HU213107B - Process for producing acetic acid derivatives and pharmaceutical compositions containing them - Google Patents

Description

The present invention relates to novel acetic acid amide derivatives and to pharmaceutical compositions containing them.

The novel compounds of the present invention are represented by Formula I wherein R is hydrogen and

B is piperazino optionally substituted with halo-substituted phenyl or optionally halo-substituted benzyl or pyridyl or pyrimidinyl or 8-aza-spiro [4,5] decane-7,9-dion-8-yl or 1,2,4-triazolo [4,3-a] pyridin-3 (2H) -one-2-yl.

The present invention also relates to the preparation of pharmaceutically acceptable acid addition salts of the compounds of formula (I).

It is therefore an object of the present invention

- a process for the preparation of the compounds of formula I and their pharmaceutically acceptable acid addition salts; and

a process for the preparation of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.

The novel compounds of the present invention have valuable therapeutic effects, more particularly in the treatment of Alzheimer's disease, and have few side effects.

Dementia is a common diagnosis in old age, which is an impairment of cognitive function, and of adapting to the recognition of situations in everyday life. The neuropathological basis is the plaque-depressing plaque described by Alois Alzheimer in 1906, and these symptoms are called Alzheimer's disease.

The spread of the disease is increasing rapidly with the average age and the spread of urbanization. Currently, about 15% of the population over 65 and 20% of those over 80 suffer from some form of dementia. In the United States in 1982 10 (Terry and Katzman, 1983) spent $ 34 billion in 1985 and $ 40 billion in 1987 for the care of patients with all forms of dementia. In 1985, 2.5 million people were affected. According to Szilágyi (1985) the situation was similar in Hungary in terms of proportions as well.

To our knowledge, it is impossible to cure Alzheimer's disease, so far the following methods have been used to treat it:

(a) The reduction of the cholinergic system malfunction was improved by high dose administration of the acetylcholine precursor choline. The method was ineffective for most treatments. (John et al., 1983).

b) another approach is to reduce the rate of acetylcholine degradation in the synaptic cleft, thereby enhancing the effect of the reduced amount of acetylcholine released, with a temporary improvement in Alzheimer's disease by cholinesterase inhibition (Doris et al., 1982, 1983). patients.

However, inhibition of non-CNS cholinesterases also increases acetylcholine levels in the visceral organs. The resulting fall in blood pressure, increased bowel function, and heart rate slowdown cause unpleasant side effects when using this medication. Therefore, the aim is to develop drugs which inhibit brain acetylcholine degradation at low concentrations in which peripheral serum cholinesterase has no, or only very limited, effect.

Physostigmine was used as a cholinesterase inhibitor, which has significant side effects (vomiting, epileptiform cramps, nausea, etc.). Due to its side effects its use is limited.

Tetrahydro-amino-acridine (Tacrin) (Koopmans Summers et al.) Was also used as a reversible cholinesterase inhibitor. al., Engl. J. Med. 315: 1241-45 (1986)].

Tacrin American Multicentric Trial [Javik,

L. E, Alzheimer's Disease and Associated Diserders 1, 123-127 (1987)] has been stopped because of its severe hepatotoxicity. Later [Pharm. Ind. 53, (12) 277-78 (1991)] proposed the FDA's "Extended Accessibility" program to 2-3000 patients. This program allows doctors to prescribe Tacrine to patients who do not respond to other drugs despite their side effects. About 15,000 patients are currently being treated with funding from the manufacturing company.

Several attempts have been made to modify the structure of Tacrin, and numerous Tacrin derivatives have been described in the literature, including U.S. Pat. Nos. 411,534, 427,636, and 319,429. European patent applications discloses Tacrin derivatives acylated on the amino group. These acridine derivatives are known to be useful in the treatment of Alzheimer's disease. Khim Farm. Zh. 23, (12) 1441-2 (1989) substituted tetrahydroacridines are antidepressant and are comparable to amitriptyline.

It is an object of the present invention to overcome the above-mentioned drawbacks of Tacrin and to provide novel compounds which retain the inhibitory action of Tacrin reversible cholinesterase while being free of the adverse side effects of Tacrin.

The above object was solved by the preparation of new compounds of formula (I).

Preferred compounds of formula (I) are the following: N- (1,2,3,4-Tetrahydroacridin-9-yl) -2- [4- (3-chlorophenyl) piperazin-1-yl] - acetamide;

N- (1,2,3,4-tetrahydroacridin-9-yl) -2- [4- (N-benzyl) piperazin-1-yl] acetamide;

N- (1,2,3,4-tetrahydroacridin-9-yl) -2- [4- (4-fluorobenzyl) piperazin-1-yl] acetamide;

N- (1,2,3,4-tetrahydroacridin-9-yl) -2- [4- (2-pyridyl) piperazin-1-yl] acetamide;

N- (l, 2,3,4-tetrahydroacridin-9-yl) -2- [4- (2-pyrimidyl) piperazin-1-yl] acetamide.

Pharmaceutically acceptable salts of the compounds of formula (I) include inorganic acids (e.g., hydrogen halides such as hydrochlorides or hydrobromides; sulfates, nitrates, phosphates), organic acids (e.g. succinates, ascorbates, tartrates, etc.) or salts with sulfonic acids (e.g., benzenesulfonates, methanesulfonates, ptoluenesulfonates).

HU 213 107 Β

According to the present invention, the compounds of formula (I) and their pharmaceutically acceptable acid addition salts are prepared by reacting a haloacetamide derivative of formula (Π) wherein Hig is chlorine, bromine or iodine in the presence of a basic condensing agent (V). reacting a compound of formula (I) wherein B is as defined above, optionally converting the resulting compound of formula (I) into a pharmaceutically acceptable acid addition salt or liberating the salt thereof.

In the process of the present invention, the reaction of the compounds of formula (Π) and (V) may be carried out in a manner known per se. The reaction is preferably carried out in an inert organic solvent. Preferably, the reaction medium is protic solvents, especially aliphatic alcohols (e.g., ethyl alcohol, isopropyl alcohol, etc.) or aromatic hydrocarbons (e.g., benzene, toluene or xylene) or ethers (e.g., diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane). The reaction is carried out in the presence of a basic condensing agent. Organic bases (e.g., pyridine, picoline, lutidine, or triethylamine) or alkali metal carbonates (e.g., sodium carbonate or potassium carbonate) may be used. The reaction may be carried out at a temperature of ΟΙ 30 ° C; preferably at temperatures between 40 ° C and 90 ° C.

The compounds of formula (I) obtained can be isolated from the reaction mixture by methods known per se.

The compound of formula (I) may be converted into its pharmaceutically acceptable acid addition salts by treatment with the appropriate acid in a manner known per se or in a known manner.

The acetamide derivative of formula (használt) used as starting material for the process of the invention can be prepared according to Chem. Listy, 57, 1906-8 (1957).

The present invention further relates to the preparation of a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. These pharmaceutical compositions may contain other pharmaceutically active substances in addition to the active ingredient. The formulations contain inorganic solid or liquid, organic or inorganic carriers customary in the pharmaceutical field. The compositions may be prepared in oral (e.g., tablet, coated tablet, capsule, dragee, drop, solution or suspension), rectal (e.g., suppository) or parenteral (e.g., intravenous, subcutaneous or intramuscular injection) form. Solid compositions for oral administration include, e.g. starch, lactose, etc. contain. Solid compositions may also contain conventional excipients (eg lubricants, stabilizers, disintegrants, emulsifiers, salts or buffers to produce osmotic pressure changes). The capsules may be hard or soft gelatin capsules. Suppositories may contain conventional synthetic or natural suppository bases (e.g., cocoa butter, fatty acid triglycerides, Witepsol, etc.). Injection preparations are generally aqueous solutions which are isotonic with saline.

The formulations are prepared by known methods of drug manufacture.

The daily dose of the compounds of formula I may vary within wide limits and will depend on several factors (e.g., route of administration, age and condition of the patient, severity of the disease, etc.). In general, the daily dose for oral administration is usually about 1 1 mg and 1000 mg, while parenteral treatment generally has a dose of about 1 mg to 1000 mg. 0.1 mg and ca. 100 mg. The preferred parenteral dose is about 10 mg / kg. 0.1-50 mg. The above dosages may be administered in one or more daily doses, e.g. in three installments - you can enter. The above dose levels are, of course, indicative and will always be determined by the attending physician, taking into account all circumstances of the particular case.

The compounds of formula I are distinguished by their low toxicity and selective cholinesterase inhibitory activity.

The effect of the compounds on rat brain acetylcholinesterase and human serum pseudocholinesterase enzymes was investigated. Enzyme activity measurements were performed by G. L. Ellman, K. D. Country and U. J. Andres, Biochem. Pharmacology 7, 88-95 (1961).

The inhibition ratio of the two types of enzymes provides information on the specificity of the inhibition.

In essence, these enzymes cleave thiocholine esters more than their physiological substrate. The thiocholine formed by the action of the enzyme can be determined photometrically by reaction with dithiobisitrobenzoate (DTNB).

The rate of inhibition of the two enzymes provides information on the specificity of the inhibition.

Tacrine was used as reference material.

The degree of inhibition (% inhibition) and the IC ₅₀ values for the test compounds at ^10-5 M are shown in the table below.

Example Rat brain ACE inhibition% ICs, [μΜ] 6th ΙΟ ⁵ M 3.6 - 7th 9.6 - 5th 80.6 1.81 First 85.4 0.59 Third 82.8 1.68 Second 70.3 3.50 tacrine ΙΟ ⁵ 85.5 0.23

Example Human Serum ACE inhibition% ICjolpM] 6th ΙΟ ⁵ M 23.0 - 7th 5.7 - 5th 39.8 13.20 First 54.5 8.20 Third 65.0 6.00 Second 63.7 6.20 tacrine 10 ^ M 95.1 0.02

HU 213 107 Β

Example 3

N- (1,2,3,4-Tetrahydroacridin-9-yl) -2- [4- (4-fluorobenzyl) piperazin-1-yl] acetamide

Example 1 except that (4-fluorobenzyl) piperazine (8.55 g, 0.044 mol) was used as the amine.

Example Human serum pCE inhibition% ICjotpM] 6th ΙΟ ' ⁵ M 18.9 - 7th 13.3 - 5th 33.8 16.90 First 55.4 9.17 Third 62.2 6.50 Second 58.8 7.10 tacrine ^{6 -6} M 96.5 0.04

The results show that while Tacrin inhibits serum cholinesterases better than cerebral acetylcholinesterase, the compounds of Example 5 and Example 1 inhibit cerebral cholinesterase at a half-maximal concentration (IC50) of 10 to 16-fold. 20 non-specific serum cholinesterases.

The following examples further illustrate the invention without limiting it to the examples.

/. example

N- (1,2,3,4-Tetrahydroacridin-9-yl) -2- [4- (3-chlorophenyl) piperazin-1-yl] acetamide

9-Chloroacetylamino-1,2,3,4-tetra-hydroacridine (11.0 g, 0.04 mol) at 80-85 ° C in 22 ml of pyridine (8.65 g, 0.044 mol) Reaction with 1- (3-chlorophenyl) piperazine for 5 hours. After distilling off the excess amine and solvent, the product is purified by acid-alkaline conversion or recrystallization. 35

Yield: 14.9 g (85.6%) Mp: 136-139 'C (toluene)

Analysis calculated for C 25 H 27 ClN 4 O (434.98): 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 ε: 11,879; 40

242 nm 47,064

Example 2

N- (1,2,3,4-Tetrahydroacridin-9-yl) -2 - [(N-benzyl) piperazin-1-yl] acetamide

Example 1 except that N-benzylpiperazine (7.76 g, 0.044 mol) was used as the amine.

Yield: mp 129.7-130.4 ° C

15.38 g (92.8%) (cyclohexane)

Hydrochloride (1/3) Mp: 184-190 'C

Analysis calculated for C ₂₆ H ₃₃ Cl ₃ N ₄ O (523.95):

Calculated: C 59.60% H6.35% Cl 20.30% N 10.69%; Found: C, 59.05; H, 6.57; Cl, 19.88; N, 10.75.

UV λ: 233 nm ε: 37,167;

307 nm 6524;

320nm 7567

Yield:

15.6 g (90.2%) hydrochloride (1/3)

147.8-149.3 ° C (acetonitrile)

M.p. 212.9-213.4 ° C (96% ethyl alcohol)

Analysis calculated for C ₂₆ H ₃₂ Cl ₃ FN ₄ O (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%

UV λ: 233 nm ε: 36,070;

307 nm 6406;

321 nm 7322

Example 4

N- (1,2,3,4-Tetrahydroacridin-9-yl) -2- [4- (2-pyridyl) piperazin-1-yl] acetamide

Example 1 except that the amine was 1- (2-piphidylpiperazine (7.18 g, 0.044 mol).

Yield: mp 170.8-171.3 ° C

11.7 g (68.9%) (acetonitrile)

Ethyl Hydrochloride (1/3/1) Mp: 263-264 ° C

Analysis calculated for C ₂₆ H ₃₆ Cl ₃ N ₅ O ₂ (556.985):

Calculated: C, 56.07; H, 6.52; N, 12.57;

Found: C'56.79% H 6.64% N 12.43%

UVX: 316 nm ε: 20439;

239 nm 57,974

Example 5

N- (1,2,3,4-Tetrahydro-macridin-9-yl) -2- [4- (2-pyrimidyl) -piperazin-1-yl] -acetamide

Example 1 except that the amine was 1- (2-pyrimidinyl) piperazine (7.22 g, 0.044 mol).

Yield; 185-189 ° C

11.2 g (69.7%) (acetonitrile)

Analysis calculated for C ₂₃ H ₂₆ N ₆ O (402.51):

Calculated: C, 68.63; H, 6.51; N, 20.88;

Found: C, 69.20; H, 6.53; N, 20.47.

UVX: 235 nm ε: 58 922;

287 nm 6168;

307 6337;

320 6337

Example 6

N- (1,2,3,4-Tetrahydroacridin-9-yl) -2- (8-aza-spim [4,5] decane-7,9-dione-8-yl) -acetamide

Example 1 except that 8-azaspiro [4,5] decane-7,9-dione (7.36 g, 0.044 mol) was used as the amine.

HU 213 107 Β

Yield: mp: 257-260 ° C

11.4 g (70.1%) (acetonitrile)

Analysis calculated for C24H27N3O3 (405.49):

Calculated: C, 71.08; H, 6.71; N, 10.36;

Found: C 70.63% H6.34% N 10.08%

UV λ: 230 nm ε: 39,806;

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) -on-2-yl) acetamide

Example 1, except that the reaction is carried out in a 20: 1 mixture of isopropyl alcohol: dimethylformamide and the amine is 1,2,4-triazolo [4,3-a] pyridine-3 (2H) -. on (5.94 g, 0.044 mol).

Yield: 10.93 g (73.2%) Mp: 288-290 ° C

Analysis calculated for C ₂₁ H ₁₉ N ₅ O ₂ (373.42): C, 65.54; H, 5.31; N, 18.76.

Found: C, 67.10; H, 5.23; N, 18.97.

UV λ: 262 nm ε: 6427;

294 nm 7378;

307 nm 8105;

321nm 9121

Example 8

Tablets containing 25 mg of active ingredient

Active ingredient 25.0 mg

Corn starch 97.0 mg

Poly (vinylpyrrolidone) 175.0 mg

Magnesium stearate 3.0 mg

300.0 mg

manufacture:

The active ingredient and the corn starch mixture were granulated with a 10-15% aqueous solution of polyvinylpyrrolidone and then dried at 40-50 ° C. The dry granulate is repeatedly sieved through a sieve with talc and mixed with magnesium stearate and tabletted.

Weight of one tablet: 300.0 mg

Example 9

Tablets containing 250 mg of active ingredient Composition of one tablet:

Active ingredient 250.0 mg

Lactose 270.0 mg

Corn starch 75.0 mg

Magnesium stearate 5.0 mg was previously rubbed through a sieve and mixed with magnesium stearate and talc and tabletted.

Weight of one tablet: 600.0 mg

Example 10

Dragee with 25 mg of active ingredient Composition of a dragee core:

Active ingredient 25.0 mg

Corn starch 245.0 mg

Talcum 18.0 mg

Gelatin 8.0 mg

Magnesium stearate 4.0 mg

300.0 mg

Előálb'tás:

Granulation of the active ingredient and corn starch was performed after wetting with 10% aqueous gelatin solution and dried at 40-50 ° C. The dry granulate was repeatedly sieved through a sieve, homogenized with talc and magnesium stearate, and pressed into 300.0 mg dragee cores.

Example 11

Powder containing 50.0 mg of active ingredient

Composition of a dragee seed:

Active ingredient 50.0 mg

Milk sugar 97.0 mg

Poly (vinylpyrrolidone) 2.0 mg

Magnesium stearate 1.0 mg

150.0 mg

manufacture:

The granulate is prepared as described in the previous example.

Weight of the dragee seed: 150.0 mg

manufacture:

The dragee kernels are coated in a known manner with a layer of sugar and talc. The finished dragee is colored with non-toxic food coloring to the desired color and polished with beeswax.

Example 72

Gelatin capsules containing 5.0 mg of active substance

Composition of a gelatin capsule:

Active ingredient 5.0 mg

Corn starch 40.0 mg. Aerosil ”3.0 mg

Magnesium stearate 2.0 mg

50.0 mg

manufacture:

The materials are homogenized and filled into gelatin capsules of appropriate size.

600.0 mg

manufacture:

The active ingredient, lactose and corn starch are mixed with aqueous humidification and granulated and dried at 40-50 ° C. The dry granulate is

Example 13

Gelatin capsules containing 25 mg of active substance. Composition of a gelatin capsule:

HU 213 107 Β

Active ingredient 25.0 mg

Corn starch 265.0 mg. Aerosil 6.0 mg

Magnesium stearate 4.0 mg

300.0 mg

manufacture:

After homogenization, the materials are filled into gelatin capsules of appropriate size.

Example 14

Gelatin capsule containing 50 mg of active ingredient Gelatin capsule composition:

Active ingredient 50.0 mg

Lactose 90.0 mg. Aerosil 6.0 mg

Magnesium stearate 4.0 mg

150.0 mg

manufacture:

After homogenization, the materials are filled into capsules of appropriate size.

Example 15

Gelatin capsule containing 250.0 mg of active ingredient Composition of a gelatin capsule:

Active ingredient 250.0 mg

Lactose 148.0 mg

Magnesium stearate 2.0 mg

400.0 mg

manufacture:

After homogenization, the materials are filled into capsules of appropriate size.

Example 16

Injection containing 25.0 mg of active substance

Composition of an ampoule:

Active ingredient 25.0 mg

Sodium chloride 5.0 mg cm ³ dissolved in double distilled water.

manufacture:

The active ingredient and sodium chloride are dissolved in an appropriate volume of double-distilled water for injection. After filtration, the solution is filled into an ampoule and sterilized.

Example 17

Injection with 50.0 mg of active ingredient

Composition of an ampoule:

Active ingredient 50.0 mg

Sodium chloride 10.0 mg

manufacture:

The active ingredient is dissolved in the required amount of double-distilled water, sodium chloride and filled into an ampoule under sterile conditions.

Example 18

Suppositories containing 250 mg of active ingredient

Composition of a cone:

Active ingredient 250.0 mg

Fatty acid glyceride 750.0 mg

1000.0 mg

The fatty acid glyceride is melted and the active ingredient is homogenized and then molded. One suppository containing 1000.0 mg of active ingredient 250.0 mg.

Example 19

Drops containing 10% 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

Deionized water 1.0 mg

Flavoring substance 1.0 mg

500.0 mg

manufacture:

The sorbitol, the active ingredient, citric acid and sodium citrate are dissolved in an aqueous solution of propylene glycol and after dissolution, the flavoring agent is added, filtered and placed in a drop dispenser.

Claims (9)

A process for preparing acetic amides of formula (I): R is hydrogen and B is piperazino optionally substituted with halo-substituted phenyl or optionally halo-substituted benzyl or pyridyl or pyrimidinyl or 8-aza-spiro [4,5] -decan-7,9-dion-8-yl or A process for preparing 1,2,4-triazolo [4,3-a] pyridyl-3 (2H) -on-2-yl] and their pharmaceutically acceptable acid addition salts by reacting a haloacetamide of formula II a compound of formula (V) wherein B is as defined above, optionally converting the resulting compound of formula (I) to a pharmaceutically acceptable acid addition salt thereof, or a salt thereof; It is released. Process according to claim 1, characterized in that the basic condensing agent is organic bases, preferably pyridine, picoline, lutidine or triethylamine. The method of claim 1, wherein The use of alkali metal carbonates, preferably sodium carbonate or potassium carbonate as the basic condensing agent. 4. Process according to any one of claims 1 to 4, characterized in that the reaction is carried out in an inert organic solvent. 5. The process according to claim 4, wherein the inert solvent is selected from the group consisting of protic solvents, preferably aliphatic alcohols, or aromatic hydrocarbons or ethers. 6. The process according to claim 5, wherein the inorganic organic solvent used is ethyl alcohol, isopropyl alcohol, benzene, toluene, xylene, diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane. 7. Process according to any one of claims 1 to 4, characterized in that the reaction is carried out at a temperature of 0 to 130 ° C, preferably 40 to 90 ° C. 8. A method according to any one of claims 1 to 6 N- (1,2,3,4-tetrahydroacridin-9-yl) -2- [4- (3-chlorophenyl) piperazin-1-yl] acetamide; N- (1,2,3,4-tetrahydroacridin-9-yl) -2- [4- (N-benzyl) piperazin-1-yl] acetamide; N- (1,2,3,4-tetrahydroacridin-9-yl) -2- [4- (4-fluorobenzyl) piperazin-1-yl] acetamide; N- (1,2,3,4-tetrahydroacridin-9-yl) -2- [4- (2-pyridyl) piperazin-1-yl] acetamide; N- (1,2,3,4-tetrahydroacridin-9-yl) -2- [4- (2-pyrimidinyl) piperazin-1-yl] acetamide and pharmaceutically acceptable acid addition salts thereof. suitable starting materials are used. 9. A process for the preparation of a pharmaceutical composition comprising mixing a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof according to claim 1 with inert solid or liquid pharmaceutical carriers and bringing it into a galenic form. ΗΝ ~ C0 ~ CH2Hlg II.