Claims
- 1. A compound of the formula
- wherein R is hydrogen, halogen or loweralkyl; R.sup.1 is, halogen or hydroxy; R.sup.2 is hydrogen or a group of the formula COR.sup.3 wherein R.sup.3 is loweralkyl; an optical or geometric isomer, or a salt thereof.
- 2. The compound of claim 1 which is 4-(2-fluorobenzoyl)-4-hydroxypiperidine.
- 3. The compound of claim 1 which is 4-(2,5-difluorobenzoyl)-4-hydroxypiperidine.
- 4. The compound of claim 1 which is 1-acetyl-4-(2-fluorobenzoyl)-4-hydroxypiperidine.
- 5. The compound of claim 1 which is 1-acetyl-4-(2,5-difluorobenzoyl)-4-hydroxypiperidine.
- 6. The compound of claim 1 which is 1-acetyl-4-(2,5-difluorobenzoyl)-4-bromopiperidine.
CROSS REFERENCE TO RELATED APPLICATIONS
This is a continuation of application Ser. No. 917,886 filed Oct. 14, 1986, now abandoned, which is a division of application Ser. No. 725,853 filed Apr. 22, 1986, now U.S. Pat. No. 4,654,336, granted Mar. 31, 1987.
The present invention relates to ethanobenzazepines. More particularly, the present invention related to ethanobenzazepines of the formula ##STR1## wherein R is hydrogen, halogen or lower alkyl; X is C.dbd.O or CHOH; Y is COH or a group of the formula COCOR.sup.1 wherein R.sup.1 is lower alkyl; and X and Y taken together with their common bond form a group of the formula ##STR2## wherein R.sup.2 and R.sup.3 are independently hydrogen, lower alkyl or phenyl; an optical or geometric isomer thereof, or a pharmaceutically acceptable acid addition salt thereof, which are useful for alleviating pain alone or in combination with inert adjuvants.
Subgeneric to the ethanobenzazepines of the present invention are compounds wherein:
(a) X is C.dbd.O; and Y is COH or a group of the formula COCOR.sup.1 wherein R.sup.1 is loweralkyl;
(b) X is CHOH; Y is COH; and
(c) X and Y taken together with their common bond form a group of the formula ##STR3## wherein R.sup.2 and R.sup.3 are independently hydrogen, lower alkyl or phenyl.
The present invention also relates to 4-(2-fluorobenzoyl)piperidines of the formula ##STR4## wherein R is hydrogen, halogen or lower alkyl; R.sup.1 is hydrogen, bromo or hydroxy; R.sup.2 is hydrogen or a group of the formula COR.sup.3 wherein R.sup.3 is lower alkyl, and 1-oxa-6-azaspiro[2,5]octanes of the formula ##STR5## wherein R is hydrogen, halogen or lower alkyl; and R.sup.4 and R.sup.5 are lower alkyl, as intermediates for the preparation of the present ethanobenzazepines.
As used through the specification and appended claims, the term "alkyl" refers to a straight or branched chain hydrocarbon radical containing no unsaturation and having 1 to 8 carbon atoms such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-pentyl, 2-pentyl,3-hexyl, 4-heptyl, 2-octyl, and the like; the term "alkoxy" refers to a monovalent substitutent which consists of an alkyl group linked through an ether oxygen and having its free valence bond from the ether oxygen such as methoxy, ethoxy, propoxy, butoxy, 1,1-dimethylethoxy, pentoxy, 3-methylpentoxy, 2-ethylpentoxy, octoxy, and the like; the term "alkanol" refers to a compound formed by a combination of an alkyl group and a hydroxy radical. Examples of alkanols are methanol, ethanol, 1- and 2-propanol, 2,2-dimethylethanol, hexanol, octanol, and the like. The term "alkanoic acid" refers to a compound formed by combination of a carboxyl group with a hydrogen atom or alkyl group. Examples of alkanoic acids are formic acid, acetic acid, propionic acid, butanoic acid, pentanoic acid, hexanoic acid, octanoic acid, and the like; the term "halogen" refers to a member of the family consisting of fluorine, bromine or iodine. The term "alkanone" refers to a compound formed by the combination of a carbonyl group and two alkyl groups. Examples of alkanones are acetone, 2 -butanone, 3-pentanone, 3-hexanone, 2-octanone, and the like. The term "alkanal" refers to a compound formed by the combination of a carbonyl group, an alkyl group and a hydrogen atom. Examples of alkanals are formaldehyde, acetaldehyde, propanal, pentanal, hexanal, octanal, and the like. The term "lower" as applied to any of the aforementioned groups refers to a group having a carbon skeleton containing up to and including 6 carbon atoms.
The compounds of the present invention which lack an element of symmetry exist as optical antipodes and as the racemic forms thereof. The optical antipode may be prepared from the corresponding racemic forms by standard optical resolution techniques, involving, for example, the separation of diasteromeric salts of those instant compounds characterized by the presence of a basic amino group and an optically active acid, or by the synthesis from optically active precursors.
The present invention comprehends all optical isomers and racemic forms thereof and all geometric isomers of the compounds disclosed and claimed herein. The formulas of the compounds shown herein are intended to encompass all possible geometric and optical isomers of the compounds so depicted.
The novel ethanobenzazepines of the present invention are prepared by the processes illustrated in the Reaction Scheme.
To prepare the parent ethanobenzazepine system, i.e., a 1,4-ethano-4-hydroxy-2,3,4,5-tetrahydro-5H-1-benzazepin-5-one 12 wherein R is as hereinbeforedescribed, a 2-fluorobenzoyl-4-hydroxypiperidine 11 wherein R is as hereinbeforedescribed, the synthesis of which is hereinafterdescribed, is cyclized in a suitable solvent in the presence of an acid acceptor to afford a compound of formula 12. Among suitable solvents there may be mentioned lower alkylalkanotes such as methyl acetate, ethyl acetate, ethyl propionate, n-butyl acetate and the like, and dipolar aprotic solvents such as dimethylacetamide, dimethylformamide, hexamethylphosphoramide, dimethylsulfoxide and the like, alone or in combination. A combination of n-butyl acetate and dimethylformamide is preferred. Acid acceptors include alkali metal carbonates and bicarbonate, e.g., sodium and potassium carbonate and sodium and potassium bicarbonates, potassium carbonate being preferred. The temperature at which the cyclization is performed is not narrowly critical. To facilitate the cyclization, the reaction is conveniently carried out at a temperature within the range of about 50.degree. C. to the reflux temperature of the reaction medium being preferred. A promotor such as sodium or potassium iodide may be employed, also to facilitate the cyclization. Potassium iodide is preferred.
To prepare an alkanoyl derivative 15 wherein R and R.sup.1 are as hereinbeforedescribed of the ketol 12, the ketol 12 is acylated with an alkanoic acid of the formula R.sup.1 CO.sub.2 H wherein R.sup.1 is the hereinbeforedescribed or the anhydride thereof of the formula (R.sup.1 CO).sub.2 O in an appropriate solvent in the presence of a base. Appropriate solvents include halocarbons such as dichloromethane, trichloromethane, dichloroethane and the like. Bases include tertiary amines such as trimethyl-, triethyl-, tri-n-butylamine, pyridine, lutidine, s-collidine, quinoline, and the like. Dichloromethane and triethylamine are the preferred solvent and base, respectively. A catalytic amount of a 4-dialkylaminopyridine, e.g., 4-dimethylaminopyridine, may be utilized to promote the conversion. The acylation proceeds readily at about ambient temperature. Elevated reaction temperatures within the range of about 30.degree. to about 80.degree. C. may be employed, however, to facilitate the conversion.
To synthesize a diol of formula 13 wherein R is as hereinbeforedescribed, the ketol 12 is reduced with an alkali metal borohydride, for example, lithium, sodium or potassium borohydride, in an alkanol such as methanol, ethanol, 2-propanol and the like, or an alkali metal aluminum hydride, for example, lithium aluminum hydride, in an ethereal solvent such as diethyl ether, di-isopropyl ether, dimethoxyethane, dioxane and tetrahydrofuran, alone or in combination Sodium borohydride and a combination of methanol and tetrahydrofuran are the preferred reducing agent and solvent systems, respectively. The reduction is conveniently accomplished at about ambient temperature. Higher reduction temperatures within the range of about 250 to the reflux temperature of the reaction medium may be employed to promote the reduction.
To elaborate the dioxolo function, i.e., to prepare a compound of formula 14 wherein R, R.sup.2 and R.sup.3 are as hereinbefore defined, a diol 13 is treated with an alkanal of the formula R.sup.2 CHO, an alkanone of the formula R.sup.2 R.sup.3 CO wherein R.sup.2 and R.sup.3 are as hereinbeforedefined, or the acetal or ketal derivatives of the formula R.sup.2 CH(OR.sup.5).sub.2 wherein R.sup.5 is lower alkyl, in an ethereal solvent such as diethyl ether, di-isopropyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, preferably tetrahydrofuran, in the presence of a mineral acid such as sulfuric acid, an aromatic sulfonic acid such as p-toluene sulfonic acid, or a Lewis acid such as boron trifluoride etherate, preferably boron trifluoride etherate, at a reaction temperature within the range of about 15.degree. to 65.degree. C., preferably at about ambient temperature.
The 2-fluorobenzqyl-4-hydroxypiperidine 11, the precursor for the fabrication of the ethanobenzazepines of the present invention are prepared from readily available starting materials according to the conventional processes depicted in the Reaction Scheme.
Thus condensation of the fluorobenzene 2 wherein R is as hereinbeforedefined with a 1-alkanoyl-4-piperidine carbonyl halide 3, the preparation of which is described in R. L. Duncan, et al., J. Med. Chem., 13, 1 (1970), wherein R.sup.4 is as hereinbeforedefined and Hal is bromo or chloro in the presence of a Friedel-Crafts catalyst such as aluminum chloride at the reflux temperature of the reaction medium affords a 4-(2-fluorobenzoyl)piperidine 4 wherein R and R.sup.4 are as definednereinbefore, which is halogenated by means of bromine, in an alkanoic acid such as acetic acid at a reduced temperature within the range of about 10.degree. to 30.degree. C., a temperature range of about 10.degree.-12.degree. C. being preferred, to a 4-bromo-4-(2-fluorobenzoyl)piperidine 5 wherein R and R.sup.4 are as defined above and converted to a 2-alkoxy-6-azaspiro[2,5]octane 6 wherein R and R.sup.4 are as defined hereinbefore and R.sup.5 is lower alkyl with an alkali metal alkoxide such as sodium methoxide in the corresponding alkanol, ethanol, at about the reflux temperature of the reaction medium. Rearrangement of a 2-alkoxy-6-azaspiro[2,5]octane 6 with a mineral acid such as hydrochloric acid in an alkanol such as ethanol at about ambient temperature provides a 4-(2-fluorobenzoyl)-4-hydroxypiperidine 10 wherein R and R.sup.4 are as described above which is hydrolyzed with a mineral acid, e.g, hydrochloric acid, at about the relux temperature of the reaction medium to the presursor 11 wherein R and R.sup.4 have the meaning hereinbeforedisclosed.
Alternatively, a fluorobenzene 2 is treated with N-methylformanilide 7 in a hydrocarbon-ethereal solvent such as n-hexane-tetrahydrofuran in the presence of an alkyalkali metal such as n-butyllithium at a reduced temperature of about -45.degree. C. to about -60.degree. C. to afford a 2-fluorobenzaldehyde 8 wherein R is as definedhereinbefore which is silyated with trimethylsilylcyanide in the presence of a Lewis acid such as, for example, zinc iodide, at a temperature within the range of about 65.degree. to about 95.degree. C. to provide a trimethylsilyl-2-fluorobenzaldehyde cyanohydrin 9 wherein R is as hereinbeforedefined and condensed with a 1-alkanoyl-4-piperidine of the formula ##STR6## wherein R.sup.4 is as defined above, in a hydrocarbon-ether solvent, e.g., n-hexane-tetrahydrofuran, in the presence of an alkali metal dialkylamide such as lithiumdiisopropylamide at a reduced temperature within the range of about -80.degree. to about -20.degree. C. to afford a 1-alkanoyl-4-(2-fluorobenzyl)-4-hydroxypiperidine 10. Hydrolysis of 10 by the process described above provides the precursor 11 for the preparation of the instant 1,4-ethano-1,2,3,4-tetrahydrobenzazepines.
The 1,4-ethanobenzazepines of the present invention are useful as analgetics due to their ability to alleviate pain in mammals. The analgetic utility is demonstrated in the phenyl-p-quinone writhing assay in mice, a standard assay for analgetic activity [Proc. Soc. Exptl. Biol med., 95 729 (1957)]. Thus, for instance, at a subcutaneous dose of 20 mg/kg the percent decrease in writhes in mice produced in this assay is as shown in the Table.
Analgesia production is achieved when the present ethanobenzazepines are administered to a subject requiring such treatment as an effective oral, parenteral or intravenous dose of from 0.01 to 100 mg/kg of body weight per day. A particularly effective amount is about 25 mg/kg of body weight per day. It is to be understood, however, that for any particular subject, specific dosage regimens should be adjusted according to the individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compound. It is to be further understood that the dosages set forth herein are exemplary only and that they do not, to any extent, limit the scope or practice of the invention.
Effective amounts of the compounds of the present invention may be administered to a subject by any one of the several methods, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. The 1,4-ethanobenzazepines of the present invention, while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable addition salts for purposes of stability, convenience or crystallization, increased solubility and the like.
Preferred pharmaceutically acceptable addition salts include salts of mineral acids, for example, hydrochloric acid, sulfuric acid, nitric acid and the like, salts of monobasic carboxylic acids such as, for example, acetic acid, propionic acid and the like, salts of dibasic carboxylic acids such as, for example, maleic acid, fumaric acid and the like, and salts of tribasic carboxylic acids such as, for example, carboxysuccinic acid, citric acid and the like.
Effective quantities of the compounds of the invention may be administered orally, for example, with an inert diluent or with an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purposes of oral therapeutic administration, the aforesaid compounds may be incorporated with an excipient and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations should contain at least 0.5% of active compound, but may be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit. The amount of active compound in such composition is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between 1.0-300 milligrams of the active compound.
The tablets, pills, capsules, troches and the like may also contain the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth or gelatine; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, corn starch and the like; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin, or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring may be added. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes, colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
For the purpose of parenteral therapeutic administration, the active compounds of the invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1% of active compound, but may be varied between 0.5 and about 50% of the weight thereof. The amount of active compounds in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.5 to 100 milligrams of active compound.
The solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parentereal preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic. The following examples are for illustrative purposes only and are not to be construed as limiting the invention.
US Referenced Citations (2)
| Number |
Name |
Date |
Kind |
| 4021564 |
Hernstam et al. |
May 1977 |
|
| 4355037 |
Strupczewski et al. |
Oct 1982 |
|
Divisions (1)
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Number |
Date |
Country |
| Parent |
725853 |
Apr 1986 |
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Continuations (1)
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Number |
Date |
Country |
| Parent |
917886 |
Oct 1986 |
|
Patent Grant
5057611
