N-heterocyclic-N-(4-piperidyl) amides

Abstract: Compounds of the formula have analgesic or antagonist properties. In the formula: R is a saturated or unsaturated heterocyclic ring system of from 4 to 10 carbon atoms, including 1 to 3 nitrogen atoms, and 0 to 1 sulphur or oxygen atoms; R¹ is a furanyl, thienyl or lower alkyl lower alkoxy group; and R² is a phenyl lower alkyl group. The heterocyclic ring may be unsubstituted or substituted by a halogen or by a lower alkyl, lower alkoxy, halogenated lower alkyl, or lower alkylthio group, or combinations thereof.

Description: The present invention relates to a class of N-heterocyclic-N-(4-piperidyl)amides, compositions employing such compounds, and methods of making the compounds. A number of patents disclose certain N-heterocyclic-N-(4-piperidyl)amides having therapeutic activity. For example, U.S. Patent No. 4,546,105 to Effland et al. discloses pyrrolylamidopiperidines useful for the alleviation of pain. An article entitled "Synthesis and Analgesic Activity of Derivatives of Fentanyl" by Zhu Youcheng et al, printed in Acta Pharmaceutica Sinica, Vol. XVI, No. 3, March 1981 (pp 199-209) discloses various N-heterocyclic substituted amidopiperidines which possess morphine-like effects. Sigmar Grossmann, Ulrich Moser and Ernest Mutschler, in Arch. Pharm. (Weinheim) 311, 1010-1015 (1978) disclose various pyridine analogues of fentanyl possessing analgesic activity. Frans Janssens et al., in Journal of Medicinal Chemistry, Vol. 28, No. 12, 1934-1947 (1985) disclose various N-heterocyclic 4-piperidinamides possessing antihistaminic properties. DE-A-2 341 965 discloses N-pyridyl-N-(4-piperidyl)amides possessing analgesic activity without morphine-like poisoning symptoms. EP-A-0 160 422 describes N-aryl-N-(4-piperidyl)amides having central nervous system depressant properties such as analgesia, hypnosis, sedation, muscle relaxation and so on. Antagonists in general possess the property of reversing a previously administration drug (the agonist). For example, the antagonist naloxone is well known for use in reversing selected properties of narcotic agonists. Antagonists of narcotics are believed to function by binding competitively to opioid receptors,thereby preventing occupation of the agonist. At least four types of opioid receptors have been identified in the central nervous system-mu, kappa, sigma, and delta. The affinity of a particular antagonist for each receptor may not be equal. However, antagonist compounds may act centrally or peripherally, at specific opiate receptors, through a non-specific analeptic mechanism, or through a neurotransmitter system. The full understanding of the complex affects of antagonists must await the elucidation of opioid physiology. The prior art antagonist compound naloxone has gained wide-spread use in anesthesia for the purpose of antagonizing opioid induced respiratory depression and sedation, (Editorial, British Journal of Anesthesia, Vol. 57, No. 6, June 1985 (pp 547-549). The use of naloxone in the presence of unwanted opioid effects has predominantly occurred in the immediate post operative period. Recent information has supported the need for caution in the use of the naloxone antagonist. This need for caution is based on reports of unwanted side effects of naloxone itself, including ventricular dysrhythmia, hypertension and pulmonary oedema following intravenous administration. Another disadvantage of naloxone as an art agonist is that naloxone tends also to reverse or antagonize the analgesic component of opioids. There is therefore a need for alternative antagonists, for example, a safe antagonist of opioid agonists which will selectively antagonize respiratory depression without the undesirable side effects of naloxone and which does not antagonize the analgesia component of the opioid agonists. It has now been found that very desirable antagonist properties are provided by compounds of the formula: optically active isomeric forms thereof, and/or pharmaceutically acceptable acid addition salts thereof. In the Formula (I) above, R is pyrrolyl, piperidyl, pyrazyl, triazolyl, quinolyl, benzisoxazolyl or benzisothiazolyl, all of which may be unsubstituted or substituted, wherein the or each substituent is selected from halogen, alkyl, alkoxy, halogenated alkyl and alkylthio groups, each alkyl of these groups containing from 1 to 7 carbon atoms; R¹ is a furanyl or a thienyl or an alkoxy alkyl group, each alkyl of this group containing from 1 to 7 carbon atoms, and R² is a phenyl alkyl group, the alkyl group containing from 1 to 7 carbon atoms. Compounds according to the invention possess antagonist or antagonist and agonist properties. The compounds of the present invention selectively reverse respiratory depression of narcotic or opiate analgesics without reversal of analgesia at that dose. Agonist-antagonists of this class of compounds are useful for post-operative pain control where respiratory depression but not analgesia must be reversed. Such compounds may be used pre- operatively or intra-operatively, including as a supplement to general anaesthesia. The agonist effect of the present compounds causes analgesia, decreased awareness of sensation and increased pain threshold. Preferred compounds of the present invention exhibit comparatively low cardiorespiratory adverse effects. At higher doses, compounds of the invention produce sedation, loss of righting reflex, hypnosis and loss of consciousness. A preferred class of compounds within the scope of the present invention are those, wherein the or each substituent of the heterocyclic ring R is a halogen (more preferably chlorine or fluorine) or an alkyl group of 1 to 7 carbon atoms or combinations thereof; and R¹ is a furanyl or thienyl group, or an alkoxy alkyl of 2-6 carbon atoms. Suitable R groups include 1-pyrrolyl, 1,2,4-triazol-4-yl, 1-piperidyl, 2-pyrazyl, 3-quinolyl, 2,1-benzisothiazol-3-yl, 1,2-benzisoxazol-3-yl, 5-chloro-1,2-benzisoxazol-3-yl, 1,2-benzisothiazol-3-yl. Preferred R groups are 2-pyrazyl and 1-piperidyl. The furanyl or thienyl group is preferably attached to the carbonyl carbon at the 2 or 3 position of the ring. Examples of suitable R¹ groups include methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, 1-butoxymethyl, 1-pentoxymethyl, 1-hexoxymethyl, 1-heptoxymethyl, 1-methoxyethyl, 1-ethoxy-1-ethyl, 1-butoxy-1-ethyl, 2-furanyl, 3-furanyl, 2-thienyl and 3-thienyl. 2-furanyl and 3-furanyl are particularly preferred. Suitable R² groups in Formula I above include 2-phenylethyl, 1-phenyl-2-propyl and 2-phenyl-1-propyl. The alkyl or alkoxy groups containing from 1 to 7 carbon atoms may be branched or unbranched groups. Preferred alkyl or alkoxy groups contain from 1 to 5 carbon atoms, and the most preferred from 1 to 3 carbon atoms. The compounds of the invention can exist in the form of the free base or therapeutically or pharmaceutically acceptable acid addition salts by treatment of the base with an appropriate acid, such as an inorganic acid, e.g., hydrochloric, hydrobromic, sulfuric, nitric, phosphoric acids and the like; or an organic acid such as acetic, trifluoroacetic, propionic, hydroxyacetic, methoxyacetic, benzoic, citric, oxalic, methanesulfonic, ethanesulfonic, benzenesulfonic, toluenesulfonic, succinic, tartaric, and like acids. Preferred acid addition salts are the chloride, oxalate and citrate. These acid addition salts can be prepared by conventional methods. Compounds of the invention having at least one asymmetric carbon atom can exist in optically active isomeric forms. For example, in compounds in which R² is a 2-phenyl- 1-propyl or 1-phenyl-2-propyl group, etc., the carbon adjacent to the piperidinyl nitrogen is an asymmetric carbon and such compounds can therefore exist in optical active isomeric (enantiomeric) forms. Such isomeric forms can be isolated from the racemic mixtures by techniques known to those skilled in the art. The compounds of the invention, prepared as the free base, can be combined with a pharmaceutically acceptable carrier to provide a pharmaceutical composition. Suitable carriers for the free bases include propylene glycol-alcohol water, isotonic water, sterile water for injection, USP, emulphor™-alcohol-water, cremophor-EL™ or other carriers known to those skilled in the art. The compounds of the invention prepared as the pharmaceutically acceptable acid addition salts can also be combined with a pharmaceutically acceptable carrier to provide a pharmaceutical composition. Suitable carriers for the acid addition salts may include an isotonic aqueous solution, or sterile water for injection, USP, alone or in combination with other solubilizing agents such as ethanol, propylene glycol, or other conventional solubilizing agents known to those skilled in the art. Of course, the carrier will vary depending upon the mode of administration desired for the pharmaceutical composition as is conventional in the art. A preferred carrier is an isotonic aqueous solution containing from 0.01 mg/ml to 4.0 mg/ml of at least one of the compounds of this invention depending upon the pharmacology of the individual compounds being employed in the formulation. The compounds of the invention can be administered to mammals, e.g., animals or humans, in amounts effective to provide the desired therapeutic effect. The compounds can be administered intravenously, intramuscularly or subcutaneously in the previously described carriers. These compounds may also be administered orally, sublingually, rectally, or transcutaneously with a suitable pharmaceutically acceptable carrier for that mode of administration as is conventional in the art. As noted above, an effective amount of the compounds of the present invention is employed to obtain the desired therapeutic effect. Since the activity of the compounds and the depth of the desired therapeutic effect vary, the dosage level employed of the compound also varies. The actual dosage administered will be determined by such generally recognized factors as the body weight of the patient or the idiosyncrasies of the particular patient. Thus, the unit dosage for a particular patient (man) can be as low as 0.30 mg/Kg, which the practitioner may titrate to the desired effect. The compounds of the present invention can be prepared by various methods. In general, the desired compounds of Formula I above can be prepared by reacting a compound of the formula with a compound of the formula or ( R¹CO)₂0 or by reacting a compound of the formula with a compound of the formula R² X wherein R, R¹, and R², have the meanings given above and X represents a halide or other radical reactive with the N-bonded hydrogen atom. Several convenient routes for the preparation of the compounds of the invention begin with known piperidones as shown below: The compound 4-(2-phenylethyl)-piperidone can be prepared according to the procedure published by A.H. Becket, A.F. Casey and G. Kirk, J. Med Pharm. Chem. , Vol. 1, 37 (1959). The compound 4-benzyl-1- piperidone can be prepared in an analogous manner by the procedures described by C.R. Ganellin and R.G. Spickch, J. Med. Chem. , Vol. 8, 619 (1965) or P.M. Carabateas and L. Grumbach, J. Med. Pharm. Chem. , Vol. 5, 913(1962). In one example of a process of the invention, 4-benzyl or 4-(2-phenylethyl)-piperidone may be reacted with a heterocyclic amine or a substituted heterocyclic amine and the resulting Schiff base may be reduced with, for example, sodium borohydride to give 1-benzyl or 1-(2-phenylethyl)-4-hetero-cyclic-aminopiperidine or the corresponding substituted heterocyclic compound if the substituted heterocyclic amine is used. See for example, Grossman, S. et al., Arch. Pharm. (Weinheim) 311 , 1010 (1978). The following reaction scheme, wherein R represents a heterocyclic group according to the present invention, illustrates such a method: The last compound can be reacted with the appropriate acid halide (e.g., R¹(COCl) or anhydride [(R¹CO)₂0] to introduce the R¹-CO- group into the amino-nitrogen. A second method for the preparation of the compounds of the invention utilizes the intermediate, 4 amino-1-R²-piperidine, for example, 4-amino-1-phenethyl piperidine. This method employs an aromatic nucleophilic substitution to obtain a secondary amino precursor for acylation. See, for example, Zhu, Y. et al, Acta Pharm Sinica, 16 , 199 (1981). The following reaction scheme, where R represents a heterocyclic group according to the present invention, illustrates such a method: A third method for the preparation of compounds of the present invention also utilizes the intermediate 4-amino-1-R²-piperidine, for example, 4-amino-1-phenylethyl piperidine. In this regard, see Langhein, et al., Offenlegungsschrift, 234 1965 (1975); Chem. Abstr. 82 , 156121W (1975). This method involves reacting an oxo derivative of the heterocycle R with said intermediate to form a secondary amine which is reduced prior to acylation. The following examples are presented for purposes of demonstrating the compounds or compositions of this invention. EXAMPLE 1 An oxime intermediate was prepared as follows. Prior to use, N-(phenylethyl) piperidone was recrystallized from hexane in a 2000 ml beaker. 50 g (0.246 mol) of N-(phenylethyl) piperidone was dissolved in 200 ml of ethanol with necessary heat. This solution was added to a warm solution of 34.2 g (0.492 mol) of hydroxylamine hydrochloride and 200 ml of deionized water. An additional 500 ml of water was added to dissolve the phenylethylpiperidone oxime hydrochloride which began to precipitate. Solid NaHCO₃ (41.3 g, 0.492 mol) was added in portions. The mixture was then heated nearly to boiling and set aside to cool to room temperature. Enough ice to fill a 1000 ml beaker was added and the mixture was stirred overnight. The solid product was filtered, washed with water (5 x 200 ml), and dried in vacuo. The crude oxime (52 g, 97%, mp 132-133°C) was sufficiently pure for use in the next reaction. An analytically pure sample (mp 132.5-134.5°C) was obtained by recrystallization from 95% ethanol. Calcd Found C 71.52 71.76 H 8.31 8.23 N 12.84 13.04 EXAMPLE II The oxime of Example I was reduced as follows. Prior to use, tetrahydrofuran was dried by distillation from LiAlH₄ followed by storage over 3A molecular sieves. To a continuously stirred suspension of 8.7 g (0.23 mol) of LiAlH₄ in 100 ml of dry tetrahydrofuran (THF), was added dropwise (at such a rate as to maintain a brisk reflux) a solution of 50 g (0.23 mol) of oxime from Example I in 400 ml of THF. On completion of addition, the reaction mixture was heated under reflux overnight. The heating mantle was carefully replaced with a ice-water bath. Quenching, to liberate the basic product, consisted of successive additions of 8.7 ml of H₂O, 8.7 ml of 15% NaOH, and 26.1 ml of H₂O. The insoluble material was filtered, washed with THF (3 x 200 ml), and the combined filtrates concentrated in vacuo. The residual oil was dissolved in CH₂Cl₂ (300 ml), washed with water (2 x 100 ml), and dried over Na₂SO₄. Vacuum distillation of the crude oil, left after evaporation of solvent, gave a colorless product [35 g, 74%, bp 142° (0.10 mm Hg)]. The storage container was tightly capped and placed in a dessicator as this strongly basic amine forms salts of atmospheric carbon dioxide (H₂CO₃). An analytically pure sample was obtained as the dihydrogen oxalate hemihydrate from i-PrOH-H₂O (mp 191-192°). Calcd Found C 51.90 51.58 H 6.41 6.21 N 7.12 7.11 EXAMPLE III An intermediate compound was prepared as follows. A mixture of 13 g (64 mmol) of the product of Example II, 3.6 g (32 mmol) of chloropyrazine, and 2.0 g (32 mmol) of copper powder was stirred at 170-180° for 6 hr. On cooling, a green mixture solidified. The solid was broken into chunks with a spatula and gradually churned into a thick soup in 10% HCl (100 ml). This was filtered and the filtrate extracted with ether (50 ml). Alkalinization with 12N NaOH liberated the free base which was extracted with methylene chloride (2 x 50 ml). The organic extract was washed with water (50 ml), brine (50 ml), and dried over Na₂SO₄. The green solid left after evaporation of a solvent was eluted through 600 g of fine silica. This required successive passages of CHCl₃-MeOH- NH₃ (4000 ml of 100:1:0.1, 1800 ml of 90:1:0.1, 1600 ml of 80:1:0.1, 4000 ml of 70:1:0.1) to yield 4.0 g (44%) of the following product as a beige solid. EXAMPLE IV A compound according to the invention was prepared from the product of Example III as follows. To a continuosly stirred mixture of the product of Example III (1.5 g, 5.3 mmol), with 1.5 ml of triethylamine, and 13 ml of chloroform there was added, with a disposable pipet, 0.63 ml (6.4 mmol) of 2-furoyl chloride in 2 ml of chloroform. The resulting mixture was stirred under reflux for 5 hr, then cooled and concentrated in vacuo. The residue was partitioned between 10% HCl (50 ml) and ether (50 ml). The aqueous phase was alkalinized with 12N NaOH and extracted with methylene chloride (2 x 50 ml). The organic extract was washed with water (50 ml), brine (30 ml), and dried over Na₂SO₄. Purification by flash chromatography (55 g fine silica; CHCl₃-MeOH-NH₃, 30:1:0.1) gave the product as a white solid (0.9 g, 45%). The hydrogen oxalate salt was initially precipitated from isopropyl alcohol and recrystallized from an isopropyl alcohol solution (containing the minimal amount of aqueous methanol required to dissolve salt) to yield finally 690 mg of a crude powder (mp 206-207°C) an oxalate salt of a compound having the following structure. Calcd Found C 61.79 62.17 H 5.62 5.61 N 12.01 12.28 EXAMPLE V - XII Further examples of compounds within the scope of the present invention which may also be prepared by procedures analogous to those described above include: N-(1-pyrrolyl)-N-[1-(2-phenylethyl)-4-piperidyl]-2-furamide; N-(1,2,4-triazoly-4-yl)-N-[1-(2-phenylethyl)-4-piperidyl]-3-furamide; N-(2,1-benzisothiazol-3-yl)-N-[1-(2-phenylethyl)-4-piperidyl-3-furamide; N-(1,2-benzisoxazol-3-yl)-N-[1-(2-phenylethyl)-4-piperidyl]-3-furamide; N-[5-chloro-1,2-benzisoxazol-3-yl)-N-(2-phenylethyl)-4-piperidyl] -3-furamide; N-[1,2-benzisothiazol-3-yl)-N-[1-(2-phenylethyl)-4-piperidyl)-2-furamide; N-[6-chloro-1,2-benzisoxazol-3-yl]-N-[1-(2-phenylethyl)-4-piperidyl)-2-furamide; N-(pyrazin-2-yl)-N-[1-(2-phenyethyl)-4-piperidyl]-2-thienylamide; and those compounds listed in Example XIII below. EXAMPLE XIII A number of compounds in accordance with the present invention were tested for their analgesic and reversal properties. Specifically, the acid addition salt of each test compound was dissolved in sterile water for injection, USP, to form a solution whose concentratioon varied from 0.00001 mg/ml to 5 mg/ml. The solution was administered intravenously in a mouse tail vain. The ED₅₀ values were obtained from the mouse hot plate analgesia test (58°C) described in Domer, Floyd R., Animal Experiments in Pharmacological Analysis , Charles C. Thomas, Springfield, 1971, p. 283 ff. The compounds listed in Table 1 below were tested by this procedure and found to have the analgesic activities listed in Table 1. The reversal characteristics with respect to morphine were investigated in rabbits. The number 1 indicated reversal of only morphine respiratory depression.

Claims: Claims for the following Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A compound of the formula optically active isomeric forms thereof, and/or pharmaceutically acceptable acid addition salts thereof, in which formula: R is pyrrolyl, piperidyl, pyrazyl, triazolyl, quinolyl, benzisoxazolyl or benzisothiazolyl, all of which may be unsubstituted or substituted, wherein the or each substituent is selected from halogen, alkyl, alkoxy, halogenated alkyl and alkylthio groups, each alkyl of these groups containing from 1 to 7 carbon atoms; R¹ is a furanyl or a thienyl or an alkoxy alkyl group, each alkyl of this group containing from 1 to 7 carbon atoms, and R² is a phenyl alkyl group, the alkyl group containing from 1 to 7 carbon atoms. A compound according to claim 1, in which formula the or each substituent of the heterocyclic ring R is a halogen or an alkyl group of 1 to 7 carbon atoms or combinations thereof; and R¹ is a furanyl or thienyl group, or an alkoxy alkyl group of 2 to 6 carbon atoms. A compound according to claim 2, which comprises N-(2-pyrazyl)-N-[1-(2-phenylethyl)-4-piperidyl]-2-furamide, or N-(1-piperidyl)-N-[1-(2-phenylethyl)-4-piperidyl]-2-furamide. A narcotic antagonistic and/or analgesic composition comprising a non-toxic pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to any one of claims 1 to 3. A compound according to any one of claims 1 to 3, or a composition according to claim 4, for use as a narcotic antagonist or a narcotic antagonist and analgesic. A method of preparing a compound of formula (I) according to claim 1 wherein either a compound of the formula: is reacted with a compound of the formula: or ( R¹CO)₂0 or a compound of the formula: is reacted with a compound of the formula: R²X wherein X is a halogen atom or its reactive equivalent, to form said compound of formula (I). A method according to claim 6, wherein the compound of formula (II) is prepared by reacting a compound of formula: with an amine of formula: RNH₂ wherein R² is the 2-phenylethyl group or the benzyl group, to form a Schiff base which is then reduced to form the compound of formula (II). A method according to claim 7, wherein the Schiff base is reduced by sodium borohydride. A method according to claim 6, wherein the compound of formula (II) is prepared by reacting a compound of formula: with a compound of formula RX. A method according to claim 6, wherein the compound of formula (II) is prepared by reacting a compound of formula: with an oxo derivative of a compound of formula RX, to form the corresponding secondary amine, and then reducing the oxo-substituted secondary amine to form the compound of formula II. Claims for the following Contracting States : ES, GR A method of preparing a compound of formula: wherein either a compound of the formula: is reacted with a compound of the formula: or ( R¹CO)₂0 or a compound of the formula: is reacted with a compound of the formula: R²X to form said compound of formula (I), wherein: R is pyrrolyl, piperidyl, pyrazyl, triazolyl, quinolyl, benzisoxazolyl or benzisothiazolyl, all of which may be unsubstituted or substituted, wherein the or each substituent is selected from halogen, alkyl, alkoxy, halogenated alkyl, alkylthio and combinations thereof, each alkyl of these groups containing from 1 to 7 carbon atoms; R¹ is furanyl, thienyl or alkoxy alkyl group, each alkyl of this group containing from 1 to 7 carbon atoms; R² is a phenyl alkyl group, the alkyl group containing from 1 to 7 carbon atoms; and X is a halogen atom or its reactive equivalent. A method according to claim 1, wherein the or each substituent of the heterocyclic ring R is a halogen or an alkyl group of 1 to 7 carbon atoms or combinations thereof; and R¹ is a furanyl or thionyl group or an alkoxy alkyl group of 2 to 6 carbon atoms. A method according to claim 1 or 2, wherein the compound of formula (II) is prepared by reacting a compound of formula: with an amine of formula: RNH₂ to from a Schiff base which is then reduced to form the compound of formula (II), wherein R² is the 2-phenylethyl group or the benzyl group, and R is as defined in claim 1 or 2. A method according to claim 3, wherein the Schiff base is reduced by sodium borohydride. A method according to claim 1 or 2, wherein the compound of formula (II) is prepared by reacting a compound of formula: with a compound of formula RX, where R, R² and X are as defined in claim 1 or 2. A method according to claim 1 or 2, wherein the compound of formula (II) is prepared by reacting a compound of formula: with an oxo derivative of a compound of formula RX, to form the corresponding secondary amine, and then reducing the oxo-substituted secondary amine to form the compound of formula II, wherein R, R² and X are as defined in claim 1 or 2.

Inventors: BAGLEY JEROME R, SPENCER H KENNETH, BAGLEY, JEROME R., SPENCER, H. KENNETH
Applicants: OHMEDA PHARMA PROD, OHMEDA PHARMACEUTICAL PRODUCTS DIVISION INC.
Application year: 1988
Main classification: C07D417
IPC codes: A61P25, C07D409, A61K31, C07D413, A61P23, C07D417, C07D211, C07D401, C07D403, C07D405