Claims
- 1. A method of treating a mammal for:
- a disease treated by direct neuronal protection, selected from the group: focal and global ischemia, and neuronal cell ischemia associated with spinal injuries and head trauma;
- a disease treated by diuresis; or
- a disease treated by calcium channel antagonism, said disease selected from:
- a cardiovascular disease, selected from the group: hypertension, angina, stable and unstable angina, Prinzmetal angina, arrhythmia, thrombosis, embolism, and congestive heart failure including chronic or acute congestive heart failure; or
- a disease characterized by ischemia of lower legs due to peripheral vascular disease, including intermittent claudication;
- a disease characterized by spasms of smooth muscle, selected from the group: spasms of the ureter, spasms of the bladder, uterine cramps, and irritable bowel syndrome; or
- prevention of vasoconstriction and/or ischemic tissue damage during a surgical procedure, selected from the group: bypass grafts, angiography, angioplasty, organ preservation during transplant, hypertensive crisis or post operative hypertension;
- said method comprising administering to the mammal a therapeutically effective amount of a compound represented by the formula: ##STR14## 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 two;
- 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 wherein the disease is irritable bowel syndrome.
- 3. A method of treating a mammal for uraemic or hyponatraemic encephalopathy;
- said method comprising administering to the mammal a therapeutically effective amount of a compound represented by the formula: ##STR15## 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 two;
- 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.
- 4. The method of claim 1 comprising administering to the mammal a therapeutically effective amount of the compound wherein R.sup.1 is aryl or cycloalkyl.
- 5. The method of claim 2 comprising administering to the mammal a therapeutically effective amount of the compound wherein R.sup.1 is aryl or cycloalkyl.
- 6. The method of claim 3 comprising administering to the mammal a therapeutically effective amount of the compound wherein R.sup.1 is aryl or cycloalkyl.
- 7. The method of claim 1 comprising administering to the mammal a therapeutically effective amount of the compound wherein R.sup.2 is aryl or lower alkyl.
- 8. The method of claim 1 comprising administering to the mammal a therapeutically effective amount of the compound wherein R.sup.2 is aryl or lower alkyl.
- 9. The method of claim 3 comprising administering to the mammal a therapeutically effective amount of the compound wherein R.sup.2 is aryl or lower alkyl.
- 10. The method of claim 4 comprising administering to the mammal a therapeutically effective amount of the compound wherein R.sup.2 is aryl or lower alkyl.
- 11. The method of claim 5 comprising administering to the mammal a therapeutically effective amount of the compound wherein R.sup.2 is aryl or lower alkyl.
- 12. The method of claim 6 comprising administering to the mammal a therapeutically effective amount of the compound wherein R.sup.2 is aryl or lower alkyl.
- 13. The method of claim 1 comprising administering to the mammal a therapeutically effective amount of the compound 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine or a pharmaceutically acceptable salt thereof.
- 14. The method of claim 2 comprising administering to the mammal a therapeutically effective amount of the compound 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine or a pharmaceutically acceptable salt thereof.
- 15. The method of claim 3 comprising administering to the mammal a therapeutically effective amount of the compound 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine or a pharmaceutically acceptable salt thereof.
- 16. A method of treating a mammal for the symptoms of a neurological disease treated by direct neuronal protection, selected from the group: Alzheimer's disease and Huntington's chorea;
- said method comprising administering to the mammal a therapeutically effective amount of a compound represented by the formula: ##STR16## 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 two;
- 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.
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a division of pending application Ser. No. 07/260,969, filed Oct. 21, 1988, now U.S. Pat. No. 5,043,447 incorporated by reference; which is a continuation-in-part of U.S. Ser. No. 042,181, filed Apr. 24, 1987 now U.S. Pat. No. 4,829,065 incorporated herein by reference, and claims priority from EPO application Ser. No. 88.303646.9, filed Apr. 22, 1988, also incorporated herein by reference.
This application is also related to U.S. Ser. No. 260,628, filed contemporaneously herewith and incorporated herein by reference, wherein preferred parenteral formulations, most preferably with 1-(diphenylmethyl)-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine, tartrate are disclosed.
This application is also related to U.S. Ser. No. 260,965, filed contemporaneously herewith and incorporated herein by reference, wherein related synthetic processes are disclosed.
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 have calcium entry blocking activity with 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 useful for treating mammals having any of a variety of disease states, including:
Substituted piperazines have been described as having a variety of pharmaceutical activities.
For example, U.S. Pat. No. 3,362,956 and its CIP U.S. Pat. No. 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, compounds of the formula: ##STR1## wherein R.sup.1 is a lower-alkyl, hydroxy-lower alkyl, phenyl or substituted-phenyl, phenyl-lower-alkyl, or substituted-phenyl-lower alkyl, benzhydryl or substituted benzhydryl, phenyl-lower-alkenyl or substituted-phenyl-lower-alkenyl, or pyridyl radical; R.sup.2 is hydrogen or from one to two lower-alkyl radicals; Y is lower-alkylene of from one to six carbon atoms; and Het is a heterocyclic radical selected from the group consisting of bicyclic aromatic nitrogen heterocyclic radicals having fused five and six membered rings and containing from two to three ring nitrogen atoms which can be in any position of the two rings, for example, radicals derived from indazole (e.g. 2-azaindole, 4-azaindole, 5-azaindole, 6-azaindole, 7-azaindole), pyrrolo[2,3-d]-pyrimidine, benzimidazole and pyrido[2,1-c]-s-triazole; a benz[g]-3-indolyl radical; a 4(5)-imidazolyl radical; a 3-thianaphthenyl radical; a 3-quinolyl radical; a 3,4-dihydro-1-isoquinolyl radical; or 1,2,3,4-tetrahydro-1-isoquinolyl radical or such heterocyclic radicals substituted in any available position by from one to three substituents, defined hereinafter as R.sup.2, for example, methyl, ethyl, propyl, and isobutyl; lower-alkoxy, for example, methoxy, ethoxy, propoxy, and butoxy; halogen, including fluorine, chlorine, bromine, and iodine; lower-alkylmercapto, for example, methylmercapto, ethylmercapto, propylmercapto, and isobutylmercapto; lower-alkylsulfinyl, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, and isobutylsulfinyl; lower-alkylsulfonyl, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl; trifluoromethyl; hydroxy; methylenedioxy; or ethylenedioxy, wherein the lower-alkyl moiety of the said substituents contain from one to four carbon atoms; are disclosed.
In the '098 patent compounds of the formula: ##STR2## wherein R is hydrogen or a lower-alkyl, hydroxy-lower-alkyl, phenyl, phenyl-lower-alkyl, benzhydryl, phenyl-lower-alkenyl, cycloalkyl-lower- alkyl, or pyridyl radical; Y is lower-alkylene of from one to six carbon atoms; and Het is a 4(5-imidazolyl radical; are disclosed.
None of the prior art teaches 4(5)-imdazolyl-substituted piperazine or diazepine derivatives substituted or useful in the manner of this invention Compounds having the range of 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: ##STR3## 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 wherein R.sup.3 is lower alkyl or hydrogen and n is zero, by reacting a substituted amidine of the formula: ##STR4## with a substituted dione of the formula: ##STR5## wherein a is an integer from zero to four; and a substituted-4-piperazine or a substituted-4-diazepine of the formula: ##STR6## in the presence of a lithium reagent.
A still further aspect of the present invention encompasses methods of treating a mammals having any of a variety of disease states, including:
Another aspect of the present invention encompasses pharmaceutical formulations comprising a compound of Formula A and a pharmaceutically acceptable excipient.
The numbering of the piperazines and diazepines of the present invention is as follows: ##STR7## 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:
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-chlorphenyl, 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:
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-descried acids.
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, and the tartrate salts.
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.
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 2 or 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, e.g., 1-(diphenylmethyl)-4-[(2-phenyl-5-methyl-1H-imidazol-4-yl)methyl]piperazine.
Most preferred is the compound 1-(diphenylmethyl) -4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]-piperazine and the trihydrochloride and tartrate salts thereof.
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.
The compounds of this invention are particularly useful for treating cerebrovascular disease states, for example, stroke.
Generally, the disease states treated with the compounds of the present invention 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.
Testing for activity in treating the above-described disease states can be undertaken in vitro and/or in vivo using assay procedures known in the literature. The following are examples of such assay procedures.
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).
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 A. 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.
For example, in methods of treating stroke, particularly acute ischemic stroke, an active compound of Formula A can be co-administered with one or more agents active in reducing the risk of stroke, such as aspirin or ticlopidine (preferably ticlopidine, which has been demonstrated to reduce the risk of a second ischemic event). Co-administration can be in the form of a single formulation (combining, for example, a compound of Formula A and ticlopidine with pharmaceutically acceptable excipients, optionally segregating the two active ingredients in different excipeient mixtures designed to independently control their respective release rates and durations) or by independent administration of separate formulations containing the active agents.
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.
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/5.
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.
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/%.
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. Preferred parenteral formulations are described in copending application Ser. No. 260,628, incorporated herein by reference.
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, Pa. 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.
The compounds of this invention can be made as shown in Reaction Schemes I-VI, 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, X is halo, and a is an integer from zero to four. ##STR8##
I. Preparation of Formula A Where R.sup.3 is Hydrogen
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, chloroform 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) and Arch. Pharm., 307, 46 (1973)]; Imbach et al., Bull. Soc. Chim. France, 3, 1059 (1971); Cornforth and Huang, J. Chem. Soc., (1948) 731-735; Ewins, J. Chem Soc., 99 2052 (1911); or U.S. Pat. No. 4,107,307. 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, methanol, ethanol, or a mixture such as ethanol and water, methanol and water, acetone in water, dimethylformamide in water, isopropanol in water, tetrhydrofuran in water; in the ratio of from about 10:90 to about 90:10, 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 24 hours, preferably about 2 to 5 hours, the condensed product of Formula A.sup.1 is separated from the reaction mixture either by precipitation or evaporation under reduced pressure. The reaction mixture is allowed to stand at room temperature, for example, for about 8 to 24 hours, or overnight. If the product precipitated, the resulting crystals are removed by filtration and recrystallized in an alcohol, preferably methanol or ethanol giving the free base of Formula A.sup.1. If the product is an oil, the oil is washed with water and dissolved in diethyl ether. Acid is added and the product is precipitated as the acid addition salt using ethanol.
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.
The salt of a compound of formula A can be converted to another salt by methods known in the art for interconversion of salts. ##STR9##
II. Preparation of Formula A Where R.sup.3 is Methyl and n is 0
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., Nippon Kagaku 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 2 to 16 hours, e.g., overnight, and the resulting solid material, of Formula 5, is removed by filtration (using reduced pressure if necessary), 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. ##STR10##
III. Preparation of Formula A Where R.sup.3 is Hydroxyl and n is 2
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. Thus, the ketone of Formula 7 is dissolved in a solvent such as water, methanol, ethanol, or acetic acid and formaldehyde is introduced. The amine is then added and the reaction mixture is refluxed. If necessary a small amount of an acid such as hydrochloric acid, may be introduced to assure that the reaction mixture is not basic.
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. ##STR11##
IV. Preparation of Formula A Where R.sup.3 is Hydroxyl and n is 1
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. ##STR12##
V. Preparation of Formula A Where R.sup.3 is Lower Alkyl
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. ##STR13##
High yields of the compounds of Formula A where n is zero, can be obtained by the synthetic method illustrated in Reaction Scheme VI. It is preferred for the synthesis of compounds where n is zero, R.sup.2 is lower alkyl and R.sup.3 is lower alkyl having one carbon atom less than R.sup.2 (or R.sup.3 is hydrogen when R.sup.2 is methyl).
Notably, the last step of this process can be completed in a single reaction vessle and produce a crystalline form of the end product, which requires no recrystallization or milling before incorporation into a pharmaceutical formulation. Thus, the process is preferred for its improved yield, the reduced time and manpower requirements for carrying it out, and the crystalline nature of the resulting product.
Referring to Reaction Scheme VI, in Step VI-A, a nitrile of Formula 14 (preferably 4-methylbenzonitrile) is dissolved in an alcohol (preferably methanol or ethanol, more preferably 99% ethanol), the solution is saturated with an excess of dry HCl gas and stirred at room temperature for from 1 to 24 hours, preferably overnight. The imine precipitate (the compound of Formula 15) is filtered, washed and dried. A second crop of precipitate can be collected by placing the mother liquors in a freezer overnight, after which the resulting precipitate is washed and dried.
In Step VI-B, the imine of Formula 15 is added slowly with stirring to an alcohol (preferably methanol), which is saturated with ammonia. Once the imine is dissolved, the solution is stirred at room temperature for from 1 to 24 hours, preferably overnight. The solution is reduced by 2/3 volume under vacuum, then diluted with 3 times its volume with isopropylacetate. An amidine precipitate (the compound of Formula 16) is formed, filtered and dried.
In Step VI-C, the amidine of Formula 16 is then dissolved in alcohol (preferably methanol or ethanol, more preferably 99% ethanol). A slight molar excess of a substituted dione compound of Formula 17 (preferably wherein H(CH.sub.2).sub.a --CH.sub.2 is the same as R.sup.2, most preferably butanedione) is added dropwise and the reaction mixture refluxed for 1 to 40 hours, preferably 15 to 25 hours, more preferably about 20 hours. The mixture is then cooled to 15.degree. to 40.degree. C., preferably about 30.degree. C., a compound of Formula 3 [preferably N-(diphenylmethyl)piperazine] is added, followed by the addition of water, a base (such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and the like, preferably sodium hydroxide) and a slight molar excess of a metal halide (such as lithium bromide, lithium iodide, lithium chloride, potassium bromide, preferably lithium bromide). Any insoluble material is removed by filtration and the solution is refluxed for 1 to 10 hours, preferably 4 to 6 hours. The reaction mixture is cooled and stirred at room temperature for 1 to 24 hours, preferably overnight, to form a precipitate (the compound of Formula A.sup.6, i.e., Formula A where n is zero).
Optionally, in cases where the resulting product contains in excess of, e.g., about 0.2% of mineral impurities, a reslurring step can be performed, wherein the precipitate is then filtered, and poured into an alcohol/water mixture (such as methanol/water, ethanol/water, isopropanol/water in a ratio of from 10:90 to about 90:10, preferably 60:40). The solution is warmed to 50.degree. to 80.degree. C., preferably about 70.degree. C., for 15 minutes to 4 hours, preferably about 1 hour, then cooled, and the precipitate filtered and dried.
Compounds prepared by the above-described preferred process of the invention may be identified (e.g., using mass spectroscopy, NMR spectroscopy, or preferably, atomic absorption spectroscopy) by the presence of a slight, but detectable amount of lithium compound used in the process as a reagent (e.g., LiBr) or produced in it as a side product (e.g., LiOH). While it is well known that pharmaceuticals must meet pharmacopoeia standards before approval and/or marketing, and that synthetic reagents or side products should not exceed the limits prescribed by pharmacopoeia standards, final compounds prepared by a process of the present invention may have minor, but detectable, amounts of such materials present. It is important to monitor the purity pharmaceutical compounds for the presence of such materials, which presence is additionally disclosed as a method of detecting use of a process of the invention.
The compounds of the present invention can be prepared by the following last steps, in which non-essential substituents are not referenced, but will be apparent from reference to the foregoing reaction schemes:
US Referenced Citations (8)
Foreign Referenced Citations (1)
| Number |
Date |
Country |
| 0054974 |
Jun 1982 |
EPX |
Divisions (1)
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Number |
Date |
Country |
| Parent |
260969 |
Oct 1988 |
|
Continuation in Parts (1)
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Number |
Date |
Country |
| Parent |
42181 |
Apr 1987 |
|
Patent Grant
5276034
