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Justia Patents US Patent for 1-(Naphthyl-n-propyl)imidazole derivatives Patent (Patent # 4,293,561)
1-(Naphthyl-n-propyl)imidazole derivatives
Mar 9, 1979 - Syntex (U.S.A.) Inc.
Compounds of the formula ##STR1## wherein Z is C.sub.1 and C.sub.4 alkoxymethylene, hydroxymethylene, esterified hydroxymethylene, carbonyl, or ketal-protected carbonyl, and the pharmaceutically acceptable acid addition salts thereof, are useful as anticonvulsant and anti-secretory agents.
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DESCRIPTION OF THE INVENTION
The present invention relates to certain 1-(naphthyl-n-propyl)imidazole derivatives. More particularly, the present invention relates to compounds of formula (I), namely: ##STR2## wherein Z is hydroxymethylene, esterified hydroxymethylene, C.sub.1 to C.sub.4 alkoxymethylene, carbonyl, of ketal-protected carbonyl; and the pharmaceutically acceptable acid addition salts thereof.
As used in the specification and appended claims, unless specified to the contrary, the following terms have the meanings indicated. The term "esterified hydroxymethylene" refers to a hydroxymethylene group which has been esterified with an alkanoic acid having from 1 to 8 carbon atoms or with benzoic acid. Typical alkanoic acids which may be mentioned are formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid and octanoic acid. The term "alkoxymethylene" refers to a hydroxymethylene group which has been alkylated on oxygen with a straight or branched chain group having from 1 to 4 carbon atoms. Representative of such alkyl groups are methyl, ethyl, isopropyl, n-butyl, etc. The term "ketal-protected carbonyl" refers to (i) a carbonyl group protected as an acyclic ketal derived from a monohydric straight chain alkanol having from 1 to 4 carbon atoms such as, for example, the dimethyl-, diethyl-, di(n-propyl)-and di(n-butyl)ketals, and (ii) a carbonyl group protected as a cyclic ketal derived from a dihydric alcohol having 2 or 3 carbon atoms which may optionally be substituted by one or more methyl groups, for example, the ethylenedioxy-, 1,3-propylenedioxy-, 1,2-propylenedioxy-, 2,2-dimethyl-1,3-propylenedioxy-, 1-methyl-1,3-propylenedioxy-, 1,3-dimethyl-1,3-propylenedioxy- and 2,3-butylenedioxyketals. The term "pharmaceutically acceptable acid addition salts" refers to salts of the free bases of formula (I), which salts possess the desired pharmacological activity and which are neither biologically nor otherwise undesirable. Such salts may be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; or with organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and the like.
Compounds of formula (I) wherein Z is hydroxymethylene, esterified hydroxymethylene or alkoxymethylene possess a chiral center. Accordingly, these compounds may be prepared in either optically active form, or as a racemic mixture. Unless otherwise specified, the compounds described herein are all in the racemic form. However, the scope of the subject invention is not to be limited to the racemic form but is to encompass the individual optical isomers of the subject compounds.
If desired, compounds of formula (I) wherein Z is hydroxymethylene, esterified hydroxymethylene or alkoxymethylene may be prepared in optically active form by conventional resolution means known per se, for example, by the separation (e.g., fractional crystallization) of the diastereomeric salts formed by reaction of, e.g., racemic compounds of formula (I) wherein Z is hydroxymethylene or esterified hydroxymethylene, or alkoxymethylene with an optically active acid, or by separation of the diastereomeric esters formed by reaction of such a racemic alcohol wherein Z is hydroxymethylene with an optically active acid. Exemplary of such optically active acids are the optically active forms of camphor-10-sulfonic acid, .alpha.-bromocamphor-.pi.-sulfonic acid, camphoric acid, menthoxyacetic acid, tartaric acid, malic acid, diacetyltartaric acid, pyrrolidone-5-carboxylic acid, and the like. The separated pure diastereomeric salts or esters may then be cleaved by standard means to afford the respective optical isomers of the desired compound.
Compounds of formula (I) exhibit a broad spectrum of CNS related activity such as anticonvulsant activity (as demonstrated by the maximal electroshock seizure test), anorexigenic, antidepressant and muscle relaxing activity; as well as activity of other types such as inhibition of gastric secretion, antihypertensive and spermatostatic/spermatocidal activities.
One aspect of the present invention relates to a method for treating and/or preventing convulsions in a mammalian subject comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof. Another aspect of the present invention relates to pharmaceutical compositions useful for the treatment and/or prevention of convulsions in a mammalian subject comprising a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, in admixture with a pharmaceutically acceptable non-toxic carrier. For this utility compounds of formula (I) wherein Z is carbonyl, ketal-protected carbonyl or alkoxymethylene are particularly preferred.
Yet another aspect of the present invention relates to a method for inhibiting gastric secretion in a mammalian subject comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof. Still another aspect of the present invention relates to pharmaceutical compositions useful for the inhibition of gastric secretion in a mammalian subject comprising a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, in admixture with a pharmaceutically acceptable non-toxic carrier.
In the practice of the above described methods of the present invention a therapeutically effective amount of the compound of formula (I) or a pharmaceutical composition containing same is administered via any of the usual and acceptable methods known in the art, either singly or in combination with another compound or compounds of the present invention or other pharmaceutical agents. These compounds or compositions can thus be administered orally or parenterally (i.e. intramuscularly, subcutaneously and intraveneously), and can be administered either in the form of solid or liquid dosages including tablets, solutions, suspensions, and the like, as discussed in more detail hereinbefore. Oral administration is preferred. The administration can be conducted in a single unit dosage form the continuous therapy or in single dosage therapy ad libitum. The method of the present invention may be practiced when relief of symptoms is specifically required, i.e. therapeutically, or as continuous or prophylactic treatment.
In view of the foregoing as well as in consideration of the degree of severity of the condition being treated, age of subject and so forth, all of which factors are determinable by routine experimentation by one skilled in the art, the effective dosage in accordance herewith can vary over a wide range. Generally, a therapeutically effective amount for anticonvulsant use ranges from about 0.1 to about 300 mg./kg. body weight per day. In alternate terms, for an average adult human subject, a therapeutically effective amount in accordance herewith would be, in preferred embodiments, from about 70 mg. to about 7 g per day per subject. A therapeutically effective amount for inhibition of gastric secretion ranges from about 0.1 to about 300 mg./kg. body weight per day and preferably from about 0.25 to about 100 mg./kg. body weight per day. In alternate terms, for an average adult human subject, a therapeutically effective amount in accordance herewith would be, in preferred embodiments from about 18 mg. to about 7 g per day per subject.
Useful pharmaceutical carriers for the preparation of the pharmaceutical compositions hereof can be solids or liquids. Thus, the compositions can take the form of tablets, pills, capsules, powders, sustained release formulations, solutions, suspensions, elixirs, and the like. Carriers can be selected from the various oils, including those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. Suitable pharmaceutical carriers and their formulations are described in "Remington's Pharmaceutical Sciences" by E. W. Martin. Such compositions will, in any event, contain a therapeutically effective amount of the active compound together with a suitable amount of carrier so as to prepare the proper dosage form for proper administration to the subject.
Compounds related to those of formula (I) have been previously described in applicant's co-pending application Ser. No. 848,548, filed Nov. 4, 1977 now U.S. Pat. No. 4,150,153, issued Apr. 17, 1979, as intermediates for the preparation of compounds having anti-fungal, antibacterial and antiprotozoal activity. The disclosure in said co-pending application is hereby incorporated by reference herein.
The compounds of the present invention may be prepared according to methods well known in the art. For example, compounds of formula (I) wherein Z is carbonyl may be prepared in a manner analogous to that described in U.S. Pat. No. 4,078,071 to the applicant for the corresponding phenyl compounds. This method comprises reacting a haloethyl naphthyl ketone, or a vinyl naphthyl ketone or the Mannich base quaternary intermediate thereof with imidazole in an inert organic solvent. The starting haloethyl naphthyl ketones are known or may be prepared by the Friedel-Crafts reaction of naphthalene with .beta.-chloropropionyl chloride. Vinyl ketones, insofar as they may not be known or generally available, may be prepared by a variety of methods well known in the synthetic organic chemistry art, for example, by the addition of vinyl lithium to the corresponding carboxylic acid; by the addition of vinyl lithium to the corresponding aldehyde followed by oxidation of the allylic alcohol thus produced to the vinyl ketone (e.g., J. Chem. Soc (C), 1966, p. 1972; J. Chem Soc. (London), 1956, p. 3070); or by Mannich reaction of the corresponding methyl ketone, quaternization and elimination. The preparation of ketones of formula (I) by the above described method may be carried out in an inert organic solvent, for example, dimethylformamide at a temperature between about -10.degree. and +40.degree. C.
Preparation of compounds of formula (I) wherein Z is hydroxymethylene may be accomplished by the reduction of the corresponding ketone or acid addition salt thereof under standard conditions, for example, by the use of sodium tetrahydroborate in a protic solvent, for example, methanol, at a temperature between about -20.degree. and +20.degree. C.
Compounds of formula (I) wherein Z is esterified hydroxymethylene may be prepared under usual esterification conditions from the corresponding alcohol by treatment of the alcohol with the desired acid halide or anhydride in the presence of a base, preferably a tertiary amine such as pyridine or triethylamine, at a temperature between about 0.degree. and +40.degree. C. in a solvent such as pyridine, tetrahydrofuran, dichloromethane, chloroform, and the like.
Compounds of formula (I) wherein Z is ketal-protected carbonyl may be prepared according to the following reaction sequence: ##STR3## wherein X is halo (especially chloro or bromo).
In this sequence the naphthyl haloethyl ketone is first converted to the halo ketal (II). Ketalization to form cyclic ketals may be performed by methods well known in the art, e.g. by treatment of the ketone with the desired dihydric alcohol in the presence of a strong acid, for example a sulfonic acid such as p-toluene-sulfonic acid or a Lewis acid such as boron trifluoride. Water is preferably removed as an azeotrope with the solvent, for example an aromatic hydrocarbon such as benzene or toluene, at a temperature sufficient to effect such azeotropic removal, e.g. from about 75.degree. to about 150.degree. C. Ketalization to form acyclic ketals may be performed by employing an orthoester (e.g. methyl orthoformate or ethyl orthoformate) in the presence of an acid or Lewis acid, e.g. boron trifluoride, p-toluenesulfonic acid, perchloric acid, fuming sulfuric acid, and the like. The haloketal (II) is then converted to (I) by treatment with imidazole in a polar aprotic solvent such as dimethylformamide, dimethylsulfoxide acetonitrile or tetrahydrofuran at a temperature between about 20.degree. and 130.degree. C.
Compounds of formula (I) wherein Z is alkoxymethylene may be prepared by alkylation of the corresponding alcohols. The alkylation is carried out by converting the alcohol to a metal salt, preferably an alkali metal salt, by treatment with a strong base such as, for example, an (alkali) metal hydride such as sodium hydride or an (alkali) metal amide such as sodium amide or potassium amide and the like. This is preferably done in an inert organic solvent such as dimethylformamide, hexamethylphosphoramide, tetrahydrofuran and the like. The (alkali) metal salt is then contacted with an alkylating agent, e.g. an alkyl halide, sulfate or sulfonate ester, preferably an alkyl halide, preferably in the same solvent system, at a temperature between -20.degree. and 100.degree. C., most preferably between 0.degree. and 60.degree. C., for a period of 30 minutes to 18 hours.
The subject compounds of formula (I) can be isolated as free bases; however, since many of the compounds in base form are oils and gums and/or not water soluble it is often more convenient to isolate and further characterize such compounds as acid addition salts. These salts are prepared in the usual manner, i.e., by reaction of the free base with a suitable inorganic or organic acid, for example one of the pharmaceutically acceptable acids described above. If desired, the salt can be readily converted to the free base by treatment with a base such as potassium or sodium carbonate or potassium or sodium hydroxide.
Especially preferred are the following compounds:
1-[2-(2-naphthoyl)ethyl]imidazole;
1-[3-hydroxy-3-(2-naphthyl)-n-propyl]imidazole;
1-[3-methoxy-3-(2-naphthyl)-n-propyl]imidazole;
1-[3-acetoxy-3-(2-naphthyl)-n-propyl]imidazole;
1-[3-benzoyloxy-3-(2-naphthyl)-n-propyl]imidazole;
1-[3,3-ethylenedioxy-3-(2-naphthyl)-n-propyl]imidale; and
1-[2-(1-naphthoyl)ethyl]imidazole.
A further aspect of the present invention concerns a process for the preparation of a free base compound of the formula ##STR4## wherein Z is hydroxymethylene, esterified hydroxymethylene, (C.sub.1 to C.sub.4) alkoxymethylene, carbonyl, or ketal-protected carbonyl; or a pharmaceutically acceptable non-toxic acid addition salt thereof, which process comprises:
(a) the preparation of a compound of formula (I) wherein Z is carbonyl by reaction of a .beta.-haloethyl naphthyl ketone or a naphthyl vinyl ketone, or the Mannich base quaternary intermediate with imidazole, or
(b) the preparation of a compound of formula (I) wherein Z is hydroxyethylene by reduction of a compound of formula (I) wherein Z is carbonyl, or
(c) the preparation of a compound of formula (I) wherein Z is esterified hydroxymethylene by esterification of a compound of formula (I) wherein Z is hydroxymethylene, or
(d) the preparation of a compound of formula (I) wherein Z is C.sub.1 to C.sub.4 alkoxymethylene by alkylation of a compound of formula (I) wherein Z is hydroxymethylene, or
(e) the preparation of a compound of formula (I) wherein Z is ketal-protected carbonyl by reaction of a compound of the formula ##STR5## wherein X is halo, with imidazole or an alkali metal salt thereof, or
(f) optionally converting a free base to the corresponding acid addition salt, or
(g) optionally converting an acid addition salt to the corresponding free base.
The following specific description is given to enable those skilled in the art to more clearly understand and practice the present invention. It should not be considered as a limitation upon the scope of the invention but merely as illustrative and representative thereof.
A solution of 34 g of 2-acetonaphthone, 13.5 g of paraformaldehyde, 24.46 g of dimethylamine hydrochloride and 0.2 ml of concentrated hydrochloric acid in 100 ml ethanol is heated under reflux for 24 hours. The solvent is removed and the resulting white solid, 2-naphthyl 2-dimethylaminoethyl ketone hydrochloride is recrystallized twice from acetone/methanol. The hydrochloride salt (31.3 g) is neutralized with aqueous potassium carbonate solution, extracted with ether, dried (MgSO.sub.4) and filtered. Treatment of the ethereal solution with 15 ml of iodomethane causes precipitation of [2-(2-naphthoyl)ethyl]trimethylammonium iodide, as a white solid, washed with acetone and dried in air.
Yield: 35.5 g.
To a stirred, ice-cooled solution of 4.76 g of imidazole in 30 ml of dry dimethylformamide is added 17.66 g of crude [2-(2-naphthoyl)ethyl]trimethylammonium iodide. The mixture is stirred overnight at room temperature and at 75.degree. C. for one day. The resulting solution is poured into water and the precipitate filtered off, washed with water and dried in air. The resulting 1-[2-(2-naphthoyl)ethyl]imidazole is dissolved in ethyl acetate and converted to its hydrochloride acid addition salt by addition of ethereal hydrogen chloride until precipitation is complete. The crude salt (11.3 g) is recrystallized from methanol/acetone to yield colorless crystals of 1-[2-(2-naphthoyl)ethyl]imidazole hydrochloride, m.p. 182.5.degree.-186.degree. C.
Similarly prepared using the corresponding [2-(1-naphthoyl)ethyl]trimethylammonium iodide is 1-[2-(1-naphthoyl)ethyl]imidazole and its hydrochloride salt.
To 2.86 g of the above obtained 1-[2-(2-naphthoylethyl]imidazole hydrochloride in 150 ml of methanol at 0.degree.-5.degree. C. is added, with stirring, excess sodium tetrahydroborate. After stirring overnight at room temperature, the reaction mixture is evaporated to dryness. The resulting residue is treated with 20 ml of water, the product extracted with ether and the extracts washed, dried (MgSO.sub.4) and evaporated. The resulting colorless oil crystallizes on addition of ether and scratching, and is recrystallized from ethyl acetate to give 2.4 g of 1-[3-hydroxy-3-(2-naphthyl)-n-propyl]imidazole. The hydrochloride salt is prepared by treatment of an ethereal solution of the free base with ethereal hydrogen chloride until precipitation is complete. The precipitate is collected and recrystallized from methanol/acetone to give 1-[3-hydroxy-3-(2-naphthyl)-n-propyl]imidazole hydrochloride, m.p. 166.7.degree.-168.1.degree. C.
Similarly prepared from 1-[2-(1-naphthoyl)ethyl]-imidazole hydrochloride is 1-[3-hydroxy-3-(1-naphthyl)-n-propyl]imidazole and its hydrochloride salt.
A solution of 1.2 g of 1-[3-hydroxy-3-(2-naphthyl)-n-propyl]imidazole in 20 ml of dry hexamethylphosphoramide is treated between 5.degree.-10.degree. C. with stirring under nitrogen with 0.24 g of a 50% dispersion of sodium hydride in mineral oil. The mixture is stirred one hour at 10.degree. C., one hour at 50.degree. C., and then cooled in ice. Methyl iodide (0.8 g.) in 2 ml of hexamethylphosphoramide is added with stirring maintaining the temperature below 10.degree. C. and the mixture stirred at 5.degree. C. for 1 hour and overnight at room temperature. The resulting mixture is poured into water, the product extracted with ether and the extracts washed, dried (MgSO.sub.4) and evaporated to give a yellow oil. Chromatography on silica gel eluting with 10% methanol in dichloromethane gives pure 1-[3-methoxy-3-(2-naphthyl)-n-propyl]imidazole. This is converted to its hydrogen sulfate addition salt by dropwise addition of sulfuric acid to a solution in ether and recrystallized from methanol/ethyl acetate to give 1-[3-methoxy-3-(2-naphthyl)-n-propyl]imidazole hydrogen sulfate, m.p. 122.degree.-122.5.degree. C.
A solution of 1.36 g of 2-chloroethyl-2-naphthyl ketone, 6.05 g ethylene glycol and a crystal of p-toluenesulfonic acid monohydrate in 50 ml of toluene is heated for 8 hours under reflux through a Dean-Stark trap. After cooling, the mixture is neutralized by pouring into excess aqueous potassium carbonate, extracted with 200 ml ether and the organic phase washed, dried (MgSO.sub.4), and evaporated to yield 2-(2-naphthyl)-2-(2-chloroethyl)-1,3-dioxolane. Without further purification the crude ketal (1.36 g.) is heated with 1.77 g of imidazole in 2 ml of acetonitrile at 85.degree. overnight. The resulting mixture is evaporated to dryness, treated with water and the product extracted with ether. The extracts are washed well with water, dried (MgSO.sub.4), evaporated and the residue chromatographed on silica gel eluting with 5% methanol/dichloromethane to give 0.78 g of 1-[3,3-ethylenedioxy-3-(2-naphthyl)-n-propyl]imidazole.
A solution of 1.26 g 1-[3-hydroxy-3-(2-naphthyl)-n-propyl]imidazole in 20 ml pyridine is treated dropwise with stirring with 0.72 ml of benzoyl chloride and the mixture stirred overnight. The resulting solution is poured into 100 ml water, extracted with ethyl acetate and the extracts washed, dried (MgSO.sub.4) and evaporated in vacuo to remove residual pyridine and afford 1-[3-benzoyloxy-3-(2-naphthyl)-n-propyl]imidazole. The residue is dissolved in ether, treated with ethereal hydrogen chloride and the resulting precipitate recrystallized from acetone/methanol to give the hydrochloride salt.
Repeating the procedure of Example 4, utilizing the appropriate ketone and alkylene diol there may be prepared the following compounds which may be further characterized as the acid addition salts indicated:
1-[3,3-(1,3-propylenedioxy)-3-(2-naphthyl)-n-propyl]-imidazole;
1-[3,3-(2,2-dimethyl-1,3-propylenedioxy)-3-(2-naphthyl)-n-propyl]imidazole;
1-[3,3-(1-methyl-1,3-propylenedioxy)-3-(2-naphthyl)-n-propyl]imidazole;
1-[3,3-ethylenedioxy-3-(1-naphthyl)-n-propyl]imidazole;
1-[3,3-(2,3-butylenedioxy)-3-(2-naphthyl)-n-propyl]-imidazole; and
1-[3,3-(2,3-butylenedioxy)-3-(1-naphthyl)-n-propyl]-imidazole.
Repeating the procedure of Example 5, utilizing 1-[3-hydroxy-3-(2-naphthyl)-n-propyl]imidazole or 1-[3-hydroxy-3-(1-naphthyl)-n-propyl]imidazole, and the appropriate acid halide or anhydride, there may be prepared the following compounds:
1-[3-propionyloxy-3-(2-naphthyl)-n-propyl]imidazole;
1-[3-butyryloxy-3-(2-naphthyl)-n-propyl]imidazole;
1-[3-isobutyryloxy-3-(2-naphthyl)-n-propyl]imidazole;
1-[3-hexanoyloxy-3-(2-naphthyl)-n-propyl]imidazole;
1-[3-hexanoyloxy-3-(1-naphthyl)-n-propyl]imidazole; and;
1-[3-benzoyloxy-3-(1-naphthyl)-n-propyl]imidazole.
A solution of 2.18 g of 2-chloroethyl-2-naphthyl ketone, 1.7 g trimethyl orthoformate and a few crystals of p-toluenesulfonic acid (anhydrous) in 20 ml anhydrous methanol is heated under reflux for two hours. After cooling to room temperature, two drops of phenolphthalein solution are added and a solution of sodium methoxide in methanol is added dropwise until a pink color persists. After removal of the solvent under reduced pressure the resulting oil is dissolved in ether, decolorized with charcoal and the ether removal to give 2-chloroethyl-2-naphthyl ketone dimethyl ketal as a colorless oil.
2-Chloroethyl-2-naphthyl ketone dimethyl ketal 1.93 g in 5 ml acetonitrile is heated with 3.5 g of imidazole for 24 hours at 85.degree. under nitrogen. The resulting solution is poured into water, extracted with ether and the extracts washed, dried (MgSO.sub.4) and evaporated. After chromatography on silica gel eluting with 5% methanol/dichloromethane the product is recrystallized from toluene to give 1-[3-(2-naphthyl)-3,3-dimethoxy-n-propyl]imidazole as a colorless solid.
Repeating the procedure of Example 8, utilizing 2-chloroethyl 2-naphthyl ketone or 2-chloroethyl 1-naphthyl ketone and the appropriate alkyl orthoformate, there may be prepared the following compounds:
1-[3-(2-naphthyl)-3,3-diethoxy-n-propyl]imidazole;
1-[3-(2-naphthyl)-3,3-di(n-propoxy)-n-propyl]imidazole;
1-[3-(2-naphthyl)-3,3-di-(n-butoxy)-n-propyl]imidazole;
1-[3-(1-naphthyl)-3,3-dimethoxy-n-propyl]imidazole;
1-[3-(1-naphthyl)-3,3-di(n-propoxy)-n-propyl]imidazole; and
1-[3-(1-naphthyl)-3,3-di(n-butoxy)-n-propyl]imidazole.
Ethereal hydrogen chloride is added dropwise to a solution of 1.0 g 1-[2-(2-naphthoyl)ethyl]imidazole in 100 ml anhydrous benzene until precipitation is complete. The product is filtered, washed with ether, air dried and recrystallized from methanol/acetone to yield 1-[2-(2-naphthoyl)ethyl]imidazole hydrochloride, m.p. 182.5.degree.-186.degree. C.
In a similar manner, all compounds of formula (I) in free base form may be converted to the acid addition salts by treatment with the appropriate acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and the like.
1-[2-(2-Naphthoyl)ethyl]imidazole hydrochloride (1.0 g.) suspended in 50 ml of ether is stirred with excess dilute aqueous potassium carbonate solution until the salt is completely dissolved. The organic layer is then separated, washed twice with water, dried over magnesium sulfate and evaporated to yield 1-[2-(2-naphthoyl)ethyl]imidazole.
In a similar manner the acid addition salts of all compounds of formula (I) may be converted to the corresponding compounds in free base form.
The following illustrates a pharmaceutical composition for oral administration which may be prepared for the compounds of the present invention, e.g.
1-[2-(2-naphthoyl)ethyl]imidazole hydrochloride or
1-[3,3-ethylenedioxy-3-(2-naphthyl)-n-propyl]imidazole,
______________________________________ parts by weight ______________________________________ Active compound 200 Magnesium stearate 3 Starch 30 Lactose 116 Polyvinylpyrrolidone 3 ______________________________________
The above ingredients are combined and granulated using methanol as the solvent. The formulation is then dried and formed into tablets (containing 200 mg of active compound each) with an appropriate tabletting machine.
1. A compound of the formula ##STR6## wherein Z is a carbonyl group protected as an acyclic ketal derived from a monohydric straight chain alkanol having from one to four carbon atoms, or a carbonyl group protected as a cyclic ketal wherein the cyclic ketal is selected from the group consisting of ethylenedioxy, 1,3-propylenedioxy, 1,2-propylenedioxy, 2,2-dimethyl-1,3-propylenedioxy, 1-methyl-1,3-propylenedioxy, 1,3-dimethyl-1,3-propylenedioxy, and 2,3-butylenedioxy and the pharmaceutically acceptable acid addition salts thereof.
2. The compound of claim 1 which is 1-[3,3-ethylenedioxy-3-(2-naphthyl)-n-propyl]imidazole and the pharmaceutically acceptable acid addition salts thereof.
3. The compound of claim 1 which is 1-[3,3-(1,3-propylenedioxy)-3-(2-naphthyl)-n-propyl]imidazole and the pharmaceutically acceptable acid addition salts thereof.
5. A pharmaceutical composition for the prevention and treatment of convulsions or inhibiting gastric secretion in mammals comprising a therapeutically effective amount of a compound of the formula ##STR7## wherein Z is a carbonyl group protected as an acyclic ketal derived from a monohydric straight chain alkanol having from one to four carbon atoms, or a carbonyl group protected as a cyclic ketal wherein the cyclic ketal is selected from the group consisting of ethylenedioxy, 1,3-propylenedioxy, 1,2-propylenedioxy, 2,2-dimethyl-1,3-propylenedioxy, 1-methyl-1,3-propylenedioxy, 1,3-dimethyl-1,3-propylenedioxy, and 2,3-butylenedioxy or a pharmaceutically acceptable acid addition salt thereof; in admixture with a pharmaceutically acceptable, non-toxic carrier.
6. A method for treating and preventing convulsions in a mammalian subject comprising administering to said subject in need thereof a therapeutically effective amount of a compound of the formula ##STR8## wherein Z is carbonyl, a carbonyl group protected as an acyclic ketal derived from a monhydric straight chain alkanol having from one to four carbon atoms, or a carbonyl group protected as a cyclic ketal derived from a dihydric alcohol having two or three carbon atoms which may be optionally substituted by one or more methyl groups or a pharmaceutically acceptable acid addition salt thereof.
7. A method for inhibiting gastric secretion in a mammalian subject comprising administering to said subject in need thereof a therapeutically effective amount of a compound of the formula ##STR9## wherein Z is carbonyl, a carbonyl group protected as an acyclic ketal derived from a monhydric straight chain alkanol having from one to four carbon atoms, or a carbonyl group protected as a cyclic ketal derived from a dihydric alcohol having two or three carbon atoms which may be optionally substituted by one or more methyl groups or a pharmaceutically acceptable acid addition said thereof.
4085209 April 18, 1978 Miller et al.
4141908 February 27, 1979 Heeres
4150153 April 17, 1979 Walker
4156008 May 22, 1979 Heeres
4172141 October 23, 1979 Walker
Filed: Mar 9, 1979
Date of Patent: Oct 6, 1981
Assignee: Syntex (U.S.A.) Inc. (Palo Alto, CA)
Inventor: Keith A. M. Walker (Los Altos Hills, CA)
Primary Examiner: Henry R. Jiles
Assistant Examiner: Natalia Harkaway
Attorneys: Annette M. Moore, Alan M. Krubiner
Application Number: 6/19,201
Current U.S. Class: 424/273R; 548/336; 548/341
International Classification: A61K 31415; C07D23360; C07D40506;


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Got this to entertain a lifelong pet lover, while waiting to get ready for bed, or while I'm puttering around the room. Also for days she's under the weather and can't do much. HUGE HIT! She's hypnotized by this. There's a bit less contrast than I'd have expected, some kittens are similar color to the background, but she sees them fine despite vision issues. You have to choose between several videos of different kittens (they don't look all that different), and then choose music, but once you get it going, it plays endless loop which is great. The motion is lively. She doesn't tire of it. The kittens chase each other or play with toys or climb a cat condo. She smiles and occasionally comments. It's also been useful to improve mood- when she's feeling out of sorts or frustrated, it calms and brings a smile to her face. We paired this with a stuffed toy cat for her lap and she pets it and speaks to it while watching the video. Cheers me up too, they're pretty cute.


LB - Yesterday we discussed your work, for over 15 years, at Labofex. Why the ABRI effort now?
PC - I would say it is the result of several joyful conjunctions. A conjunction of the theoretical work we have pursued in physics and mathematics, with the tools originally provided by Reich and Aspden, and which led to entire new sets of concepts and functions in Aetherometry; with the theoretical work we have pursued in analytical philosophy - employing tools developed by Nietzsche, Bergson, Deleuze; and with the experimental work in physics and biology, largely inspired by Tesla, Szent-Gyorgyi and Reich, which we have carried on for over two decades aside from the Labofex effort. This experimental work began by building a medical ORAC for my father - and then went on to study both the physical and biological responses of human beings to daily exposure in the cabinet. Very early on, the physical and biological effects of the device became apparent - the cabinet always sustained a positive temperature difference on days of good weather, and there was always a half-degree centigrade increase in body temperature after a 20 to 30 minute exposure. At the same time we began reproducing Reich's blood tests - the T vs B reaction, the autoclavation test - and then his experiments in biogenesis, with great success. By then I was doing my undergraduate sciences, and became fascinated with biochemistry - in particular by the work of Lehninger in mitochondria, of Szent-Gyorgyi in electronic biology, of Pauling and Monod in allosteric reactions, of Thom and Zeeman in catastrophe theory and morphology, of Oparin, Miller, Fox, Orgel and others in biogenesis. It seemed to me that Reich had a grand vision of the unity of biological functioning and that he had gone as far as he could in his efforts to comprehend both biology and its energetic physics, but that these molecular biologists in turn held many new and important pieces in their hands which here and there had critically weak links because the unity of functioning to which they always brought things to, was still mechanistic. My first glimpse at establishing a connection between molecular biology and Reich's orgonomic thinking came in a study of existing molecular and biophysical theories that claimed to explain the simple phenomenon of amoeboid motion.
AC - By then we were engaged in reproducing the entirety of Reich's biophysical work - with ORACs, electroscopes, pendulums, orgone field meters, induction coils, vacuum tubes, radiation counters and so on. Then this third line, the experimental biophysical line, finally began interacting and congealing with the other two, with a functionalist physico-mathematical theory and a novel approach to a philosophy of nature. When we were able to bring about a conjunction of these lines, we also cracked the structure of the electron and rediscovered the functioning principle of Reich's Orgone Motor. Then we improved upon it.
LB - When did that happen?
PC - The discovery of the principle at the bench took place in mid-1998. By the spring of 1999 we had developed our improved version. Since then we have steadily increased its performance. We have succeeded in driving it from a superimposition of the aether energy streams from the ORAC, with the earth, a body of water, living bodies, atmospheric antennas, vacuum cavities, and so on, employing or not vacuum tubes for this purpose. The experimental breakthrough came simultaneously with one of the critical developments in Aetherometry - a new understanding of the relation between heat and electricity, and in particular between what is called "latent heat" and electricity. But by then we had already cracked the structure of the electron and the functions that associate its mass-energy with any of a variety of physically distinct kinetic energies. Effectively this leap permitted us to understand the simplicity and reality of massless charge, as opposed to electrons or any other form of massbound charge, whether leptonic or hadronic.
LB - You had been previously accused in public of having stolen the OR motor principle from Reich, with your patent for the electromechanical transduction of plasma impulses - but now you claim to have rediscovered it?
PC - Yes indeed, the breakthrough came in several plateaus - on the experimental front alone we had to understand how to tap the latent aether energy accumulated in the ORAC, decode Factor Y, understand what was going on with his Vacor tubes and how one superimposes two distinct aether energy streams, bypass Reich's need for an electric input to the motor, reproduce all the motor response anomalies he encountered, and then proceed to make critical changes to every aspect of it. The previous accusation you alluded to - which was gravely marred by a personal vendetta on the part of the accuser - came from someone who understood absolutely nothing either about our PAGD technology, or about Reich's work. And it was withdrawn. The facts are that many have now claimed, one way or the other, to have decoded Reich's OR Motor work. But no one has succeeded in demonstrating its existence. It's a bit like a holy grail for the mystics of Orgonomy. Reich undoubtedly would have experienced a profound nausea contemplating the confusionism and the poverty of thought, not to mention the greed and malevolence surrounding this pursuit. You can probably count on two hands those who carried on with any part of his work that did not make him turn in his grave. Some fellow recently claimed that Factor Y stood for You. So another confused the PAGD inverter with the OR Motor - that is already a step forward, wouldn't you say?
AC - It gets worse, because there is a tremendous greed surrounding this matter that prevents any form of lucidity. Friendships of years and even decades reveal their worthlessness when it comes down to the madness of these grails. Reich saw correctly into the Mocenigo phenomenon - one is hounded even by supposed friends, but the masks drop because, most often, they make their moves too early and sloppily. We have experienced intense attempts at dispossessing our process and findings - to this day this does not cease to amaze us. One of the reasons why we are publishing this material is precisely to straighten out some of these false friends of knowledge, and the false notions they peddle like the latest soap.
PC - This, not to mention the complete disregard to which what passes for Orgonomy has condemned any understanding of the Aether, let alone the OR Motor - they are still convinced that only one of their thoroughly analyzed neurotics could touch such an ultimate truth and resolve the holy of holies. But look at the misery: instead of concentrating on studying the functions, most of the little chapels pursued in secret the mythical KS motor, as if reaching its magical possession held a miracle in abeyance. We did not even come into possession of KS motors until two years after our rediscovery of the OR Motor.
LB - So you have had no contacts with what passes for Orgonomy?
PC - That is a difficult question. Alexandra and I have met most of the old guard and some of the new - but these are fragmented guards assembled in different institutional frames, all at war with the others, and all equally poor in most of what they do. There are people who have done very good work in specific aspects of the field, but they are few and far between, and rarely are they part of a chapel. But even those, in general, lack any sense of an analytical criticism of Reich. Look, very few people have written decent books or even articles or papers on Reich that didn't make him turn in his grave. The quantity of garbage and idle speculation is immense. It is all part of the cottage industry mentality, the stealing from one another, the debasement and equalization of the work of Reich, not orgonomy but mercantile anorgonomy. We had some public confrontations, years back, with several of these dimwits. So far these and others like them have managed to monopolize interest in Reich's work precisely by mystifying it. It is little wonder that serious inquiry turns away, when one hears and sees the misery to which Reich's beautiful, sensitive and intelligent work has been condemned.
AC - We both hope and expect them to ignore us. Exact science is not their forte. For them, Reich's work is to be enshrined and gawked at, and not seized as a box of critical tools that one needs to sharpen and improve upon. His machines are seldom studied with exact methods, and this in turn forbids genuine understanding. Often, when you see someone building an ORAC, or a cloud buster or a DOR-buster, and so on, it is as a gizmo for sale, to make a buck, and the evidence they provide is summarily ridiculous - like seeing auras or choosing materials by touch and smell. We are not saying that there is no energy field surrounding each living system - nor that there are no seers or senses to pay attention to. What we are saying is that such claims have no validity if they cannot or are not corroborated by objective investigation, by analytical measurement, by a functional understanding. Reich always strove to accomplish this, even if he fell short of the goal here and there. That's the nature of the scientific process. But without it, one is left totally at the mercy of the claims of exhibitionists and con-artists that lack any real powers, let alone extraordinary powers, save for the power of hooking onto the gullibility of people and abusing their ignorance of science.
PC - But we do not even have to go that extreme route, because the ignorance of these matters is also and above all the ignorance of scientists. Burr, as far back as the early thirties, argued that he had demonstrated the existence of standing electric potentials in all living systems. Yet, as Reich pointed out much later, how can we reconcile the tens of thousands of electrostatic volts which an insulated human body can develop by contact or loss of contact with the ground, with the millivoltages detected at the tissue interfaces or over erogenous zones? But if this problem itself was difficult enough, there are still two other angles to this. Indeed, the electrostatic potentials may not be what is indicative of a specifically biological energy, a bioelectricity. They may well be the result of capacitative functions of charge resulting from the interaction of the body with the ground, the earth, just as the millivolt potentials are established at fluid junctions by limited ion fluxes. But none of this is of primary importance - at least that is what biophysical Aetherometry tells us. Others, like Ravitz, realizing the incapacity of static electric fields to account for bioelectric fields, suggested that there is no specific biological energy because these fields are after all simply electromagnetic, even if only slowly changing over time. However, as we see it, the primary biological energy fields are neither electrostatic nor electromagnetic, even if there is in fact a derived electromagnetic field.
AC - Indeed, auras exist and the fact that they can be seen, photographed and measured is clear indication that there is a local photon field to each living system - simply this field is neither primary nor specific to the living. The heat or thermal photons emanating from the body are a clue to the nature of the underlying massfree electric energy that is both drawn into the body and discharged by it. Here we begin to approach a dynamic electric energy that is indeed specific to the living. But, in our own understanding, we are still very far - with this realization - from understanding exactly what it is that constitutes the energy of the living. The electromagnetic field or aura of the body, we were saying, is the result of a more fundamental massfree and electrically ambipolar field that produces it. It is this massfree electric energy that we claim constitutes in fact the true meaning of orgone energy - yet, even this electrically ambipolar field itself is also the result of a still more fundamental form of massfree energy, nonelectric and nonelectromagnetic.
PC - It is easy to demonstrate this, since, whether insulated or not, the action of the body is always to draw charge by contact with metallic objects charged with either polarity, and draw the kinetic energy of charge from the same objects through the radiative field of the body. If the ambipolar electric field were the dominant form of biological energy - and not the result of a transformation from a still more fundamental form of energy, neither electric nor electromagnetic - then the action of the body by contact, and in the absence of 'friction' with the ground, should charge metallic objects and, more important than any such residual rectification, the approach of the body, insulated or not, to the electroscope should not depress the charged state of the latter independently of electric polarity. Since none of this is observed, and since we demonstrate most rigorously that the action of the ORAC, the so-called orgone effect, it too is neither electric, nor electromagnetic, we are led to conclude that the most primitive layer of massfree energy which is specific to the living pertains to a realm others have referred to as latent energy, though no one presently knows exactly what its physical expressions are, nor how to connect or link them. This is what Aetherometry ties together into a stunning conclusion - there are all types of ways in which we can measure this fundamental nonelectric and nonelectromagnetic energy from which arise all the massfree electric and the 'tertiary' electromagnetic effects, and these paths have - up until now - remained unexplored with respect not just to action of the fundamental energy field of living systems, or the electroscope, but also with respect to such basic natural phenomena as cloud-formation, the intrinsic potential energy of molecules, the OR effect of the ORAC, the energy content of water and so on. This is what ultimately led us to understand the nature of both gravity and antigravity, or Celeritas, in a new way. And this is also the fundamental subject matter of experimental Aetherometry.
AC - Now you know how one can make very different types of meters to detect energy fields associated with living systems - one can detect their electrostatic fields, their electromagnetic fields, and even their ambipolar electric fields - but none of these, which are there and quite present and distinct, should be confused with the nonelectric and nonelectromagnetic field of 'latent massfree energy' specific to the living that gives rise to all the others.
PC - Little wonder then that there is so much confusion and glib assertion even among scientists - they rarely bother to create the filters which permit separation of the field effects of one or the other manifestation of energy in living systems. The result is confusion, simplistic mechanism and vendor's mysticism. One says it's all about electrostatics, the other about heat, and still another about electromagnetic energy, period. And most of the time they don't even bother to separate the effect that one type of field has upon the detection of the other. Yet, one can precisely and exactly separate all these bioenergetic field effects - and thus state that truly specific to the living is only massfree energy in either of its two interconvertible manifestations: "latent" nonelectric and ambipolar electric. The biological specificity is neither electrostatic, as Burr pretended, nor electromagnetic, as Ravitz thought. The specificity is energetic and refers to massfree energy alone, whether electric or not, to the exclusion of both massbound electricity and electromagnetism. Thus the specificity of the living had to be articulated both experimentally and theoretically as energy manifestations altogether distinct from ion fluxes, potentials of massbound charge, or photonic fields.
LB - What set you on this novel understanding of latent and sensible heats?
PC - If you can believe it - understanding what is happening in that marvelous machine called the electroscope, which Reich renamed the orgonoscope. It was Reich's experiments with variation in the spontaneous rate of discharge of electroscopes, and a letter that William Washington addressed to him, which got me thinking about the problem of using the electroscope to measure the levels of what, at the time, I thought was orgone energy in the environment. As it turns out, orgone energy is massfree aether energy in an ambipolar electric state, and what affects directly that electroscope - or the massbound charges trapped in its conduction band - is not orgone, not directly so, but the massfree latent "heat" in the surrounding environment, and this can indeed be measured with the employment of electroscopes. What finally set us in what we believe is the right direction was a mistake I made in calculating the energy and power of various spontaneous rates of discharge - and Harold Aspden caught that mistake and told me that all I needed was the critical frequency term of what turns out is the gold graviton. Once we realized we already had that answer, things began unraveling, and we were capable of differentiating between the electric and basically unknown nonelectric functions of the electroscope. Later we came to understand that the nonelectric functions, even though responsive to sensible heat, responded above all to variations in latent "heat".
AC - This understanding was critical. There is little doubt in our minds that the OR effect of an ORAC is the result of an accumulation of latent "heat" - a concentration of massfree aether energy in a nonelectric state. The effect is directly beneficial to living systems - as Reich systematically demonstrated in his Cancer Biopathy.
PC - Once we understood latent "heat", we were able to tie the whole phenomenon of the nonelectric functions of the electroscope to the work which massbound charges trapped in a conductor must perform to counteract local gravity. This is the subject of the first volume of Experimental Aetherometry that we are releasing at present.
AC - We will cover several territories - going into the problem of electromagnetism and aether electric energy in volume two, then on to the Aether Motor in volume three, and we are reserving a little surprise for the last volume of Experimental Aetherometry. At the same time we intend to release, through AKRONOS, as you know, the volumes of Theoretical Aetherometry, beginning with the Aether Wars in XXth century Physics. We have a packed, relentless program.
LB - How did the ABRI effort congeal? What led you to it?
PC - The ABRI effort formally began with Aetherometry - eight years ago, when Alexandra and I felt completely discouraged by the difficulties we encountered in trying to communicate - let alone commercialize - the Labofex technology. Ultimately, we came to view this failure as a stroke of extraordinary good luck - it became clear to us that we didn't want to live our lives managing the applications of our inventions, in bed with the types of individuals we were coming in contact with - uncomprehending sponsors, frivolous speculators or dubious friends - who could at any moment turn into snakes while eyeing our economies as collateral. What we really wanted was to pursue our process of life and creation - and this was then possible, more than ever.
AC - We felt we were at a critical crossroads - we needed new tools of thought, basic physical and mathematical insights upon which we could build a new understanding of fundamental phenomena. Without them, there would have been no point in pursuing further experimental efforts. How can all these researchers speak so much of the electron and have so little idea of what the beast is actually like? Another slight of hand is how they unconsciously slide from using the term electron to the term charge, as if they were interchangeable! We had to make both the mathematical and semiological languages of science become more precise, more exacting. The phenomenon of charge is more universal and fundamental than that of inertia or mass.
PC - So we focused our energies upon understanding the electron without preconceived notions - following Einstein's advice, precisely. Uri was very supportive of this theoretical development and accompanied its early stages with great interest. It would take us two years to fully disengage its structure - the mystery of its wave structure and how and why it changes between electric and electromagnetic configurations, as well as decode its volumetric aspects, and the relation between charge and inertia. No one at present has any idea of the actual electron structure. We intend to publish this material very soon - since this is ground that our modern physicists purport to understand and know full well, and yet do not. Our departure point was a confrontation of Aspden's brilliant theory of the electron and the quon particle with the conventional 'understanding' of the electron. In the process, we came to finally understand the conversion of mass into length that Reich had proposed as early as 1944, and which we had cracked numerically, but without fully understanding, in 1991. This opened the doors to the electromagnetic fine structure of the electron mass-energy, which inevitably led us to a new structure also of the proton and the hydrogen atom. Then came the problem of charge - which for years had been dogging us: how to understand charge? How to reduce it to fundamental dimensionality? How to extract the electric structure? Is charge always associated with inertia? Why are electrodynamic anomalies only observed in open or interrupted circuits? How to understand the coupling of kinetic energy to the mass-energy of an electron? Aspden here too, on these topics, wrote many beautiful pages that were of great inspiration to us. His notion that massbound charge resists acceleration because of an electric property of inertia which obeys conservation of the carrier's mass-energy was cardinal for our understanding.
AC - This theoretical immersion led us to continue, in parallel, another effort - one which we have kept under wraps for nearly three decades - an experimental effort aimed at solving the basic difficulties that exist when one attempts to find a common functional language for basic energetic facts - accepted and anomalous - in thermodynamics, electrodynamics and gravitation. We began by reproducing the most fundamental work of Reich and Tesla - where we had essentially left it before engaging in our attempts at commercializing the PAGD technology. We were forced to separate, as it were, the electric from the electromagnetic - and the non-electromagnetic and non-electric from the other two. Physicists are only too eager to assume that all energy is electromagnetic, and that only electromagnetic radiation exists. But the photon is like Oedipus in ethnology or psychoanalysis - a shallow and local rivulet. There are other forms of radiation besides electromagnetic energy. Specifically, there are forms of radiation which are electrical and massfree, as well as nonlocal. And there are still other radiative manifestations which are neither electrical nor electromagnetic, nor even gravitational, to speak properly, since the gravitational field - at any rate - only acts in the sense of attracting masses. The great difficulty lies here, in the sorting of these distinct physical effects, in the tracking of their conversion pathways, their fine distinctions. Effectively, modern physics knows nothing about these energy realms - it knows nothing about electric energy because it is ignorant of massfree electricity, nothing about gravity because it reduces it to mere questions of topological description, concentration of mass and geometry, and nothing either about energy capable of developing negative gravity. Even electromagnetic energy - the best known realm of physical science - is very poorly understood. We contend, for instance, that, aside from locally assembling a photon, there are no electromagnetic waves propagating light across space. Light is always produced locally in response to the propagation of an electrically ambipolar, longitudinal wave.
PC - The interaction of the experimental approach with the theoretical development was critical for the continuation of our process - we effectively began developing new methods of mathematical analysis that permitted a new understanding of what we were doing experimentally, and we realized that one can experiment as much with a pencil and paper as at the bench, if one is to follow a functionalist approach with either work method - that is, one based upon developing the micro-functionalist, constructivist principles Reich taught and applying them to that part of accepted Physics and Biology which is solid, as well as to anomalies that we could ourselves experimentally verify and explore. When these lines of experimentation merged, Alexandra and I came back to the notion that this research should be pursued in the context of an institute dedicated to integrating a wider scope of research with the aetherometric tools we were creating. This was the beginning of ABRI.
AC - In a sense, ABRI started with the electron, proceeded to Aetherometry and led to our rediscovery of the OR motor, as well as our improvement of it in the form of the Aether Motor. Then the idea grew on its own to include not just a new approach to natural sciences, to physics, mathematics and biology, but also to the philosophy of nature, to analytical experiments in collective media and libidinal economy. For us Aetherometry really began with Nietzsche - he was the first thinker to raise the specter of a natural Philosophy of Time and he attempted to conceptualize it with what were then vaguely scientific tools. Gilles Deleuze taught us admiration for the deep thought of this discarded philosopher - he wrote two courageous books on Nietzsche that wiped out a century of malevolent miscomprehension and abuse. And it was our interest in Nietzsche and Deleuze that led us, in a serendipitous way, to our encounter with Dr. Malgosia Askanas, mathematician, logician, puppeteer and performance artist, an open spirit with diverse and wonderfully creative interests, and one of the two founders of the Spoon Collective. She whole-heartedly embraced the concept of a research institute like the ABRI, and has dedicated endless amounts of time and effort to move the project forward. Soon we found ourselves speculating about the implications and connections to art, theater, urbanism, philosophy of nature, the politics of desire - how to open up the ABRI to other creative possibilities.
PC - Yes, in fact, Alexandra and I doubt very much whether we would ever have published at all any of this material in experimental and theoretical Aetherometry, if it were not for Malgosia, her constant and thoughtful incitement to do so for the past five years, her willingness to make it happen and make the ABRI happen, her desire to learn, read and understand thousands of pages of material, her unwavering friendship to us and to life-affirmative knowledge, her creation of a beautiful website for our work. She and Uri have been the two greatest friends of this particular effort of ours.
LB - What is your present intention with respect to the technologies that the ABRI is concentrating on?
PC - We do not want to say too much about this. We have tried, discreetly and persistently, to find a suitable sponsor to develop both the weight-cancellation and Aether Motor technologies. Our intention is that this knowledge should be used, from the beginning, for benign applications - this will give it a headstart over those who would like nothing more than to use it for malignant purposes. Once we release this information, it is inevitable that malignant as well as fake usages will follow. But to this day we have not encountered a suitable sponsor.
AC - In fact, we have come to this conclusion over and over again - only we can develop these technologies and guide this project to a good term. There is no institution we can trust, and no courageous 'old fighter' either that we have come across. We intend therefore to release this information in steps. If it is well received, we might release the entire story, since it has many chapters indeed.
PC - That's right. The Aether Motor is only a small part of it. The shifts demanded are not paradigmatic but geological. Whole continents will have to move.
LB - Why did you not opt to call your work orgonomy, or a continuation of orgonomy?
PC - We owe much too much to Reich, but also to Aspden and Deleuze. They were all our teachers. Aetherometry not only clarifies what Reich was investigating, but also goes well beyond him. Its errors are not Reich's but our own, and the same applies to what is novel and different about it. For us, the only Orgonomy which ever existed was Reich's work - and it has not been orgonomically understood... We would not dream of completing it - not in its own terms, since these proved often to be insufficient - and our effort could never be seen as an attempt to complete it. No, Reich's work is to be continued and re-examined seriously with functional scientific methodologies. But when you look around you, you see what it left as its legacy - it's a veritable spectacle or parody where primitive notions are dominant, like the view that living bodies emanate a life force, or that the electroscopic charge is not electric but 'orgonotic'. There is no life force. There is a very specific massfree life energy - a will to power and not a will for Power - and it is but one of the manifestations of massfree energy; and no one knows its electric and nonelectric frequency spectra at present but us. Likewise, there is a specific aether energy which is noxious to cellular life. And there is an Aether, a more fundamental concept still, which encompasses distinct domains of massfree energy functions that have to this day been lumped together with all-sweeping mystical notions of orgone charge and the like. There is only one type of charge in nature, and that is the electric charge, ambipolar in a massfree state - Aether - and monopolar in massbound or condensed states - Matter. Moreover, massfree charge does not exhaust the entire domain of the Aether, or massfree energy, nor its manifestations in association with Matter, or mass-energy. It is the lack of these distinctions, at once physical, energetic, experimental and theoretical, which hampered Reich's own theoretical process. It did not produce the general abortion of his work that one witnesses with great pain, but made it possible. We assume however, that there is much which he knew and most sensibly took to the grave - and of which his followers have in general no inkling. Before he died, he was already saddened and embarrassed by most of them.
AC - Think carefully about his profound words in the tape 'Alone'. The question is very basic. These self-styled Reichians blow their horns hard but have never even once explained exactly why orgone is not electromagnetic energy, and how exactly it relates to electromagnetic energy. Likewise with respect to electricity. Reich never explained either distinction adequately - though he claimed that orgone energy was neither electric nor electromagnetic. And so, these Reichians, these 'honest and hard-working people', just take these differences for granted, like Muslims drinking the Koran. Working hypotheses become mystic dogmas. But then they proceed to attribute to orgone energy all of the properties of electromagnetic radiation. And as if that weren't bad enough, they next assimilate it to the electric action of ions, and so on. Who, in their right mind, more than a century since Maxwell, would continue in our epoch to mix the action of electromagnetic fields, whether ionizing or not, with that of electric fields? Obviously they profit as much from confusionism as the real enemies of Reich have. The smashing majority of the followers of Reich have kept knowledge of the Aether and Orgone separate from any sensible contact with the scientific process, and thoroughly amalgamate the concept of Orgone energy to simplistic mysticisms. And official science is only too happy to comply. One of the targets of our work is to end this charade. To denounce it and expose it. It is neither life nor knowledge that this situation befriends. Confusion only breeds confusion.
LB - Can this be seen as a confirmation that this knowledge is, in a manner of speaking, self-selective? After all, isn't that what Reich argues when he talks of the unpreparedness of the repressed character structure to comprehend and assimilate the problems, the distinctions, the differences, the datum and factum? Likewise - isn't this also like what you claim Nietzsche proposed - an esoteric knowledge doubling up an exoteric guise?
AC - Well, yes, the living process is not reducible to masks, to their representation, or their human signification. The spectacle of a phoney culture affects the entirety of the living - yet it begins essentially as an affair of representation, an affair of masks and dressing the human over the animal that ran amok. Knowledge at the service of life is today a knowledge against culture, or against what is left of it, against the established dogmas of official science, against moralistic and repressive values. We are all constrained to bear masks, yet few make the masks flee - and therefore it is not the esoteric that doubles up the trivial guise. The guise, the mask or now disguise, has been compelled to be so distorted, that to talk of esoteric knowledge would be tantamount to demanding an entirely different way of being alive, of becoming alive, of seeing and acting. Nietzsche might have been able to hide his secret doctrine behind the popular mysticism of a wheel of Time, but what is always in a relation of doubling is representation, not the domain of energy and emotional intensities. Rather, the latter alone is primary. After the deeply analytical work of Deleuze and Guattari, it has become difficult, if not impossible, to speak of character structure the way Reich did. It is all a matter of energy investments and their regimes, even Oedipus. The problem with respect to Psychiatry is no different than that in science. There is a specific scientific Oedipus that is called forth in both, as part of the stamp that science must receive from the State and Capital, but at the end of the day it is all a matter of desire, of investments of desire, of regimes of libidinal economy, of ways of relating knowledge and life. The modern way is to validate knowledge by letting it be selected by market forces, supported by the State with the public purse and reassessed by peers protecting vested interests - knowledge has been, by that very same fact, made subordinate to human values that are set above life, to intermediaries that are in fact foreign to science and impose these values upon its quest. What we propose with Aetherometry is that knowledge only matters if it serves Life, if it serves as a line of escape from institutionalized Survival. Deleuze wrote some very profound pages on how the specific analytical approach of Guattari varied from that of Reich - how he had to conceive of libidinal economy not as the subjective internalization of political economy, an ideological prolongation of the latter, but as the immanence of a field of energy. And when you think of it, this is a profoundly Reichian view which Reich never successfully articulated. The sexuality, the creativity of desire is immanent to the whole social field, it is directly in the flows that at once form and escape the structures of signs, objects and subjects of desire. All social investments are directly libidinal or 'orgonotic'. How they turn into deadly and malignant fluxes is precisely the object of every serious analytical effort.
PC - It is really a problem of lines, of wavelines, to follow the inspiration of Deleuze and Parnet in their Dialogues. Most people go through life as if only molar lines and differences mattered - desire being regimented by the usual blocks of labour-leisure, private-public, male-female, old-new, pain-pleasure, health-sickness, and so on. They call it - the sedentary line, the molar line or what Scott Fitzgerald called the line of 'cuts'. The concentrationary universe is made up of 'big cuts', the ramparts of the armor - and any breakdown of these typically raises the specter of anomy and the reacting deliria of the fanatics of order. The entirety of our attention as human beings is concentrated on this line - it is our validation, both social and historical. Desire clearly settles on it when we demand that science be judged by peer review and the manipulated so-called "forces of the market". Family, State, Church, Army, Capital, these are the main blocks of this line - our character, or personality, is composed of the sedimentations and intermingling of these blocks of the armor. Sometimes harder, sometimes softer, these blocks confront us from birth. We have learned to entrust our personal safety to them - and that is even the very rationale for armoring - to defend ourselves from our internal impulses and become formed by the pressure of molar or mass structures that assault us from without and use the passage of Time, our duration, to their advantage. Then there are people, fewer in total, perhaps, who appear to be crisscrossed by softer lines, where the outcome of events present a domain of undecidability - a crack here or there may be a breakthrough or a set-back. Beneath softer blocks, there are lines of deformation and deconstruction at work. Systems of balance where cracks are patched and entire blocks move through cracks. What we could do yesterday we can no longer endure today - it is a line of discrete, punctual changes, which Deleuze and Parnet denote as a segmentary line, a migrant line. It no longer centralizes or sedentarizes everything in centripetal systems, but goes from point to point, in a migrant pathway filled with little territories and blackholes. Mechanisms of power, segments of survival, systems of perversion, coding devices that encompass these soft segments now overtake us. People today talk of the open communication of the internet but, in fact, it is only and still, at present, an instrument for power mechanisms that code our daily life.
AC - ...and this brings one to consider the third line, the line of molecular perception - precisely the line both philosophy and science should strive to reach. Only movement and energy need concern us here - for they are inseparable from Duration and the map of a creation. The line of escape, the nomadic line, as Deleuze, Parnet and Guattari called it.
PC - The line of absolute speed. Fitzgerald called it the line of rupture. It is the line of Life and also the line which, when things turn out wrongly, becomes a line of self-abolition.
AC - Rupture with the regime of the molar and migrant lines - rupture as a different regime of desire, a different regime of libidinal economy.
PC - Reich himself realized the impossibility of defining genitality as a form of health, and later changed the notion of a genital character to that of an orgonomic character - making the notion of cure or its type ever more elusive. Life is a process - there can be no cure, no static concept of health, and no certificate either. Health is to pursue one's process of creation, a line of rupture and creation. What Reich was after was the third line - how to awaken in people awareness of movement, how to find creative outlets for the sexuality of the unconscious, new ways to move with absolute speed, how to find lines of escape that provide consistency to life projects, that liberate creative potentialities without subordinating them by the same token to the logic of money, to military logic or to religious and bureaucratic impositions; how to turn around this collective and libidinal machine of global death and self-destruction without becoming even more disneyfied and zombified than we already are, how to overcome this molar machinery of death with molecular machineries of joy. It all must begin by a certain and determined refusal to continue to play the game of the molar machinery.
LB - You do not have any personal dreams you want to achieve with this project?
AC - What is a personal dream? Every dream is part of a collective dream, a collective machinery of dreams, of fixing dreams, of giving them body, of selecting some and not others, of turning most into nightmares. Reich's dream of a functional knowledge of the aether was first repressed and then made to return under conditions that give of the repressed a disfiguring representation. It was oedipalized, zombified, banalized. Turned into a little nightmare. The dream returns but as a weak echo separated from science. It has become a nearly empty apparition. But Reich's dream was a machinery of joy - not one of religion, fanaticism, opportunism and stupidity. It was a factory - as Deleuze and Guattari once described it - and not a small, little theater. Roger Dadoun's work was of great inspiration to us in this - dreams are all about the real life of people, whether awake or asleep; and dreams are a matter of dreamwork, of programme of desire, of a consistent assemblage of libidinal fluxes - a machine of joy. So note that by a machinery of joy we really mean taking stock and hold of our dreams. The systems of organized oppression and repression are no less means whereby our dreams run amok. Which dream do we want - the ready made dreams of representation, or the dream machine, the dreamwork? For us, the entire work of Castaneda and Florinda Donner addresses this question in a most poignant way. The fundamental discovery of Nietzsche and Reich is that sexual repression results from an internalization of social repression. And it is with the same lack of control that we dream awake or asleep. No internalization would have been possible if we were both more responsible and selective about our dreams. A hygiene of dreams belongs entirely to what one means by libidinal economy or a third line.
PC - It is about dreaming and not a dream or the dream. It's about the journey and not the aim or the stations along the way. We have no mission. Just a process we want to keep consistent.
AC - We follow the rails, and lay new ones ahead as we remove the ones behind.
PC - Isn't that from the Machineries of Joy?
AC - By Bradbury. Deleuze and Parnet end one of their chapters with a quote from him. There he follows the rails, even old abandoned lines. But here we have to continue ahead by lifting the track left behind. All to confuse the enemy and discover a no man's land.
PC - So, in a sense, it is our escape dream - laying rails and bare traces of rails in a growingly desertified and urbanized earth, hoping that one of these days 'we will go down the Mississippi' and might yet see the regreening of this planet.
"And thus happily sent forth, at our best, with good grace and fine wit, on calm noons, in fair climes, are we not [Aether]'s Machineries of Joy?"
"Anywhere the rails lead us, anywhere at all and if we come to an old offshoot rail line we don't know anything about, what the hell, we'll just take it, go down it, to see where it goes. And some year, by God, we'll boat down the Mississippi, always wanted to do that. Enough to last us a lifetime. And that's just how long I want to take to do it all"


text:
Q: How can I check a boolean expr is literally either TRUE or FALSE? I created the following program:
context c;
expr x = c.int_val(1);
expr y = c.int_val(2);
expr b = (x > y).simplify();
std::cout << "b = " << b << "\n";

The output said that b = false. But how can I check whether b is the false constant? I want to do something based on b as follows:
if (b is false) {
  // do something
}

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