HUT76345A - Spiro(quinazolyl-piperidine)derivatives, pharmaceutical compositions containing them and process for producing the same - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to novel spiro (quinazolinylpiperidine) derivatives of formula (I) and optionally pharmaceutically acceptable acid addition salts thereof, wherein X is carbonyl, carbonyl, -CONH, -CSNH, or sulfonyl; R is a straight or branched C 1-4 alkyl group optionally substituted with 1 to 3 halogen atoms, or aryl optionally substituted with 1 to 5 halogen atoms, C 1-4 alkyl, C 1-4 alkoxy, or 1-2 nitro groups; or aralkyl; or X and R are together hydrogen. The novel compounds of the invention have mainly a memory-enhancing effect.

Description

The present invention relates to novel spiro (quinazolinylpiperidine) derivatives of the formula I and their pharmaceutically acceptable acid addition salts.

- where

X is carbonyl, carbonyloxy, -CONH, -CSNH, or sulfonyl;

R is C 1 -C 4 alkyl, straight or branched, optionally substituted with 1 to 3 halogens; or aryl or aralkyl optionally substituted with 1 to 5 halogen atoms, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or 1 to 2 nitro groups; obsession

X and R together are hydrogen;

and a process for the preparation of the compounds by reacting the anthranilic acid amide of formula (II) in an aromatic hydrocarbon solvent, optionally in the presence of a proton catalyst, with the 1-ethoxycarbonyl-4-piperidone of formula (III); removing the ethoxycarbonyl group of the compound of formula (I) containing an oxy group, R is an ethyl group, by hydrolyzing the compound of formula (I) wherein X and R together are hydrogen, acylating or reacting with isocyanates or isothiocyanates, if desired converting a compound of formula I wherein X and R together are hydrogen into a pharmaceutically acceptable acid addition salt.

The compounds of the present invention are novel and have significant biological activity, of which the memory enhancer is the most significant. The compounds are useful in the treatment of dementias of various etiologies, in the improvement of cognitive function, and thus in the scope of the invention are pharmaceutical compositions containing the compounds of the formula I as an active ingredient, as well as processes for their preparation.

Also within the scope of the invention are methods of treatment comprising administering to a mammal, including a human being, a therapeutically effective dose of a compound of formula (I) or a salt thereof.

In the formula (I), when the substituent R is halogen, halogen may be fluorine, chlorine or bromine. R 1 is C 1-4 straight or branched chain alkyl, methyl, ethyl, ηpropyl, i-propyl, η-butyl, sec-butyl, or tert-butyl. C 1 -C 4 alkoxy means alkoxy groups corresponding to the alkyl groups listed above. When R is aryl or aralkyl, the aryl may be, for example, phenyl, pyridyl, thienyl, furyl, naphthyl, preferably phenyl.

The anthranilic acid amide compound (II) and the 1-ethoxycarbonyl-4-piperidone compound (III) used as starting material are commercially available. The acid anhydrides, acid halides, isocyanates and isothiocyanates used as reaction partners are also commercially available.

Compounds structurally related to the compounds of formula (I), but having substantially different activities, are known in the art. Alkyl and / or alkyl groups similar to those of the present invention are also preferred. aralkylspiro (quinazolinylpiperidine) derivatives are disclosed in U.S. Pat. U.S. Patent No. 3,714,093 with bronchodilator effect and Japanese Patent No. 80,143,980 with antiallergic effect.

In contrast to structurally related compounds known in the art, the compounds of formula (I) according to the invention have mainly a memory enhancing effect.

The pharmacological activity of the novel compounds of the invention was demonstrated by the following assays.

1. Passive avoidance test

The passive prevention method is the most widely used animal model for studying the effects of substances on cognitive function. It is based on the inhibition of genetically determined dark-seeking behavior in rodents (mice, rats). The one-time electric shock suffered in the dark box serves as a memory trace, the retention and recall of which can be checked after a longer period of time. Advantages of the passive prevention method include that it is based on a quick-to-learn behavior, that the learned behavior is relatively stable for a long time, and that it can be accurately determined when memory storage begins.

1.1. Diazepam-induced anterograde amnesia

1. Clarké, P.R.F. et al .:

The amnesic effect of diazepam.

Br. J. Anesth., 42: 690-697 (1970).

2. Jarvik, M.E .; Kopp, R .:

An improved one trial passive avoidance situation.

Psychol. Rep., 21: 221-224 (1974).

3. Brown, J.; Lewis, V.; Brown, M .:

A comparison between transient amnesias induced by two drugs (diazepam and lorazepan and amnesic of organic origin).

Neuropsychologic, 20: 55-69 (1982).

4. Wolkowitz, D.M. et al .:

Diazepam-induced Amnesia: a Neuropharmacological Model of An

Organic Amnesia Syndrome.

Am J Psychiatry, 144: 25-29 (1987).

Ϊ, vV _x · -, _{/ ν} Λ

Mice weighing 20-22 g were subjected to a memory test using a passive avoidance technique based on the genetically determined darkness-loving behavior of rodents. Pre-selected animals (the mouse enters the dark space within 30 seconds from the illuminated space) were placed in the illuminated space during the training. When the animal entered the dark space, it received an unpleasant electric shock (1 mA for 3 seconds) and time to space (latency) was measured. After the test, the animals were again placed in the illuminated space 24 hours later and the time to passage through the dark space (retention time) (limit time = 300 seconds) was measured.

To induce anterograde amnesia, animals were treated with diazepam 3 mg / kg intraperitoneally 30 minutes prior to study. The compound was treated orally at 0.1 and 10.0 mg / kg 1 hour prior to training. The protection effect% (P%) was calculated using the formula below.

T treated + DIA T placebo + DIA

P% = ----------------------------------------------- ---- x 100

T placebo * I placebo + DIA

1.2. Carbon dioxide induced retrograde amnesia

5. Yamanishi, A. et al.

Effects of KC-404 on Experimental Amnesia in Mice.

Jpn. J. Pharmacof. (49, Supp, 270P, 1989).

In this study, to induce retrograde amnesia, NMRI mice weighing 25-28 g were placed in a carbon dioxide-flowed box immediately after training until the momentary respiratory movement ceased (~ 15-20 seconds), followed, if necessary, by artificial ventilation. The compound was treated orally at doses of 0.1 and 10.0 mg / kg 1 hour prior to control. The protective effect of memory recall on% b (P%) was calculated using the following formula.

+ CO treated

-T placebo + CC> 2

-------------------------------------------------- --X 100 placebo placebo + C02

1.3. Electroshock (ECS) -induced retrograde amnesia

6. McGaugh, J.L .; Landfield, P.W .:

Delayed development of amnesia following electroshock.

Physiol. Behav., 5: 1109-1113 (1970).

In this study, to induce retrograde amnesia in NMRI mice weighing 24-26 g, one hour after training, auricular electroshock was applied at 20 mA for 0.2 seconds. Test materials were administered 2 hours after study. The protective effect in% (P%) was calculated using the formula below.

ECS treatment +

-T placebo + ECS

-------------------------------------------------- -X 100 placebo

-T placebo + ECS

The test results obtained are summarized in the following tables:

Table 1

Effect of Spirofinazophinylpiperidine Compounds on Diazepam-Induced Anterograde Amnesia

Compound Dose (mg / kg) p.o. Prevention% 01 10444 0.1 45 10.0 7 01 10515 0.1 114 10.0 114 01 10516 0.1 134 10.0 141 01 10517 0.1 118 10.0 82 01 10518 0.1 0 10.0 36 01 10519 0.1 143 10.0 114 01 10550 0.1 90 10.0 103 01 11239 0.1 42 10.0 109 Linopirin (DuP 996) 0.1 100 10.0 150 vinpocetine 0.1 0 10.0 123

Table 2

Effect of Spiro (Quinazophinyl-Piperidine) Compounds on Carbon-Induced Retrograde Amnesia

Compound Dose (mg / kg) p.o. Prevention% 01 10615 0.1 33 10.0 43 01 10517 0.1 0 10.0 44 01 10519 0.1 0 10.0 62 01 10550 0.1 0 10.0 31 Linopirin (DuP 996) 0.1 64 10.0 29 vinpocetine 0.3 41 10.0 10

Table 3

Effect of spiro (quinazolinylpiperidine) compound 0110519 on ECS-induced retrograde amnesia

Compound Dose (mg / kg) Prevention% 01 10519 0.1 90 10.0 51 TDN 345 1.0 24 10.0 57 TRH 1.0 77 10.0 35

The novel spiro (quinazolinylpiperidine) derivatives of the formula (I) according to the invention have been found to be very effective in the so-called cognitive function modeling. in a passive avoidance study. In the diazepam-induced anterograde amnesia test, both doses of the compounds used (0.1; 10 mg / kg) prevented amnesia. Comparing their effects with the pharmaceutically effective linopyrin and vinpocetine, their activity outweighs that of the reference compounds. 0.1 and 10 mg / kg p.o. their efficacy at doses demonstrates their anti-amnesic activity over a wide dosage range.

The compounds of the invention also appeared to be active in the CO ₂ -induced retrograde amnesia model. One of the most potent compounds, compound 0110519, showed a 62% protective effect when administered at a dose of 10 mg / kg po, which is well comparable to that of the reference compounds. The anti-amnesic effect of this compound was also demonstrated in an electro-shock-induced retrograde amnesia model. The 90% activity of the compound at a dose of 0.1 mg / kg po is superior to that of the reference compounds.

In summary:

Almost all of the compounds tested, and in particular compounds 0110515, 0110517, 0110519, 0110550 and 0111239, have significant anti-amnesic activity. Compound 0110519 is capable of inhibiting both anterograde and retrograde amnesia. The compound was 0.1 and 10.0 mg / kg p.o. activity at doses indicates that the compound has a wide range of anti-amnesic activity.

A common and defining property of cognitive stimulants or nootropic drugs is to enhance the resistance of learning and memory processes to the effects of anterograde and retrograde amnesia. Cognitive impairment exemplified in different ways is similar to the deficits that naturally occur during aging. Many members of the family of compounds of the present invention exhibit outstanding anti-amnesic activity, suggesting that they may be useful in the natural treatment of cognitive impairment associated with aging. The expected therapeutic dose of the compounds is 0.1-40 mg / kg body weight, once or several times a day, by oral administration.

The preparation of the novel compounds of formula I according to the invention is described in detail below.

The commercially available anthranilic acid amide (II) is reacted with the commercially available (III) 1-ethoxycarbonyl-4-piperidone in an aromatic hydrocarbon solvent such as toluene or xylene in the presence of a proton catalyst such as p-toluenesulfonic acid. boiling point. The resulting compound of formula (I) wherein X is carbonyloxy, R is ethyl, which crystallizes from the reaction mixture may be purified, if desired, by recrystallization from an alcohol, preferably ethyl alcohol, and optionally hydrolyzed to give (I). ) wherein X and R together are hydrogen. Alkaline hydrolysis may be carried out in a manner known per se (Chem. Pharm. Bull. 42 (1), 74-84 (1994)): the product obtained in an ethereal solvent such as ethylene glycol monomethyl ether or ethylene glycol monoethyl. boiling in ether, preferably potassium hydroxide, to remove the ethoxycarbonyl group. To isolate the resultant compound of formula (I) wherein X and R together are hydrogen, the reaction mixture is diluted with water and extracted with chloroform, the extract is concentrated under reduced pressure and the residue is crystallized from ether, possibly recrystallized from ethyl alcohol. The resulting compound is reacted with acid anhydrides, carboxylic or sulphonic acid halides or isocyanates or isothiocyanates in a chlorinated hydrocarbon, preferably dichloromethane, at a temperature in the range of about 0 ° C to give the various compounds of formula I in X and R groups. The product obtained is preferably crystalline from the reaction mixture and can be isolated by filtration. When acid halides are used, the acid binder is an inorganic or organic base, preferably triethylamine. At this time, the reaction mixture was diluted with sodium bicarbonate solution to give a pure product. Preferably, the product crystallizes out and can be isolated by filtration. In some cases, the compounds are isolated from the diluted reaction mixture by extraction with chlorinated hydrocarbon, evaporation of the extract under reduced pressure, and crystallization or recrystallization of the evaporation residue. The compound of formula (I) wherein X and R together are hydrogen may, if desired, be converted into a pharmaceutically acceptable acid addition salt.

The active ingredient of formula (I) may be formulated in pharmaceutical compositions with admixed non-toxic inert solid or liquid carriers suitable for parenteral or enteral administration. Suitable carriers include solid or liquid materials conventionally used in pharmaceutical technology. The active ingredient may be formulated in the form of conventional pharmaceutical compositions, in particular solid forms such as tablets, dragees, capsules, and the like. The amount of solid carrier can be varied over a wide range, preferably from about 25 mg to about 1 mg. The formulations may optionally contain conventional pharmaceutical excipients. They may be prepared by conventional pharmaceutical techniques and may, if desired, be subjected to further conventional procedures such as sterilization.

The following examples illustrate the preparation of the compounds of the present invention, without limiting them to these examples.

Example 1: - (4-Ethoxycarbonyl} spiro [piperidine-4,2 '(1' H) -quinazoline] -b H) -one (X = Carbonyloxy, R = Ethyl) 01 10444

A mixture of 7.3 g of 0.042 (mole) 1- t -oxycarbonyl-4-piperidone (III), 5.4 g (0.040 mole) of anthranilic acid amide (II), 40 ml of toluene and 0.1 g of p-toluenesulfonic acid was stirred. while refluxing for 5 hours. After cooling the reaction mixture, the precipitate was filtered off and recrystallized from ethyl alcohol.

Yield: 7.3 g (63%) M.p .: 211-213 ° C

Example 2

Spiro [piperidine-4,2 '(1'H) -quinazoline] -4' (3'H) -one (X and R together = H) 01 11239

14.5 g (0.050 mol) of 1- (ethoxymethyl karbonilUpiro [piperidine-4,2 ^'(r 1 H) -quinazoline] -4'(3'H) -one (I), X = -COO, R = Et ), Potassium hydroxide (10 g, 0.175 mol) and ethylene glycol monomethyl ether (150 ml) were stirred at reflux for 20 hours. After cooling, the mixture was poured into water (150 ml) and extracted with chloroform (3 x 100 ml). The chloroform solution was evaporated under reduced pressure, and the residue was crystallized by trituration with ether and then recrystallized from ethyl alcohol.

Yield: 8.2 g (75%) M.p .: 218-220 ° C

Example 3

-Acetyl-spiro [piperidine-4,2 '(TH) -quinazolinj-4' (3'H) -one (X = carbonyl, R = methyl) 01 10519

To a suspension of 16.3 g (0.075 mol) of spiro [piperidine-4,2 '(1 H) -quinazolin] -4' (3 'H) -one (X and R together = H) in 160 ml of dichloromethane with stirring. At a temperature below 0 ° C, 14.1 ml (0.150 mol) of acetic anhydride are added dropwise. After stirring for 2 hours, the precipitate was filtered off and washed with ether.

Yield: 17.7 g (91%) M.p .: 241-244 ° C

Following the procedure described in Example 3, the appropriately substituted isocyanate and / or isocyanate, respectively. Using the isothiocyanate, starting from the compound of Example 2, wherein -X-R- is hydrogen, the following derivatives were prepared:

1- (propylcarbamoyl) spiro [piperidine-4,2 '(1 H) -quinazoline] -4' (3 'H' on (X = -CONH, R = propyl)).

M.p. 245-248 ° C (dichloromethane)

1- (phenylcarbamoyl) -spiro [piperidine 4,2 '(1'H) -quinazoline] -4' (3'H) -cr (X = -CONH, R = phenyl) 01 11270

Mp: above 250 ° C (dichloromethane)

1- (phenylthiocarbamoyl) -spiro [piperidine-4,2 '(1' H) -quinazoline] -4 '(3'H) -one (X = -CSNH, R = phenyl) 01 11271

M.p. 246-248 ° C (dichloromethane)

Example 4

1-Benzoyl-spiro [piperidine-4,2 '(1''H) -quinazolin] -4' (3'H) -one (X = carbonyl, R = phenyl) 01 10518

2.2 g (0.010 mol) of spiro [piperidine-4,2 '(1 Ή) -quinazolin-4' (3'H) -one (X and R together = H) prepared in Example 2 were treated with 20 ml of dichloromethane. Triethylamine (4.2 mL, 0.030 mol) was added to a suspension of methane and benzoyl chloride (2.3 mL, 0.020 mol) was added with stirring at a temperature below 10 ° C. The mixture was stirred for 2 hours and then poured into 100 ml of sodium 14 bicarbonate solution. After stirring for half an hour, the precipitate was filtered off, washed with water and then with ether.

Yield: 2.9 g (91%) m.p.

In the same manner as in Example 4, using the appropriate acid chloride, starting from the compound of Example 2, wherein X-R- is hydrogen, the following derivatives were prepared:

1- (phenylacetyl) spiro [piperidine-4,2 '(1'H) -quinazolin] -4' (3'H) -one (X = carbonyl, R = benzyl) 01 10516

M.p. 234-237 ° C (dichloromethane)

1- (4-Chloro-benzoyl) -spiro [piperidine-4,2 '(1'H) -quinazolin] -4' (3'H) -one (X = carbonyl, R = 4-chloro-phenyl) 10515

M.p.> 260 ° C (methanol)

1-tosyl-spiro [piperidine-4,2 '(1 H) -quinazolin] -4' (3 'H) -one (X = sulfonyl, R = 4-methylphenyl) 01 10550

Mp: above 260 ° C (nitromethane)

Example 5

(Benzyloxycarbonyl) -spiro [piperidine-4,2 '(1 H) -quinazolin-4 (y H) -one (X = Carbonyloxy, R = Benzyl) 01 10517

The procedure described in Example 4 was followed except that 2.85 ml (0.020 mol) of benzyloxycarbonyl chloride was used as reaction partner. After working up the reaction mixture, the reaction mixture diluted with sodium bicarbonate solution is extracted with dichloromethane (3 x 30 ml), the solvent is evaporated under reduced pressure, the residue is crystallized by trituration with diisopropyl ether and recrystallized from ethyl alcohol.

Yield: 1.25 g (36%) M.p .: 166-168 ° C

Claims (7)

Claims What is claimed is: 1. A spiro (quinazolinylpiperidine) derivative represented by the general formula (I) and, optionally, a pharmaceutically acceptable acid addition salt thereof, wherein X is carbonyl, carbonyloxy, CONH, -CSNH, or sulfonyl; R is C 1 -C 4 alkyl, straight or branched, optionally substituted with 1 to 3 halogens; or aryl or aralkyl optionally substituted with 1 to 5 halogens, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or 1 to 2 nitro groups; obsession X and R together are hydrogen. 2'-Acetyl-spiro [piperidine-4,2 '(1'-H) -quinazolin] -4' (3 '-H) -one. A pharmaceutical composition comprising, as an active ingredient, a compound of formula (I): wherein X is carbonyl, carbonyloxy, -CONH, -CSNH, or sulfonyl; R is C 1 -C 4 alkyl, straight or branched, optionally substituted with 1 to 3 halogens; or aryl or aralkyl optionally substituted with 1 to 5 halogen atoms, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or 1 to 2 nitro groups; obsession X and R together represent hydrogen, or optionally a pharmaceutically acceptable acid addition salt thereof, in addition to pharmaceutically acceptable carriers and excipients. 4. A process for the preparation of novel spiro (quinazolinylpiperidine) derivatives of formula (I) and optionally pharmaceutically acceptable acid addition salts thereof, wherein: X is carbonyl, carbonyloxy, -CONH, -CSNH or sulfonyl; R is C 1 -C 4 alkyl, straight or branched, optionally substituted with 1 to 3 halogens; or aryl or aralkyl optionally substituted with 1 to 5 halogen atoms, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or 1 to 2 nitrogen atoms; obsession X and R are taken together to form a hydrogen atom, characterized in that the anthranilic acid amide of formula (II) is reacted with the 1-ethoxycarbonyl-4-piperidone of formula (III) and, if desired, the compound of formula (I), where X and R together are hydrogen, the resulting X is a carbonyloxy group, The compound of formula (I) wherein R is ethyl is hydrolyzed and, if desired, the compounds of formula (I) wherein X and R are independently as defined in the foregoing are prepared by acylating or reacting a compound wherein X and R are hydrogen together with an appropriately substituted isocyanate or isothiocyanate and /; optionally converting a compound of formula (I) wherein X and R together are hydrogen into a pharmaceutically acceptable acid addition salt. 5. A method according to claim 4, characterized in that the antranilsavamidot and (III), 1-ethoxycarbonyl-4-piperidone of formula (II) in a solvent, Proton presence of a catalyst and an aromatic hydrocarbon - - ⁱ · a In the preparation of a compound of general formula (I) wherein X and R together are hydrogen, the hydrolysis of a compound containing X is a carbonyl group, R is an ethoxy group is carried out in an ethereal solvent in an alkaline medium and> wherein X and R are each independently acylating a compound of formula (I) wherein X and R together are hydrogen, in a chlorinated hydrocarbon solvent, optionally in the presence of an acid scavenger. 6. A process for the preparation of a pharmaceutical composition, which process comprises the preparation of a compound of formula I wherein: X is carbonyl, carbonyloxy, -CONH, -CSNH or sulfonyl; R is a linear or branched aryl or aralkyl group having 1 to 4 carbon atoms, optionally substituted with 1 to 3 halogen atoms, or optionally substituted with 1 to 5 halogen atoms, 1 to 4 carbon atoms, C1 to 4 alkoxy or 1-2 nitro groups. ; obsession X and R together represent a hydrogen atom, or an optionally pharmaceutically acceptable acid addition salt thereof, in admixture with a carrier or excipient conventional in the pharmaceutical industry to form a pharmaceutical composition. 7. A method of treating a mammal, including a human, comprising administering to a subject or animal a novel spiro (quinazolinylpiperidine) derivative of formula (I) wherein: X is carbonyl, carbonyloxy, -CONH, CSNH or sulfonyl; R is C 1 -C 4 alkyl, straight or branched, optionally substituted with 1 to 3 halogens; or aryl or aralkyl optionally substituted with 1 to 5 halogens, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or 1 to 2 nitro groups; obsession X and R together are hydrogen - or a pharmaceutically acceptable acid addition salt thereof, optionally in pure form or in the form of a pharmaceutical composition containing the above compound as an active ingredient.