a) the reaction of the compounds of general formulae (II) and (V) is carried out in a known manner. The reaction is preferably performed in an inert organic solvent. As reaction medium preferably protic solvents, particularly aliphatic alcohols (e.g. ethanol or isopropanol) , aromatic hydrocarbons (e.g. benzene, toluene or xylene) or ethers (e.g. diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane) can be used. The reaction is carried out in the presence of a basic condensing agent. For this purpose organic bases (e.g. pyridine, picoline, lutidine or triethylamine) or alkali carbonates (e.g. sodium carbonate or potassium carbonate) can be used. The reaction is carried out at a temperature between 0 °C and 130 °C, preferably at a temperature between 40 °C and 90 °C. According to process variant b) an amino compound of formula (III) is reacted with a compound of general formula (IV) by methods known per se . The compounds of general formula (IV) used as starting substances may be, depending on the meaning of X, free carboxylic acids, acid halides, esters, acid anhydrides or mixed anhydrides. It is preferable to apply carboxylic acids of general formula (IV) , wherein X represents hydroxy, acid halides (X stands for chlorine or bromine) or esters (X stands for lower alkoxy such as methoxy or ethoxy) . The reaction of the compounds of general formulae (III) and (IV) can be carried out in an inert solvent. As reaction medium the solvents mentioned in connection with process variant a) can be used. The reaction is preferably performed under heating.
The thus-obtained compounds of general formula (I) can be isolated from the reaction mixture by methods known per se .
The compounds of general formula (I) can be converted into pharmaceutically acceptable acid-addition salts with the appropriate acids by methods known per se , or can be liberated from their salts in a known manner. The 9-amino-l,2,3,4-tetrahydroacridine of general formula (III) used as starting substance for the process according to the invention can be prepared as specified in J. Soc. Chem. Ind. 64, 16972 (1945) . The acetamide derivatives of general formula (II) can be produced as specified in Chem. Listy 5_1, 1906-8 (1957) and the substituted acetic acid derivatives of general formula (IV) can be prepared as described e.g. in Acta Univ. Szegediensis, Acta Phys. et Chem. 6_, 80-6, 1960 or Acta Pharm. Hung. 3.1, 113-21 (1961) or in the U.S. patent specification No. 2,568,141.
According to a further aspect of the present invention there are provided pharmaceutical compositions comprising as active ingreident a compound of general formula (I) or a pharmaceutically acceptable acid-addition salt thereof in admixture with suitable inert solid or liquid pharmaceutical carriers.
The pharmaceutical compositions of the present invention can be prepared by methods known per se by admixing the active ingredient with suitable inert solid or liquid carriers and bringing the mixture to galenic form.
The pharmaceutical compositions of the present invention may be suitable for oral (e.g. tablet, pill, coated pill, dragee, capsule, drop, solution or suspension) , parenteral (e.g. injection solution) or rectal (e.g. suppository) administration.
As carrier for the preparation of pharmaceutical compositions to be administered orally e.g. corn starch, potato starch, lactose, etc. can be used. The solid pharmaceutical compositions may comprise usual additives (such as lubricants, stabilizers, emulsifiers, disintegrating agents, salts or buffers causing the change of osmotic pressure) . The capsules may be soft or hard gelatin capsules. The suppositories may contain usual synthetic or natural base materials (e.g. cocoa butter, fatty acid triglycerides, Witepsol, etc.). The injections are usually aqueous solutions which can be isotonized with sodium chloride.
The daily dose of the compounds of general formula (I) can vary within wide ranges depending on several factors, e.g. on the activity of the active ingredient, the patient's condition and age, the severity of the disease, etc. The oral dose is generally 1 to 1000 mg/day, while the parenteral dose is generally 0.1 to 100 mg/day, preferably 0.1 to 50 mg/day. The daily dose of the compounds of the present invention may be administered at once or in several (e.g. three) portions with appropriate intervals. Determination of the proper dosage for a particular situation is within the skill of the art.
According to a further aspect of the present invention there is provided a process for the preparation of pharmaceutical compositions, which comprises admixing a compound of general formula (I) or a pharmaceutically acceptable acid-addition salt thereof with suitable inert solid or liquid therapeutical carriers.
According to a further aspect of the present invention there is provided the use of the compounds of general formula (I) or pharmaceutically acceptable acid-addition salts thereof for the preparation of pharmaceutical compositions useful for the treatment of Alzheimer's disease. According to a still further aspect of the present invention there is provided a method for the treatment of Alzheimer's disease, which comprises administering to a patient an effective amount of a compound of general formula (I) or a pharmaceutically acceptable acid-addition salt thereof. The new compounds of general formula (I) are remarkable for their low toxicity and selective cholinesterase- inhibiting effect.
We have studied the effect of the new compounds on acetylcholine esterase of the rat brain and on human serum pseudocholine esterase. The experiments were carried out according to the method of Ellman et al. [Ellman. G.L., Country, K.D. and Adreas, U.J.: Biochem. Pharmacology 1_, 88- 95 (1961)].
The ratio of the inhibitions exerted on the two kinds of enzyme provides information on the specificity of the inhibition. These enzymes are much more liable to split thiocholine esters than the physiological substrates thereof. Thiocholine formed as a consequence of the enzyme activity can be determined by photometry when reacted with dithio-bis-nitrobenzoic acid (DTNB) .
Tacrine waε used as reference substance. The inhibitory activity of the test compounds at a concentration of 10~5 M (inhibition %) and ID50 values are shown in the following Tables.
Tablβ 1
Compound Concentration ACE, rat brain (No. of Example) M inhibition % IC50 [MM]
6 10-5 3.6
7 10-5 9.6 5 10-5 80.6 1.81 1 10-5 85.4 0.59 3 10-5 82.8 1.68 2 10-5 70.3 3.50
Tacrine 10 -5 85.5 0.23
Table 2
Compound Concentration Human serum ACE (No. of Example) M inhibition % IC50 [ M]
6 10-5 23.0 7 10-5 5.7 5 10-5 39.8 13.20 1 10-5 54.5 8.20 3 10-5 65.0 6.00 2 10-5 63.7 6.20
Tacrine 10 -6 95.1 0.02 Table 3
Compound Concentration Human serum pCE (No. of Example) M inhibition % IC50 [MM]
6 10"5 28.9
7 10-5 13.3 5 10"5 33.8 16.90 1 10"5 55.4 9.17 3 10-5 62.2 6.50 2 10"5 58.8 7.10
Tacrine 10-6 96.5 0.04
The data of the above Tables show that while tacrine inhibits serum choline esterases more effectively than cerebral acetylcholine esterase, the compounds of Examples 5 and 1 inhibit cerebral choline esterase 10-16 times more effectively than they inhibit the non-specific serum choline esterases.
The invention is further illustrated by the following examples of non-limiting character.
Example 1
N-(1,2,3,4-Tetrahydroacridin-9-yl)-2-[ (3-chlorophenyl) piperazin-l-y1]-acetamide
11.0 g (0.04 mole) of 9-(chloroacetylamino)-1,2,3,4- -tetrahydroacridine dissolved in 22 ml of pyridine are reacted with 8.65 g (0.044 mole) of 1-(3-chlorophenyl)- -piperazine at a temperature between 80 °C and 85 °C for 5 hours. The excess of the amine and the solvent are distilled off and the product is purified by acidic-alkaline precipitation or recrystallization.
Yield: 14.9 g (85.6 %) .p. : 136-139 °C (toluene) Analysis for the formula C25H27CIN4O (434.98):
Calculated: C: 69.03 % H: 6.26 % Cl: 8.15 % N: 12.88 %
Found: C: 69.20 % H: 6.20 % Cl: 8.03 % N: 12.84 %
UV: λ 324 nm e: 11879 242 nm 47064
Example 2
N-(1,2,3,4-Tetrahydroacridin-9-yl)-2-[ (N-benzyl)- -piperazin-1-yl]-acetamide
One proceeds according to Example 1 except that N- benzyl-piperazine (7.76 g, 0.0044 mole) is used as amine. Yield: 15.38 g (92.8 %) M.p. : 129.7-130.4 °C (cyclohexane) Hydrochloride (1/3) M.p.: 184-190 °C
Analysis for the formula C26H33CI3N4O (523.95): Calculated: C: 59.60 % H: 6.35 % Cl: 20.30 % N: 10.69 % Found: C: 59.05 % H: 6.57 % Cl: 19.88 % N: 10.75 % UV: λ 233 nm e: 37167 307 nm 6524
320 nm 7567
Example 3
N-(1,2,3,4-Tetrahydroacridin-9-yl)-2-[ (4-fluorobenzyl) - -piperazin-1-yl]-acetamide
One proceeds as specified in Example 1 except that (4- fluorobenzyl) -piperazine (8.55 g, 0.44 mole) is used as amine. Yield: 15.6 g (90.2 %) M.p.: 147.8-149.3 °C (aceto- nitrile) Hydrochloride (1/3) M.p.: 212.9-213.4 °C (96 % ethanol) Analysis for the formula C26H32CI3FN4O (541.95): Calculated: C: 57.62 % H: 5.95 % F: 3.51 % N: 10.34 % Found: C: 57.05 % H: 6.06 % F: 3.47 % N: 10.20 %
N-(1,2,3,4-Tetrahydroacridin-9-yl) -2-[1-(2-pyridyl)- piperazin-l-yl]-acetamide
One proceeds as specified in Example 1 except that 1- (2-pyridinyl)-piperazine (7.18 g, 0.044 mole) is used as amine. Yield: 11.7 g (68.9 %) M.p.: 170.8-171.3 °C (aceto- nitrile) Hydrochloride-ethanol (1/3:1) M.p.: 263-264 °C Analysis for the formula C26H36CI3N5O2 (556.985): Calculated: C: 56.07 % H: 6.52 % N: 12.57 % Found: C: 56.79 % H: 6.64 % N: 12.43 % UV: Λ 316 nm e: 20439
239 nm 57974
Example 5
N-(1,2,3,4-Tetrahydroacridin-9-yl) -2-[4-(2-pyrimidyl)- piperazin-l-yl]-acetamide
One proceeds as specified in Example 1 except that 1- (2-pyrimidinyl) -piperazine (7.22 g, 0.044 mole) is used as amine.
Yield: 11.2 g (69.7 %) M.p.: 185-189 °C (aceto- nitrile) Analysis for the formula C 3H26 6θ (402.51): Calculated: C: 68.63 % H: 6.51 % N: 20.88 % Found: C: 69.20 % H: 6.53 % N: 20.47 % UV: 235 nm e: 58922 287 n 6168 307 nm 6337
320 nm 6337 Example 6
N-(1,2,3,4-Tetrahydroacridin-9-yl) -2-(8-azaspiro-
[4,5]decane-7.9-dion-8-yl)-acetamide
One proceeds as specified in Example 1 except that 8- azaspiro[4.5]decane-7.9-dione (7.36 g, 0.044 mole) is used as amine.
Yield: 11.4 g (70.1 %) M.p.: 257-260 °C (aceto- nitrile) Analysis for the formula C24H27N3O3 (405.49) : Calculated: C: 71.08 % H: 6.71 % N: 10.36 % Found: C: 70.63 % H: 6.34 % N: 10.08 % UV: A 230 nm e: 39806 292 nm 5524 306 nm 5787
320 nm 6318
Example 7
N-(1,2,3,4-Tetrahydroacridin-9-yl) -2-(1,2,4-triazolo- [4,3-a]pyridyl-3 (2H) -one)-acetamide
One proceeds as specified in Example 1 except that the reaction is carried out in a 20:1 mixture of isopropanol and dimethylformamide and 5.94 g (0.044 mole) of 1,2,4- triazolo[4, 3-a]pyridin-3 (2H) -one are used as amine. Yield: 10.93 g (73.2 %) M.p.: 288-290 °C Analysis for the formula C21H19N5O2 (373.42): Calculated: C: 65.54 % H: 5.13 % N: 18.76 % Found: C: 67.10 % H: 5.23 % N: 18.97 % uv: Λ 262 nm e: 6427 294 nm 7378
307 nm 8105
321 nm 9121
Example 8
Tablet comprising 25 mg of active ingredient Composition of one tablet is as follows :
Active ingredient 25. 0 mg
Corn starch 97. 0 mg
Polyvinylpyrrolidone 175. 0 mg Magnesium stearate 3. 0 mσ
300.0 mg
The tablet is prepared as follows:
The active ingredient and the corn starch are admixed, then wetted with 10-15 % by weight of aqueous polyvinyl¬ pyrrolidone solution and the mixture is granulated, then dried at a temperature of 40 to 50 °C. The dry granules are rubbed through a sieve, mixed with talc and magnesium stearate and tablets are prepared from the mixture. The weight of one tablet is 300 mg.
Example 9
Tablet comprising 250 mg of active ingredient
Composition of one tablet is as follows :
Active ingredient 250. 0 mg
Lactose 270. 0 mg
Corn starch 75. 0 mg
Magnesium stearate 5. 0 mσ 600. 0 mg
The tablet is prepared as follows:
The active ingredient, the lactose and the corn starch are wetted and mixed, granulated and dried at a temperature of 40 to 50 °C. The dry granules are rubbed through a sieve, mixed with magnesium stearate and tablets are formed.
The weight of one tablet is 600.0 mg.
Example 10 Dragee comprising 25 mg of active ingredient The composition of one dragee core is as follows:
Active ingredient 25.0 mg
Corn starch 245.0 mg
Talc 18.0 mg Gelatin 8.0 mg
Magnesium stearate 4.0 mg
300.0 mg
The dragee is prepared as follows: The active ingredient and the corn starch are mixed, wetted with 10 % by weight aqueous gelatin solution, granules are formed from the wet mixture and the granules are dried at a temperature of 40 to 50 °C. The dry granules are rubbed through a sieve, homogenized with talc and magnesium stearate and dragee cores of 300.0 mg are compressed from the mixture.
Example 11
Dragee comprising 50.0 mg of active ingredient
The composition of one dragee core is as follows:
Active ingredient 50.0 mg
Lactose 97.0 mg
Polyvinylpyrrolidone 2.0 mg Magnesium stearate l.o mσ
150.0 mg
The granules are prepared as described in Example 10. The weight of one dragee core is 150.0 mg. The dragee cores are coated with a layer containing sugar and talc in a manner known per se . The dragee thus obtained is painted with non-toxic food paint to the desired colour and polished with bee-wax.
Example 12
Gelatin capsule comprising 5.0 mg og active ingredient The composition of one gelatine capsule is as follows:
Active ingredient 5.0 mg
Corn starch 40.0 mg
Aerosil 3.0 mg Magnesium stearate 2.0 aσ
50.0 mg
The components are homogenized and filled into gelatin capsules of suitable size.
Example 13
Gelatine capsule comprising 25.0 mg of active ingredient
The composition of one gelatin capsule is as follows: Active ingredient 25.0 mg
Corn starch 265.0 mg
Aerosil 6.0 mg
Magnesium stearate 4.0 mα 300.0 mg
The ingredients are homogenized and filled into gelatin capsules of suitable size.
Example 14
Gelatine capsule comprising 50 mg of active ingredient
The composition of one gelatin capsule is as follows:
Active ingredient 50.0 mg corn starch 90.0 mg
Aerosil 6.0 mg
Magnesium stearate 4.0 mg
150.0 mg
The ingredients are homogenized and filled into gelatin capsules of suitable size. Example 15
Gelatine capsule comprising 250 mg of active ingredient
The composition of one gelatin capsule is as follows : Active ingredient 250. 0 mg
Lactose 148. 0 mg
Magnesium stearate 2 . 0 mg
400. 0 mg
The ingredients are homogenized and filled into gelatine capsules of suitable size .
Example 16
Injection comprising 25. 0 mg of active ingredient
The composition of one ampoule is as follows: Active ingredient 25.0 mg
Sodium chloride 5.0 mg dissolved in 5 cm3 of twice-distilled water.
The active ingredient and sodium chloride are dissolved in the necessary amount of twice-distilled water suitable for making injections . The solution is filtered, filled into ampoules and sterilized.
Example 17
Injection comprising 50.0 mg of active ingredient
The composition of one ampoule is as follows : Active ingredient 50.0 mg
Sodium chloride 10.0 mg
The active ingredient and sodium chloride are dissolved in the necessary amount of twice-distilled water, then filled into ampoules under sterile conditions. Example 18
Suppository comprising 250.0 mg of active ingredient
The composition of one suppository is as follows: Active ingredient 250.0 mg
Fatty acid glyceride 750.0 mg
1000.0 mg
The fatty acid glyceride is melted, the active ingredient is homogenized, then poured into a mould. One suppository weights 1000.0 mg and comprises 250.0 mg of active ingredient.
Example 19 Drop comprising 10 % of active ingredient
Active ingredient 50.0 mg
Sorbitol 340.0 mg
Polyethylene glycol 100.0 mg Citric acid 1.0 mg
Sodium citrate 3.0 mg
Ion-free water 1.0 cm3
Flavourant 1.0 mg
500.0 mg
The sorbitol, the active ingredient, the citric acid and the sodium citrate are dissolved in the aqueous solution of propylene glycol, then after dissolution of the solid materials the flavourant is added. The solution is filtered and filled into flasks supplied with a drop-dispenser.

Claims

What we claim is:
1. Acetic acid amide derivatives of general formula (I),
wherein
R stands for hydrogen and
B represents piperaz ino, 8-azaspiro[4,5]decane-7,9-dion-8-yl or 2-(1,2,4-triazolo[4,3-a]pyridyl-3(2H)-on-2-yl) optionally carrying an aryl, aralkyl or heteroaryl substituent
and pharmaceutically acceptable acid addition salts thereof.
2. Compounds of general formula (I), wherein B stands for piperaz ino optionally carrying a phenyl or benzyl substituent optionally substituted by halogen, pyridiyl or pyrimidinyl, and pharmaceutically acceptable acid-addition salts thereof.
3. The following compounds of general formula (I):
N-(1,2,3,4-tetrahydroacridin-9-yl)-2-[(3-chlorophenyl)-piperazin-1-yl]-acetamide,
N-(1,2,3,4-tetrahydroacridin-9-yl)-2-[(N-benzyl)-piperazin- 1-yl]-acetamide,
N-(1,2,3,4-tetrahydroacridin-9-yl)-2-[(4-fluorobenzyl)-piperazin-1-yl]-acetamide,
N-(1,2,3,4-tetrahydroacridin-9-yl)-2-[1-(2-pyridiyl)-piperazin-1-yl]-acetamide,
N-(1,2,3,4-tetrahydroacridin-9-yl)-2-[4-(2-pyrimidyl)-piperazin-1-yl]-acetamide,
and pharmaceutically acceptable acid-addition salts thereof.
4. Pharmaceutical compositions comprising as active ingredient a compound of general formula (I) or a pharmaceutically acceptable acid-addition salt thereof in admixture with suitable inert solid or liquid pharmaceutical carriers.
5. A process for the preparation of pharmaceutical compositions according to claim 4, which comprises admixing a compound of general formula (I) or a pharmaceutically acceptable acid-addition salt thereof with suitable inert solid or liquid pharmaceutical carriers.
6. Use of compounds of general formula (I) or pharmaceutically acceptable acid-addition salts thereof for the preparation of pharmaceutical compositions useful for the treatment of Alzheimer's disease.
7. A method for the treatment of Alzheimer's disease, which comprises administering to a patient an effective amount of a compound of general formula (I) or a pharmaceutically acceptable acid-addition salt thereof.
8. A process for the preparation of compounds of general formula (I) and pharmaceutically acceptable acid-addition salts thereof, which comprises
a) reacting a haloacetamide derivative of general formula (II),
wherein Hlg stands for chlorine, bromine or iodine ,
with a compound of general formula (V) , (v)
HB wherein B is as stated above; or
b) reacting an amino compound of formula (III)
with a reactive acetic acid derivative of general
formula (IV),
B-CH2-CO -X (Iv) wherein X is a reactive group and Hlg is as stated above,
and, if desired, converting the thus-obtained compound of general formula (I) into a pharmaceutically acceptable acid-addition salt or setting free a base of general formula (I) from an acid-addition salt.
9. A process as claimed in claim 8. a), which comprises using organic bases, preferably pyridine, picoline, lutidine or triethylamine, as basic condensing agent.
10. A process as claimed in claim 8. a), which comprises using alkali carbonates, preferably sodium carbonate or potassium carbonate, as basic condensing agent.
11. A process as claimed in any of claims 8. a), 9 or 10, which comprises carrying out the reaction in an inert organic solvent.
12. A process as claimed in claim 11, which comprises using protic solvents, preferably aliphatic alcohols, or aromatic hydrocarbons or ether as inert solvent.
13. A process as claimed in claim 12, which comprises using ethanol, isopropanol, benzene, toluene, xylene, di ethyl ether, diisopropyl ether, tetrahydrofuran or dioxane as inert organic solvent
14. A process as claimed in any of claims 8.a) or 9 to 13, which comprises carrying out the reaction at a temperature between 0 °C and 130 °C, preferably between 40 °C and 90 °C.
15. A process as claimed in claim 8.b), which comprises using compounds of general formula (IV), wherein X represents hydroxy, chlorine, bromine or lower alkoxy, preferably methoxy or ethoxy, as starting substance.
16. A process as claimed in claim 15, which comprises carrying out the reaction in an inert organic solvent.
17. A process as claimed in claim 16, which comprises using protic solvents (preferably aliphatic alcohols), aromatic hydrocarbons or ethers as inert solvent.
18. A process as claimed in claim 17, which comprises using ethanol, isopropanol, benzene, toluene, xylene, diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane as inert organic solvent.
19. A process as claimed in any of claims 8.b) or 15 to 18, which comprises carrying out the reaction under heating.
20. A process as claimed in any of claims 8 to 19 for the preparation of compounds of general formula (I) containing in the place of B piperazino optionally carrying a phenyl or benzyl substituent optionally substituted by a halogen atom, pyridyl and pyrimidinyl, which comprises using the appropriate starting substances.
21. A process as claimed in claim 20 for the preparation of the following compounds:
N-(1,2,3,4-tetrahydroacridin-9-yl)-2-[(3-chlorophenyl)-piperazin-1-yl]-acetamide,
N-(1,2,3,4-tetrahydroacridin-9-yl)-2-[(N-benzyl)-piperazin-1-yl]-acetamide,
N-(1,2,3,4-tetrahydroacridin-9-yl)-2-[(4-fluorobenzyl)-piperazin-1-yl]-acetamide,
N-(1,2,3,4-tetrahydroacridin-9-yl)-2-[1-(2-pyridiyl)- piperazin-1-yl]-acetamide,
N-(1,2,3,4-tetrahydroacridin-9-yl)-2-[4-(2-pyrimidyl)-piperazin-1-yl]-acetamide,
and pharmaceutically acceptable acid-addition salts thereof, which comprises using the appropriate starting substances.
EP95909911A 1994-02-23 1995-02-22 Acetic acid amide derivatives and process for the preparation thereof Withdrawn EP0746549A1 (en)

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HU9400517A HU213107B (en) 1994-02-23 1994-02-23 Process for producing acetic acid derivatives and pharmaceutical compositions containing them
PCT/HU1995/000003 WO1995023137A1 (en) 1994-02-23 1995-02-22 Acetic acid amide derivatives and process for the preparation thereof

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EP1415651A4 (en) * 2001-08-06 2005-11-09 Mitsubishi Pharma Corp Preventives/remedies for cholinergic neuropathy
JP4598674B2 (en) * 2003-01-08 2010-12-15 田辺三菱製薬株式会社 Schizophrenia treatment
US7378524B2 (en) 2003-04-11 2008-05-27 Taigen Biotechnology Co., Ltd. Aminoquinoline compounds
CA2521619A1 (en) 2003-04-11 2004-10-28 Taigen Biotechnology Aminoquinoline compounds
GB0316094D0 (en) 2003-07-09 2003-08-13 Neuropharma Sa Acetylcholinesterase dual inhibitors
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CN105367553A (en) * 2015-12-04 2016-03-02 广东工业大学 Tacrine-8-hydroxyl(amine)quinoline derivative and application thereof

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