GB1580168A - 4 - piperidyl xanthene - 9 - carboxylate and its use in pharmaceutical compositions - Google Patents

Description

(54) A 4-PIPERIDYL XANTHENE-9-CARBOXYLATE AND ITS USE IN PHARMACEUTICAL COMPOSITIONS (71) We, RICHTER GEDEON VEGYESZETI GYAR RT., a body corporate organised under the laws of Hungary of 21, Gyomroi u., Budapest X., Hungary, do hereby declare this invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The invention relates to a novel xanthenic acid derivative having a therapeutic effect on the heart and especially on the coronary arteries. More particularly, the invention relates to I - isopentyl - 4 (xanthene - 9 carbonyloxy) - piperidine and its pharmaceutically acceptable acid addition salts, as well as to its preparation and pharmaceutical compositions containing the said compound as active ingredient.

U.S. Patent Specification No. 2,650,230 describes N-alkyl- and N - alkenyl (xanthene - 9 - carbonyloxy) - piperidines having spasmolytic, parasympatholytic and ganglion-blocking activity. This specification also describes quaternary salts of the said compounds, which are useful for combatting parasites.

However, the 1 - isopentyl - 4 - (xanthene - 9 - carbonyloxy) - piperidine of the present invention and the acid addition salts thereof are not disclosed in U.S.

Patent Specification No. 2,650,230, although this compound is within the general formula defined therein.

It has been found surprisingly that this compound, 1 - isopentyl - 4 (xanthene - 9 - carbonyloxy) - piperidine, which we have prepared and described for the first time, has a very significant coronary-dilating activity. The activity exceeds the similar activity of the known coronary-dilating agent, 2,6 - bis (diethanolamino) - 4,8 - dipiperidino - pyrimido[5,4 - dipyrimidine (known as dipyridamole), whidh has ac'hieved wiae jherapeutic use. This activity of I isopentyl - 4 - (xanthene - 9 - carbonyloxy) - piperidine, which could not be expected on the basis of its chemical structure, was examined by the method of Langendorff, on isolated rat heart [cf. E. Vanremoortere, Arch. Int.

Pharmacodyn, 95, 466 (1953)]. Six parallel experiments were performed with each of the different dosages; the average values of the results are summarized in the following table. The values given in this table indicate percentage increase of the blood flow in the coronary artery, in comparison with the corresponding values measured before the administration of the test compound.

Doses 1 ug 0.5 ug 0.2 ug The new compound of the invention 36.7 23.8 14.2 Dipyridamole 27.2 17.8 The new compound of the invention, 1 - isopentyl - 4 - (xanthene - 9 carbonyloxy)- piperidine and the acid addition salts thereof are prepared according to the present invention by acylating 1 - isopentyl - 4 - hydroxy piperidine with xanthene - 9 - carboxylic acid or with a reactive derivative thereof, and, if desired, converting the obtained product into an acid addition salt According to one embodiment of the invention, the 1 - isopentyl - 4 hydroxy - piperidine is acylated with xanthene - 9 - carboxylic acid. This reaction is performed suitably in the presence of an activator of the carboxyl group and/or of a water-binding agent. Mainly halogenated phenols or nitrohalophenols, preferably pentachlorophenol and/or N,N' - dicyclohexyl carbodiimide may be used as activators of the carboxyl group.

According to another preferred embodiment I - isopentyl - 4 - hydroxy piperidine is acylated with a halide, preferably the chloride of xanthene - 9 carboxylic acid.

Other reactive derivatives of xanthene - 9 - carboxylic acid, which may be used in the process of the invention, are the esters formed with aliphatic alcohols containing 1 to 5 carbon atoms, preferably the methyl and ethyl esters of xanthene - 9 - carboxylic acid. The acylation with such esters is performed preferably in the presence of catalytic amounts of sodium or potassium methoxide or ethoxide.

The reaction can be performed in the presence of an anhydrous inert solvent, e.g. of aromatic hydrocarbon, such as benzene, toluene or xylene, a chlorinated hydrocarbon, such as chloroform or tetrachloromethane, or an aliphatic ketone, such as acetone, or methyl isobutyl ketone.

The reaction temperature may vary within wide limits; it is, however, preferable to add the acylating agent at a temperature between 0 and 70"C, to the solution of the 1 - isopentyl - 4 - hydroxy - piperidine.

More particularly, if an acid chloride is used as acylating agent, the preferred reaction temperature is between 0 and 30"C, while the acylation with esters is carried out preferably at between 5 and 70"C. Towards the end of the reaction it is advisable to keep the reaction mixture at an elevated temperature, preferably at the boiling temperature thereof.

The product is then recovered in the usual manner from the reaction mixture, and may be converted, if desired, into a pharmaceutically acceptable acid addition salt.

Inorganic acids, as hydrohalogenic acids, e.g. hydrochloric, hydrobromic or hydroiodic acid, sulphuric acid, phosphoric acid, or organic acids, e.g. acetic, propionic, butyric, maleic, fumaric, citric, malic or tartaric acid may be used for the preparation of acid addition salts.

The I - isopentyl - 4 - (xanthene - 9 - carbonyloxy) - piperidine and the pharmaceutically acceptable acid addition salts thereof can be used as active materials in pharmaceutical compositions prepared by the usual methods. The pharmaceutical composition containing 1 - isopentyl - 4 - (xanthene - 9 carbonyloxy) - piperidine or the salts thereof as active material, can be administered orally, rectally or parenterally.

For oral administration the composition is prepared in the form of tablets, dragees or capsules. For the preparation of tablets lactose or starch may be used as solid carriers, and e.g. gelatine, sodium, carboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidone or starch paste as binders or granulating materials. As disintegration-adjuvants potato starch or microcrystalline cellulose are agents of choice, but also ultra-amylopectin or formaldehyde-casein may be used for this purpose. Talc, colloidal silicic acid, stearin, calcium or magnesium stearate can be used as lubricants and anti-adhesive agents.

The tablets can be prepared by wet granulation and subsequent pressing. The mixture of the active material and of the diluents, and optionally of a part of the disintegration-adjuvant is wetted with the aqueous, alcoholic or aqueousalcoholic solution of the binding agents and granulated in an appropriate equipment, the granulate is dried and then the remaining part of the disintegration-adjuvant, the lubricant and the anti-adhesive agent are admixed thereto and finally this mixture is pressed into tablets. The tablets may be provided with dividing scores to facilitate the dosage (e.g. 1030 mg per unit dose).

Tablets may be pressed also directly from the mixture of the active material and of appropriate auxiliary materials.

The tablets may also be converted, if desired, into dragees by coating them with the usual coating mixtures containing protecting, flavouring and/or colouring materials, e.g. sugar, cellulose derivatives (methyl or ethyl cellulose and sodium carboxymethyl cellulose), polyvinyl pyrrolidone, calcium phosphate, food colours and laquers and iron oxide pigments.

Capsules are prepared by filling the mixture of the active material and of the auxiliary materials into gelatine capsules.

For rectal administration the composition is prepared in the form of suppositories containing the active material mixed with a suppository base; the latter may consist of a vegetable fat, e.g. of hardened vegetable oils or triglycerides of fatty acids having 12 to 18 carbon atoms. The active material is distributed homogenously in the molten suppository base and the suppositories are made by the usual moulding process.

The compositions for parenteral administration are prepared in the form of injection ampoules. The injectable solutions are prepared by dissolving the active material, optionally in the presence of a solubility-promoting agent, e.g. of polyoxyethylene sorbitan monolaurate, monooleate or monostearate (Tween 20, Tween 60, Tween 80, "Tween" is a registered Trade Mark) in distilled water and/or in various organic solvents, e.g. in C14 - aliphatic alcohols or in glycol ethers, e.g. in ethyleneglycol monoethyl ether. The injectable solution may contain also various auxiliary materials, e.g. preserving agents, such as benzyl alcohol, p-hydroxybenzoic acid methyl or propyl ester, phenylmercury-borate or benzalkonium chloride, antioxidants, such as sodium pyrosulfate, ascorbic acid, tocopherol, agents for binding traces of metals, such as ethylenediaminetetraacetic acid, pH-adjusting agents, buffers and optionally local anesthetic agents, such as lidocaine.

The injectable solution made according to the present invention is filtered before filling it into ampoules and then the ampoules are sterilized.

The pharmaceutical compositions containing the new compounds of the present invention are administered in cases of heart attacks preferably intraveneously; for maintainance therapy oral or rectal administration is recommended. The daily doses maybe, depending on the condition of the patient, between 0.05 mg/kg and 0.8 mg/kg, preferably 0.2 to 0.3 mg/kg, administered in a single daily dose or divided into smaller doses, administered in different periods of the day.

The invention is illustrated in more detail by the following examples.

Example 1 a) I-Isopentyl-4-hydroxy-piperidine A mixture of 15.2 g. of 4 - hydroxy - piperidine; 32.5 g. of isopentyl iodide and 28 g. of anhydrous potassium carbonate in 200 ml. of ethanol is refluxed for 10 hours. The reaction mixture is then cooled to OOC, filtered, the ethanol is distilled off from the filtrate and the residue is purified by distillation in vacuo. 20 g. of I isopentyl - 4 - hydroxy - piperidine (77.75% of the theoretical yield) are obtained; m.p. 124--1260C/3 mm Hg; n2 =1.4710.

b) 1 - Isopentyl - 4 - (xanthene - 9 - carbonyloxy) - piperidine hydrochloride 3.6 g. of xanthene - 9 - carboxylic acid chloride are dissolved in 15 ml. of benzene, the solution is cooled to 10 C and the solution of 2.5 g. of I - isopentyl 4 - hydroxy - piperidine in 15 ml. of benzene is added thereto under cooling. The reaction mixture is refluxed for 30 minutes and then cooled to OOC and extracted twice with 10 ml. each of an aqueous 10% sodium hydroxide solution. The benzene phase is separated, dried over anhydrous sodium sulphate, filtered and the benzene is distilled off from the filtrate. The distillation residue is dissolved in 20 ml. of ethanol and an ether solution of hydrochloric acid is added dropwise thereto. The precipitated acid addition salt is separated by filtration and recrystallized from 15 ml. of ethanol. 3.2 g. of 1 - isopentyl - 4 - (xanthene - 9 carbonyloxy) - piperidine (52.6% of the theoretical yield) are obtained; m.p.

206--208"C.

Example 2 l-Isopentyl-4-(xanthene-9-carbonyloxy)-piperidine hydrochloride I ml of 10% sodium methoxide solution is added at 600C to a mixture of 4.2 g of I - isopentyl - 4 - hydroxy - piperidine and 9.6 g of xanthene - 9 - carboxylic acid methyl ester, and the reaction mixture is kept at 1000C to 1100C for 6 hours.

During this time, the methanol formed in the reaction is distilled off from the mixture. The reaction mixture is then cooled to 200C, 25 ml of benzene are added thereto and the benzene solution is extracted with 20 ml. of an aqueous 10% hydrochloric acid solution. The acid extract is treated with 1.5 g. of decolourizing charcoal and then solid sodium hydroxide is added thereto at room temperature, until the pH-value is raised to 10. The alkaline solution is extracted with three 25 ml portions of diethyl ether. The ether phases are combined, dried over anhydrous sodium sulphate, filtered and the ether is distilled off from the filtrate. The distillation residue is converted into the acid addition salt as described in Example I b. Yield: 3.7 g.

Example 3 Preparation of tablets of 300 mg: The following ingredients are used for the preparation of a pharmaceutical composition in the form of tablets: 1 - isopentyl - 4 - (xanthene - 9 - carbonyloxy) - piperidine hydrochloride 30 g.

talcum 9 g.

magnesium stearate 3 g.

polyvinyl pyrrolidone 6 g.

potato starch 84 g.

lactose 168 g.

1000 tablets weighing each 300 mg. are pressed from the above ingredients by the usual wet granulation method.

Example 4 Preparation of an injectable solution.

The following ingredients are used to prepare a pharmaceutical composition in the form of injectable solution: 1 - isopentyl - 4 - (xanthene - 9 - carbonyloxy) - piperidine hydrochloride 10 g.

sodium chloride 9 g.

benzyl alcohol 3 g.

distilled water (injection grade) 1000 ml.

The active substance and the sodium chloride are dissolved in the distilled water and then the benzyl alcohol is added to the solution. The resulting solution is filtered, filled into 1000 ampoules in portions of I ml. each and the sealed ampoules are sterilized by heating in the usual way.

WHAT WE CLAIM IS: 1. 1 - Isopentyl - 4 - (xanthene - 9 - carbonyloxy) - piperidine and pharmaceutically acceptable acid addition salts thereof.

2. 1 - Isopentyl - 4 - (xanthene - 9 - carbonyloxy) - piperidine hydrochloride.

3. A process for the preparation of I - isopentyl - 4 - (xanthene - 9 carbonyloxy) - piperidine which comprises reacting I - isopentyl - 4 hydroxypiperidine with xanthene - 9- carboxylic acid or an ester-forming derivative thereof.

4. A process according to claim 3 wherein 1 - isopentyl - 4 hydroxypiperidine is reacted with xanthene - 9 - carboxylic acid in the presence of a halogenated phenol, nitro-halophenol or a water-binding agent.

5. A process according to claim 3 wherein 1 - isopentyl - 4 hydroxypiperidine is acylated with the acid chloride of xanthene - 9 - carboxylic acid.

6. A process according to claim 3 wherein 1 - isopentyl - 4 hydroxypiperidine is acylated with xanthene - 9 - carboxylic acid methyl or ethyl ester in the presence of a catalytic amount of sodium or potassium methoxide or ethoxide.

7. A process according to any of claims 3 to 6 including the further step of converting the product into a pharmaceutically acceptable acid addition salt thereof.

8. A process according to claim 3, substantially as illustrated in Example 1 or 2.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (13)

1. **WARNING** start of CLMS field may overlap end of DESC **.

   thereto and the benzene solution is extracted with 20 ml. of an aqueous 10% hydrochloric acid solution. The acid extract is treated with 1.5 g. of decolourizing charcoal and then solid sodium hydroxide is added thereto at room temperature, until the pH-value is raised to 10. The alkaline solution is extracted with three 25 ml portions of diethyl ether. The ether phases are combined, dried over anhydrous sodium sulphate, filtered and the ether is distilled off from the filtrate. The distillation residue is converted into the acid addition salt as described in Example I b. Yield: 3.7 g.

   Example 3 Preparation of tablets of 300 mg: The following ingredients are used for the preparation of a pharmaceutical composition in the form of tablets: 1 - isopentyl - 4 - (xanthene - 9 - carbonyloxy) - piperidine hydrochloride 30 g.

   talcum 9 g.

   magnesium stearate 3 g.

   polyvinyl pyrrolidone 6 g.

   potato starch 84 g.

   lactose 168 g.

   1000 tablets weighing each 300 mg. are pressed from the above ingredients by the usual wet granulation method.

   Example 4 Preparation of an injectable solution.

   The following ingredients are used to prepare a pharmaceutical composition in the form of injectable solution: 1 - isopentyl - 4 - (xanthene - 9 - carbonyloxy) - piperidine hydrochloride 10 g.

   sodium chloride 9 g.

   benzyl alcohol 3 g.

   distilled water (injection grade) 1000 ml.

   The active substance and the sodium chloride are dissolved in the distilled water and then the benzyl alcohol is added to the solution. The resulting solution is filtered, filled into 1000 ampoules in portions of I ml. each and the sealed ampoules are sterilized by heating in the usual way.

   WHAT WE CLAIM IS: 1. 1 - Isopentyl - 4 - (xanthene - 9 - carbonyloxy) - piperidine and pharmaceutically acceptable acid addition salts thereof.
2. 2. 1 - Isopentyl - 4 - (xanthene - 9 - carbonyloxy) - piperidine hydrochloride.
3. 3. A process for the preparation of I - isopentyl - 4 - (xanthene - 9 carbonyloxy) - piperidine which comprises reacting I - isopentyl - 4 hydroxypiperidine with xanthene - 9- carboxylic acid or an ester-forming derivative thereof.
4. 4. A process according to claim 3 wherein 1 - isopentyl - 4 hydroxypiperidine is reacted with xanthene - 9 - carboxylic acid in the presence of a halogenated phenol, nitro-halophenol or a water-binding agent.
5. 5. A process according to claim 3 wherein 1 - isopentyl - 4 hydroxypiperidine is acylated with the acid chloride of xanthene - 9 - carboxylic acid.
6. 6. A process according to claim 3 wherein 1 - isopentyl - 4 hydroxypiperidine is acylated with xanthene - 9 - carboxylic acid methyl or ethyl ester in the presence of a catalytic amount of sodium or potassium methoxide or ethoxide.
7. 7. A process according to any of claims 3 to 6 including the further step of converting the product into a pharmaceutically acceptable acid addition salt thereof.
8. 8. A process according to claim 3, substantially as illustrated in Example 1 or 2.
9. 9. 1 - Isopentyl- 4 - (xanthene - 9- carbonyloxy) - piperidine and

   pharmaceutically acceptable acid addition salts thereof made by the process of any of claims 3 to 8.
10. 10. A pharmaceutical composition comprising a pharmacologically effective amount of a compound of claim 1 or 2 and a pharmaceutically acceptable carrier.
11. 11. A composition according to claim 10 in unit dosage form.
12. 12. A composition according to claim 11 wherein each unit dose contains 10--30 mg of said compound.
13. 13. A composition according to claim 11, substantially as illustrated in Example 3 or 4.