Claims
- 1. A compound represented by the formula: ##STR11## wherein: R is selected from the group consisting of hydrogen, cyano, lower alkyl, lower alkenyl, and aralkyl;
- each of R.sup.1, R.sup.2 and R.sup.3 is independently selected from the group consisting of: hydrogen, hydroxy, halo, trifluoromethyl, nitro, lower alkoxy, lower alkyl, and lower alkylthio; and
- Y is lower alkylene having from two to four carbon atoms;
- or a pharmaceutically acceptable salt thereof.
- 2. The compound of claim 1 wherein Y is --(CH.sub.2).sub.2 -- or --(CH.sub.2).sub.3 --.
- 3. The compound of claim 2 wherein Y is --(CH.sub.2).sub.2 --.
- 4. The compound of claim 3 wherein R is alkyl.
- 5. The compound of claim 4 wherein R is methyl.
- 6. The compound of claim 5 wherein R.sup.1 and R.sup.2 are hydrogen, and R.sup.3 is not hydrogen.
- 7. The compound of claim 6 wherein R.sup.3 is halo or lower alkoxy.
- 8. The compound of claim 7 wherein R.sup.3 is chloro.
- 9. The compound of claim 7 wherein R.sup.3 is methoxy.
- 10. The compound of claim 2 wherein Y is --(CH.sub.2).sub.3 --.
- 11. The compound of claim 10 wherein R is alkyl.
- 12. The compound of claim 11 wherein R is methyl.
- 13. The compound of claim 12 wherein R.sup.1 and R.sup.2 are hydrogen, and R.sup.3 is not hydrogen.
- 14. The compound of claim 13 wherein R.sup.3 is halo or lower alkoxy.
- 15. The compound of claim 14 wherein R.sup.3 is chloro.
- 16. The compound of claim 14 wherein R.sup.3 is methoxy.
- 17. The compound of claim 1 wherein R is alkyl.
- 18. The compound of claim 17 wherein R is methyl.
- 19. The compound of claim 1 wherein R.sup.1 and R.sup.2 are hydrogen, and R.sup.3 is not hydrogen.
- 20. The compound of claim 19 wherein R.sup.3 is halo or lower alkoxy.
- 21. The compound of claim 20 wherein R.sup.3 is chloro.
- 22. The compound of claim 20 wherein R.sup.3 is methoxy.
- 23. The HCl or HBr salt of a compound of claim 1.
- 24. A pharmaceutical composition comprising a pharmaceutically acceptable non-toxic excipient and a therapeutically effective amount of a compound of claim 1.
- 25. A pharmaceutical composition for oral administration comprising a pharmaceutically acceptable non-toxic excipient and a therapeutically effective amount of a compound of claim 1.
- 26. A method of treating depression, anxiety or hypertension in mammals, which comprises administering to a mammal suffering therewith a therapeutically effective amount of a compound represented by the formula: ##STR12## wherein: R is selected from the group consisting of hydrogen, cyano, lower alkyl, lower alkenyl, and aralkyl;
- each of R.sup.1, R.sup.2 and R.sup.3 is independently selected from the group consisting of: hydrogen, hydroxy, halo, trifluoromethyl, nitro, lower alkoxy, lower alkyl, and lower alkylthio; and
- Y is lower alkylene having from two to four carbon atoms; or a pharmaceutically acceptable salt thereof.
- 27. The method of claim 26 which comprises administering to a mammal suffering with depression a therapeutically effective amount of said compound.
- 28. The method of claim 26 which comprises administering to a mammal suffering with anxiety a therapeutically effective amount of said compound.
- 29. The method of claim 26 which comprises administering to a mammal suffering with hypertension a therapeutically effective amount of said compound.
BACKGROUND OF THE INVENTION
This is a division of pending application Ser. No. 050,977, filed May 15, 1987, incorporated herein by reference, now abandoned.
1. Field of the Invention
The present invention relates to pharmaceutical compositions, particularly to cycloalkanoazepines and derivatives thereof, and to their use as CNS agents, e.g., as antidepressants, anxiolytics and antihypertensives. These compositions demonstrate affinity for .alpha..sub.2 and 5-HT.sub.1A receptors.
2. Background Information and Related Disclosures
Tricyclic antidepressants, such as those described in U.S. Pat. No. 3,991,059 include three six-membered rings, one of which has a nitrogen atom. Those described in French patent No. 2,493,842 include a six and a seven membered ring with a two-membered bridge, the bridge including a nitrogen atom.
U.S. Pat. No. 4,465,677 shows .alpha..sub.2 antagonists for cardiovascular and antihypertensive uses, which are described as N-substituted 2,3,4,5-tetrahydro-1H-3-benzazepines, where the 6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine is preferred.
Compounds that are specific for .alpha..sub.2 and/or 5-HT.sub.1A and are useful as antihypertensives and cardiovascular agents have, however, remained desired.
One aspect of the present invention concerns 1,9-Alkano-bridged-2,3,4,5-tetrahydro-1H-3-benzazepines, and the derivatives thereof, i.e, the compounds of Formula I: ##STR2## wherein: R is selected from the group consisting of: hydrogen, cyano, lower alkyl, lower alkenyl, and aralkyl;
In yet another aspect, the invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof admixed with at least one pharmaceutically acceptable excipient.
In still another aspect, the invention relates to a method of treating CNS disorders, depression, anxiety or hypertension in a mammal by administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
Another aspect of the invention relates to processes for making the compounds of Formula I and the pharmaceutically acceptable salts thereof, including certain precursors thereto, represented by Formula II: ##STR3## wherein: R is selected from the group consisting of hydrogen, cyano, lower alkyl, lower alkenyl, and aralkyl;
A process for making the compounds of Formula I entails contacting a compound of Formula II with a reducing agent or an acid at conditions sufficient to convert R.sup.4 or R.sup.5 to H.sub.2 and/or the double bond represented by the dashed line to a single bond.
The following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
The naming and numbering of the compounds of the present invention is illustrated in Formulae III-V as follows: ##STR4##
The compounds of the invention in which Y is --(CH.sub.2).sub.2 -- will be named using the numbering system of Formula III, e.g., as 1,3,4,8,9,9a-hexahydro-2H-indeno[1,7-cd]azepine (where R, R.sup.1, R.sup.2 and R.sup.3 are hydrogen). ##STR5##
The compounds of the invention in which Y is --(CH.sub.2).sub.3 -- will be named using the numbering system of Formula IV, e.g., as 2-methyl-1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azepine (where R is methyl, and R.sup.1, R.sup.2 and R.sup.3 are hydrogen). ##STR6##
The compounds of the invention in which Y is --(CH.sub.2).sub.4 -- will be named using the numbering system of Formula V, e.g., as 1,3,4,8,9,10,11,11a,-octahydro-2H-cyclohepta[c,d][3]benzazepine (where R, R.sup.1, R.sup.2 and R.sup.3 are hydrogen).
As used herein, the term "alkyl" refers to a fully saturated monovalent radical containing only carbon and hydrogen, and which may be a cyclic, branched or straight chain radical. This term is further exemplified by radicals such as methyl, ethyl, t-butyl, pentyl, pivalyl, heptyl and adamantyl.
The term "lower alkyl" refers to a cyclic, branched or straight chain monovalent alkyl radical of one to six carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, i-butyl (or 2-methylpropyl), cyclopropylmethyl, i-amyl, n-amyl, and hexyl.
The term "alkylene" refers to a fully saturated divalent radical containing only carbon and hydrogen, and which may be a branched or straight chain radical. This term is further exemplified by radicals such as methylene, ethylene, n-propylene, t-butylene, i-pentylene, and n-heptylene.
The term "lower alkylene" refers to a divalent alkyl radical of one to six carbon atoms. This term is further exemplified by such radicals as methylene, ethylene, n-propylene, i-propylene, n-butylene, t-butylene, i-butylene (or 2-methylpropylene), isoamylene, pentylene, and n-hexylene.
The term "alkenyl" refers to a both straight-chain and branched-chain mono- or poly-olefinically-unsaturated hydrocarbyl monovalent radical containing only carbon and hydrogen, having one or more double bonds (preferably not more than two) and having no triple bonds. This term is further exemplified by radicals such as allyl; 2-methylallyl; buten-2-yl; penten-2-, 3-, or 4-yl; hexen-2-, 3-, 4-, or 5-yl; hepten-2-, 3-, 4-, 5-, or 6-yl; and pentadien-2,4-yl.
The term "aryl" refers to a substituted or unsubstituted monovalent unsaturated aromatic carbocyclic radical having a single ring (e.g., phenyl) or two condensed rings (e.g., naphthyl).
The term "aralkyl" refers to the group -R'-Ar, where Ar is an aryl group and R' is straight-chain or branched-chain lower alkylene.
As used herein, the term "halo" refers to fluoro, bromo, chloro and iodo.
Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can, of course, also be used.
A "pharmaceutically acceptable salt" may be any salt derived from an inorganic or organic acid. The term "pharmaceutically acceptable anion" refers to the anion of such acid addition salts. The salt and/or the anion are chosen not to be biologically or otherwise undesirable.
The anions are derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid (giving the sulfate and bisulfate salts), nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, salicylic acid, p-toluensulfonic acid and the like.
As used herein, the terms "inert organic solvent" or "inert solvent" mean a solvent inert under the conditions of the reaction being described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran, diethyl ether, chloroform, methylene chloride, pyridine and the like).
As used herein, the term "treatment" or "treating" means any treatment of a disease in a mammal, including:
(i) preventing the disease, that is, causing the clinical symptoms of the disease not to develop;
(ii) inhibiting the disease, that is, arresting the development of clinical symptoms; and/or
(iii) relieving the disease, that is, causing the regression of clinical symptoms.
Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about 10.degree. C. to about 100.degree. C., more preferably from about 10.degree. C. to about 50.degree. C., and most preferably at about room (or ambient) temperature, e.g., about 20.degree. C.
For purposes of the following description of preparation of Compounds of Formula I, and in the Examples, R.sup.1, R.sup.2 and R.sup.3 are collectively represented by the radical "X".
The compounds of Formula I are prepared, for example as illustrated in Reaction Scheme 1, from 1,2-benzo-3-oxo-cyclo-(C.sub.5 to C.sub.7)-alkanes, i.e., the compounds of Formula 1 where X is hydrogen (see Reaction Scheme 1), which are readily available from commercial sources. For the substituted benzene compounds of Formula I (i.e., those compounds where R.sup.1, R.sup.2 and/or R.sup.3 are not hydrogen) the starting materials are represented by Formula 1 where X is not hydrogen; some of these materials are also commercially available, and where not, they can be easily prepared according to procedures that are well known to the art and published in the literature.
It is also possible to modify X during the course of the synthesis, for example, by halogenation or nitration of the intermediates of Formula 3 according to the procedure of Tetsuya, et al. [Chem. Pharm. Bull., 25(12), 3198-3209 (1977)], or by similar reaction of Formula I-a.
The choice of a starting material depends on the desired length of Y. Thus, for example, to prepare the compounds where Y has two carbon atoms, a starting material is 1-indanone (available from Aldrich). A starting material for the compounds of Formula I where Y has three carbon atoms is 1-oxo-1,2,3,4,-tetrahydronaphthalene (or 1-tetralone, available from Aldrich). A starting material for the compounds of Formula I where Y has four carbon atoms is 1,2-benzo-3-oxo-cycloheptane (or 1-benzosuberone, available from Aldrich.)
Referring to Reaction Scheme 1, which follows, Formula 1 can be converted to the intermediates of Formulae 2 and 3, according to the procedure described by Belletire, et al. [Synthetic Commun., 12(10), 763-770 (1982)]. For example, a compound of Formula 1 is mixed with about an equimolar amount of trimethylsilyl cyanide and a Lewis Acid catalyst (such as ZnI.sub.2, AlCl.sub.3, or BF.sub.3 etherate; preferably ZnI.sub.2), optionally with an aprotic solvent [such as dichloromethane, dichloroethane, ether, or THF ("tetrahydrofuran"); preferably dichloromethane]. The reaction takes place over a period of about 2 to 60 hours, preferably 4 to 40 hours, and most preferably about 16 hours. A temperature range of about -20.degree. C. to 115.degree. C., preferably 0.degree. C. to 40.degree. C., and most preferably about 20.degree. C. is used. The intermediate of Formula 2 is isolated and purified in the usual manner. ##STR7##
The compound of Formula 2 is dissolved in a protic solvent (such as an alkyl carboxylic acid; preferably acetic acid) reacted with an equimolar amount of stannous chloride in the presence of a small amount of an aqueous mineral acid (preferably concentrated HCl). The reaction takes place over a period of about 12 to 100 hours, preferably 12 to 48 hours, and most preferably about 24 hours. A temperature range of about 20.degree. C. to 200.degree. C., preferably 80.degree. C. to 150.degree. C., and most preferably about 120.degree. C. is used. The intermediate of Formula 3 is isolated and purified in the usual manner.
Alternatively, for compounds of Formula I where Y has two carbons, an intermediate of Formula 3 can be prepared by first reacting indene with n-butyllithium and then quenching the resulting indenyllithium with carbon dioxide, according to the method of Cromwell, et al. [J. Am. Chem. Soc., 74, 4448-4449 (1952)] to give indane-carboxylic acid, which can be hydrogenated to give 1-indanecarboxylic acid (i.e., Formula 3 where Y is --CH.sub.2 --CH.sub.2 --).
A compound of Formula 3 (e.g., 6-methoxy-1-indane-carboxylic acid), optionally dissolved in an aprotic solvent (such as methylene chloride, tetrachloroethylene, ether, or toluene; preferably methylene chloride), is reacted with a slight molar excess of a halide of a mineral or oxalic acid (such as oxalyl chloride, thionyl chloride, or phosphoryl chloride; preferably oxalyl chloride) in the presence of one drop of DMF ("dimethylformamide"). The reaction takes place over a period of about 15 minutes to 16 hours, preferably 30 minutes to 4 hours, and most preferably about 2 hours. A temperature range of about -20.degree. C. to 100.degree. C., preferably 0.degree. C. to 50.degree. C., and most preferably about 35.degree. C. is used. The intermediate of Formula 4 is concentrated under vacuum and stirred for about 30 minutes, leaving the desired acid chloride in sufficiently pure form to be used for the next step.
A compound of Formula 4, dissolved in an aprotic solvent [such as methylene chloride, ether, or pyridine; preferably methylene chloride] and added dropwise to a stirred solution of an acetal of methylaminoacetaldehyde (preferably a slight molar excess of the dimethylactal of methylaminoacetaldehyde) in the presence of about 1 molar equivalent of triethylamine (itself dissolved in an aprotic solvent such as methylene chloride). The reaction takes place over a period of about 4 to 48 hours, preferably 4 to 24 hours, and most preferably about 16 hours. A temperature range of about -10.degree. C. to 100.degree. C., preferably 0.degree. C. to 40.degree. C., and most preferably about 20.degree. C. is used. The amide of Formula 5 is then concentrated to a small volume, treated with ether and water, and the resulting organic layer washed with saturated sodium carbonate and sodium chloride. After drying, the ether solution is concentrated to yield the amide as an oil.
A compound of Formula 5 is dissolved in a polar but aprotic solvent (such as an ether, preferably diethylether or THF) followed by adding in excess of two molar equivalents of a reducing agent [such as lithium aluminum hydride ("LiAlH.sub.4 " or "LAH"), trimethoxylithium aluminum hydride, or BH.sub.3.THF; preferably LAF, e.g., also in ether]. The reaction takes place over a period of about 1 to 48 hours, preferably 2 to 24 hours, and most preferably about 16 hours. A temperature range of about -20.degree. C. to 60.degree. C., preferably 0.degree. C. to 40.degree. C., and most preferably about 20.degree. C. is used. The reaction mixture is treated dropwise with about 1 ml of water, 1 ml of a base (e.g., NaOH) and then 3 ml of water. Insoluble inorganic materials are removed by filtration and the filtrate is concentrated to give the aminoacetal of Formula 6, which is used without further purification.
A compound of Formula 6, optionally mixed with a halocarbon solvent such as methylene chloride, is treated slowly with a very strong acid, such as trifluoromethane sulfuric acid, with stirring. The reaction takes place over a period of about 1 to 48 hours, preferably 6 to 24 hours, and most preferably about 16 hours. A temperature range of about -10.degree. C. to 120.degree. C., preferably -10.degree. C. to 40.degree. C., and most preferably about 20.degree. C. is used. The reaction is quenched with crushed ice and the resulting acid solution is extracted with ether to remove neutral materials. The remaining acid solution is made alkaline (e.g., by adding a base such as NaOH) and the desired intermediate of Formula 7 is extracted with ether.
A compound of Formula 7 is dissolved in an organic solvent optionally in the presence of an acid (such as an alcohol or THF; preferably ethanol with aqueous HCl) and subjected to catalytic hydrogenation (using H.sub.2 and Ni, Pt or Pd; preferably H.sub.2 and Pd/C or Pt/C as the catalyst). The reaction takes place over a period of about 15 minutes to 24 hours, preferably 30 minutes to 10 hours, and most preferably about 2 hours. A temperature range of about -10.degree. C. to 100.degree. C., preferably 0.degree. C. to 40.degree. C., and most preferably about 20.degree. C. is used. The catalyst is removed by filtration and the filtrate concentrated, followed by the addition of a base (such as aqueous NaOH) to yield the product compound of Formula I-a, as the free base.
A compound of Formula I where R is alkyl (e.g., Formula I-a where R is methyl) is dissolved in an inert solvent (such as toluene, carbon tetrachloride, or tetrachloroethylene; preferably toluene) and reacted with cyanogen bromide for about 30 minutes to 24 hours, preferably 2 to 16 hours, and most preferably about 4 hours. A temperature range of about 0.degree. C. to 120.degree. C., preferably about 50.degree. C. is used. The intermediate of Formula 8 is isolated and purified in the usual manner.
An alkylamine of Formula I (e.g., R=methyl) is dissolved in an inert solvent (such as benzene) and reacted with a slight molar excess of a stirred solution of trichloroethyl chloroformate. A small amount of potassium carbonate is then added and the mixture is heated to reflux. The progress of the reaction may be followed by TLC. When the conversion is substantially completed (about 30 minutes to 20 hours, preferably about 6 hours) the mixture is allowed to cool and is then filtered. The filtrate is then concentrated and the trichloroethyl carbamate intermediate of Formula 8a is isolated for use in the next step without purification.
A compound of Formula 8 is dissolved in a protic solvent (such as a carboxylic acid, preferably acetic acid) and treated with an aqueous mineral acid (such as 20-37% HCl or 20-50% H.sub.2 SO.sub.4 ; preferably concentrated HCl). The reaction takes place for about 4 to 40 hours, preferably about 24 hours. A temperature range of about 40.degree. C. to 150.degree. C., preferably about 100.degree. C. is used. The product of Formula I-b is isolated and purified in the usual manner.
A compound of Formula 8a is dissolved (e.g., in a mixture of methanol and acetic acid; preferably from 5% acetic acid to 100% acetic acid, but not in the absence of acetic acid; most preferably 10-20% acetic acid in methanol). The solution is stirred at ambient temperature and Zinc dust is added in portions (a total of 5-10 g At. of zinc is used for each mole of the carbamate of Formula 8a). The mixture is then filtered, the filtrate is concentrated, and the remaining solid is chromatographed to yield the product of Formula I-b.
A compound of Formula I-b is dissolved in a protic solvent or a polar aprotic solvent (such as ethanol, or DMF; preferably ethanol) and reacted with an alkyl halide, an alkenyl halide, or an aralkyl halide (such as ethyliodide, allyl bromide, prop-2-enylchloride, and benzyl chloride; depending on what is desired as R). The reaction takes place for about 1 to 48 hours, preferably 2 to 16 hours, and most preferably about 16 hours. A temperature range of about 0.degree. C. to 120.degree. C., preferably -20.degree. C. to 100.degree. C., and most preferably about 65.degree. C. to 80.degree. C. is used. The product of Formula I-c is isolated and purified in the usual manner.
This first alternative preparation is illustrated in Reaction Scheme 2, which follows.
A compound of Formula 5 is dissolved in a protic solvent (such as a carboxylic acid, preferably acetic acid) and treated with an aqueous mineral acid (such as HCl, HBr, or H.sub.2 SO.sub.4 ; preferably concentrated HCl). The reaction takes place for about 15 minutes to 24 hours, preferably about 1 to 16 hours, and most ##STR8## preferably about 6 hours. A temperature range of about 20.degree. C. to 200.degree. C., preferably about 60.degree. C. to 120.degree. C., and most preferably about 80.degree. C. is used. The reaction is quenched over ice and extracted with ether. The ether extract is made alkaline with, e.g., saturated sodium bicarbonate, dried, filtered and concentrated to yield the intermediate of Formula 9, which is used without further purification.
A compound of Formula 9 is dissolved in an organic solvent (such as a lower alcohol; preferably ethanol), optionally in the presence of an acid, and subjected to catalytic hydrogenation (using H.sub.2 and Ni, Pt or Pd; preferably H.sub.2 and Pt/C as the catalyst). The reaction takes place over a period of about 2 to 60 hours, preferably 4 to 48 hours, and most preferably about 24 hours. A temperature range of about -10.degree. C. to 80.degree. C., preferably 0.degree. C. to 40.degree. C., and most preferably about 20.degree. C. is used. The catalyst is removed by filtration and the filtrate concentrated, followed by the addition of a base (such as aqueous NaOH) to yield the lactam intermediate compound of Formula 10, which is used without further purification in the following preparation, or in Preparation 17.
A compound of Formula 10 is dissolved in an aprotic solvent (such as an ether, preferably diethylether or THF) followed by adding in excess of two molar equivalents of a reducing agent (such a hydride of aluminum or boron; preferably LAH or BH.sub.3.THF; preferably LAH, e.g., also in ether). The reaction takes place over a period of about 1 to 60 hours, preferably 4 to 48 hours, and most preferably about 24 hours. A temperature range of about -20.degree. C. to 50.degree. C., preferably 0.degree. C. to 50.degree. C., and most preferably about 20.degree. C. is used. The reaction mixture is worked up in the usual manner (aqueous). Insoluble inorganic materials are removed by filtration and the filtrate concentrated to give the product compound of Formula I-a, as the free base.
This second alternative preparation is illustrated in Reaction Scheme 3, which follows.
A compound of Formula 4 is dissolved in an aprotic solvent (such as a halocarbon or an ether; preferably methylene chloride) and added slowly to a stirred solution of in excess of two molar equivalents of an aminoalkanol [such as 2-(methylamino)ethanol]. Alternatively, one molar equivalent of the aminoalkanol can be used plus another base. The reaction takes place ##STR9## over a period of about 5 minutes to 24 hours, preferably about 30 minutes. A temperature range of about -40.degree. C. to 80.degree. C., preferably 20.degree. C. to 40.degree. C., and most preferably about 0.degree. C. is used. Water is added and the organic layer is then washed, e.g., with a dilute acid, water, saturated NaHCO.sub.3 and saturated NaCl. The intermediate of Formula 11 is then dried, concentrated and used without further purification.
A compound of Formula 11 is dissolved in an aprotic solvent (such as an ether, preferably diethylether or THF) followed by adding an excess of a reducing agent (such a borane or a metal hydride; preferably LAH, BH.sub.3.THF or BH.sub.3.(CH.sub.3).sub.2 S; preferably BH.sub.3.THF). The reaction takes place over a period of about 10 minutes to 24 hours, preferably 10 minutes to 16 hours, and most preferably about 30 minutes. A temperature range of about 0.degree. C. to 100.degree. C., preferably 0.degree. C. to 80.degree. C., and most preferably about 65.degree. C. is used. The reaction mixture is worked up in the usual manner (aqueous). Insoluble inorganic materials are removed by filtration and the filtrate concentraed to give the intermediate of Formula 12, which is used without further purification.
A compound of Formula 12 is dissolved in a high-boiling, aprotic solvent (such as trichlorobenzene, nitrobenzene, or tetrachloroethylene; preferably trichlorobenzene) followed by adding slightly less than half a molar equivalent of a phosphorous chloride (such as phosphorous oxychloride, phosphorous trichloride, or phosphorous pentachloride; preferably phosphorous pentachloride). The mixture is then heated to between about 80.degree. C. and 150.degree. C., preferably about 110.degree. C., and about two molar equivalents of a metal chloride (such as aluminum chloride) is added slowly (over a period of about 15 minutes to 1 hour, preferably about 30 minutes). The temperature is then increased to between about 150.degree. C. and 250.degree. C., preferably about 200.degree. C. and the mixture is stirred for an additional 1 to 8 hours, preferably about 3 hours. The reaction mixture is allowed to cool to about 60.degree. C. to 100.degree. C., preferably about 80.degree. C., and acidified, for example by adding 12% HCl. Toluene is added and the organic layers are separated. The remaining aqueous phase is made alkaline by the addition of a base (e.g., 50% NaOH) and the product is extracted with ethyl acetate, which is then evaporated and the remaining crude product purified by conventional means to yield the product compound of Formula I-a, as the free base.
This third alternative preparation is illustrated below in Reaction Scheme 4. ##STR10##
A compound of Formula 4 is dissolved in a solvent (such as ether, ethylacetate, or methylene chloride; preferably ethylacetate) and added slowly to an excess of a stirred, ice bath-cooled solution of an amine, such as 40% aqueous methylamine or N-propylamine. The reaction takes place for about 1 to 48 hours, preferably about 1 to 16 hours, and most preferably about 4 hours. A temperature range of about 0.degree. C. to 80.degree. C., preferably about 0.degree. C. to 40.degree. C., and most preferably about 0.degree. C. to 20.degree. C. is used. The organic layer is separated, washed and evaporated to give the intermediate of Formula 13, which is used without further purification.
A compound of Formula 13 is dissolved in an aprotic solvent (such as an ether, preferably diethylether or THF; most preferably an ether-THF mixture) and slowly added to in excess of two molar equivalents of a reducing agent (such a hydride of aluminum or boron; preferably LAH, BH.sub.3.THF, or BH.sub.3.Me.sub.2 S; most preferably LAH). The reaction takes place over a period of about 1 to 48 hours, preferably 1 to 16 hours, and most preferably about 6 hours. A temperature range of about 0.degree. C. to 80.degree. C., preferably 60.degree. C. is used. The reaction mixture is digested by treating dropwise with water, a base (e.g., NaOH) and then water. The intermediate of Formula 14 is used without further purification.
A compound of Formula 14 is dissolved in a two-phase solvent system (such as water and ethylacetate, ether or methylene chloride; preferably water and ethylacetate) in the presence of an acid scavenger (such as potassium carbonate). The mixture is stirred over an ice bath and a molar equivalent of an acylating agent (such as chloroacetylchloride) is added slowly. The reaction takes place for about 30 minutes to 16 hours, preferably about 1 to 6 hours, and most preferably about 1.5 hours. A temperature range of about -10.degree. C. to 80.degree. C., preferably about 0.degree. C. to 30.degree. C., and most preferably about 5.degree. C. to 20.degree. C. is used. The organic layer is separated, and concentrated to give the intermediate of Formula 15, which is used without further purification.
Intermediate 16 is prepared by introducing a compound of Formula 15 into in excess of two molar equivalents of a Friedel-Crafts catalyst (such as AlCl.sub.3, AlBr.sub.3 or SnCl.sub.4 ; preferably AlCl.sub.3) dissolved in a high-boiling halocarbon solvent (such as trichlorobenzene or tetrachloroethylene; preferably trichlorobenzene), preheated to about 80.degree. C. to 180.degree. C., preferably about 80.degree. C. to 150.degree. C., and most preferably about 110.degree. C. The reaction takes place for about 2 to 7 hours, preferably about 5 hours, and is then quenched and extracted to give the intermediate of Formula 16. This can be reduced as described in Reaction Scheme 2, as described below, or when X is represents R.sup.1, R.sup.2 and R.sup.3 being hydrogen, Formula 16 can be converted to a halo-substituted benzene compound, illustrated as the 5-chloro compound of Formula 17.
A product of Formula 16 can be halogenated by dissolving it in a polar solvent (such as acetonitrile or a acetic acid; preferably acetonitrile) optionally in the presence of water, and reacting it with chlorine or a source of chloride ion (such as N-chlorosuccinimide) in the presence of FeCl.sub.3. The reaction takes place for about 1 to 48 hours, preferably about 1 to 24 hours, and most preferably about 6 hours. A temperature range of about -10.degree. C. to 50.degree. C., preferably about 0.degree. C. to 20.degree. C. is used. The reaction mixture is concentrated and treated with ether and water to give the intermediate of Formula 17, e.g., shown where R.sup.3 is chloro, which is used without further purification.
A compound of Formula 16 or Formula 17 is dissolved in an aprotic solvent (such as an ether, preferably diethylether or THF) followed by adding in excess of two molar equivalents of a reducing agent (such as hydride of aluminum or boron; preferably LAH, BH.sub.3.THF, or NaBH.sub.4.transition metal chloride; most preferably BH.sub.3.THF). The reaction takes place over a period of about 1 to 48 hours, preferably 1 to 24 hours, and most preferably about 16 hours. A temperature range of about -10.degree. C. to 60.degree. C., preferably 0.degree. C. to 40.degree. C., and most preferably about 20.degree. C. is used. The reaction mixture is treated dropwise with methanol and the solvents removed under vacuum. The residue is treated with a dilute acid (such as HCl) and digested on a steam bath for about 3 hours. After cooling, the aqueous solution is washed with ether, made alkaline with a base (such as NaOH) and extracted with ether. The ether extract is concentrated to give the product compound of Formula I where R is Methyl, and X is hydrogen or chloro, as the free base, yielding Formula I-a from Formula 16 and yielding Formula I-d from Formula 17.
Some of the compounds of Formula I may be converted to corresponding acid addition salts. The conversion is accomplished by treatment with a stoichiometric amount of an appropriate acid, such as hydrochloric acid, sulfuric acid, methanesulfonic acid, HBr, or the like. Typically, the free base is dissolved in a polar organic solvent such as ethanol or methanol, and the acid added in water, ethanol or methanol. The temperature is maintained at 0.degree.-50.degree. C. The resulting salt precipitates spontaneously or may be brought out of solution with a less polar solvent.
The acid addition salts of the compounds of Formula I may be decomposed to the corresponding free bases by treating with an excess of a suitable base, such as ammonia or sodium bicarbonate, typically in the presence of aqueous solvent, and at a temperature of between 0.degree. and 50.degree. C. The free base form is isolated by conventional means, such as extraction with an organic solvent.
The compounds of Formula I where Y has two or three carbon atoms are preferred. Also, those compounds where R is alkyl, particularly methyl, are preferred. Similarly preferred are those compounds where R.sup.1 and R.sup.2 are hydrogen and R.sup.3 is not hydrogen, particularly where R.sup.3 is chloro or methoxy. The salts of Formula I are also preferred, especially the HCl and HBr salts.
Particularly preferred are the compounds of Formula I where:
Most preferred is the compound of Formula I where R is methyl, R.sup.1 and R.sup.2 are hydrogen, R.sup.3 is chloro and Y is --(CH.sub.2).sub.3 --, especially the HCl salt, i.e., 2-methyl-5-chloro-1,3,4,8,9,10,10a-octahydro-2H-naphth[1,8-cd]azepine hydrochloride.
The compounds of the present invention can be prepared according to the following last steps:
contacting a 2-methyl-optionally-5-, 6- and/or 7-substituted-1,8,9,10,11,11a-hexahydro-2H-cyclohepta[c,d][3]-benzazepine with an acid in the presence of a catalyst to yield the corresponding 2-methyl-optionally-5-, 6- and/or 7-substituted-1,3,4,8,9,10,11,11a-octahydro-2H-cyclohepta[c,d][3]benzazepine;
contacting a 2-methyl-optionally-5-, 6- and/or 7-substituted-1,8,9,10,10a-hexahydro-2H-naphth[1,8-cd]azepine with an acid in the presence of a catalyst to yield the corresponding 2-methyl-optionally- 5-, 6- and/or 7-substituted-1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azepine;
contacting a 2-methyl-optionally-5-, 6- and/or 7-substituted-1,8,9,9a-tetrahydro-2H-indeno[1,7-cd]-azepine with an acid in the presence of a catalyst to yield the corresponding 2-methyl-optionally- 5-, 6- and/or 7-substituted-1,3,4,8,9,9a-hexahydro-2H-indeno[1,7-cd]azepine;
contacting a 2-cyano-optionally- 5-, 6- and/or 7-substituted-1,3,4,8,9,10,11,11a-octahydro-2H-cyclohepta[c,d][3]benzazepine with an acid to yield the corresponding optionally-5-, 6- and/or 7-substituted-1,3,4,8,9,10,11,11a-octahydro-2H-cyclohepta[c,d][3]benzazepine;
contacting a 2-cyano-optionally- 5-, 6- and/or 7-substituted-1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azepine with an acid to yield the corresponding optionally-5-, 6- and/or 7-substituted-1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azepine;
contacting a 2-cyano-optionally- 5-, 6- and/or 7-substituted-1,3,4,8,9,9a-hexahydro-2H-indeno[1,7-cd]azepine with an acid to yield the corresponding optionally-5-, 6- and/or 7-substituted-1,3,4,8,9,9a-hexahydro-2H-indeno[1,7-cd]azepine;
contacting a 2-trichloroethylcarbamoyl-optionally-5-, 6- and/or 7-substituted-1,3,4,8,9,10,11,11a-octahydro-2H-cyclohepta[c,d][3]benzazepine with zinc dust to yield the corresponding optionally-5-, 6- and/or 7-substituted-1,3,4,8,9,10,11,11a-octahydro-2H-cyclohepta[c,d][3]benzazepine;
contacting a 2-trichloroethylcarbamoyl-optionally-5-, 6- and/or 7-substituted-1,2,3,4,8,9,10,10a-octahydro-2H-naphth[1,8-cd]azepine with zinc dust to yield the corresponding optionally-5-, 6- and/or 7-substituted-1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azepine;
contacting a 2-trichloroethylcarbamoyl-optionally-5-, 6- and/or 7-substituted-1,3,4,8,9,9a-hexahydro-2H-indeno[1,7-cd]azepine with zinc dust to yield the corresponding optionally-5-, 6- and/or 7-substituted-1,3,4,8,9,9a-hexahydro-2H-indeno[1,7-cd]azepine;
contacting an optionally-5-, 6- and/or 7-substituted-1,3,4,8,9,10,11,11a-octahydro-2H-cyclohepta[c,d][3]benzazepine with an alkenyl-halide to yield the corresponding 2-alkyl-optionally-5-, 6- and/or 7-substituted-1,3,4,8,9,10,11,11a-octahydro-2H-cyclohepta[c,d][3]benzazepine;
contacting an optionally-5-, 6- and/or 7-substituted-1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azepine with an alkenyl-halide to yield the corresponding 2-alkyl-optionally-5-, 6- and/or 7-substituted-1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azepine;
contacting an optionally-5-, 6- and/or 7-substituted-1,3,4,8,9,9a-hexahydro-2H-indeno[1,7-cd]azepine with an alkenyl-halide to yield the corresponding 2-alkyl-optionally-5-, 6- and/or 7-substituted-1,3,4,8,9,9a-hexahydro-2H-indeno[1,7-cd]azepine;
contacting a 1-oxo-2-methyl-optionally- 5-, 6- and/or 7-substituted-1,3,4,8,9,10,11,11a-octahydro-2H-cyclohepta[c,d][3]benzazepine with a reducing agent to yield the corresponding 2-methyl-optionally-5-, 6- and/or 7-substituted-1,3,4,8,9,10,11,11a-octahydro-2H-cyclohepta[c,d][3]benzazepine;
contacting a 1-oxo-2-methyl-optionally- 5-, 6- and/or 7-substituted-1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azepine with a reducing agent to yield the corresponding 2-methyl-optionally-5-, 6- and/or 7-substituted-1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azepine;
contacting a 1-oxo-2-methyl-optionally- 5-, 6- and/or 7-substituted-1,3,4,8,9,9a-hexahydro-2H-indeno[1,7-cd]azepine with a reducing agent to yield the corresponding 2-methyl-optionally-5-, 6- and/or 7-substituted-1,3,4,8,9,9a-hexahydro-2H-indeno[1,7-cd]azepine;
contacting a 1-[N-(2-hydroxyethyl)methylaminomethyl]benzosubarane with a phosphorous chloride and a metal halide to yield the corresponding 2-methyl-optionally-5-, 6- and/or 7-substituted-1,3,4,8,9,10,11,11a-octahydro-2H-cyclohepta[c,d][3]benzazepine;
contacting a 1-[N-(2-hydroxyethyl)methylaminomethyl]-1,2,3,4-tetrahydronaphthalene with a phosphorous chloride and a metal halide to yield the corresponding 2-methyl-optionally-5-, 6- and/or 7-substituted-1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azepine;
contacting a 1-[N-(2-hydroxyethyl)methylaminomethyl]indane with a phosphorous chloride and a metal halide to yield the corresponding 2-methyl-optionally-5-, 6- and/or 7-substituted-1,3,4,8,9,9a-hexahydro-2H-indeno[1,7-cd]azepine;
contacting a 2-methyl-3-oxo-optionally- 5-, 6- and/or 7-substituted-1,3,4,8,9,10,11,11a-octahydro-2H-cyclohepta[c,d][3]benzazepine with a reducing agent to yield the corresponding 2-methyl-optionally-5-, 6- and/or 7-substituted-1,3,4,8,9,10,11,11a-octahydro-2H-cyclohepta[c,d][3]benzazepine;
contacting a 2-methyl-3-oxo-optionally- 5-, 6- and/or 7-substituted-1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azepine with a reducing agent to yield the corresponding 2-methyl-optionally-5-, 6- and/or 7-substituted-1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azepine;
contacting a 2-methyl-3-oxo-optionally- 5-, 6- and/or 7-substituted-1,3,4,8,9,9a-hexahydro-2H-indeno[1,7-cd]azepine with a reducing agent to yield the corresponding 2-methyl-optionally-5-, 6- and/or 7-substituted-1,3,4,8,9,9a-hexahydro-2H-indeno[1,7-cd]azepine;
contacting a 5-chloro-2-methyl-3-oxo-1,3,4,8,9,10,11,11a-octahydro-2H-cyclohepta[c,d][3]benzazepine with a reducing agent to yield the corresponding 5-chloro-2-methyl-1,3,4,8,9,10,11,11a-octahydro-2H-cyclohepta[c,d][3]benzazepine;
contacting a 5-chloro-2-methyl-3-oxo-1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azepine with a reducing agent to yield the corresponding 5-chloro-2-methyl-1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azepine;
contacting a 5-chloro-2-methyl-3-oxo-1,3,4,8,9,9a-hexahydro-2H-indeno[1,7-cd]azepine with a reducing agent to yield the corresponding 5-chloro-2-methyl-1,3,4,8,9,9a-hexahydro-2H-indeno[1,7-cd]azepine;
contacting a pharmaceutically acceptable acid with a compound of Formula I to form the corresponding acid addition salt of Formula I;
substituting a pharmaceutically acceptable acid salt of Formula I with another pharmaceutically acceptable acid; and
contacting an acid addition salt of Formula I with a base to form the corresponding free base compounds of Formula I.
The compounds of the present invention, including the pharmaceutically acceptable salts thereof, and the compositions containing them, are useful as CNS agents, including such uses as antidepressants, anxiolytics and antihypertensives in mammals, whether domestic (cattle, pigs, sheep, goats, horses), pets (cats, dogs), or preferably humans. These utilities are associated with binding to .alpha..sub.2 and 5-HT.sub.1A receptors. The compounds can be used both prophylactically (e.g., to prevent allograft rejection) and therapeutically.
In vitro testing for .alpha..sub.2 activity is done, for example, using an .alpha..sub.2 binding affinity assay, as described by Clark, et al., J. Med. Chem., 26 855 (1983), or as described by Cheung, et al., Europ. J. Pharmacol., 84 79-85 (1982).
In vitro testing for 5-HT.sub.1A activity is done, for example, using a modification of the 5-HT.sub.1A binding affinity assay, as described by Gozlan, et al., Nature, 305 140-142 (1983) or Norman et al., Mol. Pharmacol., 28 487 (1986). The use of 8-OH-DPAT in such assays has been described by Peroutka and Demopulos, Europ. J. Pharmacol., 199-200 (1986).
In vivo testing to demonstrate the described activity of the present compounds is done by the reversal of 8-OH DPAT effects in rodents method, described by Tricklebank, et al., Europ. J. Pharmacol., 106 271-282 (1984).
Administration of the active compounds of Formula I, in pure form or in an appropriate pharmaceutical composition can be carried out via any of the accepted modes of administration of agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally or topically, in the form of solid, semi-solid or liquid dosage forms, such as for example, tablets, suppositories, pills, capsules, powders, solutions, suspensions, emulsions, creams, lotions, aerosols, ointments or the like, preferably in unit dosage forms suitable for simple administration of precise dosages. The compositions will include a conventional pharmaceutical carrier or excipient and an active compound of Formula I and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.
Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of the pharmaceutically active compound of this invention and 99% to 1% by weight of suitable pharmaceutical excipients. Preferably, the composition will be about 5 to 75% by weight of a pharmaceutically active compound, with the rest being suitable pharmaceutical excipients.
The preferred manner of administration, for the conditions detailed above, is oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. For such oral administration, a pharmaceutically acceptable, non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like. Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like.
Preferably the compositions will take the form of a pill or tablet and thus the composition will contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a disintegrant such as starch or derivatives thereof; a lubricant such as magnesium stearate and the like; and a binder such as a starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose and derivatives thereof, and the like.
The active compounds of Formulas I may be formulated into a suppository using, for example, about 0.5% to about 50% active ingredient disposed in a carrier of polyethylene glycols (PEG) [e.g., PEG 1000 (96%) and PEG 4000 (4%)].
Liquid pharmaceutically administerable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound (about 0.5% to about 20%), as described above, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension.
If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.
Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 16th Ed., (Mack Publishing Company, Easton, Pa., 1980). The composition to be administered will, in any event, contain a quantity of the active compound(s) in a pharmaceutically effective amount for relief of the particular condition being treated when administered in accordance with the teachings of this invention.
Generally, the compounds of the invention are administered in a therapeutically effective amount, i.e., a dosage sufficient to effect treatment, which will vary depending on the individual and condition being treated. Typically, a therapeutically effective daily dose is from 0.1 to 100 mg/kg of body weight per day of an active compound of Formula I. Most conditions respond to treatment comprising a dosage level on the order of 0.4 to 30 mg/kg of body weight per day, and most preferably about 10 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range would be about 7.0 mg to 7 g per day, preferably about 28.0 mg to 2.1 g per day.
US Referenced Citations (1)
| Number |
Name |
Date |
Kind |
| 4769368 |
Kaiser |
Sep 1988 |
|
Non-Patent Literature Citations (1)
| Entry |
| Hackh's Chemical Dictionary, 5th Ed. (1987), p. 30. |
Divisions (1)
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Number |
Date |
Country |
| Parent |
50977 |
May 1987 |
|
Patent Grant
4957914
