WO1989005799A1 - Novel tetrahydropyridine derivatives, pharmaceutical compositions containing them and process for preparing same - Google Patents
Novel tetrahydropyridine derivatives, pharmaceutical compositions containing them and process for preparing same Download PDFInfo
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- WO1989005799A1 WO1989005799A1 PCT/HU1988/000078 HU8800078W WO8905799A1 WO 1989005799 A1 WO1989005799 A1 WO 1989005799A1 HU 8800078 W HU8800078 W HU 8800078W WO 8905799 A1 WO8905799 A1 WO 8905799A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Definitions
- the invention relates to novel tetrahydropyridine derivatives of the formula (I),
- R 1 means hydrogen or a C 1-6 alkyl group
- R 2 and R3 stand, independently from each other, for hydrogen or a C 1-6 alkyl group; or alternatively
- R 2 and R 3 together represent a chemical bond
- R 4 means halogen, a trifluoromethyl or a C 1-6 alkyl group
- R 1 and R 3 are in Z (cis) or E (trans) position in their mutual relation when R2 and R 3 do not form together a chemical bond or the meaning of R 1 is different from that of R 2 , with the proviso that R 1 and R 2 are different from hydrogen when R 4 means a 4-methyl group, as well as their pharmaceutically acceptable acid addition salts and pharmaceutical compositions containing these compounds. Furthermore, the invention relates to a process for the preparation of those compounds.
- C 1-6 alkyl includes straight or branched alkyl groups containing 1 to 6 carbon atoms, e.g.
- Halogen means chloro, fluoro, bromo and iodo.
- novel tetrahydropyridine derivatives of the formula (I) according to the invention possess a gastric acid secretion inhibiting action and in addition, a strong gastric mucosa-protecting, i.e. so-called "gastroprotective" effect. Due to these effects, the compounds of the formula (I) are useful to prevent gastric ulcers.
- the gastric acid secretion-inhibiting and gastroprotective effects of the compounds according to the invention were determined by the following pharmacological investigations.
- the gastric acid secretion-inhibiting action was studied by the test method of Shay et al. [Gastroenterology 5, 43 (19450]. These examinations were carried out on female Hannover-Wistar rats with a body-weight of 120 to 150 g. After a starvation for 24 hours, a pylorus ligature was made on the animals. The compounds of the formula (I) were orally administered to the animals 30 minutes before the surgical intervention. Four hours following the operation, the animals were killed and the acid content of the gastric juice was determined.
- the gastric acid secretion-inhibiting action of the compounds tested was determined by comparing the results obtained to the acid content measured in the gastric juice of the untreated control animals. The results are summarized in Table I.
- 1-allyl-4-(4'-chlorophenyl-1,2,3,6-tetrahydropyridine with an ED 50 value of 18.1 mg/kg proved to be a particularly active substance.
- Cimetidine a known antiulcer drug, gave an ED 50 value of 50 mg/kg under the conditions described above.
- the gastroprotective effect was characterized by the percentage value of the average total length of bleedings in relation to the average total length measured in the contro group (treated only with acidic alcohol). The results are summar ized in Table II.
- 1-allyl-4-(4'-chlorophenyl)-1,2,3,6-tetrahydropyridine with an ED 50 value of 4 mg/kg proved to be a particularly active substance.
- Sucralfate a known drug, gave an ED 50 value of 150 mg/kg in the gastric lesion test under the conditions described hereinabove.
- the tetrahydropyridine derivatives of the formula (I) according to the invention efficiently inhibited also the aspirin or stress-induced gastric ulcers.
- the number of the punctiform ulcers appearing in the stomach was evaluated by using a so-called ulcer score from 0 to 5 in such a way that the value of the control not treated by the test compound was taken as 5 and the stomach showing the least number of ulcers was considered to be 0.
- the results are summarized in Table III.
- a peroral dose of 500 mg/kg of this compound administered to rats does not evoke toxic effects.
- R 4 is as defined above, or an acid addition salt thereof, with a compound of the formula (III)
- R 1 , R 2 and R 3 are as defined above and X means a leaving group and, if desired, converting the compound of the formula (I) obtained to its acid addition salt.
- a 4-aryltetrahydropyridine base or its hydrochloride is alkylated in an apolar or dipolar--aprotic solvent, preferably e.g. in benzene, toluene, di-methylformamide, acetone, acetonitrile and the like, in the presence of an acid binding agent such as preferably triethylamine or sodium carbonate.
- the reaction mixture is worked up in the usual manner, e.g. by pouring into water.
- the product is isolated by filtration or extraction.
- the compounds of the formula (I) are used as bases or, when necessary, in the form of a salt (such as hydrochloride, fumarate, lactate or the like) with a non- -toxic acid.
- the acid addition salts are prepared in an inert solvent, e.g. in a C 1-6 aliphatic alcohol in such a way that after dissolving the compound of the formula (I) in the above solvent, the appropriate acid or a solution thereof in the above solvent is portionwise added until the pH of the solution becomes acidic, then the acid addition salt is separated from the system in a suitable way, e.g. by filtration.
- an inert solvent e.g. in a C 1-6 aliphatic alcohol in such a way that after dissolving the compound of the formula (I) in the above solvent, the appropriate acid or a solution thereof in the above solvent is portionwise added until the pH of the solution becomes acidic, then the acid addition salt is separated from the system in a suitable way, e.g. by filtration.
- the starting substances of the process according to the invention are known compounds described in the literature
- the phenylpiperidine derivatives of the formula (II) bearing a phenyl group substituted by halogen have been described in the United States patent specification No. 2,973,363 and in the Czechoslovakian patent specification No. 218,028.
- the compounds of the formula (III) are commercially available.
- the compounds according to the invention can be converted into pharmaceutical compositions in a known manner.
- the pharmaceutical composition may preferably be administered in the oral route.
- the composition may be formulated as a tablet, dragee or capsule.
- lactose or starch may be used as carriers.
- Gelatine, carboxymethylcellulose sodium, methylcellulose, polyvinylpyrrolidone or starch gum are suitable binding or granulating agents.
- disintegrating agents mainly potato starch or microcrystalline cellulose may be added though ultraamylopectin or formaldehyde-casein are also useful.
- Talc, colloidal silicic acid, stearin, calcium or magnesium stearate and the like are suitable anti-adhesive and sliding agents.
- Tablets may be prepared e.g. by compression following the wet granulation.
- the mixture of the active ingredient with the carriers and optionally with a part of the disintegrating additive is granulated with an aqueous, alcoholic or aqueous-alcoholic solution of the binding agents in a suitable equipment, then the granulate is dried. Subsequently, after mixing the other disintegrating, sliding and anti--adhesive additives to the dried granulate, the mixture is compressed to tablets. If desired, the tablets may be provided with a groove in order to facilitate the administration. Tablets may also directly be prepared from a mixture containing the active ingredient and suitable additives.
- the compositions may optionally contain the commonly used pharmaceutical additives, e.g.
- Dragees may be prepared in the usual manner. Capsulated compositions are prepared by filling a mixture of the active ingredient with the additives into capsules.
- the patient is treated with a dose needed to ensure the desired effect.
- This dose depends upon several factors like the severity of the disease, the body-weight of the patient and the route of administration.
- the dose to be used is in every case to be defined by the physician.
- the invention also relates to a method for treating the gastric acid-induced mucosa lesions and gastric ulcer. This process comprises administering a therapeutically effective amount of an active ingredient of the formula (I) to the patient.
- Components Amount 1-Allyl-4-(4'-chlorophenyl)-1,2,3,6-tetrahydropyridine 180 mg Lactose 100 mg Avicel 100 mg Starch 100 mg Polyvinylpyrrolidone 25 mg Talc 20 mg Magnesium stearate 25 mg
- the active ingredient is mixed with the additives according to the above ratio of the components, the mixture is granulated as wet and then compressed to tablets with the above composition.
Abstract
The invention relates to novel tetrahydropyridine derivatives of formula (I) and pharmaceutically acceptable acid addition salts thereof, pharmaceutical compositions containing them and a process for their preparation. In formula (I), R1 means hydrogen or a C1-6 alkyl group; R2 and R3 stand, independently from each other, for hydrogen or a C1-6 alkyl group; or alternatively R2 and R3 together represent a chemical bond; R4 means halogen, a trifluoromethyl or a C1-6 alkyl group; R1 and R3 are in Z (cis) or E (trans) position in their mutual relation when R2 and R3 do not form together a chemical bond or the meaning of R1 is different from that of R2, with the proviso that R1 and R2 are different from hydrogen when R4 means a 4-methyl group. The compounds of formula (I) show a strong cytoprotective action on the gastric mucosa by inhibiting the gastric acid secretion and are useful antiulcer agents.
Description
NOVEL TETRAHYDROPYRIDINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND PROCESS FOR PREPARING SAME
The invention relates to novel tetrahydropyridine derivatives of the formula (I),
wherein R1 means hydrogen or a C1-6alkyl group;
R2 and R3 stand, independently from each other, for hydrogen or a C1-6alkyl group; or alternatively
R2 and R3 together represent a chemical bond;
R4 means halogen, a trifluoromethyl or a C1-6alkyl group;
R1 and R3 are in Z (cis) or E (trans) position in their mutual relation when R2 and R3 do not form together a chemical bond or the meaning of R1 is different from that of R2, with the proviso that R1 and R2 are different from hydrogen when R4 means a 4-methyl group,
as well as their pharmaceutically acceptable acid addition salts and pharmaceutical compositions containing these compounds. Furthermore, the invention relates to a process for the preparation of those compounds. In formula (I), in the meaning of R1, R2, R3 and R4 C1-6alkyl includes straight or branched alkyl groups containing 1 to 6 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and similar pentyl and hexyl groups. "Halogen" means chloro, fluoro, bromo and iodo.
Compounds with a similar structure have been described in the following references: M. G. Beretta et al.: Synthesis 1975, 440; M. Kimura et al.: Chem. Pharm. Bull. 24 , 515 (1976). According to the papers cited above, analogous N-allyltetrahydropyridine derivatives were prepared in two steps: first, pyridine derivatives were reacted with substituted 2-alkenyl halides and then the N-allylpyridinium compounds obtained were reduced by sodium borohydride. The tetrahydropyridine derivatives thus prepared were used as starting substances in the synthesis of azabicyclo[3.3.1]non-6-ene compounds.
According to the United States patent specification No. 2 , 750 , 385 1-allyl-4-(4,-methylphenyl)-1,2,3,6-tetrahydropyridine derivatives were prepared by the acidic rearrangement of 3-substituted-6-methyl-6-phenyItetrahydro--1,3-oxazines. These compounds were used as additives in the acidic cleaning of metal surfaces.
According to the United States patent specification No. 4,180,669 suitable 1,2,3,6-tetrahydropyri dines were used as intermediates in the synthesis of 4-arylpiperidines bearing a polysubstituted aryl group; the 4-(polysubstituted aryl)-1,2,3,6-tetrahydropyridine-type intermediates were obtained by condensing resorcinol derivatives with N-substituted 4-piρeridones.
Anorectogenic compounds, being close in their structure to the compounds of the formula (I) according to the invention, have been published in the French patent specification No. 2,416,886; however, these compounds contain the m- -trifluoromethylphenyl group in the 3-position of the 1,2,3,6- -tetrahydropyridine ring.
On the contrary, it has now surprisingly been found that the novel tetrahydropyridine derivatives of the formula (I) according to the invention possess a gastric acid secretion inhibiting action and in addition, a strong gastric mucosa-protecting, i.e. so-called "gastroprotective" effect. Due to these effects, the compounds of the formula (I) are useful to prevent gastric ulcers.
The gastric acid secretion-inhibiting and gastroprotective effects of the compounds according to the invention were determined by the following pharmacological investigations.
The gastric acid secretion-inhibiting action was studied by the test method of Shay et al. [Gastroenterology 5, 43 (19450].
These examinations were carried out on female Hannover-Wistar rats with a body-weight of 120 to 150 g. After a starvation for 24 hours, a pylorus ligature was made on the animals. The compounds of the formula (I) were orally administered to the animals 30 minutes before the surgical intervention. Four hours following the operation, the animals were killed and the acid content of the gastric juice was determined.
The gastric acid secretion-inhibiting action of the compounds tested was determined by comparing the results obtained to the acid content measured in the gastric juice of the untreated control animals. The results are summarized in Table I.
Based on the results obtained, 1-allyl-4-(4'-chlorophenyl-1,2,3,6-tetrahydropyridine with an ED50 value of 18.1 mg/kg proved to be a particularly active substance. Cimetidine, a known antiulcer drug, gave an ED50 value of 50 mg/kg under the conditions described above.
The so-called gastroprotective effect of the compounds of formula (I) was studied by using the test method of A. Robert [Gastroenterology 77 , 761 ( 1919) ] based on the gastric lesion induced by acidic alcohol.
These experiments were carried out on male rats with a body-weight of 120 to 150 g, which had been starved for 24 hours. A mixture consisting of 1 ml concentrated hydrochloric acid and 50 ml of absolute alcohol was used as necrotizing agent in an amount of 1 ml/100 g of body-weight.
The compounds of the formula (I) were introduced to the stomach 30 minutes before administering the acidic alcohol. One hour after the administration of the acidic alcohol, the animals were killed and the average total length, calculated for one stomach, of the longi tudinal bleedings induced on the glandular part of the stomach by the acidic alcohol treatment was determined.
The gastroprotective effect was characterized by the percentage value of the average total length of bleedings in relation to the average total length measured in the contro group (treated only with acidic alcohol). The results are summar ized in Table II.
Based on the results obtained, 1-allyl-4-(4'-chlorophenyl)-1,2,3,6-tetrahydropyridine with an ED50 value of 4 mg/kg proved to be a particularly active substance. Sucralfate, a known drug, gave an ED50 value of 150 mg/kg in the gastric lesion test under the conditions described hereinabove.
The tetrahydropyridine derivatives of the formula (I) according to the invention efficiently inhibited also the aspirin or stress-induced gastric ulcers.
The gastric ulcer-inhib i ting effect was studied by using the method described by K. D. Rainsford [ Agents and Actions 5.1 553 (1975)].
These measurements were carried out on female Hannover-Wistar rats with a body-weight of 120 to 150 g. After a starvation for 24 hours, the animals were orally
treated with the compounds of the formula (I) to be tested. After 60 minutes, the rats were orally given aspirin in a dose of 50 mg/kg of body-weight. After additional 30 minutes, the animals were immobilized and placed into water of 22 ºC temperature. After a stress effect lasting for 1 hour, the animals were let repose and then killed.
The number of the punctiform ulcers appearing in the stomach was evaluated by using a so-called ulcer score from 0 to 5 in such a way that the value of the control not treated by the test compound was taken as 5 and the stomach showing the least number of ulcers was considered to be 0. The results are summarized in Table III.
Based on the results obtained, 1-allyl-4-(4'-chlorophenyl)-1,2,3,6-tetrahydropyridine with an ED50 value of 32 mg/kg proved to be a particularly active substance.
A peroral dose of 500 mg/kg of this compound administered to rats does not evoke toxic effects.
Table I
The gastric acid secretion-inhibiting action of the compound described in Example 1
Dose mg/kg Gastric juice Inhibition of the p.o. Volume Acid content gastric acid n ml/100 g μmol/100 g secretion
%
Control 5.5 569.7 0 10
10 3.9 361.9 36.5 5
20 3.3 302.3 46.9 5
40 2.6 144.2 74.7 8
n = number of the animals investigated p.o. = oral
Table II
The inhibiting effect of the compound described in Example 1 in the gastric lesion test
Dose mg/kg n Lesion p . o . mm/stomach Inhibition
Control 35 86.2 -
25 mg/kg 6 8.5 90%
10 mg/kg 7 10.8 88%
5 mg/kg 6 10.8 88%
2.5 mg/kg 15 37.9 46%
1 mg/kg 16 82.1 5%
n = number of the animals investigated p.o. = oral
Table III The gastric ulcer-inhibiting effect of the compound described in Example 1 in the "aspirin plus stress" model
Dose Average ulcer Inhibition related to mg/kg n score the control p . o . %
Control 8 4.6 0 5 5 3.8 15.6 25 5 2.8 37.8 50 9 1.6 64.4
n = number of the animals investigated p.o. = oral
According to an other aspect of the invention, there is provided a process for the preparation of the compounds of the formula (I) and their pharmaceutically acceptable acid addition salts, which comprises alkylating a tetrahydropyridine derivative of the formula (II)
wherein R4 is as defined above, or an acid addition salt thereof, with a compound of the formula (III)
wherein R1, R2 and R3 are as defined above and X means a leaving group and, if desired, converting the compound of the formula (I) obtained to its acid addition salt.
According to a preferred embodiment of the process according to the invention, a 4-aryltetrahydropyridine base or its hydrochloride is alkylated in an apolar or dipolar--aprotic solvent, preferably e.g. in benzene, toluene, di-methylformamide, acetone, acetonitrile and the like, in the presence of an acid binding agent such as preferably
triethylamine or sodium carbonate. The reaction mixture is worked up in the usual manner, e.g. by pouring into water. The product is isolated by filtration or extraction. After purification, the compounds of the formula (I) are used as bases or, when necessary, in the form of a salt (such as hydrochloride, fumarate, lactate or the like) with a non- -toxic acid.
The acid addition salts are prepared in an inert solvent, e.g. in a C1-6 aliphatic alcohol in such a way that after dissolving the compound of the formula (I) in the above solvent, the appropriate acid or a solution thereof in the above solvent is portionwise added until the pH of the solution becomes acidic, then the acid addition salt is separated from the system in a suitable way, e.g. by filtration.
The starting substances of the process according to the invention are known compounds described in the literature The phenylpiperidine derivatives of the formula (II) bearing a phenyl group substituted by halogen have been described in the United States patent specification No. 2,973,363 and in the Czechoslovakian patent specification No. 218,028. The compounds of the formula (III) are commercially available.
The compounds according to the invention can be converted into pharmaceutical compositions in a known manner. The pharmaceutical composition may preferably be administered in the oral route. For this type of administration, the composition may be formulated as a tablet, dragee or capsule. In order to prepare oral compositions, e.g. lactose or starch
may be used as carriers. Gelatine, carboxymethylcellulose sodium, methylcellulose, polyvinylpyrrolidone or starch gum are suitable binding or granulating agents. As disintegrating agents, mainly potato starch or microcrystalline cellulose may be added though ultraamylopectin or formaldehyde-casein are also useful. Talc, colloidal silicic acid, stearin, calcium or magnesium stearate and the like are suitable anti-adhesive and sliding agents.
Tablets may be prepared e.g. by compression following the wet granulation. The mixture of the active ingredient with the carriers and optionally with a part of the disintegrating additive is granulated with an aqueous, alcoholic or aqueous-alcoholic solution of the binding agents in a suitable equipment, then the granulate is dried. Subsequently, after mixing the other disintegrating, sliding and anti--adhesive additives to the dried granulate, the mixture is compressed to tablets. If desired, the tablets may be provided with a groove in order to facilitate the administration. Tablets may also directly be prepared from a mixture containing the active ingredient and suitable additives. The compositions may optionally contain the commonly used pharmaceutical additives, e.g. protective, flavouring or colouring agents such as sugar, cellulose derivatives (methyl- or ethylcellulose, carboxymethylcellulose sodium and the like), polyvinylpyrrolidone, calcium phosphate, calcium carbonate, food dyes, aromatizing agents or iron oxide pigments. Dragees may be prepared in the usual manner. Capsulated compositions are prepared by filling a mixture of the active ingredient
with the additives into capsules.
On using the pharmaceutical composition of the invention the patient is treated with a dose needed to ensure the desired effect. This dose depends upon several factors like the severity of the disease, the body-weight of the patient and the route of administration. The dose to be used is in every case to be defined by the physician.
The invention also relates to a method for treating the gastric acid-induced mucosa lesions and gastric ulcer. This process comprises administering a therapeutically effective amount of an active ingredient of the formula (I) to the patient.
The invention is illustrated in detail by the aid of the following non-limiting Examples.
Example 1
Prepara tion of 1-all yl -4- ( 4 ' -chlorophenyl )-1 , 2 , 3 , 6 - -tetrahydro-pyridine
After adding 4.21 g (55 mmol) of allyl chloride to the mixture of 11.57 g (50 mmol) of 4-(4'-chlorophenyl)- -1,2,3,6-tetrahydropyridine hydrochloride, 120 ml of toluene and 15.4 ml of triethylamine, the mixture is stirred at 80 °C for 16 hours, then 2 ml of allyl chloride are again added to the mixture and the heating is continued for additional 10 hours. After cooling down, the precipita ted salt is filtered off and washed with toluene. The combined toluene solution is washed twice with 50 ml of water each, dried over anhydrous sodium sulfate and evaporated. The crystalline
residue weighing 10.52 g is recrystallized from a 8:2 mixture of methanol and water under clarifying with activated carbon to give 7.94 g (68%) of the title compound, m.p . : 76 ºC. IR (KBr, cm-1): 2760 (N-CH2), 1645 (C=C), 1096 (Ar-Cl).
Example 2
Preparation of 1-allyl-4-(3'-chlorophenyl)-l,2,3,6- -tetrahydropyridine hydrochloride After adding 4.40 ml (54 mmol) of allyl chloride to the mixture of 10.35 g (45 mmol) of 4-(3'-chlorophenyD--1,2,3,6-tetrahydropyridine hydrochloride, 120 ml of toluene and 12.6 ml of triethylamine, the mixture is stirred at 60 °C for 18 hours, then 2 ml of allyl chloride are again added to the mixture and the heating is continued for additional 48 hours. The reaction mixture is worked up as described in Example 1, then the crude product obtained is purified by column chromatography by using silica gel as sorbent and an 8:1:1 mixture of benzene/methanol/acetone as eluent to give 5.21 g of an oily crude product which, being not crystallizable, is converted to its hydrochloride by adding ethyl acetate saturated with gaseous hydrogen chloride and then precipitating by adding ether. Thus, 5.59 g (46%) of the title hydrochloride salt are obtained which is recrystallized from ethanol by adding ether, m.p.:
200-202 ºC
IR (KBr, cm-1): 2800-2000 (NH+), 1648 (C=C), 1472 (N-CH2),
1100 (Ar-Cl).
Example 3
Preparation of 1-allyl-4-(4'-fluorophenyl)-1,2,3,6- -tetrahydropyridine fumarate
2.85 ml (35 mmol) of allyl chloride are added to the mixture of 5.34 g (25 mmol) of 4-(4'-fluorophenyl)-tetrahydropyridine hydrochloride, 50 ml of toluene and 3.5 ml of triethylamine. Further on, the process described in Example 1 is followed. The crude product weighing 4.22 g is purified by column chromatography on silica gel by using an 8:1:1 mixture of benzene/methanol/acetone as eluent to give 2.91 g (53%) of an oily product.
2.53 g (11.6 mmol) of this base are dissolved together with 1.35 g (11.6 mmol) of fumaric acid in ethanol and the salt obtained after evaporation is recrystallized from acetonitrile to give 2.99 g (77% calculated for the base) of the title fumarate salt, m.p.: 118-120 °C. IR (KBr, cm-1): 3200-2100 (NH+ and OH), 1700b (C=0),
1223 (Ar-F).
Example 4
Preparation of 4-(4'-chlorophenyp-1-propargyl-1,2,3,6- -tetrahydropyridine
After adding 6.54 g of propargyl bromide to the mixture of 11.50 g (50 mmol) of 4-(4'-chlorophenyl)-1,2,3,6--tetrahydropyridine hydrochloride, 120 ml of toluene and 15.4 ml of triethylamine, the reaction mixture is stirred at 80 °C for 20 hours, then a further amount of 7 ml of
triethylamine and 2.1 ml of propargyl bromide are added to the mixture and the heating is continued for 16 hours. The working up is carried out according to Example 1 to obtain 9.15 g of a crystalline crude product which is recrystallized from an 8:2 mixture of methanol and water to yield 6.62 g (57%) of the title product, m.p.: 79-80 °C. IR (KBr cm-1): 3290 (≡CH), 2750 (N-CH2), 1100 (Ar-Cl).
Example 5 Preparation of 4-(3'-chlorophenyl)-1-propargyl-1,2,3,6- -tetrahydropyridine hydrochloride
After adding 4.75 g (38 mmol) of propargyl bromide to a suspension containing 7.00 g (30 mmol) of 4-(3'-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride, 8.12 g of anhydrous sodium carbonate and 60 ml of dimethylformamide, the mixture is stirred at 80 °C for 10 hours. The reaction mixture is poured into water and extracted into ethyl acetate. The ethyl acetate solution is washed with water, dried over sodium sulfate and evaporated. Thus, 7.30 g of an oily product are obtained which is converted to the hydrochloride by adding ethanol saturated with gaseous hydrogen chloride and precipitating with ether. Thus, 4.93 g (71%) of the title product are obtained, m.p.: 216-217 °C after recrystallization from ethanol. IR (KBr cm-1): 3210 (≡CH) , 2140 (C=C), 1650 (C=C).
Example 6
Preparation of 1-(2-buten-1-yl)-4-(4'-chlorophenyl)- 1,2,3,6-tetrahydropyridine
After adding 9.53 g (60 mmol) of crotyl bromide (of 85% purity) to the suspension of 11.50 g (50 mmol) of 4-(4'-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride in 120 ml of toluene and 19.6 ml of triethylamine, the mixture is stirred at 80 to 90 °C for 18 hours. The reaction mixture is worked up following the Example 1 to give 10.7 g of a crystalline crude product which is recrystallized from an 8:2 mixture of methanol and water. Thus, 3.95 g of the title product are obtained, m.p.: 78-79 °C. From the mother liquor, a mixture of isomers may be obtained by further evaporation. IR (KBr cm-1): 2730 (N-CH2), 1645 (C=C), 1085 (Ar-Cl).
Example 7
Preparation of tablets
Components Amount 1-Allyl-4-(4'-chlorophenyl)-1,2,3,6-tetrahydropyridine 180 mg Lactose 100 mg Avicel 100 mg Starch 100 mg Polyvinylpyrrolidone 25 mg Talc 20 mg Magnesium stearate 25 mg
The active ingredient is mixed with the additives according to the above ratio of the components, the mixture is granulated as wet and then compressed to tablets with the above composition.
Claims
1. Tetrahydropyridine derivatives of the formula (I)
wherein
R1 means hydrogen or a C1-6alkyl group;
R2 and R3 stand, independently from each other, for hydrogen or a 0, .alkyl group; or alternatively R2 and R3 together represent a chemical bond; R4 means halogen, a trifluoromethyl or a C1-6alkyl group; R1 and R3 are in Z (cis) or E (trans) position in their mutual relation when R2 and R3 do not form together a chemical bond or the meaning of RI is different from that of R2, with the proviso that R1 and R2 are different from hydrogen when R4 means a 4-methyl group, as well as the pharmaceutically acceptable acid addition salts of these compounds.
2. A compound selected from the group consisting of 1-allyl-4-(4'-chlorophenyl)-1,2,3,6-tetrahydropyridine, 1-allyl-4-(3'-chlorophenyl)-1,2,3,6-tetrahydropyridine,
1-allyl-4-(4'-fluorophenyl)-1,2,3,6-tetrahydropyridine,
4-(4'-chlorophenyl)-1-propargyl-1,2,3,6-tetrahydropyridine,
4-(3'-chlorophenyl)-1-propargyl-1,2,3,6-tetrahydrαpyridine,
1-(2-buten-1-yl)-4-(4'-chlorophenyl)-1,2,3,6-tetrahydropyridine, as well as the pharmaceutically acceptable acid addition salts of these compounds.
3. A pharmaceutical composition, which comprises as active ingredient a novel tetrahydropyridine derivative of the formula (I), wherein R1, R2, R3 and R4 are as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof, in admixture with carriers and/or additives commonly used in the pharmaceutical industry.
4. A process for the preparation of the novel tetrahydropyridine derivatives αf the formula (I),
wherein means hydrogen or a C1-6 alkyl group; R2 and R3 stand, independently from each other, for hydrogen or a C1-6alkyl group; or alternatively R2 and R3 together represent a chemical bond; R4 means halogen, a trifluoromethyl or a C1-6 alkyl group; R1 and R3 are in Z (cis) or E (trans) position in their mutual relation when R2 and R3 do not form together a chemical bond or the meaning of R1 is different from that of R2, with the proviso that R1 and R2 are different from hydrogen when R4 means a 4-methyl group, as well as the pharmaceutically acceptable acid addition salts of these compounds, which comprises alkylating a tetrahydropyridine derivative of the formula (II)
wherein R4 is as defined above, or an acid addition salt thereof, with a compound of the formula (III)
5. A process as claimed in claim 4, which comprises using as starting substance compounds of the formula (III), wherein R1, R2 and R3 are as defined in claim 1 and X stands for halogen or an alkylsulfonyloxy or arylsulfonyloxy group.
6. A process as claimed in claim 4 or claim 5, which comprises carrying out the reaction in a solvent which is inert to the reaction conditions.
7. A process as claimed in any of the claims 4 to 6, which comprises carrying out the reaction in the presence of an acid binding agent.
8. A process for the preparation of a pharmaceutical composition, which comprises mixing as active ingredient a novel tetrahydropyridine derivative of the formula (I), wherein R1, R2, R3 and R4 are as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof prepared by using the process as claimed in claim 4, with carriers and/or additives commonly used in the pharmaceutical industry and transforming them to a pharmaceutical composition.
9. Method for treating patients suffering from gastric acid-induced gastric lesions or gastric ulcer, characterized by using a therapeutically effective amount of a tetrahydropyridine derivative of the formula (I), wherein R1, R2, R3 nd R4 are as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof .
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1019890701520A KR900700452A (en) | 1987-12-14 | 1989-08-12 | Tetrahydropyridine derivatives, pharmaceutical composition containing same and manufacturing method thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU5634/87 | 1987-12-14 | ||
HU875634A HU198454B (en) | 1987-12-14 | 1987-12-14 | Process for production of new derivatives of tetrahydrospiridin and medical compositions containing these compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1989005799A1 true WO1989005799A1 (en) | 1989-06-29 |
Family
ID=10970514
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/HU1988/000078 WO1989005799A1 (en) | 1987-12-14 | 1988-12-13 | Novel tetrahydropyridine derivatives, pharmaceutical compositions containing them and process for preparing same |
Country Status (4)
Country | Link |
---|---|
KR (1) | KR900700452A (en) |
CN (1) | CN1034922A (en) |
HU (1) | HU198454B (en) |
WO (1) | WO1989005799A1 (en) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6903120B2 (en) | 1999-12-22 | 2005-06-07 | A. Carlsson Research Ab | Modulators of dopamine neurotransmission |
US7579474B2 (en) | 2004-06-08 | 2009-08-25 | Nsab, Filial Af Neurosearch Ab, Sverige | Substituted piperidines as modulators of dopamine neurotransmission |
USRE41315E1 (en) | 1999-12-22 | 2010-05-04 | Nsab, Filial Af Neurosearch Sweden Ab | Modulators of dopamine neurotransmission |
US7763639B2 (en) | 2004-06-08 | 2010-07-27 | Nsab, Filial Af Neurosearch Sweden Ab, Sverige | Disubstituted phenylpiperidines/piperazines as modulators of dopamine neurotransmission |
US7851629B2 (en) | 2004-06-08 | 2010-12-14 | Nsab, Filial Af Neurosearch Sweden Ab, Sverige | Disubstituted phenylpiperidines as modulators of dopamine and serotonin neurotransmission |
US7923459B2 (en) | 2004-10-13 | 2011-04-12 | Nsab, Filial Af Neurosearch Sweden Ab, Sverige | Process for the synthesis of 4-(3-methanesulfonylphenyl)-1-N-propyl-piperidine |
US8501777B2 (en) | 2005-10-13 | 2013-08-06 | Nsab, Filial Af Neurosearch Sweden Ab, Sverige | 3,5-disubstituted phenyl-piperidines as modulators of dopamine neurotransmission |
US9012476B2 (en) | 2011-12-08 | 2015-04-21 | IVAX International GmbH | Hydrobromide salt of pridopidine |
USRE46117E1 (en) | 1999-12-22 | 2016-08-23 | Teva Pharmaceuticals International Gmbh | Modulators of dopamine neurotransmission |
US11207308B2 (en) | 2012-04-04 | 2021-12-28 | Prilenia Neurotherapeutics Ltd. | Pharmaceutical compositions for combination therapy |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3125488A (en) * | 1964-03-17 | Method of inducing analgesia by | ||
US4180669A (en) * | 1976-12-13 | 1979-12-25 | Abbott Laboratories | 2-(N-phenethyl-4-piperidino)-5-pentyl resorcinol |
FR2501682A1 (en) * | 1981-03-11 | 1982-09-17 | Sanofi Sa | TRIPLUOROMETHYLPHENYLPYRIDINES WITH ANOREXIGENE ACTIVITY, A PREPARATION PROCESS AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME |
-
1987
- 1987-12-14 HU HU875634A patent/HU198454B/en not_active IP Right Cessation
-
1988
- 1988-12-13 WO PCT/HU1988/000078 patent/WO1989005799A1/en unknown
- 1988-12-13 CN CN88108568A patent/CN1034922A/en active Pending
-
1989
- 1989-08-12 KR KR1019890701520A patent/KR900700452A/en not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3125488A (en) * | 1964-03-17 | Method of inducing analgesia by | ||
US4180669A (en) * | 1976-12-13 | 1979-12-25 | Abbott Laboratories | 2-(N-phenethyl-4-piperidino)-5-pentyl resorcinol |
FR2501682A1 (en) * | 1981-03-11 | 1982-09-17 | Sanofi Sa | TRIPLUOROMETHYLPHENYLPYRIDINES WITH ANOREXIGENE ACTIVITY, A PREPARATION PROCESS AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6903120B2 (en) | 1999-12-22 | 2005-06-07 | A. Carlsson Research Ab | Modulators of dopamine neurotransmission |
US7417043B2 (en) | 1999-12-22 | 2008-08-26 | Neurosearch Sweden Ab | Modulators of dopamine neurotransmission |
USRE41315E1 (en) | 1999-12-22 | 2010-05-04 | Nsab, Filial Af Neurosearch Sweden Ab | Modulators of dopamine neurotransmission |
USRE46117E1 (en) | 1999-12-22 | 2016-08-23 | Teva Pharmaceuticals International Gmbh | Modulators of dopamine neurotransmission |
US7579474B2 (en) | 2004-06-08 | 2009-08-25 | Nsab, Filial Af Neurosearch Ab, Sverige | Substituted piperidines as modulators of dopamine neurotransmission |
US7763639B2 (en) | 2004-06-08 | 2010-07-27 | Nsab, Filial Af Neurosearch Sweden Ab, Sverige | Disubstituted phenylpiperidines/piperazines as modulators of dopamine neurotransmission |
US7851629B2 (en) | 2004-06-08 | 2010-12-14 | Nsab, Filial Af Neurosearch Sweden Ab, Sverige | Disubstituted phenylpiperidines as modulators of dopamine and serotonin neurotransmission |
US8314126B2 (en) | 2004-06-08 | 2012-11-20 | Nsab, Filial Af Neurosearch Sweden Ab, Sverige | Disubstituted phenylpiperdines/piperazines as modulators of dopamine neurotransmission |
US7923459B2 (en) | 2004-10-13 | 2011-04-12 | Nsab, Filial Af Neurosearch Sweden Ab, Sverige | Process for the synthesis of 4-(3-methanesulfonylphenyl)-1-N-propyl-piperidine |
US8501777B2 (en) | 2005-10-13 | 2013-08-06 | Nsab, Filial Af Neurosearch Sweden Ab, Sverige | 3,5-disubstituted phenyl-piperidines as modulators of dopamine neurotransmission |
US9012476B2 (en) | 2011-12-08 | 2015-04-21 | IVAX International GmbH | Hydrobromide salt of pridopidine |
US11207308B2 (en) | 2012-04-04 | 2021-12-28 | Prilenia Neurotherapeutics Ltd. | Pharmaceutical compositions for combination therapy |
Also Published As
Publication number | Publication date |
---|---|
HUT48210A (en) | 1989-05-29 |
CN1034922A (en) | 1989-08-23 |
KR900700452A (en) | 1990-08-13 |
HU198454B (en) | 1989-10-30 |
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