Claims
- 1. A method of treating a mammal for a cerebrovascular disease, said method comprising administering to said mammal a therapeutically effective amount of a compound represented by the formula: ##STR9## wherein: R.sup.1 is aryl, lower alkyl, cycloalkyl or hydrogen;
- R.sup.2 is aryl, lower alkyl or hydrogen;
- provided that both R.sup.1 and R.sup.2 are not hydrogen;
- R.sup.3 is lower alkyl, hydroxy, or hydrogen;
- R.sup.4 is aryl or hydrogen;
- R.sup.5 is aryl or hydrogen;
- m is three;
- n is zero, one or two,
- provided that when R.sup.3 is hydroxy, n is one or two; and
- q is zero, one, two, or three;
- or a pharmaceutically acceptable salt thereof.
- 2. The method of claim 1 comprising administering to said mammal a therapeutically effective amount of the compound wherein R.sup.2 is aryl or lower alkyl.
- 3. The method of claim 1 comprising administering to said mammal a therapeutically effective amount of the compound wherein R.sup.1 is aryl or cycloalkyl.
- 4. The method of claim 1 comprising administering to said mammal a therapeutically effective amount of the compound 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]diazepine.
- 5. The method of claim 1 comprising administering to said mammal a therapeutically effective amount of the compound 1-diphenylmethyl-4-[(2-phenyl-5-methyl-1H-imidazol-4-yl)methyl]diazepine.
- 6. A method of treating a mammal for stroke, migraine or epilepsy, said method comprising administering to said mammal a therapeutically effective amount of a compound represented by the formula: ##STR10## wherein: R.sup.1 is aryl, lower alkyl, cycloalkyl or hydrogen;
- R.sup.2 is aryl, lower alkyl or hydrogen;
- provided that both R.sup.1 and R.sup.2 are not hydrogen;
- R.sup.3 is lower alkyl, hydroxy, or hydrogen;
- R.sup.4 is aryl or hydrogen;
- R.sup.5 is aryl or hydrogen;
- m is three;
- n is zero, one or two,
- provided that when R.sup.3 is hydroxy, n is one or two; and
- q is zero, one, two, or three;
- or a pharmaceutically acceptable salt thereof.
- 7. The method of claim 6 wherein the disease is stroke.
- 8. The method of claim 6 comprising administering to said mammal a therapeutically effective amount of the compound wherein R.sup.1 is aryl or cycloalkyl.
- 9. The method of claim 7 comprising administering to said mammal a therapeutically effective amount of the compound wherein R.sup.1 is aryl or cycloalkyl.
- 10. The method of claim 6 comprising administering to said mammal a therapeutically effective amount of the compound wherein R.sup.2 is aryl or lower alkyl.
- 11. The method of claim 7 comprising administering to said mammal a therapeutically effective amount of the compound wherein R.sup.2 is aryl or lower alkyl.
- 12. The method of claim 8 comprising administering to said mammal a therapeutically effective amount of the compound wherein R.sup.2 is aryl or lower alkyl.
- 13. The method of claim 6 comprising administering to said mammal a therapeutically effective amount of the compound wherein when R.sup.3 is lower alkyl or hydrogen, R.sup.1 is aryl or cycloalkyl.
- 14. The method of claim 6 comprising administering to said mammal a therapeutically effective amount of the compound 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]diazepine.
- 15. The method of claim 7 comprising administering to said mammal a therapeutically effective amount of the compound 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]diazepine.
- 16. The method of claim 6 comprising administering to said mammal a therapeutically effective amount of the compound 1-diphenylmethyl-4-[(2-phenyl-5-methyl-1H-imidazol-4-yl)methyl]diazepine.
- 17. The method of claim 7 comprising administering to said mammal a therapeutically effective amount of the compound 1-diphenylmethyl-4-[(2-phenyl-5-methyl-1H-imidazol-4-yl)methyl]diazepine.
BACKGROUND OF THE INVENTION
This is a division of pending application Ser. No. 042,181, filed Apr. 24, 1987, now U.S. Pat. No. 4,829,065.
1. Field of the Invention
This invention relates to substituted imidazolylalkyl-piperazine and diazepine derivatives, the pharmaceutically acceptable salts thereof, methods of making these compounds, and pharmaceutical compositions containing these compounds. The compounds of this invention are calcium entry blockers having selectivity for cerebral blood vessels, and have protective activity against some of the deleterious effects resultant upon cerebral ischemia. The compounds of this invention are, therefore, useful for treating mammals having a variety of disease states, such as stroke, epilepsy, hypertension, angina, migraine, arrhythmia, thrombosis, embolism and also for treatment of spinal injuries.
2. Background Information and Related Art
Substituted piperazines have been described as having a variety of pharmaceutical activities.
For example, U.S. Pat. No. 3,362,956 and its CIP 3,491,098, disclose a series of substituted piperazines to be useful as tranquilizers, sedatives, adrenolytic agents, hypothermic agents, anti-convulsants, hypotensive agents and cardiovascular agents. For example, in the '956 patent, each atom of the piperazine ring could be substituted with a plurality of radicals, for example, the 1-position with lower alkyl, benzhydryl, phenyl-lower-alkyl or phenyl-lower-alkenyl (optionally substituted on the benzene ring), among other substituents. The piperazine includes a lower alkylene (1 to 6 carbons) chain at the 4-position with an optionally-substituted heterocyclic ring at the end. Among the heterocyclic rings encompassed by the '956 disclosure is a 4(5)-imidazolyl radical. The heterocyclic ring in the '098 patent is limited the 4(5)-imidazolyl radical, but no substitutions are disclosed.
Compounds having selective vascular relaxant activity, such as those of the present invention, have remained desired.
A first aspect of this invention encompasses compounds having the structures represented by Formula A: ##STR2## wherein: R.sup.1 is aryl, lower alkyl, cycloalkyl or hydrogen;
A further aspect of the present invention encompasses methods of making compounds of Formula A, as hereinafter described.
A still further aspect of the present invention encompasses methods of treating a mammals having a variety of disease states, such as stroke, epilepsy, hypertension, angina, migraine, arrhythmia, thrombosis, embolism and also for treatment of spinal injuries, comprising administering a therapeutically effective amount of compound of Formula A to a mammal.
Another aspect of the present invention encompasses pharmaceutical formulations comprising a compound of Formula A and a pharmaceutically acceptable excipient.
Definitions
The numbering of the piperazines and diazepines of the present invention is as follows: ##STR3## The compounds of the invention will be named using the above-shown numbering system as 1-[optionally mono- or di-aryl]-alkyl-4-[(optionally 2- and/or 5-substituted-imidazolyl)-optionally-substituted-alkyl]-piperazines and -diazepines. Some representative compounds are named as follows:
the compound of Formula A where R.sup.1 is 4-methylphenyl, R.sup.2 is methyl, R.sup.3 is hydrogen, R.sup.4 is phenyl, R.sup.5 is phenyl, m is 2, n is 0 and q is 0, is named "1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine";
the compound of Formula A where R.sup.1 is 4-methylphenyl, R.sup.2 is hydrogen, R.sup.3 is hydrogen, R.sup.4 is phenyl, R.sup.5 is phenyl, m is 2, n is 0 and q is 0, is named "1-diphenylmethyl-4-[(2-(4-methylphenyl)-1H-imidazol-4yl)methyl]piperazine";
the compound of Formula A where R.sup.1 is phenyl, R.sup.2 is methyl, R.sup.3 is methyl, R.sup.4 is phenyl, R.sup.5 is phenyl, m is 2, n is 0 and q is 0, is named "1-diphenylmethyl-4-[1-(2-phenyl-5-methyl-1H-imidazol-4-yl)ethyl]piperazine";
the compound of Formula A where R.sup.1 is cyclohexyl, R.sup.2 is methyl, R.sup.3 is ethyl, R.sup.4 is phenyl, R.sup.5 is 2,3-dimethoxyphenyl, m is 2, n is 2 and q is 2, is named "1-[3-phenyl-3-(2,3-dimethoxyphenyl)propyl]-4-[3-(2-cyclohexyl-5-methyl-1H-imidazol-4-yl)pentyl]piperazine";
the compound of Formula A where R.sup.1 is phenyl, R.sup.2 is methyl, R.sup.3 is hydroxy, R.sup.4 is phenyl, R.sup.5 is phenyl, m is 2, n is 1 and q is 0, is named "1-diphenylmethyl-4-[2-(2-phenyl-5-methyl-1H-imidazol-4-yl)-2-hydroxyethyl]piperazine";
the compound of Formula A where R.sup.1 is phenyl, R.sup.2 is methyl, R.sup.3 is hydrogen, R.sup.4 is 4-fluorophenyl, R.sup.5 is 4-fluorophenyl, m is 2, n is 0 and q is 3, is named "1-[4,4-di-(4-fluorophenyl)butyl]-4-[(2-phenyl-5-methyl-1H-imidazol-4-yl)methyl]piperazine"; and
the compound of Formula A where R.sup.1 is 2,4-dihydroxyphenyl, R.sup.2 is methyl, R.sup.3 is hydrogen, R.sup.4 is phenyl, R.sup.5 is phenyl, m is 3, n is 0 and q is 0, is named "1-diphenylmethyl-4-[(2-(2,4-dihydroxyphenyl)-5-methyl-1H-imidazol-4-yl)methyl]diazepine".
Compounds of the invention where R.sup.3 is lower alkyl or hydroxy, and/or where R.sup.4 and R.sup.5 are different and neither is hydrogen will have one or two chiral centers and may display optical activity. The optical isomers may be separated using conventional methods. For purposes of the present invention, any compound having optical activity shall include each individual isomer as well as mixtures thereof.
As used herein, the term "alkyl" means a branched or unbranched saturated hydrocarbon radical having from 1-6 carbon atoms. Examples include methyl, ethyl, propyl, t-butyl, n-pentyl and n-hexyl, and the like.
As used herein, the term "cycloalkyl" means a saturated carbocyclic hydrocarbyl ring having from 3 to 7 ring carbon atoms, one of which has a single available valence. Examples include cyclopropyl, cyclopentyl, cyclohexyl, and the like.
As used herein, the term "alkoxy" means the group -OR wherein R is alkyl as defined above. Examples include methoxy, ethoxy, propoxy, t-butoxy, n-pentyloxy, n-hexyloxy, and the like.
As used herein, the term "lower" modifies alkyl and alkoxy and refers to those radicals having four carbon atoms or less.
As used herein, the term "halo" means fluoro, chloro, bromo and/or iodo.
As used herein, the term "aryl" refers to phenyl and optionally mono-, di-, and tri-substituted phenyl, wherein the optional substituents are lower alkyl, lower alkoxy, hydroxy, trifluoromethyl, or halo. Examples include 2-chlorophenyl, 2-trifluoromethylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 3,4-dimethoxyphenyl, 4-hydroxyphenyl, 4-methylphenyl, 3-t-butylphenyl, 4-hexylphenyl, and the like.
As used herein, the term "treatment" or "treating" means any treatment of a disease in a mammal, and includes:
(i) preventing the disease, i.e., causing the clinical symptoms of the disease not to develop;
(ii) inhibiting the disease, i.e., arresting the development of clinical symptoms; and/or
(iii) relieving the disease, i.e., causing the regression of clinical symptoms.
As used herein, the terms "pharmaceutically acceptable salts" refers to those salts that retain biological effectiveness and properties of the neutral parent compounds and which are not biologically or otherwise undesirable. Pharmaceutically acceptable acid addition salts may be formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and with 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, para-toluenesulfonic acid, salicylic acid, and the like. The salts may be single or multiple salts of one or more anions, e.g., from the above-described acids.
Presently Preferred Embodiments
Presently preferred embodiments of this invention are compounds of Formula A wherein R.sup.1 is aryl; further preferred are the compounds where R.sup.1 is aryl, m is 2; q is 0; n is 0; R.sup.2 is methyl; and R.sup.3 is hydrogen. The pharmaceutically acceptable salts of these compounds are also preferred, especially the mono-, di- and tri-hydrochlorides.
Particularly preferred are those compounds where R.sup.1 is 4-methylphenyl or phenyl and R.sup.4 and R.sup.5 are the same, e.g., both phenyl, i.e., 1-(diphenylmethyl)-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine and 1-(diphenylmethyl)-4-[(2-phenyl-5-methyl-1H-imidazol-4-yl)methyl]piperazine and the trihydrochloride salts thereof.
Other preferred compounds include those where R.sup.1 is aryl or cycloalkyl; especially those where R.sup.3 is lower alkyl, particularly methyl and isopropyl; m is 2; q is 0; n is 0; and R.sup.1, R.sup.4 and R.sup.5 are all phenyl.
Still other preferred compounds include those where q is 3; n is 0; R.sup.1 is phenyl; R.sup.3 hydrogen; and R.sup.4 and R.sup.5 are both 4-fluorophenyl.
Another preferred compound is that wherein m is 3; q is 0; n is 0; R.sup.1 is phenyl; R.sup.2 is methyl; R.sup.3 is hydrogen; and R.sup.4 and R.sup.5 are both phenyl.
General Utility
The compounds of this invention are useful for treating mammals having a variety of vascular disease states, and have protective activity against some of the deleterious effects resultant upon cerebral ischemia. Disease states that may be treated include stroke, migraine, epilepsy, hypertension, angina, arrhythmia, thrombosis, and embolism. The compounds of this invention are also useful for treating spinal injuries, and are particularly useful for treating cerebrovascular disease states, for example, stroke.
Generally, vascular disease states are found in mammals, including: domestic commercial animals such as horses, cattle, sheep and pigs; domestic house animals such as dogs, cats, and the like; and particularly humans.
Activity Testing
Activity for treating vascular disease states can be determined in vitro by determining selective vascular relaxant activity, and in vivo by determining general cardiovascular activity.
In vitro calcium antagonistic activity of the compounds of this invention is determined by an assay using rat aortic strip, which is a modification of that described by R. Kent, et al., Federation Proceedings, 40, 724 (1981). Cerebrovascular selectivity of action is determined by comparing potencies on rabbit basilar artery and rabbit ear artery using a modification of the procedure described by R. Towart, et al., Arzneim. Forsh., 32(I), 338-346 (1982).
In vivo protective effects of the compounds of this invention against the deleterious effects of cerebral ischemia are determined by use of the standard gerbil brain ischemia model. This assay is a modification of that described by T. Kirino, Brain Res., 239, 57-69P (1982).
General Administration
The compounds of this invention are administered at a therapeutically effective dosage, i.e., a dosage sufficient to provide treatment for the disease states previously described. Administration of the active compounds and salts described herein can be via any of the accepted modes of administration for agents that serve similar utilities.
Generally, a daily dose of from 0.02 to 50 mg/kg of body weight per day of the active compound of Formula I. Most conditions respond to treatment comprising a dosage level on the order of 0.1 to 4 mg/kilogram of body weight per day. Thus, for administration to a 70 kg person, the dosage range would be about 1.4 to 3500 mg per day, preferably about 7.0 to 280 mg per day.
Depending on the specific disease state, administration can be via any accepted systemic route, for example, via parenteral, oral, intravenous, or nasal routes, in the form of solid, semi-solid or liquid dosage forms, such as for example, tablets, suppositories, pills, capsules, powders, solutions, suspensions, aerosols, emulsions 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 A and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.
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.
The compounds of this invention are generally administered as a pharmaceutical composition which comprises a pharmaceutical excipient in combination with a compound of Formula A. The level of the drug in a formulation can vary within the full range employed by those skilled in the art, e.g., from about 0.01 percent weight (% w) to about 99.99% w of the drug based on the total formulation and about 0.01% w to 99.99% w excipient. Preferably, the formulation will be about 3.5 to 60% by weight of the pharmaceutically active compound, with the rest being suitable pharmaceutical excipients.
Oral Administration
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 saccarine, 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. Such compositions may contain between 0.01 wt/% and 99.99 wt/% of the compound of Formula A, but preferably such compositions will contain between 25 wt/% and about 80 wt/%.
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, polyvinylpyrrolidone, gum acacia, gelatin, cellulose and derivatives thereof, and the like.
Suppositories
For systemic administration via suppository, traditional binders and carriers include, for example, polyalkaline glycol or triglycerides [e.g., PEG 1000 (96%) and PEG 4000 (4%)]. Such suppositories may be formed from mixtures containing active ingredients in the range of from about 0.5 wt/% to about 10 wt/%; preferably from about 1 wt/% to about 2 wt/%.
Liquids
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.
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, Mack Publishing Company, Easton, Penn., 16th Ed., 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 in accordance with the teachings of this invention.
Methods of Preparation
The compounds of this invention can be made as shown in Reaction Schemes I-V, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 have the same meaning as set forth above in the Summary Of The Invention, newly introduced variable R.sup.6 is lower alkyl, and X is halo. ##STR4##
Referring to Reaction Scheme I, in Step I-A a mixture of a compound of Formula 1 with an inert hydrocarbon solvent (for example, benzene, toluene and the like) is contacted with a slight excess of a halogenating agent, for example, a thionyl halide (such as thionyl chloride), to produce the corresponding alkyl halide derivative, compound of Formula 2. Compounds of Formula 1 are obtained using the procedures of Dziuron and Sunack [Arch. Pharm., 306, 347 (1973), Arch. Pharm., 307, 46 (1973) and Bull. Soc. Chim. France, (1971), 1052] and Cornforth and Huang, J. Chem. Soc., (1948) 731-735. The reaction is conducted at a temperature from about 0.degree. C. to the reflux temperature of the solvent, but preferably between about 40.degree. C. and 65.degree. C.
In Step I-B, the compound of Formula 2 is contacted with a compound of Formula 3 in a condensation reaction, for example, at a temperature from about 25.degree.-80.degree. C., preferably at the reflux temperature of the solvent system used.
The 1-substituted piperazines of Formula 3 are commercially available or can be made by the procedures of Hamlin, et al., J. Am. Chem. Soc., 71, 31 (1949) or Cheeseman, J. Chem. Soc., (1975), 115-123. Diazepine analogs (i.e., those compounds where m is 3) can be made by this method using diazepine as the starting material instead of piperazine. An alkaline solution is made by dissolving a compound of Formula 3 in a polar solvent (for example, ethanol and water, methanol and water, or a mixture such as, acetone in water, dimethylformamide in water, isopropanol in water, tetrahydrofuran in water; in the ratio of about 10:90, preferably about 60:40), and adding a base (such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and the like). The alkaline solution is heated to reflux.
A solution of the compound of Formula 2 dissolved in the same polar solvent is added dropwise to the refluxing solution of the compound of Formula 3. After about 1 to 8 hours, preferably about 4 to 5 hours, the condensed product of Formula A.sup.1 is precipitated from the reaction mixture. The reaction mixture is allowed to stand at room temperature, for example, for about 8 to 16 hours, or overnight. The resulting crystals are removed by filtration and recrystallized in ethanol giving the free base of Formula A.sup.1.
The free base can be converted to the salt by dissolving the free base in a suitable organic solvent, such as ethanol or ether, and extracting with acidic aqueous solution. The use of heat may be required to dissolve the free base, depending upon the acid chosen.
The salt can be converted back to the free base by suspending it, for example in ether, and adding an excess of a dilute aqueous base, such as potassium carbonate, until the salt dissolves. The organic layer is separated, washed with water, dried and evaporated to yield the free base. ##STR5##
Referring to Reaction Scheme II, in Step II-A a compound of Formula 4 [obtained using the procedure of Vecchio, et al., Chim. Ind. (Milan), 58(6), 451 (1976) or of Haruki, et al., Zasshiu, 86(9), 942-946 (1965) (Japan)] is reduced by contacting it with a reducing agent, such as a hydride (for example, potassium borohydride, or lithium aluminum hydride) in an alcoholic solution (for example, methanol, ethanol, isopropanol, and the like). The solution is stirred for about 8 to 16 hours, e.g., overnight, and the resulting solid material, of Formula 5, is removed by filtration, washed, dried and used in the next step without further purification.
In Step II-B, the crude compound of Formula 5 is dissolved in an inert solvent (for example, chloroform, dichloromethane, benzene, toluene, and the like). A halogenating agent, such as thionyl chloride, is added to the solution and the resulting mixture is heated at reflux for a period of time between 1 and 10 hours, preferably between about 4 and 6 hours. After cooling, the solvent is removed under reduced pressure and the residue is triturated in acetone to give a compound of Formula 6.
In Step II-C, the compound of Formula 6 and a compound of Formula 3 are reacted together under the conditions described in Step I-B to give a compound according to Formula A.sup.2. An oil product may be separated, dissolved in ether, and acidified to precipitate. The reaction time is about 1 to 24 hours, preferably about 4 to 5 hours. ##STR6##
Referring to Reaction Scheme III, in Step III-A a methyl ketone, such as a compound of Formula 4, an amine, such as a compound of Formula 3, and formaldehyde are reacted together under the conditions typically used for a Mannich reaction, to give a compound of Formula 7.
In Step III-B, the compound of Formula 7 is reduced under conditions similar to those described in Step II-A, to give a compound of Formula A.sup.3. ##STR7##
Referring to Reaction Scheme IV, in Step IV-A a compound of Formula 4 is halogenated, by contacting it with a halogenating agent, for example, thionyl halide, under conditions similar to those described in Step I-A, to give a compound of the Formula 8.
In Step IV-B, a compound of Formula 8 and a compound of Formula 3 are condensed by contacting them under conditions similar to those described for Step I-B, to give a compound of Formula 9.
In Step IV-C, a compound of Formula 9 is reduced, by contacting it with a reducing agent under conditions similar to those described for Step III-A to give a compound of Formula A.sup.4. ##STR8##
Referring to Reaction Scheme V, in Step V-A, the Grignard reagent of a lower alkyl halide, the compound of Formula 11, is contacted with an imidazole compound of Formula 10 [obtained using the procedure of Cornforth and Huang, J. Chem. Soc., (1948), 731-735] in a neutral solvent (for example, diethyl ether, tetrahydrofuran, tetrahydropyran, and the like) and refluxed for between 15 minutes and 2 hours, preferably between 20 minutes and 40 minutes, and is then cooled and poured into ice water. The aqueous layer is extracted with a suitable organic solvent, such as diethyl ether. When the solvent is removed under reduced pressure, a residue is formed that can be recrystallized in ethanol yielding a compound of Formula 12.
In Step V-B, a compound of Formula 12 is halogenated under conditions similar to those described for Step I-A, to give a compound of Formula 13.
In Step V-C, a compound of Formula 13 and a compound of Formula 3 are contacted under conditions similar to those described for Step I-B, to give a compound of Formula A.sup.5.
Preferred Processes
The compounds of the present invention can be prepared according to the following last steps, in which non-essential substituents are not referenced, but will be apparent from reference to the foregoing reaction schemes:
a 4-haloalkyl-1H-imidazole (or a salt thereof) is condensed with an alkyl-4-piperazine to give a compound according to Formula A where m is 2;
a 4-haloalkyl-1H-imidazole (or a salt thereof) is condensed with an alkyl-4-diazepine to give a compound according to Formula A where m is 3;
a 4-(1-halo-C.sub.2 -C.sub.4 -alkyl)-1H-imidazole (or a salt thereof) is condensed with an alkyl-4-piperazine to give a compound according to Formula A where m is 2, and R.sup.3 is lower alkyl;
a 4-(1-halo-C.sub.2 -C.sub.4 -alkyl)-1H-imidazole (or a salt thereof) is condensed with an alkyl-4-diazepine to give a compound according to Formula A where m is 3, and R.sup.3 is lower alkyl;
a 1-alkyl-4-[(1H-imidazol-4-yl)-1-oxo-alkyl]piperazine is reduced to give the corresponding compound according to Formula A where m is 2, and R.sup.3 is hydroxy;
a 1-alkyl-4-[(1H-imidazol-4-yl)-1-oxo-alkyl]diazepine is reduced to give the corresponding compound according to Formula A where m is 3, and R.sup.3 is hydroxy;
exemplifying the preparation of a further substituted compound, a 2-(aryl)-4-(.omega.-haloalkyl)-5-alkyl-1H-imidazole (or a salt thereof) is condensed with a diaryl-alkyl-4-piperazine to give a compound according to Formula A where R.sup.1 is aryl, R.sup.2 is alkyl, R.sup.3 is hydrogen, R.sup.4 and R.sup.5 are aryl, m is 2, n is 0-2, and q is 0-3;
contacting a pharmaceutically acceptable acid with a compound of Formula A to form the corresponding acid addition salt of Formula A;
substituting a pharmaceutically acceptable acid salt of Formula A with another pharmaceutically acceptable acid; and
contacting an acid addition salt of Formula A with a base to form the corresponding free base compounds of Formula A.
The following examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as a limitation on the scope of the invention, but merely as being illustrative and representative thereof.
US Referenced Citations (8)
Foreign Referenced Citations (4)
| Number |
Date |
Country |
| 0054974 |
Oct 1982 |
EPX |
| 0072623 |
Jan 1983 |
EPX |
| 1551993 |
Jun 1979 |
GBX |
| 2022073 |
Jul 1979 |
GBX |
Divisions (1)
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Number |
Date |
Country |
| Parent |
42181 |
Apr 1987 |
|
Patent Grant
4935417
