Substituted (2,3-dihydro-1-oxo-1H-inden-5-yl)alkanoic acids, their derivatives and their salts

BACKGROUND OF THE INVENTION
Trauma to the brain or spinal cord caused by physical forces acting on the skull or spinal column, by ischemic stroke, arrested breathing, cardiac arrest, Reye's syndrome, cerebral thrombosis, cerebral embolism, cerebral hemorrhage, encephalomyelitis, hydrocephalus, post-operative brain injury, cerebral infections and various concussions results in edema and swelling of the affected tissues. This is followed by ischemia, hypoxia, necrosis, temporary or permanent brain and/or spinal cord injury and may result in death. The tissue mainly affected are classified as grey matter, more specifically astroglial cells. The specific therapy currently used for the treatment of the medical problems described include various kinds of diuretics (particularly osmotic diuretics), steroids (such as, 6-.alpha.-methylprednisolone succinate) and barbiturates. The usefulness of these agents is questionable and they are associated with a variety of untoward complications and side effects. Thus, the compounds of this invention comprise a novel and specific treatment of medical problems where no specific therapy is available.
A recent publication entitled "Agents for the Treatment of Brain Injury" 1. (Aryloxy)alkanoic Acids, Cragoe et al, J. Med. Chem., (1982) 25, 567-79, reports on recent experimental testing of agents for treatment of brain injury and reviews the current status of treatment of brain injury.
Some compounds having structures related to the compounds of the present invention have been reported to be diuretic and saluretic agents in U.S. Pat. No. 4,249,021 of Cragoe et al. and as useful in the treatment of calcium oxalate kidney stone formation in U.S. Pat. No. 4,342,776 of Cragoe, et al. Additionally, Williams, H. W. R. et al., J. Org. Chem., 44, 4060 (1979), a pertinent reference, reported a method of synthesis of related compounds. There is, however, no suggestion in the patents or publication that any of the compounds disclosed therein would be of use in the treatment of brain injury.
The compounds of the invention have the added advantage of being devoid of the pharmacodynamic, toxic or various side effects characteristic of the diuretics, steroids and barbiturates.
DESCRIPTION OF THE INVENTION
The compounds of the instant invention are best characterized by reference to the following structural Formula (I): ##STR1## wherein R is aryl such as phenyl, halo substituted aryl such as p-fluorophenyl or p-chlorophenyl or cycloalkyl containing from 3 to 6 nuclear carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and the like. R.sup.1 is hydrogen or lower alkyl, branched or unbranched, containing from 1 to 5 carbon atoms such as methyl, ethyl, n-propyl, isopropyl and the like. R.sup.2 is hydrogen, lower alkyl or lower alkyl-amino-lower-alkyl such as 2-(dimethylamino)ethyl. X and Y are halo or lower alkyl, and n is 2 to 6.
When the R and R.sup.1 substituents are different, the 2-position carbon atom of the indane ring is asymmetric and these compounds of the invention are racemic. However, these compounds or their precursors can be resolved so that the pure enantiomers can be prepared, thus the invention includes the pure enantiomers. This is an important point since some of the racemates consist of one enantiomer which is much more active than the other one. Furthermore, the less active enantiomer generally possesses the same intrinsic toxicity as the more active enantiomer. In addition, it can be demonstrated that the less active enantiomer depresses the inhibitory action of the active enantiomer at the tissue level. Thus, for three reasons it is advantageous to use the pure, more active enantiomer rather than the racemate.
Since the products of the invention are acidic, the invention also includes the obvious pharmaceutically acceptable salts, such as the sodium, potassium, ammonium, trimethylammonium, piperazinium, 1-methylpiperazinium, guanidinium, bis-(2-hydroxyethyl)ammonium, N-methylglucosammonium and the like salts.
It is also to be noted that the compounds of Formula I, as well as their salts, often form solvates with the solvents in which they are prepared or from which they are recrystallized. These solvates may be used per se or they may be desolvated by heating (e.g. at 70.degree. C.) in vacuo.
Although the invention primarily involves novel (2,3-dihydro-1-oxo-1H-inden-5-yl)alkanoic acids, and their salts, it also includes their derivatives, such as esters, amides, oximes, hydrazones and the like. Additionally, this invention includes pharmaceutical compositions in unit dosage form containing a pharmaceutical carrier and an effective amount of a compound of Formula I, its (-) or (+) enantiomer, or the pharmaceutically acceptable salts thereof, for treating brain injury. The method of treating a person with brain injury by administrating said compounds or said pharmaceutical compositions is also a part of this invention.
PREFERRED EMBODIMENT OF THE INVENTION
The preferred embodiments of the instant invention are realized in structural Formula II wherein: ##STR2## R.sup.3 is aryl, such as phenyl, halo substituted aryl, such as p-fluorophenyl or p-chlorophenyl, or cycloalkyl containing from 3 to 6 nuclear carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and the like; R.sup.4 is lower alkyl containing from 1 to 5 carbon atoms; n is 2 to 6.
Also included are the enantiomers of each racemate.
Preferred compounds are 5-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)pentanoic acid, its (+) and (-) enantiomers, and their salts.
Other preferred compounds are 3-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)propionic acid, its (+) and (-) enantiomers, and their salts.
Other preferred compounds are 3-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)propionic and, its (+) and (-) enantiomers, and their salts.
Especially preferred are the pure enantiomers since, in most instances, one enantiomer is more active biologically than its antipode.
Included within the scope of this invention are the pharmaceutically acceptable salts of (2,3-dihydro-1-oxo-1H-inden-5-yl)alkanoic acids since a major medical use of these compounds is solutions of their soluble salts which can be administered parenterally.
Thus, the acid addition salts can be prepared by the reaction of the substituted (2,3-dihydro-1-oxo-1H-inden-5-yl)alkanoic acids of this invention with an appropriate amine, ammonium hydroxide, guanidine, alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, quaternary ammonium hydroxide and the like. The salts selected are derived from among the non-toxic, pharmaceutically acceptable bases.
The synthesis of the (2,3-dihydro-1-oxo-1H-inden-5-yl)alkanoic acids of Formula I are generally carried out by the following route illustrated by preparation of 5-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)pentanoic acid.
The starting material, 2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-1H-inden-1-one, dissolved in dimethylformamide was treated with potassium carbonate and trifluoromethanesulfonyl chloride to form (2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)trifluoromethanesulfonate (Step 1). This material was subjected to triflate displacement by reaction with diethyl malonate to form diethyl-5-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)malonate (Step 2). The malonate of Step 2 was then alkylated with ethyl 4-bromobutyrate to form diethyl 2-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)-2-(ethoxycarbonyl)-1,6-hexanedioate (Step 3). Upon hydrolysis the hexanedioic acid is formed (Step 4) which undergoes monodecarboxylation by treatment with copper in quinoline to form a compound of the present invention such as 5-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)pentanoic acid (Step 5). The starting materials used in these examples is obtained as shown in the Journal of Medicinal Chemistry, 20, 1400 (1977); and 21, 437 (1978). This synthetic route is illustrated below: ##STR3##
Those compounds possessing an asymmetric carbon atom at the 2-position of the indane ring consist of a racemate composed of two enantiomers. The resolution of the two enantiomers may by accomplished by forming a salt of the racemic mixture with an optically active base such as (+) or (-)amphetamine, (-)cinchonidine, dehydroabiethylamine, (+) or (-)-.alpha.-methylbenzylamine, (+) or (-)(1-naphthyl)ethylamine. (+)cinchonine, brucine, or strychnine and the like in a suitable solvent such as methanol, ethanol, 2-propanol, benzene, acetonitrile, nitromethane, acetone and the like. There is formed in the solution, two diastereomeric salts, one of which is usually less soluble in the solvent than the other. Repetitive recrystallization of the crystalline salt generally affords a pure diastereomeric salt from which is obtained the desired pure enantiomer. The optically pure enantiomer of the compound of Formula I is obtained by acidification of the salt with a mineral acid, isolation by filtration and recrystallization of the optically pure antipode.
The other optically pure antipode may generally be obtained by using a different base to form the diastereomeric salt. It is of advantage to isolate the partially resolved acid from the filtrates of the purification of the first diastereomeric salt and to further purify this substance through the use of another optically active base. It is especially advantageous to use an optically active base for the isolation of the second enantiomer which is the antipode of the base used for the isolation of the first enantiomer. For example, if (+)-.alpha.-methylbenzylamine was used first, then (-)-.alpha.-methylbenzylamine is used for the isolation of the second (remaining) enantiomer.
The acid addition salts are prepared by reacting the acids of Formula I with an appropriate base, for example, alkali metal or alkaline earth bicarbonate, carbonate or alkoxide, an amine, ammonia, an organic quaternary ammonium hydroxide, guanidine and the like.
The reaction is generally conducted in water when alkali metal hydroxides are used, but when alkoxides and the organic bases are used, the reaction may be conducted in an organic solvent, such as ether, ethanol, dimethylformamide and the like.
The preferred salts are the pharmaceutically acceptable salts such as sodium, potassium, ammonium and the like.
Inasmuch as there are a variety of symptoms and severity associated with grey matter edema, particularly when it is caused by head trauma, stroke, cerebral hemorrhage or embolism, post-operative brain surgery trauma, spinal cord injury, cerebral infections and various brain concussions, the precise treatment is left to the practioner. Generally, candidates for treatment will be indicated by the results of the patient's initial general neurological status, findings on specific clinical brain stem functions and findings on computerized axial tomography (CAT) scan of the brain. The sum of the neurological evaluation is presented in the Glascow Coma Score or similar scoring system. Such a scoring system is often valuable in selecting the patients who are candidates for therapy of this kind.
The compounds of this invention can be administered by a variety of established methods, including intravenously, intramuscularly, subcutaneously, or orally. The parenteral route, particularly the intravenous route of administration, is preferred, especially for the very ill and comatose patient. Another advantage of the intravenous route of administration is the speed with which therapeutic brain levels of the drug are achieved. It is of paramount importance in brain injury of the type described to initiate therapy as rapidly as possible and to maintain it through the critical time periods. For this purpose, the intravenous administration of drugs of the type of Formula I in the form of their salts is superior.
A recommended dose range for treatment is expected to be from 0.05 mg/kg to 50 mg/kg of body weight as a single dose, preferably from 0.5 mg/kg to 20 mg/kg. An alternative to the single dose schedule is to administer a primary loading dose followed by a sustaining dose of half to equal the primary dose, every 4 to 24 hours. When this multiple dose schedule is used the dosage range may be higher than that of the single dose method. Another alternative is to administer an ascending dose sequence of an initial dose followed by a sustaining dose of 11/2 to 2 times the initial dose every 4 to 24 hours. For example, 3 intravenous doses of 8, 12 and 16 mg/kg of body weight can be given at 6 hour intervals. If necessary, 4 additional doses of 16 mg/kg of body weight can be given at 12 hour intervals. Another effective dose regimen consists of a continuous intravenous infusion of from 0.05 mg/kg/hr. to 3.0 mg/kg/hr. Of course, other dosing schedules and amount are possible.
One aspect of this invention is the treatment of persons with grey matter edema by concomitant administration of a compound of Formula I or its pharmaceutically acceptable salts, and an antiinflammatory steroid. These steroids are of some, albeit limited, use in control of white matter edema associated with ischemic stroke and head injury. Steroid therapy is given according to established practice as a supplement to the compound of Formula I as taught elsewhere herein. Similarly, a barbiturate may be administered as a supplement to treatment with a compound of Formula I.
The compounds of Formula I are utilized by formulating them in a composition such as tablet, capsule or elixir for oral administration. Sterile solutions or suspensions can be used for parenteral administration. A compound or mixture of compounds of Formula I, or its physiologically acceptable salt, is compounded by a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc. in a dosage form as called for by accepted pharmaceutical practice.
Illustrative of the adjuvants which may be incorporated in tablets, capsules and the like are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose, or saccharin; a flavoring agent such as peppermint, oil of wintergreen or cherry. When the dosage unit from is a capsule, it may contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise enhance the pharmaceutical elegance of the preparation. For instance, tablets may be coated with shellac, sugar or the like. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
Sterile compositions for injection or infusion can be formulated according to conventional pharmaceutical practice by dissolving the active sustance in a conventional vehicle such as water, saline or dextrose solution by forming a soluble salt in water using an appropriate base, such as a pharmaceutically acceptable alkali metal hydroxide, alkali metal bicarbonate, ammonia, amine or guanidine. Alternatively, a suspension of the active substance in a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate or the like may be formulated for injection or infusion. Buffer, preservatives, antioxidants and the like can be incorporated as required.
The basic premise for the development of agents for the treatment of brain injury of the types described is based on the studies in experimental head injury by R. S. Bourke et. al. (R. S. Bourke, M. A. Daze and H. K. Kimelberg, Monograph of the International Glial Cell symposium, Leige, Bel. Aug. 29-31, 1977 and references cited therein) and experimental stroke by J. H. Garcia et. al. (J. H. Garcia, H. Kalimo, Y. Kamijyo and B. F. Trump, Virchows Archiv. [Zellopath.], 25, 191 (1977).
These and other studies have shown that the primary site of traumatic brain injury is in the grey matter where the process follows a pattern of insult, edema, ischemia, hypoxia, neuronal death and necrosis followed, in many instances, by irreversible coma or death. The discovery of a drug that specifically prevents the edema would obviate the sequalae.
Experimental head injury has been shown to produce a pathophysiological response primarily involving swelling of astroglia as a secondary, inhibitable process. At the molecular level, the sequence appears to be: trauma, elevation of extracellular K.sup.+ and/or release of neurotransmitters, edema, hypoxia and necrosis. Astroglial swelling results directly from a K.sup.+ -dependent, cation-coupled, chloride transport from the extracellular into the intracellular compartment with a concommitant movement of an osmotic equivalent of water. Thus, an agent that specifically blocks chloride transport in the astroglia is expected to block the edema caused by trauma and other insults to the brain. It is also important that such chloride transport inhibitors be free or relatively free of side effects, particularly those characteristics of many chloride transport inhibitors, such as diuretic properties. Compounds of the type illustrated by Formula I exhibit the desired effects on brain edema and are relative free of renal effects.
That this approach is valid has been demonstrated by the correlation of the in vitro astroglial edema inhibiting effects of chloride transport inhibitors with their ability to reduce the mortality of animals receiving experimental in vivo head injury. As a final proof, one compound (ethacrynic acid) which exhibited activity both in vitro and in vivo assays was effective in reducing mortality in clinical cases of head injury. These studies are described in the Journal of Medicinal Chemistry, Volume 25, page 567 (1982), which is hereby incorporated by reference.
Three major biological assays can be used to demonstrate biological activity of the compounds. The (1) in vitro cat cerebrocortical tissue slice assay, (2) the in vitro primary rat astrocyte culture assay and (3) the in vivo cat head injury assay. The first assay, the in vitro cat cerebrocortical tissue slice assay has been described by Marshall, L. F.; Shapiro, H. M.; Smith, R. W. In "Seminars in Neurological Surgery: Neural Trauma"; Popp, A. J.; Bourke, R. S.; Nelson, L. R.; Kimelberg, H, K,. Eds.; Raven Press: New York, 1979; p. 347, by Bourke, R. S.; Kimelberg, H, K.; Daze, M. A. in Brain Res. 1978, 154, 196, and by Bourke, R. S.; Kimelberg, H. K,; Nelson, L. R. in Brain Res. 1976, 105, 309. This methos constitutes a rapid and accurate method of determining the intrinsic chloride inhibitory properties of the compounds of the invention in the target tissue.
The second assay method involves the in vitro primary rat astrocyte assay. The method has been described by Kimelberg, H. K.; Biddlecome, S.; Bourke, R. S. in Brain Res. 1979, 173, 111, by Kimelberg, H. K.; Bowman, C.; Biddlecome, S.; Bourke, R. S., in Brain Res. 1979, 177, 533, and by Kimelberg, H. K.; Hirata, H. in Soc. Neurosci. Abstr. 1981, 7, 698. This method is used to confirm the chloride transport inhibiting properties of the compounds in the pure target cells, the astrocytes.
The third assay method, the in vivo cat head injury assay has been described by Nelson, L. R.; Bourke, R. S.; Popp, A. J.; Cragoe, E. J. Jr.; Signorelli, A.; Foster, V. V.; Creel, in Marshall, L. F.; Shapiro, H. M.; Smith, R. W. In "Seminars in Neurological Surgery: Neural Trauma"; Popp, A. J.; Bourke, R. S.; Nelson, L. R.; Kimelberg, H. K., Eds.; Raven Press: New York, 1979; p. 297.
This assay consists of a highly relevant brain injury in cats which is achieved by the delivery of rapid repetitive acceleration-deceleration impulses to the animal's head followed by exposure of the animals to a period of hypoxia. The experimental conditions of the assay can be adjusted so that the mortality of the control animals falls in the range of about 25 to 75%. Then, the effect of the administration of compounds of this invention in reducing the mortality over that of the control animals in concurrent experiments can be demonstrated.
Using the in vitro cat cerebrocortical tissue slice assay, described in Example 1, compounds of the present invention exhibited marked activity. This test provided the principal in vitro evaluation and consisted of a determination of concentration vs. response curve. The addition of HCO.sub.3.sup.- to isotonic, K.sup.+ -rich saline-glucose incubation media is known to specifically stimulate the transport of Cl.sup.- coupled with Na.sup.+ and an osmotic equivalent of water in incubating slices of mammalian cerebral cortex. Experiments have demonstrated that the tissue locus of swelling is an expanded astroglial compartment. Thus, the addition of HCO.sub.3.sup.- to incubation media stimulated statistically significant and comparable increases in cerebrocortical tissue swelling and ion levels. After addition of drug to the incubation media, detailed drug concentration-response curves were then obtained. The data were expressed as percent HCO.sub.3.sup.- -stimulated swelling vs. drug concentration, from which the concentration of drug providing 50% inhibition of HCO.sub.3.sup.- -stimulated swelling (I.sub.50 in molarity) was interpolated. The results which illustrate the instant invention are expressed in Table I, below:
TABLE I______________________________________ Enantiomer I.sub.50, M______________________________________5-(2-methyl-6,7-dichloro- .+-. (racemate) 2 .times. 10.sup.-82-cyclopentyl-2,3-dihydro-1-oxo-1H--inden-5-yl)-pentanoic acid______________________________________
Thus, in the in vitro assay compounds of Formula I inhibit chloride transport by 50% at concentrations as low as 10.sup.-8 molar.

The following examples are included to illustrate the in vitro cerebrocortical tissue slice assay, the preparation of representative compounds of Formula I and representative dosage forms of these compounds. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the invention being indicated by the following claims.
EXAMPLE 1
In Vitro Cerebrocortical Tissue Slice Assay
Adult cats of 2-3 kg body weight were employed in tissue slice studies. Prior to sacrifice, the animals were anesthetized with ketamine hydrochloride (Ketaset), 10 mg/kg im. Eight (three control, five experimental) pial surface cerebrocortical tissue slices (0.5-mm thick; approximately 150 mg initial fresh weight) were cut successively with a calibrated Stadie-Riggs fresh tissue microtome without moistening and weighed successively on a torsion balance. During the slice preparation all operations except weighing were confined to a humid chamber. Each slice was rapidly placed in an individual Warburg flask containing 2 ml of incubation medium at room temperature. The basic composition of the incubation media, in millimoles per liter, was as follows: glucose, 10; CaCl.sub.2, 1.3; MgSO.sub.4, 1.2; KH.sub.2 SO.sub.4, 1.2; Hepes (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid, titrated with NaOH to pH 7.4), 20. Except when adding HCO.sub.3.sup.-, the osmolarity of the media was maintained isosmotic (approximately 285 mOsm/L) by reciprocal changes of Na.sup.+ or K.sup.+ to achieve a concentration of K.sup.+ of 27 mM. The basic medium was bubbled for 30 minutes with 100% O.sub.2 before use. When added, NaHCO.sub.3 or triethylammonium bicarbonate (TEAB) was initially present in the sidearm of each flask at an initial concentration of 50 mM in 0.5 ml of complete medium. Nonbicarbonate control slices were incubated at 37.degree. C. in 2.5 ml of basic medium for 60 minutes. Bicarbonate control slices were similarly incubated for an initial 20 minutes at 37.degree. C. in 2.0 ml of basic medium to which was added from the sidearm an additional 0.5 ml of incubation medium containing 50 mM HCO.sub.3.sup.-, which, after mixing, resulted in a HCO.sub.3.sup.- concentration of 10 mM and a total volume of 2.5 ml. The incubation continued for an additional 40 minutes. The various compounds tested were dissolved by forming the sodium salts by treatment with a molar equivalent of NaHCO.sub.3 and diluting to the appropriate concentrations. Just prior to incubation, all flasks containing HCO.sub.3.sup.- were gassed for 5 minutes with 2.5% CO.sub.2 /97.5% O.sub.2 instead of 100% O.sub.2.
Following the 60-minute incubation period, tissue slices were separated from incubation medium by filtration, reweighed, and homogenized in 1N HClO.sub.4 (10% w/v) for electrolyte analysis. The tissue content of ion is expressed in micromoles per gram initial preswelling fresh weight. Control slice swelling is expressed as microliters per gram initial preswelling fresh weight. The effectiveness of an inhibitor at a given concentration was measured by the amount of HCO.sub.3.sup.- -stimulated swelling that occurred in its presence, computed as a percent of the maximum possible. Tissue and media Na.sup.+ and K.sup.+ were determined by emission flame photometry with Li.sup.+ internal standard; Cl.sup.- was determined by amperometric titration. Tissue viability during incubation was monitored by manometry.
EXAMPLE 2
Preparation of 5-(2-Butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)pentanoic acid
Step A: (2-Butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)trifluoromethanesulfonate
Racemic 2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-1H-inden-1-one (34.1 g, 0.1M) was stirred in dimethylformamide (100 ml) with K.sub.2 CO.sub.3 (41.5 g, 0.3M) at 25.degree. for 20 minutes. The mixture was cooled to 15.degree., and trifluoromethanesulfonyl chloride (19.4 g, 0.115M) was added at 15.degree.-20.degree. over 20 minutes. The mixture was then stirred at 25.degree. for 30 minutes and poured into a liter of ice and water. The oil was extracted with diethyl ether (4.times.125 ml) and the combined organic extracts were thoroughly washed with water, dried over (MgSO.sub.4) and concentrated under vacuum to obtain the product as a viscous amber oil weighing 47.3 g. This product was used in the next step without further purification.
Step B: Diethyl 5-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)malonate
Diethyl malonate (43.2 g, 0.27M) dissolved in dimethylformamide (40 ml) was added with stirring under nitrogen to a suspension of 56% sodium hydride in mineral oil (11.6 g, 0.27M) in dimethylformamide (150 ml) at 8.degree.-15.degree.. The mixture was stirred at 25.degree. for 1/2 hour after the addition of malonate, cooled to 5.degree. and the (2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)trifluoromethanesulfonate (47.3 g, 0.1M) in toluene (40 ml) was added at 5.degree.-7.degree. over 1 hour. After stirring at 25.degree. for 20 hours the mixture was poured into ice water (1400 ml) and extracted with diethyl ether. The ethereal extracts were washed successively with water, diluted Na.sub.2 CO.sub.3, very dilute HCl, dried over MgSO.sub.4 and concentrated under vacuum. 59 g out of the 68 g of residual oil was chromatographed twice on silica with methylene chloride elution. The material (32 g) thus obtained was dissolved in ether washed with dilute Na.sub.2 CO.sub.3, water, dried over MgSO.sub.4 and concentrated to yield the diethyl 5-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)malonate as a viscous yellow oil weighing 31 g. This product was used directly in the next step.
Step C: Diethyl 2-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)-2-(ethoxycarbonyl)1,6-hexanedioate
The diethyl malonate (9.67 g, 0.02M) dissolved in diemethylformamide (10 ml) and toluene (15 ml) was added with stirring at 25.degree. over 1/2 hour under nitrogen to 56% sodium hydride in mineral oil (0.943 g, 0.022M) suspended in dimethylformamide (25 ml). The mixture was stirred 20 minutes after completion of the addition and then a few milligrams of KI followed by ethyl 4-bromobutyrate (4.49 g, 0.023M) in toluene (10 ml) were added. After stirring 30 hours at 88.degree. the mixture was cooled, poured into ice water and extracted with diethyl ether. The ethereal extracts were washed with water, dried over MgSO.sub.4 and concentrated under vacuum. The residue was chromatographed on silica (450 g) by first eluting with methylene chloride then 5% isopropanol/methylene chloride to obtain the product as a viscous oil (6.6 g) which was used directly in the next step.
Step D: 5-(2-Butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)pentanoic acid
The diethyl 2-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihyro-1-oxo-1H-inden-5-yl)-2-(ethoxycarbonyl)-1,6-hexanedioate (6.5 g) was refluxed with sodium hydroxide (5 g) dissolved in methanol (100 ml) and water (20 ml) for 3 hours. The mixture was cooled, diluted with water, acidified with hydrochloric acid and extracted with diethyl ether. The organic extracts were washed with water, dried over MgSO.sub.4 and concentrated to obtain 2-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)-1,6-hexanedioic acid (4.3 g). The dioic acid was heated at 130.degree.-135.degree. C. for 25 minutes with copper powder (1.52 g) in quinoline (35 ml). The mixture was cooled, poured into water and extracted with diethyl ether after acidification with hydrochloric acid. The organic extracts were washed with water, dried over MgSO.sub.4 and concentrated under vacuum. The residue was chromatographed twice on silica eluting with a mixture of toluene, dioxane and acetic acid in the ratio of 900:80:10 to obtain 2.9 g of the product as viscous oil.
Elemental analysis for: C.sub.23 H.sub.30 Cl.sub.2 O.sub.3. Calc'd: C, 64.94%; H, 7.11%; Found: C, 64.63%; H, 7.18%
EXAMPLE 3
3-(2-Butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)pentanoic acid (+)-enantiomer
By following substantially the procedure described in Example 2, Steps A through D, but substituting for the racemic 2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-1H-inden-1-one an equal quantity of (+)-2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-1H-inden-1-one (J. Med. Chem., 25, 579 (1982)) there is obtained (+)-3-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)pentanoic acid.
EXAMPLE 4
3-(2-Butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)pentanoic acid (-)-enantiomer
By following substantially the procedure described in Example 2, Steps A through D, but substituting for the racemic 2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-1H-inden-1-one an equal quantity of (-)-2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-1H-inden-1-one (J. Med. Chem., 25, 579 (1982)) there is obtained (-)-3-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)pentanoic acid.
EXAMPLE 5
3-(2-Butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)propionic acid
By following substantially the procedure described in Example 2, Steps A-D, but substituting for the ethyl 4-bromobutyrate in Step C, an equimolar amount of ethyl bromoacetate there is obtained 3-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)propionic acid.
Elemental analysis for C.sub.21 H.sub.26 Cl.sub.2 O.sub.3 : Calc'd: C, 63.47; H, 6.60; Found: C, 63.38; H, 6.83.
EXAMPLE 6
3-(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)propionic acid
By following substantially the procedure described in Example 5, but substituting for the 2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-1H-inden-1-one described in Step A an equimolar amount of 6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-5-hydroxy-1H-inden-1-one there is obtained 3-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)propionic acid which is solvated with 1/8 mole of methylene chloride from the extraction process.
Elemental analysis for C.sub.18 H.sub.20 Cl.sub.2 O.sub.3.1/8CH.sub.2 Cl.sub.2 : Calc'd: C, 59.50; H, 5.55; Found: C, 59.46; H, 5.68.
EXAMPLE 7
Parenteral Solution of the (+)-enantiomer of 5-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)pentanoic acid
(+)-5-(2-Butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)pentanoic acid (500 mg) is dissolved by stirring and warming with 0.25N sodium bicarbonate solution (5.4 ml). The solution is diluted to 10 ml and sterilized by filtration. All the water that is used in the preparation is pyrogen-free. The concentration of the active agent in the final solution is 5%.
Similar parenteral solution can be prepared by replacing the active ingredient of the above example by any of the other compounds of this invention.
EXAMPLE 8
Dry-Filled Capsules Containing 100 mg of Active Ingredient Per Capsule
______________________________________ Per Capsule______________________________________(+)-enantiomer of 5-(2-Butyl- 100 mg6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H--inden-5-yl)pentanoic acidLactose 99 mgMagnesium Stearate 1 mgCapsule (Size No. 1) 200 mg______________________________________
The (+)-enantiomer of 5-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)pentanoic acid is reduced to a No. 60 powder and then the lactose and magnesium stearate are passed through a No. 60 bolting cloth onto the powder and the combined ingredients admixed for 10 minutes and then filled into a No. 1 dry gelatin capsule.
Similar capsules can be prepared by replacing the active ingredient of the above example by any of the other compounds of this invention.

Number	Name	Date	Kind
4249021	Cragoe, Jr.	Feb 1981
4342776	Cragoe, Jr. et al.	Aug 1982

Substituted (2,3-dihydro-1-oxo-1H-inden-5-yl)alkanoic acids, their derivatives and their salts

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