2-piperidinecarboxylic acid derivatives useful as NMDA receptor antagonists

Abstract

Compounds of formula I ##STR1## wherein X is ##STR2## or .dbd.N--O--, in which R.sub.4 is hydrogen or halogen, R.sub.1, R.sub.2, and R.sub.3 independently represent hydrogen or a C.sub.1-4 alkyl group, and n has a value of zero to four are disclosed. Also disclosed are pharmaceutically acceptable salts of these compounds, pharmaceutical compositions of these compounds or salts with a pharmaceutically acceptable carrier, the use of these materials as N-methyl-D-aspartate receptor antagonists, processes for preparing these compounds and salts, and methods to treat cerebral diseases by administering an effective amount of these compounds, salts or compositions.

Description

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention concerns a series of 4-(phosphonoalkylidene)- or 4-(phosphonoalkoxyimino)-2-piperidinecarboxylic acid derivatives useful in the treatment of cerebrovascular disorders.

2. Background Information

Excessive excitation by neurotransmitters can cause the degeneration and death of neurons. It is believed that this excitotoxic action is mediated by the excitatory amino acids, glutamate and aspartate, acting at the N-methyl-D-aspartate (NMDA) receptor. This excitotoxic action is responsible for neuronal loss in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery and cerebral trauma.

The compounds of the invention, which are active as competitive antagonists of NMDA receptor-mediated ion-channel activation, are thus useful in the treatment of the above disorders. In addition, by this NMDA receptor antagonist action, the compounds of the invention are also useful for treating neurodegenerative disorders, spinal cord injury, and poisoning by exogenous NMDA poisons (for example, some forms of lathyrism). There are no specific therapies for these neurodegenerative disorders, but competitive and noncompetitive NMDA antagonists acting specifically to antagonize excitatory neurotransmission at NMDA receptors offer a novel therapeutic approach to these disorders; B. Meldrum in Neurotoxins and Their Pharmacological Implications. ed. P. Jenner, Raven Press, New York, 1987.

Recent reports in the literature have confirmed the protective action of certain NMDA antagonists in pharmacological models of neurodegenerative disorders (J. W. McDonald, F. S. Silverstein, and M. V. Johnston, Eur. J. Pharmacol., (1987) 140:359; R. Gill, A. C. Foster and G. N. Woodruff, J. Neurosci., (1987) 7:3343; S. M. Rothman, J. Thurston, R. E. Hauhart, G. D. Clark and J. S. Solomon, Neurosci., (1987) 21:673; M. P. Goldberg, P. C. Pham and D. W. Choi, Neurosci. Lett., (1987) 80:11).

In addition, U.S. Pat. Nos. 4,746,653; 4,906,621; and 4,898,854 are concerned with phosphonic acid derivatives of 2-piperidine or 2-tetrahydropyridine carboxylates, which are said to be useful as N-methyl-D-aspartate (NMDA) receptor antagonists.

STATEMENT OF THE INVENTION

The invention relates to compounds of the following General Formula I: ##STR3## wherein X is ##STR4## or .dbd.N--O--, in which R.sub.4 is hydrogen or halogen, R.sub.1, R.sub.2, and R.sub.3 independently represent hydrogen or a C.sub.1-4 alkyl group, and n is an integer having a value of zero to four and to pharmaceutically acceptable salts of the compounds of Formula I, and pharmaceutical compositions made up of these compounds and salts with pharmaceutically acceptable carriers. These compositions are useful as N-methyl-D-aspartate receptor antagonists. In other aspects, this invention provides processes for preparing these compounds and salts, and methods to treat cerebral diseases by administering to a patient an effective amount of these pharmaceutical compositions.

DETAILED DESCRIPTION OF THE INVENTION

BRIEF DESCRIPTION OF THE DRAWINGS

This invention will be described with reference to the accompanying drawings in which:

FIG. 1 is a reaction scheme for preparing compounds and salts of the invention as set out in Example 1;

FIG. 2 is a reaction scheme for preparing compounds and salts of the invention as set out in Example 2; and

FIG. 3 is a reaction scheme for preparing compounds and salts of the invention as set out in Example 3.

DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention provides compounds and pharmaceutical compositions based on them which are useful as N-methyl-D-aspartate receptor antagonists and in the treatment of cerebral diseases such as cerebral ischemia, cerebral hypoglycemia, epilepsy, anxiety and convulsion.

The Compounds

The compounds of this invention are materials of General Formula I, and pharmaceutically acceptable salts thereof: ##STR5## In this formula X is ##STR6## or .dbd.N--O-- wherein R.sub.4 is hydrogen or a halo, such as fluoro, chloro, bromo or the like. When R.sub.4 is present, it is preferably hydrogen or fluoro. "n" is an integer. It can be 0, 1, 2, 3, or 4. R.sub.1 is hydrogen or a C.sub.1-4 alkyl. The term "C.sub.1-4 alkyl" means a saturated aliphatic group Of 1, 2, 3 or 4 carbons, either branched or straight chain. "C.sub.1-4 alkyls" include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and tert-butyl groups.

R.sub.2 and R.sub.3 are also hydrogen or C.sub.1-4 alkyls R.sub.1, R.sub.2 and R.sub.3 are selected independently, but usually, for ease of synthesis, R.sub.2 and R.sub.3 are the same. Methyl and hydrogen are preferred as R.sub.2 and R.sub.3 groups.

Pharmaceutically Acceptable Salts

These compounds can exist as salts. The salt can be formed of the carboxylic acid (i.e., a salt anion replacing a hydrogen R.sub.1), and salts can be formed of the phosphonic acid (i.e., replacing the R.sub.2 and/or the R.sub.3 groups if they are hydrogens with a salt anion). All three positions can be salts.

Pharmaceutically acceptable salts are salts of these compounds which have anions that are pharmaceutically acceptable--i.e., nontoxic. These are preferably metal or ammonium salts of the compounds of the invention having a free phosphono or/and carboxyl group, more particularly alkali metal or alkaline earth metal salts such as the sodium, potassium, magnesium or calcium salt; or advantageously crystallizing ammonium salts derived from ammonia or organic amines, such as monoethylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, tris-(hydroxymethyl)aminoethane or benzyltrimethylammonium hydroxide. In addition, the NH group present in the compounds of the invention can form acid-addition salts of pharmaceutically acceptable inorganic or organic acids, such as of strong mineral acids, for example, hydrohalic, hydrochloric or hydrobromic acid; sulfuric, phosphoric or nitric acid; aliphatic or aromatic carboxylic or sulfonic acid, for example, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, gluconic, citric, ascorbic, maleic, fumaric, pyruvic, palmoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic or naphthalenesulfonic acid.

Isomers, etc.

The compounds of the invention contain at least one asymmetric carbon atom. The invention includes individual enantiomers, diastereomers, or mixtures thereof, which may be prepared or isolated by methods known in the art. The compounds of the invention also include geometrical isomers based on the olefin or imine portion. The invention includes individual E-isomers, Z-isomers and mixtures thereof, which may be prepared or isolated by the methods known in the art.

Pharmaceutical Formulations

The compounds of the invention may be administered according to any convenient or effective methods for introducing foreign substances into the blood stream of mammals, such as by oral, rectal, nasal, buccal, vaginal, or parenteral routes. The effective dosage level is, for example, 0.01 to 100 mg/kg, preferably about 0.05 to 50 mg/kg, and may be administered on a regimen of 1-4 times per day. The pharmaceutical formulations comprising the compounds of the invention may be in dosage forms such as tablets, pills, capsules, powders, or granules for oral administration.

Compounds and salts here provided can be formulated into pharmaceutical compositions by admixture with pharmaceutically acceptable nontoxic carriers. As mentioned above, such compositions may be prepared for use for parenteral (subcutaneous, intramuscular or intravenous) administration particularly in the form of liquid solutions or suspensions; for use in vaginal or rectal administration particularly in semisolid forms such as creams and suppositories; for oral or buccal administration particularly in the form of tablets or capsules; or intranasally particularly in the form of powders, nasal drops or aerosols.

The compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art, for example as described in Remingtons's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. 1975, incorporated by reference. Formulations for parenteral administration may contain as common excipients, sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like. Formulations for vaginal or rectal administration, e.g., suppositories, may contain as excipients, for example, polyalkylene glycols, petroleum jelly, cocoa butter, and the like. Formulations for inhalation administration may be solid and contain as excipients, for example, lactose, or may be aqueous or oily solutions for administration in the form of nasal drops. For buccal administration typical excipients include sugars, calcium stearate, magnesium stearate, pregelatinated starch, and the like.

For oral administration, a pharmaceutically acceptable nontoxic composition can be formed by the incorporation of any of the normally employed excipients, oral dose extenders or carriers such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium, carbonate, and the like. Such compositions can take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained-release formulations, and the like. Such compositions may contain 0.1-95% active ingredient, preferably 1-70%, with the remainder being carrier.

The materials of this invention can be employed as the sole active agent in a pharmaceutical composition or can be used in combination with other active ingredients.

The effects of the compounds of the invention can be evaluated in in vitro tests or in vivo animal tests using mammals such as mice, rats, rabbits, dogs and monkeys, or tissues, membranes, receptors or enzyme preparations thereof.

Competition binding for NMDA receptor with radio-labeled known NMDA antagonist is one convenient way to ascertain the ability of the compounds of the invention to bind to target cerebral cells. This evaluation can be made according to the method of J. Lehman et al., 1988. In addition, the ability to antagonize NMDA receptors can be evaluated according to the method of Ferkany et al., 1988.

Preparation of the Compounds

The compounds of the invention can be prepared by three processes set forth in the Schemes 1-3, which are set forth in FIGS. 1-3 respectively.

The processes of Schemes 1, 2 and 3 are fully exemplified in Examples 1, 2 and 3. The schemes illustrate the preparation of both isomers of the "olefin" X group with free acid form at both the phosphonate and the carbonyl functionalities. In this process of Scheme 1, a suitably protected amine, protected carboxylic group ketone 6 is treated with tetramethyl methylene diphosphonate at moderate temperatures. This introduces the desired phosphonate group, as a dialkyl ester. Blocking groups can be removed and various R.sub.1, R.sub.2 and R.sub.3 groups can be varied among H, and the various lower alkyls by hydrolysis and esterification reactions. Schemes 2 and 3 show variations on this general preparative process.

In Schemes 1, 2 and 3, n is generally shown as O. If one wants to have higher values i.e., 1, 2, 3, or 4) for n, and thus longer --(CH.sub.2).sub.n -- chain lengths, these can be attained. A suitably protected carbonyl such as 16 in Scheme 3 can be reacted with a triphenylphosphorane Ph.sub.3 P.dbd.CH--(CH.sub.2).sub.n --Z, or a phosphorane ylide generated from (EtO).sub.2 P(O)--CH.sub.2 (CH.sub.2).sub.n --Z wherein Z is a leaving group such as halo or a methoxy. These materials react in an inert solvent such as THF within a few hours at a moderate temperature to add the .dbd.CH--(CH.sub.2).sub.n --Z group in place of the ketone oxygen. This yields a mixture of isomers which is beneficially separated at this point. The desired isomer is then treated with diethyl phosphate anion --PO.sub.3 Et.sub.2 in an aprotic solvent such as DMF at moderate temperatures (50.degree.-100.degree. C.) for 2-12 hours. This allows the phosphate to displace the Z leaving group and give rise to the full range of n=1, 2, 3 or 4 groups depending upon the particular .dbd.CH(CH.sub.2).sub.n --Z group employed. R.sub.1, R.sub.2 and R.sub.3 can all be varied as previously described.

As shown in Schemes 1, 2 and 3, it is generally desirable to protect the various carbonyl and amine groups for these reactions. These protection-deprotection routes are known in the art.

.dbd.X can also be an ##STR7## group, wherein R.sub.4 is a halo instead of H. The R.sub.4 halo can be present as a substituent in the phosphorane reagent, in the phosphonate reagent or the methylene of the tetramethylene diphosphonate reagent. This will insert the R.sub.4 halo at the desired position.

In a final variation, .dbd.X can be .dbd.N--O--. This functionality can be introduced using well-known chemistry.

The reagents H.sub.2 N--O--CH.sub.2 --PO.sub.3 H.sub.2 and H.sub.2 N--O--(CH.sub.2).sub.2 --PO.sub.3 H.sub.2 are known and available as their HCl acid addition salts. Other equivalent materials, where n=2, 3 or 4, are preparable analogously. These reagents will react with a protected ketone such as 16 from Scheme 3 at a temperature of 0.degree.-100.degree. C., preferably from room temperature to 70.degree. C. in, for example, an appropriate solvent such as water, alcohol, dioxane or THF. This will add the .dbd.N--O--(CH.sub.2).sub.n --PO.sub.3 H.sub.3 group in place of the ketone. Thereafter, the various protecting groups can be removed and the various hydrogens and alkyl groups substituted as R.sub.1, R.sub.2 and R.sub.3 as noted above.

The pharmaceutically acceptable nontoxic salt derivatives of the compounds of Formula I are prepared by treating the free acids with an appropriate amount of pharmaceutically acceptable base. Representative pharmaceutically acceptable bases are sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copper hydroxide, manganous hydroxide, aluminum hydroxide, ferric hydroxide, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. The reaction is conducted in water, alone or in combination with an inert, water-miscible organic solvent, at a temperature of from about 0.degree. C. to about 100.degree. C., preferably at room temperature. Typical inert, water-miscible organic solvents include methanol, ethanol, isopropanol, butanol, acetone, dioxane or tetrahydrofuran. The molar ratio of compounds of Formula I to base used are chosen to provide the ratio desired for any particular salt. For preparing, for example, the calcium salts or magnesium salts, the free acid starting material of Formula I can be treated with at least one-half molar equivalent of pharmaceutically acceptable base to yield a neutral salt. When the aluminum salts of the compounds of Formula I are prepared, at least one third molar equivalent of the pharmaceutically acceptable base are employed if a neutral salt product is desired.

The salt derivatives of the compounds of Formula I can be reconverted to their respective free acids by acidifying said salts with an acid, preferably an inorganic acid, e.g. hydrochloric acid, sulfuric acid, and the like, at temperature of from about 0.degree. C. to about 50.degree. C., preferably at room temperature.

The above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents respectively and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures, and under atmospheric or super-atmospheric pressure. The preferred solvents, catalysts and reaction conditions are set forth in the appended illustrative examples. The invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure antipodes.

The following examples and illustrations are intended to illustrate the invention and are not to be construed as being limitations thereon. Reaction Schemes 1, 2 and 3 of FIGS. 1, 2 and 3 correspond to Examples 1, 2 and 3.

EXAMPLE 1

Synthesis of 4-(phosphonomethylidene)-2-piperidinecarboxylic acid (E-isomer and Z-isomer) (Scheme 1)

Commercially available 4-methoxypyridine N-oxide (50 g, 0.4 mol) was dissolved in dichloromethane (200 mL), and to it was added trimethylsilylcyanide (67.4 mL, 0.506 mol) at room temperature. Dimethylcarbamyl chloride (46.5 mL, 0.506 mol) was added dropwise with stirring to the reaction mixture over a 30-min period. The reaction mixture was stirred at room temperature for 24 hours. A solution of 10% aqueous potassium Carbonate (100 mL) was added dropwise, and stirring was continued for 15 minutes. The organic layer was separated, dried, and concentrated to afford 2-cyano-4-methoxypyridine 1 (51.5 g, 96%) as an off-white solid.

A solution of 2-cyano-4-methoxypyridine 1 (45 g, 0.34 mol) and 48% aqueous HBr (500 mL) was heated for 72 hours at reflux, then cooled to room temperature and concentrated in vacuo. To the residue was added anhydrous ethanol (1 L); then HCl gas was bubbled through the solution for 10 minutes. After heating overnight at reflux, the mixture was cooled to room temperature and concentrated to afford the desired ethyl ester 2 as a white solid (45.5 g, 80% yield).

This solid (10.1 g, 0.05 mol) was hydrogenated in ethanol/water (1:1, 100 mL) with PtO.sub.2 (5 g) at 60 psi H.sub.2 pressure at 60.degree. C. for 18 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo to afford a crude solid 3 (9.68 g, 90%) as a white solid.

The ethyl ester 3 was dissolved in dichloromethane (150 mL)/anhydrous ethanol (75 mL) and to it was added diisopropylethylamine (15.65 mL) and a solution of di-tert-butyldicarbonate (19.64 g, 0.09 mol) in 180 mL of dichloromethane in four portions. The resultant mixture was stirred at room temperature for 18 h. The reaction mixture was filtered through celite and the filtrate evaporated to dryness at reduced pressure. The residue was dissolved in CHCl.sub.3 and washed with 4% HCl. The organic phase was dried over MgSO.sub.4 and evaporated to dryness at reduced pressure to afford 16.0 g of crude t-Boc-protected product. Purification by chromatography using 600 g flash chromatography silica gel and 30-50% EtOAc/hexane gave 10.01 g of pure t-Boc-N-protected piperidine derivative 4 (39% yield).

The N-protected ester 4 (6.1 g) was heated in 25 mL of t-butylamine at 140.degree. C. for 18 h in a sealed tube to afford, after evaporation of the excess t-butylamine, the desired amide 5 .sup.1 H NMR (CDCl.sub.3, 300 MHz): .delta.4.91 (m, 1H, 2-H), 4.20 (m, 2H, 6-H.sub.2), 3.32 (m, 1H, 4-H), 1.72 [s, 9H, C(CH.sub.3).sub.3 ], 1.51 [s, 9H, C(CH.sub.3).sub.3 ] in an 85% yield. The alcohol 5 was then efficiently oxidized to the ketone with pyridinium chlorochromate (PCC). To a mixture of PCC (5.73 g, 0.027 mol), and 1.50 g powdered molecular sieves in 120 mL of CH.sub.2 Cl.sub.2 (stirred for 1 h at room temperature, then cooled in an ice-water bath) was added dropwise over 30 min the alcohol 5 (3.32 g, 0.011 mol) in 30 mL of CH.sub.2 Cl.sub.2. After stirring at room temperature for 3 h, the reaction mixture was suction-filtered directly through flash chromatography silica gel using CH.sub.2 Cl.sub.2 to remove excess PCC. The reaction mixture was then chromatographed on 100 g of flash chromatography silica gel using 25% EtOAc/hexane to afford 1.48 g (46%) of ketone 6. .sup.1 H NMR (CDCl.sub.3, 300 MHz): .delta.4.80 (m, 1H, 2-H), 1.51 [m, 9H, C(CH.sub.3).sub.3 ], 1.32 [m, 9H, C(CH.sub.3).sub.3 ]. HRMS for C.sub.15 H.sub.26 NO.sub.4 ; Calcd. M+H.sup.+ 299.1971. Found M+H.sup.+ 299.1979.

A solution of ketone 6 (1.37 g, 0.0046 mol) in THF (50 mL) was added at -78.degree. C. to the anion generated from NaH (0.387 g, 0.00968 mol) and tetramethyl methylenediphosphonate (2.247 g, 0.068 mol) in dry THF. The reaction mixture was then stirred at room temperature for 2.5 h. The THF was removed at reduced pressure water bath temperature below 30.degree. C.) to afford 3.77 g of residue. The residue showed two spots by thin-layer chromatography. Purification using 65 g flash chromatography silica gel and developed in 75% EtOAc/hexane afforded 0.625 g (36%) of the cis-protected isomer 7 and 0.710 g (39%) of the trans-protected isomer 8. HRMS for 7 C.sub.18 H.sub.33 N.sub.2 O.sub.6 P. Calcd. M+H.sup.+ 404.2154. Found M+H.sup.+ 404.2174. .sup.1 H NMR (CDCl.sub.3, 300 MHz) .delta.5.45 (d, 1H, J=16 Hz HC.dbd.C), 4.75 (m, 1H, H-2), 3.69-3.80 (m, 6H, OCH.sub.3), 1.49 [s, 9H, C(CH.sub.3).sub.3 ], 1.33 [s, 9H, C(CH.sub.3).sub.3 ].

Indeed, it seems that the amide proton of the 2-CONHR is very important in the transition state complex in directing the orientation of the phosphonate. The ketone analog 6 with the N-Boc protecting group and the t-butyl amide functionality also results in an olefin product mixture that is much more readily chromatographed, resulting in a higher and purer yield of Z-isomer 7. Removal of the protecting group was then accomplished by refluxing the phosphonate 7 and 8 in 6N HCl for 18 h to afford 9 and 10 respectively in quantitative yield. 9: EIMS (m/e): 437 (M.TMS.sub.3.sup.+); .sup.1 H NMR (400 MHz, D.sub.2 O) .delta.3.80 (dd, J=4, 12 Hz, 1H C.sub.2-H), 5.75 (d, J=16 Hz, 1H, HC.dbd.C) 10: EIMS (m/e) 437 (M.TMS.sub.3.sup.+); .sup.1 H NMR (400 MHz, D.sub.2 O) 3.86 dd, J=4,12 Hz, 1H, C.sub.2H), 5.78 (d, J=16 Hz, 1H HC.dbd.C). NOESY on 10 showed an NOE between the vinylic proton at .delta.5.78 and C-3H.sub.3 at .delta.2.8.

EXAMPLE 2

Synthesis of 4-(phosphonomethylidene)-2-piperidinecarboxylic acid (E-isomer and Z-isomer) (Scheme 2)

Treatment of 4-piperidine ethylene ketal (14 g) with N'-tert-butyl-N,N-dimethylformamidine (38 g) in toluene (100 mL) at 100.degree. C. for 24 hours afforded the formamidine ketal 11, b.p. 87.degree. C./0.15 mm, in 86% yield. A solution of the formamidine 11 (12 g) in ether (240 mL) was treated with t-butyllithium (1.5M, 42 mL) in pentane, and the anion was alkylated with ethyl chloroformate (6.6 mL). Aqueous workup and evaporation of the solvent afforded the ester 12 (90% yield). A solution of the ester 12 (9.8 g) in MeOH (12 mL) and 10% KOH in 50% MeOH/H.sub.2 O (11 mL) was refluxed for 1.5 hours, cooled to room temperature, neutralized to pH 8 with 1M HCl, and evaporated to dryness. Flash column chromatography on silica gel using ethyl acetate as solvent afforded the ketal (3.3 g, 41% yield). IR (CHCl.sub.3):3434 (N-H), 1674 cm.sup.-1 (amide). EIMS (m/z): 270 (M.sup.+). A solution of the ketal (3.2 g) in AcOH (28 mL) and H.sub.2 O (28 mL) was heated at 80.degree. C. for 2 hours, and the solvent was removed under reduced pressure. Crystallization from CH.sub.2 Cl.sub.2 --EtOAc yielded the ketone 13 (2.05 g, 75% yield). IR (CHCl.sub.3): 3395 (N-H), 1725 (ketone), 1681 cm.sup.- 1 (amide). EIMS (m/z): 226 (M.sup.+). A solution of ketone 13 (400 mg) in THF (20 mL) was added to the anion at -78.degree. C., which was generated from NaH (98 mg) and tetramethyl methylenediphosphonate (0.90 g) in THF (12 mL). The bath was replaced with a water bath at room temperature, the mixture was stirred for 5 minutes, water was added (5 mL), and the solution was evaporated to dryness. Flash column chromatography on silica gel using CHCl.sub.3 /acetone (2:8) gave the exocyclic Z-isomer 14 (102 mg) in 17% yield and the exocyclic E-isomer 15 (150 mg) in 25% yield. The 14 was crystallized from EtOAc/hexane; IR (CHCl.sub.3): 3342 (N-H), 1679 cm.sup.-1 (amide). EIMS (m/z): 332 (M.sup.+).

NMR (CDCl.sub.3, 90 MHz): .delta.5.06 (dd, J=2 and 5 Hz, 1H, 2-H), 5.51 (d, J=16 Hz. 1H, HC.dbd.C). The exocyclic E-isomer 15 was crystallized from EtOAc/hexane; IR (CHCl.sub.3): 3339 (N-H), 1678 cm.sup.-1 (amide). EIMS (m/z): 332 (M.sup.+). NMR (CDCl.sub.3, 90 MHz): .delta.4.99 (dd, J=1 and 5 Hz, 1H, 2-H), 5.60 (d, J=16 Hz, 1H, HC.dbd.C).

The Z-isomer 14 (55 mg) was heated with 6N HCl/H.sub.2 O (3 mL) at 100.degree. C. for 24 hours and evaporated to dryness. The residue was dissolved in MeOH (5 mL), treated with propylene oxide (0.5 mL), stirred for 0.5 hour, and evaporated to dryness. Purification by C.sub.18 reverse-phase flash column chromatography, using water as solvent, gave compound 9 (52 mg, 70% yield). EIMS (m/z): 437 (M+ TMS.sub.3.sup.+). NMR (D.sub.2 O, 400 MHz): .delta.3.80 (dd, J=4 and 12 Hz, 1H, 2-H), 5.75 (d, J=16 Hz, 1H, HC.dbd.C).

The exocyclic E-isomer 15 (65 mg) was similarly treated with 6N HCl/H.sub.2 O (3 mL). After workup and purification, a compound 10 (75% yield) was obtained with about 10% of isomer 9 by NMR. EIMS (m/z): 437 (M+TMS.sub.3.sup.+). NMR (D.sub.2 O, 400 MHz): .delta.3.86 (dd, J=4 and 12 Hz, 1H, 2-H), 5.78 (d, J=16 Hz, 1H, HC.dbd.C). The 9 (Z-isomer) and 10 (E-isomer) were differentiated, and their structures were predicted on the basis of NOESY and decoupling experiments.

The NOESY experiment on 10 showed an NOE between the vinylic proton at .delta.5.78 (d) and the 3H.sub..beta. at .delta.2.8. The assignment of 3-H.sub..beta. was confirmed by decoupling the 2-H proton (.delta.3.86), since the vicinal coupling of 3-H.sub..beta. to 2-H disappeared, leaving only the geminal coupling. Only the E-isomer would be expected to demonstrate this NOE between the vinylic proton and the 3-H, thus confirming that 10 is the E-isomer. In the case of the Z-isomer, there would be no coupling between the vinylic proton and 3-H.sub..beta.. However, a NOESY experiment on 9 showed the NOE between the vinylic proton and a proton at C-5, but no effect on C-3, consistent with the Z-assignment for 9.

EXAMPLE 3

Synthesis of ethyl 4-(phosphonomethylidene)-2-piperidine carboxylate (E-isomer and Z-isomer) (Scheme 3)

The intermediate 3 from Scheme 1 was required for the synthesis of ethyl 4-(phosphonomethylidene)-2-piperidinecarboxylate. The crude residue 3 from Scheme 1 (9.6 g, 0.046 mol) was dissolved in CH.sub.2 Cl.sub.2 (60 mL), anhydrous ethanol (30 mL), and diisopropylethylamine (8.01 mL). To this mixture was added di-tert-butyldicarbonate (9.5 g, 0.046 mol) in 5-mL portions every 10 minutes. The resultant mixture was stirred overnight at room temperature, then filtered through celite and concentrated in vacuo. The residue was extracted with ether-dichloromethane (2:1) and washed with 10% HCl. The organic layer was dried and evaporated to afford a light yellow clear liquid. The crude residue was purified by flash chromatography with EtOAc/hexane to afford the desired t-Boc-protected product (7.5 g, 60% yield). MS analysis showed the molecular ion peak at m/e 273. .sup.1 H NMR (90 MHz, CDCl.sub.3): .delta.4.70 (m, 1H), 4.19 (m, 3H), 3.84 (m, 1H), 3.38 (m, 2H), 2.43 (m, 1H), 2.12 (m, 1H), 1.90 (m, 1H), 1.69 (m, 1H), 1.46 (s, 9H), 1.27 (t, 3H). To a mixture of PCC (11.19 g, 0.05 mol), and 11.19 g of powdered molecular sieves, in 100 mL of dichloromethane (stirred for 1 hour at room temperature, then cooled in an ice-water bath) was added dropwise, over 30 minutes, alcohol (6.0 g, 0.022 mol) in dichloromethane (50 mL). After this solution was stirred for 3 hours at room temperature, 500 mL of ether was added and the mixture was filtered through a pad of celite (bottom) and a pad of silica gel in sintered glass funnels. The filtrate was concentrated in vacuo; then 150 mL of ether was added to the residue and the solution was filtered through silica gel. This filtrate was concentrated in vacuo to afford the desired ketone 16 as a yellow-green oil (5.70 g, 95% yield).

A solution of ketone 16 (4.3 g, 0.016 mol) in THF (60 mL) was added at -78.degree. C. to the anion, which was generated from NaH (0.652 g, 0.027 mol) and tetramethyl methylene diphosphonate (6.31 g, 0.027 mol) in THF. The reaction mixture was stirred at room temperature for 1 hour. After that, water was added and the product extracted with chloroform. The chloroform layer was dried, filtered, and evaporated to afford a colorless viscous oil (4.5 g, 75%). The .sup.1 H NMR (400 MHz) clearly showed that the oil consisted of the E-isomer 18 (85%) and the Z-isomer 17 (15%). The Z-isomer and the E-isomer were differentiated and their structures predicted on the basis of NOESY and decoupling experiments. The NOESY experiment on this mixture showed an NOE between the vinylic proton and the 3-H.sub..beta.. The assignment of 3-H.sub..beta. was confirmed by decoupling the 2-H, because the vicinal coupling of 3-H.sub..beta. to 2-H disappeared, leaving only the geminal coupling. The mixture of protected piperidine ester (17 and 18) (100 mg) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for 3 hours. After that the solvent was evaporated to afford an oil, which was triturated with ether. To the residue were added dichloromethane (50 mL) and saturated sodium bicarbonate solution; the organic layer was dried, filtered, and evaporated to give a mixture of deprotected ethylester 19 and 20 as a thick oil (70 mg, 95% yield).

To the dichloromethane solution (10 mL) of the phosphonomethylidene ester 19 and 20 (138 mg, 0.5 mmol) was added bromotrimethylsilane (4 eq., 0.300 mL), and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated, and methanol (2 mL) was added to hydrolyze the phosphonosilyl ester to give a residue. The residue was dissolved in a minimal amount of ethanol, and ether was added with HCl to give a light yellow powder. This powder was dissolved in ethanol, and propylene oxide (1 mL) was added to precipitate the mixture of phosphonic acid 21 and 22 (2:8 mixture) as a white powder (100 mg). EIMS (m/z): 393 (M+TMS.sub.2)

.sup.1 H NMR (D.sub.2 O, 400 MHz): .delta.1.28 (t, 3H, CH.sub.2), 2.5 (m, 1H, 6-H.sub..alpha.), 2.65 (bt, 1H, 3-H.sub..alpha.), 2.95 (dd, 1H, 3-H.sub..beta.), 3.12 (tt, 1H, 5-H.sub..alpha.), 3.30 (dd, 1H, 6-H.sub..beta.), 3.65 (bt, 1H, 5-H.sub..beta.), 4.2 (dd, J=4 and 12 MHz, 1H, 2-H), 4.32 (q, 3H, CH.sub.3), 5.80 (d, J=16 Hz, 1H, HC.dbd.C).

In Vitro Binding Assay using [.sup.3 H]CGS-19755 as the Radioligand at the NMDA Receptor Site

Compounds such as CGS-19755 (cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid) have been shown to be high-affinity antagonists at the NMDA recognition site (Lehman et al., 1988; Murphy et al., 1987). The compounds of the invention were tested for their ability to inhibit [.sup.3 H]CGS-19755 binding. Semipurified synaptic membranes were prepared according to the method of Bristow et al. (1986) with minor modifications. Adult male Sprague-Dawley rats were decapitated, and the forebrains were removed, weighed and homogenized in 20 volumes of 0.32M sucrose. The homogenate was centrifuged at 27,000.times.G for 15 minutes. The pellet was resuspended in 20 volumes of distilled water followed by centrifugation at 8000.times.G for minutes. Both the supernatant and the buffy coat layer, removed with 5 mM Tris-Cl (2 mL), pH 7.8, were pooled and centrifuged at 27,000.times.G for 15 minutes. The supernatant was removed and the pellet was covered with a small amount of 5 mM Tris-HCl and stored at -20.degree. C. for least 18 hours. Membranes were then washed four times in 50 mM Tris-citrate, pH 7.1, and finally resuspended in the same buffer. This suspension was used for the binding assay immediately or frozen for subsequent use.

Aliquots of membranes (800 .mu.l) were incubated with 10 nM [.sup.3 H]CGS-19755 (100 .mu.l) and varying concentrations of the test compounds (100 .mu.l) for 15 minutes at 4.degree. C. Then a filtration assay was used. The samples were filtered over glass fiber filters using a Brandel Cell Harvester. The filters were left overnight in 5 mL scintillation cocktail before counting.

Table 1 summarizes the results of the in vitro binding studies using [.sup.3 H]CGS-19755 as the radioligand at the NMDA receptor site.

Ki values were calculated from the equation: ##EQU1##

TABLE 1______________________________________In Vitro Binding Assay at the NMDA Receptor Site Ki (.mu.M)Compound [.sup.3 H]CGS19755______________________________________CGS-19755(cis-4-(phosphonomethyl)- 0.1122-piperidinecarboxylic acid)E-4-(phosphonomethylidene)-2- 0.59piperidinecarboxylic acid______________________________________

In Vivo Protection in the Mouse Against NMDA-Induced Lethality

According to the method described by Ferkany et al. (1988), the test compounds were administered ip to four male Swiss-Webster mice (26-34 g) each, following 30 minutes later, 200 mg/kg of NMDA was administered to the mice each. The LD.sub.50 of NMDA was found to be 164 mg/kg, and approximately 90% of the mice died at 200 mg/kg. Those compounds that protected three or more of the mice at any of the doses were evaluated further by determining the ED.sub.50 values using three or more doses with the eight mice per dose. The ED.sub.50 was estimated by the method of Litchfield and Wilcoxin (1949). Water-soluble compounds were dissolved in distilled water and administered in a volume of 10 mL/kg. Water-insoluble compounds were suspended in an aqueous solution of 0.5% methyl cellulose and administered in a volume of 20 mL/kg.

Table 2 also summarizes the results of this test.

TABLE 2______________________________________NMDA-Induced Lethality Test in the Mouse ConfidenceCompound PD.sub.50 (mg/kg) Limits Slope______________________________________CGS-19755 (cis-4- 2.0 1.2-3.6 2.46(phosphonomethyl)-2-piperidine-carboxylic acid)E-4-(phosphonomethyl- 1.1 0.5-2.2 1.96idene-2-piperidine-carboxylic acid______________________________________ ______________________________________Representative Composition AAn oral suspension is prepared having thefollowing compositionIngredients______________________________________Active ingredient 0.1 gfumaric acid 0.5 gsodium chloride 2.0 gmethyl paraben 0.1 ggranulated sugar 25.5 gsorbitol (70% solution) 12.85 gVeegum K (Vanderbilt Co.) 1.0 gflavoring 0.035 mLcolorings 0.5 mgdistilled water q.s. to 100 mL______________________________________Representative Composition B Quantity perIngredients tablet (mg)______________________________________active ingredient 25cornstarch 20lactose, spray-dried 153magnesium stearate 2______________________________________

The above ingredients are thoroughly mixed and pressed into single-scored tablets.

EXAMPLES 0 and 4-1125

The reactions of Examples 1 and 2 and 3 are repeated varying the feedstocks as set forth in the preparation section. This gives rise to the following compounds of the invention:

__________________________________________________________________________Example X n R.sub.1 R.sub.2 R.sub.3__________________________________________________________________________1.2 CH 0 H H H0 CH 0 H H Methyl3 CH 0 H H Ethyl4 CH 0 H H Propyl5 CH 0 H H Butyl ##STR8## 0 H Methyl Methyl7 ##STR9## 0 H Methyl Ethyl8 ##STR10## 0 H Methyl Propyl9 ##STR11## 0 H Methyl Butyl10 ##STR12## 0 H Ethyl Ethyl11 CH 0 H Ethyl Propyl12 ##STR13## 0 H Ethyl Butyl13 ##STR14## 0 H Propyl Propyl14 CH 0 H Propyl Butyl15 CH 0 H Butyl Butyl16 ##STR15## 0 H H H17 ##STR16## 0 H H Methyl18 ##STR17## 0 H H Ethyl19 ##STR18## 0 H H Propyl20 ##STR19## 0 H H Butyl21 ##STR20## 0 H Methyl Methyl22 CF 0 H Methyl Ethyl23 ##STR21## 0 H Methyl Propyl24 ##STR22## 0 H Methyl Butyl25 ##STR23## 0 H Ethyl Ethyl26 ##STR24## 0 H Ethyl Propyl27 ##STR25## 0 H Ethyl Butyl28 ##STR26## 0 H Propyl Propyl29 ##STR27## 0 H Propyl Butyl30 ##STR28## 0 H Butyl Butyl31 NO 0 H H H32 NO 0 H H Methyl33 NO 0 H H Ethyl34 NO 0 H H Propyl35 NO 0 H H Butyl36 NO 0 H Methyl Methyl37 NO 0 H Methyl Ethyl38 NO 0 H Methyl Propyl39 NO 0 H Methyl Butyl40 NO 0 H Ethyl Ethyl41 NO 0 H Ethyl Propyl42 NO 0 H Ethyl Butyl43 NO 0 H Propyl Propyl44 NO 0 H Propyl Butyl45 NO 0 H Butyl Butyl46 CH 1 H H H47 CH 1 H H Methyl48 CH 1 H H Ethyl49 CH 1 H H Propyl50 ##STR29## 1 H H Butyl51 ##STR30## 1 H Methyl Methyl52 ##STR31## 1 H Methyl Ethyl53 CH 1 H Methyl Propyl54 ##STR32## 1 H Methyl Butyl55 ##STR33## 1 H Ethyl Ethyl56 ##STR34## 1 H Ethyl Propyl57 CH 1 H Ethyl Butyl58 ##STR35## 1 H Propyl Propyl59 ##STR36## 1 H Propyl Butyl60 ##STR37## 1 H Butyl Butyl61 ##STR38## 1 H H H62 ##STR39## 1 H H Methyl63 ##STR40## 1 H H Ethyl64 ##STR41## 1 H H Propyl65 ##STR42## 1 H H Butyl66 ##STR43## 1 H Methyl Methyl67 ##STR44## 1 H Methyl Ethyl68 ##STR45## 1 H Methyl Propyl69 ##STR46## 1 H Methyl Butyl70 ##STR47## 1 H Ethyl Ethyl71 ##STR48## 1 H Ethyl Propyl72 ##STR49## 1 H Ethyl Butyl73 ##STR50## 1 H Propyl Propyl74 ##STR51## 1 H Propyl Butyl75 ##STR52## 1 H Butyl Butyl76 NO 1 H H H77 NO 1 H H Methyl78 NO 1 H H Ethyl79 NO 1 H H Propyl80 NO 1 H H Butyl81 NO 1 H Methyl Methyl82 NO 1 H Methyl Ethyl83 NO 1 H Methyl Propyl84 NO 1 H Methyl Butyl85 NO 1 H Ethyl Ethyl86 NO 1 H Ethyl Propyl87 NO 1 H Ethyl Butyl88 NO 1 H Propyl Propyl89 NO 1 H Propyl Butyl90 NO 1 H Butyl Butyl91 CH 2 H H H92 CH 2 H H Methyl93 CH 2 H H Ethyl94 ##STR53## 2 H H Propyl95 ##STR54## 2 H H Butyl96 ##STR55## 2 H Methyl Methyl97 ##STR56## 2 H Methyl Ethyl98 ##STR57## 2 H Methyl Propyl99 ##STR58## 2 H Methyl Butyl100 ##STR59## 2 H Ethyl Ethyl101 ##STR60## 2 H Ethyl Propyl102 ##STR61## 2 H Ethyl Butyl103 ##STR62## 2 H Propyl Propyl104 CH 2 H Propyl Butyl105 CH 2 H Butyl Butyl106 ##STR63## 2 H H H107 ##STR64## 2 H H Methyl108 ##STR65## 2 H H Ethyl109 ##STR66## 2 H H Propyl110 ##STR67## 2 H H Butyl111 ##STR68## 2 H Methyl Methyl112 ##STR69## 2 H Methyl Ethyl113 ##STR70## 2 H Methyl Propyl114 ##STR71## 2 H Methyl Butyl115 ##STR72## 2 H Ethyl Ethyl116 ##STR73## 2 H Ethyl Propyl117 ##STR74## 2 H Ethyl Butyl118 ##STR75## 2 H Propyl Propyl119 ##STR76## 2 H Propyl Butyl120 ##STR77## 2 H Butyl Butyl121 NO 2 H H H122 NO 2 H H Methyl123 NO 2 H H Ethyl124 NO 2 H H Propyl125 NO 2 H H Butyl126 NO 2 H Methyl Methyl127 NO 2 H Methyl Ethyl128 NO 2 H Methyl Propyl129 NO 2 H Methyl Butyl130 NO 2 H Ethyl Ethyl131 NO 2 H Ethyl Propyl132 NO 2 H Ethyl Butyl133 NO 2 H Propyl Propyl134 NO 2 H Propyl Butyl135 NO 2 H Butyl Butyl136 CH 3 H H H137 CH 3 H H Methyl138 CH 3 H H Ethyl139 ##STR78## 3 H H Propyl140 ##STR79## 3 H H Butyl141 ##STR80## 3 H Methyl Methyl142 ##STR81## 3 H Methyl Ethyl143 ##STR82## 3 H Methyl Propyl144 ##STR83## 3 H Methyl Butyl145 ##STR84## 3 H Ethyl Ethyl146 ##STR85## 3 H Ethyl Propyl147 CH 3 H Ethyl Butyl148 ##STR86## 3 H Propyl Propyl149 ##STR87## 3 H Propyl Butyl150 ##STR88## 3 H Butyl Butyl151 ##STR89## 3 H H H152 ##STR90## 3 H H Methyl153 ##STR91## 3 H H Ethyl154 ##STR92## 3 H H Propyl155 ##STR93## 3 H H Butyl156 ##STR94## 3 H Methyl Methyl157 ##STR95## 3 H Methyl Ethyl158 ##STR96## 3 H Methyl Propyl159 ##STR97## 3 H Methyl Butyl160 ##STR98## 3 H Ethyl Ethyl161 ##STR99## 3 H Ethyl Propyl162 ##STR100## 3 H Ethyl Butyl163 ##STR101## 3 H Propyl Propyl164 ##STR102## 3 H Propyl Butyl165 ##STR103## 3 H Butyl Butyl166 NO 3 H H H167 NO 3 H H Methyl168 NO 3 H H Ethyl169 NO 3 H H Propyl170 NO 3 H H Butyl171 NO 3 H Methyl Methyl172 NO 3 H Methyl Ethyl173 NO 3 H Methyl Propyl174 NO 3 H Methyl Butyl175 NO 3 H Ethyl Ethyl176 NO 3 H Ethyl Propyl177 NO 3 H Ethyl Butyl178 NO 3 H Propyl Propyl179 NO 3 H Propyl Butyl180 NO 3 H Butyl Butyl181 CH 4 H H H182 ##STR104## 4 H H Methyl183 ##STR105## 4 H H Ethyl184 CH 4 H H Propyl185 ##STR106## 4 H H Butyl186 ##STR107## 4 H Methyl Methyl187 ##STR108## 4 H Methyl Ethyl188 ##STR109## 4 H Methyl Propyl189 ##STR110## 4 H Methyl Butyl190 ##STR111## 4 H Ethyl Ethyl191 ##STR112## 4 H Ethyl Propyl192 ##STR113## 4 H Ethyl Butyl193 ##STR114## 4 H Propyl Propyl194 ##STR115## 4 H Propyl Butyl195 ##STR116## 4 H Butyl Butyl196 ##STR117## 4 H H H197 ##STR118## 4 H H Methyl198 ##STR119## 4 H H Ethyl199 ##STR120## 4 H H Propyl200 ##STR121## 4 H H Butyl201 ##STR122## 4 H Methyl Methyl202 ##STR123## 4 H Methyl Ethyl203 ##STR124## 4 H Methyl Propyl204 ##STR125## 4 H Methyl Butyl205 ##STR126## 4 H Ethyl Ethyl206 ##STR127## 4 H Ethyl Propyl207 ##STR128## 4 H Ethyl Butyl208 ##STR129## 4 H Propyl Propyl209 ##STR130## 4 H Propyl Butyl210 ##STR131## 4 H Butyl Butyl211 NO 4 H H H212 NO 4 H H Methyl213 NO 4 H H Ethyl214 NO 4 H H Propyl215 NO 4 H H Butyl216 NO 4 H Methyl Methyl217 NO 4 H Methyl Ethyl218 NO 4 H Methyl Propyl219 NO 4 H Methyl Butyl220 NO 4 H Ethyl Ethyl221 NO 4 H Ethyl Propyl222 NO 4 H Ethyl Butyl223 NO 4 H Propyl Propyl224 NO 4 H Propyl Butyl225 NO 4 H Butyl Butyl226 CH 0 Methyl H H227 CH 0 Methyl H Methyl228 CH 0 Methyl H Ethyl229 CH 0 Methyl H Propyl230 CH 0 Methyl H Butyl231 CH 0 Methyl Methyl Methyl232 ##STR132## 0 Methyl Methyl Ethyl233 ##STR133## 0 Methyl Methyl Propyl234 CH 0 Methyl Methyl Butyl235 CH 0 Methyl Ethyl Ethyl236 ##STR134## 0 Methyl Ethyl Propyl237 ##STR135## 0 Methyl Ethyl Butyl238 ##STR136## 0 Methyl Propyl Propyl239 ##STR137## 0 Methyl Propyl Butyl240 ##STR138## 0 Methyl Butyl Butyl241 ##STR139## 0 Methyl H H242 ##STR140## 0 Methyl H Methyl243 ##STR141## 0 Methyl H Ethyl244 ##STR142## 0 Methyl H Propyl245 ##STR143## 0 Methyl H Butyl246 ##STR144## 0 Methyl Methyl Methyl247 ##STR145## 0 Methyl Methyl Ethyl248 ##STR146## 0 Methyl Methyl Propyl249 ##STR147## 0 Methyl Methyl Butyl250 ##STR148## 0 Methyl Ethyl Ethyl251 ##STR149## 0 Methyl Ethyl Propyl252 ##STR150## 0 Methyl Ethyl Butyl253 ##STR151## 0 Methyl Propyl Propyl254 ##STR152## 0 Methyl Propyl Butyl255 ##STR153## 0 Methyl Butyl Butyl256 ##STR154## 0 Ethyl H H257 ##STR155## 0 Ethyl H Methyl258 ##STR156## 0 Ethyl H Ethyl259 ##STR157## 0 Ethyl H Propyl260 ##STR158## 0 Ethyl H Butyl261 ##STR159## 0 Ethyl Methyl Methyl262 CH 0 Ethyl Methyl Ethyl263 ##STR160## 0 Ethyl Methyl Propyl264 ##STR161## 0 Ethyl Methyl Butyl265 ##STR162## 0 Ethyl Ethyl Ethyl266 ##STR163## 0 Ethyl Ethyl Propyl267 ##STR164## 0 Ethyl Ethyl Butyl268 ##STR165## 0 Ethyl Propyl Propyl269 ##STR166## 0 Ethyl Propyl Butyl270 ##STR167## 0 Ethyl Butyl Butyl271 CF 0 Ethyl H H272 CF 0 Ethyl H Methyl273 CF 0 Ethyl H Ethyl274 ##STR168## 0 Ethyl H Propyl275 ##STR169## 0 Ethyl H Butyl276 ##STR170## 0 Ethyl Methyl Methyl277 ##STR171## 0 Ethyl Methyl Ethyl278 ##STR172## 0 Ethyl Methyl Propyl279 ##STR173## 0 Ethyl Methyl Butyl280 ##STR174## 0 Ethyl Ethyl Ethyl281 ##STR175## 0 Ethyl Ethyl Propyl282 ##STR176## 0 Ethyl Ethyl Butyl283 ##STR177## 0 Ethyl Propyl Propyl284 ##STR178## 0 Ethyl Propyl Butyl285 CF 0 Ethyl Butyl Butyl286 CH 0 Propyl H H287 ##STR179## 0 Propyl H Methyl288 ##STR180## 0 Propyl H Ethyl289 ##STR181## 0 Propyl H Propyl290 ##STR182## 0 Propyl H Butyl291 ##STR183## 0 Propyl Methyl Methyl292 ##STR184## 0 Propyl Methyl Ethyl293 ##STR185## 0 Propyl Methyl Propyl294 ##STR186## 0 Propyl Methyl Butyl295 ##STR187## 0 Propyl Ethyl Ethyl296 ##STR188## 0 Propyl Ethyl Propyl297 ##STR189## 0 Propyl Ethyl Butyl298 ##STR190## 0 Propyl Propyl Propyl299 ##STR191## 0 Propyl Propyl Butyl300 ##STR192## 0 Propyl Butyl Butyl301 ##STR193## 0 Propyl H H302 ##STR194## 0 Propyl H Methyl303 ##STR195## 0 Propyl H Ethyl304 ##STR196## 0 Propyl H Propyl305 ##STR197## 0 Propyl H Butyl306 ##STR198## 0 Propyl Methyl Methyl307 CF 0 Propyl Methyl Ethyl308 CF 0 Propyl Methyl Propyl309 CF 0 Propyl Methyl Butyl310 CF 0 Propyl Ethyl Ethyl311 CF 0 Propyl Ethyl Propyl312 ##STR199## 0 Propyl Ethyl Butyl313 ##STR200## 0 Propyl Propyl Propyl314 ##STR201## 0 Propyl Propyl Butyl315 ##STR202## 0 Propyl Butyl Butyl316 CH 0 Butyl H H317 CH 0 Butyl H Methyl318 ##STR203## 0 Butyl H Ethyl319 ##STR204## 0 Butyl H Propyl320 ##STR205## 0 Butyl H Butyl321 ##STR206## 0 Butyl Methyl Methyl322 ##STR207## 0 Butyl Methyl Ethyl323 ##STR208## 0 Butyl Methyl Propyl324 ##STR209## 0 Butyl Methyl Butyl325 ##STR210## 0 Butyl Ethyl Ethyl326 ##STR211## 0 Butyl Ethyl Propyl327 ##STR212## 0 Butyl Ethyl Butyl328 ##STR213## 0 Butyl Propyl Propyl329 ##STR214## 0 Butyl Propyl Butyl330 ##STR215## 0 Butyl Butyl Butyl331 ##STR216## 0 Butyl H H332 ##STR217## 0 Butyl H Methyl333 ##STR218## 0 Butyl H Ethyl334 ##STR219## 0 Butyl H Propyl335 ##STR220## 0 Butyl H Butyl336 ##STR221## 0 Butyl Methyl Methyl337 ##STR222## 0 Butyl Methyl Ethyl338 ##STR223## 0 Butyl Methyl Propyl339 ##STR224## 0 Butyl Methyl Butyl340 ##STR225## 0 Butyl Ethyl Ethyl341 ##STR226## 0 Butyl Ethyl Propyl342 ##STR227## 0 Butyl Ethyl Butyl343 ##STR228## 0 Butyl Propyl Propyl344 ##STR229## 0 Butyl Propyl Butyl345 ##STR230## 0 Butyl Butyl Butyl346 ##STR231## 1 Methyl H H347 ##STR232## 1 Methyl H Methyl348 ##STR233## 1 Methyl H Ethyl349 ##STR234## 1 Methyl H Propyl350 ##STR235## 1 Methyl H Butyl351 ##STR236## 1 Methyl Methyl Methyl352 ##STR237## 1 Methyl Methyl Ethyl353 ##STR238## 1 Methyl Methyl Propyl354 ##STR239## 1 Methyl Methyl Butyl355 ##STR240## 1 Methyl Ethyl Ethyl356 ##STR241## 1 Methyl Ethyl Propyl357 ##STR242## 1 Methyl Ethyl Butyl358 ##STR243## 1 Methyl Propyl Propyl359 ##STR244## 1 Methyl Propyl Butyl360 ##STR245## 1 Methyl Butyl Butyl361 CF 1 Methyl H H362 CF 1 Methyl H Methyl363 CF 1 Methyl H Ethyl364 CF 1 Methyl H Propyl365 CF 1 Methyl H Butyl366 ##STR246## 1 Methyl Methyl Methyl367 CF 1 Methyl Methyl Ethyl368 CF 1 Methyl Methyl Propyl369 CF 1 Methyl Methyl Butyl370 ##STR247## 1 Methyl Ethyl Ethyl371 ##STR248## 1 Methyl Ethyl Propyl372 ##STR249## 1 Methyl Ethyl Butyl373 CF 1 Methyl Propyl Propyl374 ##STR250## 1 Methyl Propyl Butyl375 ##STR251## 1 Methyl Butyl Butyl376 ##STR252## 1 Ethyl H H377 ##STR253## 1 Ethyl H Methyl378 ##STR254## 1 Ethyl H Ethyl379 ##STR255## 1 Ethyl H Propyl380 ##STR256## 1 Ethyl H Butyl381 ##STR257## 1 Ethyl Methyl Methyl382 ##STR258## 1 Ethyl Methyl Ethyl383 ##STR259## 1 Ethyl Methyl Propyl384 ##STR260## 1 Ethyl Methyl Butyl385 ##STR261## 1 Ethyl Ethyl Ethyl386 ##STR262## 1 Ethyl Ethyl Propyl387 ##STR263## 1 Ethyl Ethyl Butyl388 ##STR264## 1 Ethyl Propyl Propyl389 ##STR265## 1 Ethyl Propyl Butyl390 ##STR266## 1 Ethyl Butyl Butyl391 ##STR267## 1 Ethyl H H392 CF 1 Ethyl H Methyl393 ##STR268## 1 Ethyl H Ethyl394 ##STR269## 1 Ethyl H Propyl395 ##STR270## 1 Ethyl H Butyl396 CF 1 Ethyl Methyl Methyl397 CF 1 Ethyl Methyl Ethyl398 CF 1 Ethyl Methyl Propyl399 ##STR271## 1 Ethyl Methyl Butyl400 ##STR272## 1 Ethyl Ethyl Ethyl401 ##STR273## 1 Ethyl Ethyl Propyl402 ##STR274## 1 Ethyl Ethyl Butyl403 CF 1 Ethyl Propyl Propyl404 ##STR275## 1 Ethyl Propyl Butyl405 ##STR276## 1 Ethyl Butyl Butyl406 CH 1 Propyl H H407 CH 1 Propyl H Methyl408 ##STR277## 1 Propyl H Ethyl409 ##STR278## 1 Propyl H Propyl410 ##STR279## 1 Propyl H Butyl411 ##STR280## 1 Propyl Methyl Methyl412 ##STR281## 1 Propyl Methyl Ethyl413 ##STR282## 1 Propyl Methyl Propyl414 ##STR283## 1 Propyl Methyl Butyl415 ##STR284## 1 Propyl Ethyl Ethyl416 ##STR285## 1 Propyl Ethyl Propyl417 ##STR286## 1 Propyl Ethyl Butyl418 ##STR287## 1 Propyl Propyl Propyl419 ##STR288## 1 Propyl Propyl Butyl420 ##STR289## 1 Propyl Butyl Butyl421 ##STR290## 1 Propyl H H422 ##STR291## 1 Propyl H Methyl423 ##STR292## 1 Propyl H Ethyl424 ##STR293## 1 Propyl H Propyl425 ##STR294## 1 Propyl H Butyl426 CF 1 Propyl Methyl Methyl427 ##STR295## 1 Propyl Methyl Ethyl428 ##STR296## 1 Propyl Methyl Propyl429 ##STR297## 1 Propyl Methyl Butyl430 ##STR298## 1 Propyl Ethyl Ethyl431 ##STR299## 1 Propyl Ethyl Propyl432 ##STR300## 1 Propyl Ethyl Butyl433 ##STR301## 1 Propyl Propyl Propyl434 ##STR302## 1 Propyl Propyl Butyl435 ##STR303## 1 Propyl Butyl Butyl436 ##STR304## 1 Butyl H H437 ##STR305## 1 Butyl H Methyl438 ##STR306## 1 Butyl H Ethyl439 ##STR307## 1 Butyl H Propyl440 ##STR308## 1 Butyl H Butyl441 ##STR309## 1 Butyl Methyl Methyl442 ##STR310## 1 Butyl Methyl Ethyl443 ##STR311## 1 Butyl Methyl Propyl444 ##STR312## 1 Butyl Methyl Butyl445 ##STR313## 1 Butyl Ethyl Ethyl446 ##STR314## 1 Butyl Ethyl Propyl447 ##STR315## 1 Butyl Ethyl Butyl448 ##STR316## 1 Butyl Propyl Propyl449 ##STR317## 1 Butyl Propyl Butyl450 ##STR318## 1 Butyl Butyl Butyl451 CF 1 Butyl H H452 CF 1 Butyl H Methyl453 CF 1 Butyl H Ethyl454 ##STR319## 1 Butyl H Propyl455 ##STR320## 1 Butyl H Butyl456 ##STR321## 1 Butyl Methyl Methyl457 ##STR322## 1 Butyl Methyl Ethyl458 ##STR323## 1 Butyl Methyl Propyl459 ##STR324## 1 Butyl Methyl Butyl460 ##STR325## 1 Butyl Ethyl Ethyl461 ##STR326## 1 Butyl Ethyl Propyl462 ##STR327## 1 Butyl Ethyl Butyl463 ##STR328## 1 Butyl Propyl Propyl464 ##STR329## 1 Butyl Propyl Butyl465 ##STR330## 1 Butyl Butyl Butyl466 ##STR331## 2 Methyl H H467 ##STR332## 2 Methyl H Methyl468 ##STR333## 2 Methyl H Ethyl469 ##STR334## 2 Methyl H Propyl470 ##STR335## 2 Methyl H Butyl471 ##STR336## 2 Methyl Methyl Methyl472 ##STR337## 2 Methyl Methyl Ethyl473 ##STR338## 2 Methyl Methyl Propyl474 ##STR339## 2 Methyl Methyl Butyl475 ##STR340## 2 Methyl Ethyl Ethyl476 ##STR341## 2 Methyl Ethyl Propyl477 ##STR342## 2 Methyl Ethyl Butyl478 ##STR343## 2 Methyl Propyl Propyl479 ##STR344## 2 Methyl Propyl Butyl480 ##STR345## 2 Methyl Butyl Butyl481 ##STR346## 2 Methyl H H482 ##STR347## 2 Methyl H Methyl483 ##STR348## 2 Methyl H Ethyl484 ##STR349## 2 Methyl H Propyl485 ##STR350## 2 Methyl H Butyl486 ##STR351## 2 Methyl Methyl Methyl487 ##STR352## 2 Methyl Methyl Ethyl488 ##STR353## 2 Methyl Methyl Propyl489 ##STR354## 2 Methyl Methyl Butyl490 ##STR355## 2 Methyl Ethyl Ethyl491 ##STR356## 2 Methyl Ethyl Propyl492 ##STR357## 2 Methyl Ethyl Butyl493 ##STR358## 2 Methyl Propyl Propyl494 ##STR359## 2 Methyl Propyl Butyl495 ##STR360## 2 Methyl Butyl Butyl496 CH 2 Ethyl H H497 CH 2 Ethyl H Methyl498 CH 2 Ethyl H Ethyl499 ##STR361## 2 Ethyl H Propyl500 ##STR362## 2 Ethyl H Butyl501 ##STR363## 2 Ethyl Methyl Methyl502 ##STR364## 2 Ethyl Methyl Ethyl503 ##STR365## 2 Ethyl Methyl Propyl504 ##STR366## 2 Ethyl Methyl Butyl505 CH 2 Ethyl Ethyl Ethyl506 CH 2 Ethyl Ethyl Propyl507 ##STR367## 2 Ethyl Ethyl Butyl508 ##STR368## 2 Ethyl Propyl Propyl509 ##STR369## 2 Ethyl Propyl Butyl510 ##STR370## 2 Ethyl Butyl Butyl511 ##STR371## 2 Ethyl H H512 ##STR372## 2 Ethyl H Methyl513 ##STR373## 2 Ethyl H Ethyl514 ##STR374## 2 Ethyl H Propyl515 ##STR375## 2 Ethyl H Butyl516 ##STR376## 2 Ethyl Methyl Methyl517 ##STR377## 2 Ethyl Methyl Ethyl518 ##STR378## 2 Ethyl Methyl Propyl519 ##STR379## 2 Ethyl Methyl Butyl520 ##STR380## 2 Ethyl Ethyl Ethyl521 ##STR381## 2 Ethyl Ethyl Propyl522 ##STR382## 2 Ethyl Ethyl Butyl523 ##STR383## 2 Ethyl Propyl Propyl524 ##STR384## 2 Ethyl Propyl Butyl525 ##STR385## 2 Ethyl Butyl Butyl526 ##STR386## 2 Propyl H H527 ##STR387## 2 Propyl H Methyl528 ##STR388## 2 Propyl H Ethyl529 ##STR389## 2 Propyl H Propyl530 ##STR390## 2 Propyl H Butyl531 ##STR391## 2 Propyl Methyl Methyl532 ##STR392## 2 Propyl Methyl Ethyl533 ##STR393## 2 Propyl Methyl Propyl534 ##STR394## 2 Propyl Methyl Butyl535 ##STR395## 2 Propyl Ethyl Ethyl536 ##STR396## 2 Propyl Ethyl Propyl537 ##STR397## 2 Propyl Ethyl Butyl538 ##STR398## 2 Propyl Propyl Propyl539 ##STR399## 2 Propyl Propyl Butyl540 ##STR400## 2 Propyl Butyl Butyl541 CF 2 Propyl H H542 CF 2 Propyl H Methyl543 CF 2 Propyl H Ethyl544 CF 2 Propyl H Propyl545 ##STR401## 2 Propyl H Butyl546 ##STR402## 2 Propyl Methyl Methyl547 ##STR403## 2 Propyl Methyl Ethyl548 ##STR404## 2 Propyl Methyl Propyl549 ##STR405## 2 Propyl Methyl Butyl550 ##STR406## 2 Propyl Ethyl Ethyl551 ##STR407## 2 Propyl Ethyl Propyl552 ##STR408## 2 Propyl Ethyl Butyl553 ##STR409## 2 Propyl Propyl Propyl554 ##STR410## 2 Propyl Propyl Butyl555 ##STR411## 2 Propyl Butyl Butyl556 ##STR412## 2 Butyl H H557 ##STR413## 2 Butyl H Methyl558 ##STR414## 2 Butyl H Ethyl559 ##STR415## 2 Butyl H Propyl560 ##STR416## 2 Butyl H Butyl561 ##STR417## 2 Butyl Methyl Methyl562 ##STR418## 2 Butyl Methyl Ethyl563 ##STR419## 2 Butyl Methyl Propyl564 ##STR420## 2 Butyl Methyl Butyl565 ##STR421## 2 Butyl Ethyl Ethyl566 ##STR422## 2 Butyl Ethyl Propyl567 ##STR423## 2 Butyl Ethyl Butyl568 ##STR424## 2 Butyl Propyl Propyl569 ##STR425## 2 Butyl Propyl Butyl570 ##STR426## 2 Butyl Butyl Butyl571 ##STR427## 2 Butyl H H572 ##STR428## 2 Butyl H Methyl573 ##STR429## 2 Butyl H Ethyl574 ##STR430## 2 Butyl H Propyl575 ##STR431## 2 Butyl H Butyl576 ##STR432## 2 Butyl Methyl Methyl577 ##STR433## 2 Butyl Methyl Ethyl578 ##STR434## 2 Butyl Methyl Propyl579 ##STR435## 2 Butyl Methyl Butyl580 ##STR436## 2 Butyl Ethyl Ethyl581 CF 2 Butyl Ethyl Propyl582 CF 2 Butyl Ethyl Butyl583 ##STR437## 2 Butyl Propyl Propyl584 ##STR438## 2 Butyl Propyl Butyl585 ##STR439## 2 Butyl Butyl Butyl586 CH 3 Methyl H H587 ##STR440## 3 Methyl H Methyl588 ##STR441## 3 Methyl H Ethyl589 ##STR442## 3 Methyl H Propyl590 ##STR443## 3 Methyl H Butyl591 ##STR444## 3 Methyl Methyl Methyl592 ##STR445## 3 Methyl Methyl Ethyl593 ##STR446## 3 Methyl Methyl Propyl594 ##STR447## 3 Methyl Methyl Butyl595 ##STR448## 3 Methyl Ethyl Ethyl596 ##STR449## 3 Methyl Ethyl Propyl597 ##STR450## 3 Methyl Ethyl Butyl598 ##STR451## 3 Methyl Propyl Propyl599 ##STR452## 3 Methyl Propyl Butyl600 ##STR453## 3 Methyl Butyl Butyl601 ##STR454## 3 Methyl H H602 ##STR455## 3 Methyl H Methyl603 ##STR456## 3 Methyl H Ethyl604 CF 3 Methyl H Propyl605 CF 3 Methyl H Butyl606 CF 3 Methyl Methyl Methyl607 ##STR457## 3 Methyl Methyl Ethyl608 CF 3 Methyl Methyl Propyl609 ##STR458## 3 Methyl Methyl Butyl610 ##STR459## 3 Methyl Ethyl Ethyl611 ##STR460## 3 Methyl Ethyl Propyl612 ##STR461## 3 Methyl Ethyl Butyl613 ##STR462## 3 Methyl Propyl Propyl614 ##STR463## 3 Methyl Propyl Butyl615 ##STR464## 3 Methyl Butyl Butyl616 ##STR465## 3 Ethyl H H617 ##STR466## 3 Ethyl H Methyl618 ##STR467## 3 Ethyl H Ethyl619 ##STR468## 3 Ethyl H Propyl620 ##STR469## 3 Ethyl H Butyl621 ##STR470## 3 Ethyl Methyl Methyl622 CH 3 Ethyl Methyl Ethyl623 CH 3 Ethyl Methyl Propyl624 ##STR471## 3 Ethyl Methyl Butyl625 ##STR472## 3 Ethyl Ethyl Ethyl626 ##STR473## 3 Ethyl Ethyl Propyl627 ##STR474## 3 Ethyl Ethyl Butyl628 ##STR475## 3 Ethyl Propyl Propyl629 ##STR476## 3 Ethyl Propyl Butyl630 ##STR477## 3 Ethyl Butyl Butyl631 C F 3 Ethyl H H632 CF 3 Ethyl H Methyl633 ##STR478## 3 Ethyl H Ethyl634 ##STR479## 3 Ethyl H Propyl635 ##STR480## 3 Ethyl H Butyl636 ##STR481## 3 Ethyl Methyl Methyl637 ##STR482## 3 Ethyl Methyl Ethyl638 ##STR483## 3 Ethyl Methyl Propyl639 ##STR484## 3 Ethyl Methyl Butyl640 ##STR485## 3 Ethyl Ethyl Ethyl641 ##STR486## 3 Ethyl Ethyl Propyl642 ##STR487## 3 Ethyl Ethyl Butyl643 ##STR488## 3 Ethyl Propyl Propyl644 ##STR489## 3 Ethyl Propyl Butyl645 ##STR490## 3 Ethyl Butyl Butyl646 ##STR491## 3 Propyl H H647 ##STR492## 3 Propyl H Methyl648 ##STR493## 3 Propyl H Ethyl649 ##STR494## 3 Propyl H Propyl650 ##STR495## 3 Propyl H Butyl651 ##STR496## 3 Propyl Methyl Methyl652 ##STR497## 3 Propyl Methyl Ethyl653 ##STR498## 3 Propyl Methyl Propyl654 ##STR499## 3 Propyl Methyl Butyl655 ##STR500## 3 Propyl Ethyl Ethyl656 ##STR501## 3 Propyl Ethyl Propyl657 ##STR502## 3 Propyl Ethyl Butyl658 ##STR503## 3 Propyl Propyl Propyl659 ##STR504## 3 Propyl Propyl Butyl660 ##STR505## 3 Propyl Butyl Butyl661 ##STR506## 3 Propyl H H662 ##STR507## 3 Propyl H Methyl663 ##STR508## 3 Propyl H Ethyl664 ##STR509## 3 Propyl H Propyl665 ##STR510## 3 Propyl H Butyl666 ##STR511## 3 Propyl Methyl Methyl667 ##STR512## 3 Propyl Methyl Ethyl668 ##STR513## 3 Propyl Methyl Propyl669 ##STR514## 3 Propyl Methyl Butyl670 ##STR515## 3 Propyl Ethyl Ethyl671 ##STR516## 3 Propyl Ethyl Propyl672 ##STR517## 3 Propyl Ethyl Butyl673 ##STR518## 3 Propyl Propyl Propyl674 ##STR519## 3 Propyl Propyl Butyl675 ##STR520## 3 Propyl Butyl Butyl676 CH 3 Butyl H H677 CH 3 Butyl H Methyl678 CH 3 Butyl H Ethyl679 ##STR521## 3 Butyl H Propyl680 ##STR522## 3 Butyl H Butyl681 ##STR523## 3 Butyl Methyl Methyl682 ##STR524## 3 Butyl Methyl Ethyl683 ##STR525## 3 Butyl Methyl Propyl684 ##STR526## 3 Butyl Methyl Butyl685 CH 3 Butyl Ethyl Ethyl686 ##STR527## 3 Butyl Ethyl Propyl687 ##STR528## 3 Butyl Ethyl Butyl688 ##STR529## 3 Butyl Propyl Propyl689 ##STR530## 3 Butyl Propyl Butyl690 ##STR531## 3 Butyl Butyl Butyl691 ##STR532## 3 Propyl H H692 ##STR533## 3 Butyl H Methyl693 ##STR534## 3 Butyl H Ethyl694 ##STR535## 3 Butyl H Propyl695 ##STR536## 3 Butyl H Butyl696 ##STR537## 3 Butyl Methyl Methyl697 ##STR538## 3 Butyl Methyl Ethyl698 ##STR539## 3 Butyl Methyl Propyl699 ##STR540## 3 Butyl Methyl Butyl700 ##STR541## 3 Butyl Ethyl Ethyl701 ##STR542## 3 Butyl Ethyl Propyl702 ##STR543## 3 Butyl Ethyl Butyl703 ##STR544## 3 Butyl Propyl Propyl704 ##STR545## 3 Butyl Propyl Butyl705 ##STR546## 3 Butyl Butyl Butyl706 CH 4 Methyl H H707 CH 4 Methyl H Methyl708 CH 4 Methyl H Ethyl709 ##STR547## 4 Methyl H Propyl710 ##STR548## 4 Methyl H Butyl711 ##STR549## 4 Methyl Methyl Methyl712 ##STR550## 4 Methyl Methyl Ethyl713 ##STR551## 4 Methyl Methyl Propyl714 ##STR552## 4 Methyl Methyl Butyl715 CH 4 Methyl Ethyl Ethyl716 CH 4 Methyl Ethyl Propyl717 ##STR553## 4 Methyl Ethyl Butyl718 ##STR554## 4 Methyl Propyl Propyl719 ##STR555## 4 Methyl Propyl Butyl720 ##STR556## 4 Methyl Butyl Butyl721 CF 4 Methyl H H722 CF 4 Methyl H Methyl723 CF 4 Methyl H Ethyl724 CF 4 Methyl H Propyl725 CF 4 Methyl H Butyl726 CF 4 Methyl Methyl Methyl727 ##STR557## 4 Methyl Methyl Ethyl728 ##STR558## 4 Methyl Methyl Propyl729 ##STR559## 4 Methyl Methyl Butyl730 CF 4 Methyl Ethyl Ethyl731 ##STR560## 4 Methyl Ethyl Propyl732 ##STR561## 4 Methyl Ethyl Butyl733 ##STR562## 4 Methyl Propyl Propyl734 ##STR563## 4 Methyl Propyl Butyl735 ##STR564## 4 Methyl Butyl Butyl736 ##STR565## 4 Ethyl H H737 ##STR566## 4 Ethyl H Methyl738 ##STR567## 4 Ethyl H Ethyl739 ##STR568## 4 Ethyl H Propyl740 ##STR569## 4 Ethyl H Butyl741 ##STR570## 4 Ethyl Methyl Methyl742 ##STR571## 4 Ethyl Methyl Ethyl743 ##STR572## 4 Ethyl Methyl Propyl744 ##STR573## 4 Ethyl Methyl Butyl745 ##STR574## 4 Ethyl Ethyl Ethyl746 ##STR575## 4 Ethyl Ethyl Propyl747 ##STR576## 4 Ethyl Ethyl Butyl748 ##STR577## 4 Ethyl Propyl Propyl749 ##STR578## 4 Ethyl Propyl Butyl750 ##STR579## 4 Ethyl Butyl Butyl751 ##STR580## 4 Ethyl H H752 ##STR581## 4 Ethyl H Methyl753 ##STR582## 4 Ethyl H Ethyl754 ##STR583## 4 Ethyl H Propyl755 ##STR584## 4 Ethyl H Butyl756 CF 4 Ethyl Methyl Methyl757 CF 4 Ethyl Methyl Ethyl758 CF 4 Ethyl Methyl Propyl759 CF 4 Ethyl Methyl Butyl760 CF 4 Ethyl Ethyl Ethyl761 ##STR585## 4 Ethyl Ethyl Propyl762 CF 4 Ethyl Ethyl Butyl763 ##STR586## 4 Ethyl Propyl Propyl764 ##STR587## 4 Ethyl Propyl Butyl765 ##STR588## 4 Ethyl Butyl Butyl766 CH 4 Propyl H H767 CH 4 Propyl H Methyl768 ##STR589## 4 Propyl H Ethyl769 ##STR590## 4 Propyl H Propyl770 ##STR591## 4 Propyl H Butyl771 ##STR592## 4 Propyl Methyl Methyl772 ##STR593## 4 Propyl Methyl Ethyl773 ##STR594## 4 Propyl Methyl Propyl774 ##STR595## 4 Propyl Methyl Butyl775 ##STR596## 4 Propyl Ethyl Ethyl776 ##STR597## 4 Propyl Ethyl Propyl777 ##STR598## 4 Propyl Ethyl Butyl778 ##STR599## 4 Propyl Propyl Propyl779 ##STR600## 4 Propyl Propyl Butyl780 ##STR601## 4 Propyl Butyl Butyl781 ##STR602## 4 Propyl H H782 ##STR603## 4 Propyl H Methyl783 ##STR604## 4 Propyl H Ethyl784 ##STR605## 4 Propyl H Propyl785 ##STR606## 4 Propyl H Butyl786 ##STR607## 4 Propyl Methyl Methyl787 ##STR608## 4 Propyl Methyl Ethyl788 ##STR609## 4 Propyl Methyl Propyl789 ##STR610## 4 Propyl Methyl Butyl790 ##STR611## 4 Propyl Ethyl Ethyl791 ##STR612## 4 Propyl Ethyl Propyl792 ##STR613## 4 Propyl Ethyl Butyl793 ##STR614## 4 Propyl Propyl Propyl794 ##STR615## 4 Propyl Propyl Butyl795 ##STR616## 4 Propyl Butyl Butyl796 ##STR617## 4 Butyl H H797 CH 4 Butyl H Methyl798 ##STR618## 4 Butyl H Ethyl799 ##STR619## 4 Butyl H Propyl800 ##STR620## 4 Butyl H Butyl801 ##STR621## 4 Butyl Methyl Methyl802 ##STR622## 4 Butyl Methyl Ethyl803 ##STR623## 4 Butyl Methyl Propyl804 ##STR624## 4 Butyl Methyl Butyl805 ##STR625## 4 Butyl Ethyl Ethyl806 ##STR626## 4 Butyl Ethyl Propyl807 ##STR627## 4 Butyl Ethyl Butyl808 ##STR628## 4 Butyl Propyl Propyl809 ##STR629## 4 Butyl Propyl Butyl810 ##STR630## 4 Butyl Butyl Butyl811 ##STR631## 4 Butyl H H812 ##STR632## 4 Butyl H Methyl813 ##STR633## 4 Butyl H Ethyl814 ##STR634## 4 Butyl H Propyl815 ##STR635## 4 Butyl H Butyl816 ##STR636## 4 Butyl Methyl Methyl817 ##STR637## 4 Butyl Methyl Ethyl818 ##STR638## 4 Butyl Methyl Propyl819 CF 4 Butyl Methyl Butyl820 ##STR639## 4 Butyl Ethyl Ethyl821 ##STR640## 4 Butyl Ethyl Propyl822 ##STR641## 4 Butyl Ethyl Butyl823 ##STR642## 4 Butyl Propyl Propyl824 ##STR643## 4 Butyl Propyl Butyl825 ##STR644## 4 Butyl Butyl Butyl826 NO 0 Methyl H H827 NO 0 Methyl H Methyl828 NO 0 Methyl H Ethyl829 NO 0 Methyl H Propyl830 NO 0 Methyl H Butyl831 NO 0 Methyl Methyl Methyl832 NO 0 Methyl Methyl Ethyl833 NO 0 Methyl Methyl Propyl834 NO 0 Methyl Methyl Butyl835 NO 0 Methyl Ethyl Ethyl836 NO 0 Methyl Ethyl Propyl837 NO 0 Methyl Ethyl Butyl838 NO 0 Methyl Propyl Propyl839 NO 0 Methyl Propyl Butyl840 NO 0 Methyl Butyl Butyl841 NO 1 Methyl H H842 NO 1 Methyl H Methyl843 NO 1 Methyl H Ethyl844 NO 1 Methyl H Propyl845 NO 1 Methyl H Butyl846 NO 1 Methyl Methyl Methyl847 NO 1 Methyl Methyl Ethyl848 NO 1 Methyl Methyl Propyl849 NO 1 Methyl Methyl Butyl850 NO 1 Methyl Ethyl Ethyl851 NO 1 Methyl Ethyl Propyl852 NO 1 Methyl Ethyl Butyl853 NO 1 Methyl Propyl Propyl854 NO 1 Methyl Propyl Butyl855 NO 1 Methyl Butyl Butyl856 NO 2 Ethyl H H857 NO 2 Ethyl H Methyl858 NO 2 Ethyl H Ethyl859 NO 2 Ethyl H Propyl860 NO 2 Ethyl H Butyl861 NO 2 Ethyl Methyl Methyl862 NO 2 Ethyl Methyl Ethyl863 NO 2 Ethyl Methyl Propyl864 NO 2 Ethyl Methyl Butyl865 NO 2 Ethyl Ethyl Ethyl866 NO 2 Ethyl Ethyl Propyl867 NO 2 Ethyl Ethyl Butyl868 NO 2 Ethyl Propyl Propyl869 NO 2 Ethyl Propyl Butyl870 NO 2 Ethyl Butyl Butyl871 NO 3 Ethyl H H872 NO 3 Ethyl H Methyl873 NO 3 Ethyl H Ethyl874 NO 3 Ethyl H Propyl875 NO 3 Ethyl H Butyl876 NO 3 Ethyl Methyl Methyl877 NO 3 Ethyl Methyl Ethyl878 NO 3 Ethyl Methyl Propyl879 NO 3 Ethyl Methyl Butyl880 NO 3 Ethyl Ethyl Ethyl881 NO 3 Ethyl Ethyl Propyl882 NO 3 Ethyl Ethyl Butyl883 NO 3 Ethyl Propyl Propyl884 NO 3 Ethyl Propyl Butyl885 NO 3 Ethyl Butyl Butyl886 NO 4 Propyl H H887 NO 4 Propyl H Methyl888 NO 4 Propyl H Ethyl889 NO 4 Propyl H Propyl890 NO 4 Propyl H Butyl891 NO 4 Propyl Methyl Methyl892 NO 4 Propyl Methyl Ethyl893 NO 4 Propyl Methyl Propyl894 NO 4 Propyl Methyl Butyl895 NO 4 Propyl Ethyl Ethyl896 NO 4 Propyl Ethyl Propyl897 NO 4 Propyl Ethyl Butyl898 NO 4 Propyl Propyl Propyl899 NO 4 Propyl Propyl Butyl900 NO 4 Propyl Butyl Butyl901 NO 0 Propyl H H902 NO 0 Propyl H Methyl903 NO 0 Propyl H Ethyl904 NO 0 Propyl H Propyl905 NO 0 Propyl H Butyl906 NO 0 Propyl Methyl Methyl907 NO 0 Propyl Methyl Ethyl908 NO 0 Propyl Methyl Propyl909 NO 0 Propyl Methyl Butyl910 NO 0 Propyl Ethyl Ethyl911 NO 0 Propyl Ethyl Propyl912 NO 0 Propyl Ethyl Butyl913 NO 0 Propyl Propyl Propyl914 NO 0 Propyl Propyl Butyl915 NO 0 Propyl Butyl Butyl916 NO 0 Butyl H H917 NO 0 Butyl H Methyl918 NO 0 Butyl H Ethyl919 NO 0 Butyl H Propyl920 NO 0 Butyl H Butyl921 NO 0 Butyl Methyl Methyl922 NO 0 Butyl Methyl Ethyl923 NO 0 Butyl Methyl Propyl924 NO 0 Butyl Methyl Butyl925 NO 0 Butyl Ethyl Ethyl926 NO 0 Butyl Ethyl Propyl927 NO 0 Butyl Ethyl Butyl928 NO 0 Butyl Propyl Propyl929 NO 0 Butyl Propyl Butyl930 NO 0 Butyl Butyl Butyl931 NO 0 Butyl H H932 NO 1 Butyl H Methyl933 NO 1 Butyl H Ethyl934 NO 1 Butyl H Propyl935 NO 1 Butyl H Butyl936 NO 1 Butyl Methyl Methyl937 NO 1 Butyl Methyl Ethyl938 NO 1 Butyl Methyl Propyl939 NO 1 Butyl Methyl Butyl940 N O 1 Butyl Ethyl Ethyl941 NO 1 Butyl Ethyl Propyl942 NO 1 Butyl Ethyl Butyl943 NO 1 Butyl Propyl Propyl944 NO 1 Butyl Propyl Butyl945 NO 1 Butyl Butyl Butyl946 NO 2 Methyl H H947 NO 2 Methyl H Methyl948 NO 2 Methyl H Ethyl949 NO 2 Methyl H Propyl950 NO 2 Methyl H Butyl951 NO 2 Methyl Methyl Methyl952 NO 2 Methyl Methyl Ethyl953 NO 2 Methyl Methyl Propyl954 NO 2 Methyl Methyl Butyl955 NO 2 Methyl Ethyl Ethyl956 NO 2 Methyl Ethyl Propyl957 NO 2 Methyl Ethyl Butyl958 NO 2 Methyl Propyl Propyl959 NO 2 Methyl Propyl Butyl960 NO 2 Methyl Butyl Butyl961 NO 3 Methyl H H962 NO 3 Methyl H Methyl963 NO 3 Methyl H Ethyl964 NO 3 Methyl H Propyl965 NO 3 Methyl H Butyl966 NO 3 Methyl Methyl Methyl967 NO 3 Methyl Methyl Ethyl968 NO 3 Methyl Methyl Propyl969 NO 3 Methyl Methyl Butyl970 NO 3 Methyl Ethyl Ethyl971 NO 3 Methyl Ethyl Propyl972 NO 3 Methyl Ethyl Butyl973 NO 3 Methyl Propyl Propyl974 NO 3 Methyl Propyl Butyl975 NO 3 Methyl Butyl Butyl976 NO 4 Ethyl H H977 NO 4 Ethyl H Methyl978 NO 4 Ethyl H Ethyl979 NO 4 Ethyl H Propyl980 NO 4 Ethyl H Butyl981 NO 4 Ethyl Methyl Methyl982 NO 4 Ethyl Methyl Ethyl983 NO 4 Ethyl Methyl Propyl984 NO 4 Ethyl Methyl Butyl985 NO 4 Ethyl Ethyl Ethyl986 NO 4 Ethyl Ethyl Propyl987 NO 4 Ethyl Ethyl Butyl988 NO 4 Ethyl Propyl Propyl989 NO 4 Ethyl Propyl Butyl990 NO 4 Ethyl Butyl Butyl991 NO 0 Ethyl H H992 NO 0 Ethyl H Methyl993 NO 0 Ethyl H Ethyl994 NO 0 Ethyl H Propyl995 NO 0 Ethyl H Butyl996 NO 0 Ethyl Methyl Methyl997 NO 0 Ethyl Methyl Ethyl998 NO 0 Ethyl Methyl Propyl999 NO 0 Ethyl Methyl Butyl1000 NO 0 Ethyl Ethyl Ethyl1001 NO 0 Ethyl Ethyl Propyl1002 NO 0 Ethyl Ethyl Butyl1003 NO 0 Ethyl Propyl Propyl1004 NO 0 Ethyl Propyl Butyl1005 NO 0 Ethyl Butyl Butyl1006 NO 1 Propyl H H1007 NO 1 Propyl H Methyl1008 NO 1 Propyl H Ethyl1009 NO 1 Propyl H Propyl1010 NO 1 Propyl H Butyl1011 NO 1 Propyl Methyl Methyl1012 NO 1 Propyl Methyl Ethyl1013 NO 1 Propyl Methyl Propyl1014 NO 1 Propyl Methyl Butyl1015 NO 1 Propyl Ethyl Ethyl1016 NO 1 Propyl Ethyl Propyl1017 NO 1 Propyl Ethyl Butyl1018 NO 1 Propyl Propyl Propyl1019 NO 1 Propyl Propyl Butyl1020 NO 1 Propyl Butyl Butyl1021 NO 2 Propyl H H1022 NO 2 Propyl H Methyl1023 NO 2 Propyl H Ethyl1024 NO 2 Propyl H Propyl1025 NO 2 Propyl H Butyl1026 NO 2 Propyl Methyl Methyl1027 NO 2 Propyl Methyl Ethyl1028 NO 2 Propyl Methyl Propyl1029 NO 2 Propyl Methyl Butyl1030 NO 2 Propyl Ethyl Ethyl1031 NO 2 Propyl Ethyl Propyl1032 NO 2 Propyl Ethyl Butyl1033 NO 2 Propyl Propyl Propyl1034 NO 2 Propyl Propyl Butyl1035 NO 2 Propyl Butyl Butyl1036 NO 3 Butyl H H1037 NO 3 Butyl H Methyl1038 NO 3 Butyl H Ethyl1039 NO 3 Butyl H Propyl1040 NO 3 Butyl H Butyl1041 NO 3 Butyl Methyl Methyl1042 NO 3 Butyl Methyl Ethyl1043 NO 3 Butyl Methyl Propyl1044 NO 3 Butyl Methyl Butyl1045 NO 3 Butyl Ethyl Ethyl1046 NO 3 Butyl Ethyl Propyl1047 NO 3 Butyl Ethyl Butyl1048 NO 3 Butyl Propyl Propyl1049 NO 3 Butyl Propyl Butyl1050 NO 3 Butyl Butyl Butyl1051 NO 4 Butyl H H1052 NO 4 Butyl H Methyl1053 NO 4 Butyl H Ethyl1054 NO 4 Butyl H Propyl1055 NO 4 Butyl H Butyl1056 NO 4 Butyl Methyl Methyl1057 NO 4 Butyl Methyl Ethyl1058 NO 4 Butyl Methyl Propyl1059 NO 4 Butyl Methyl Butyl1060 NO 4 Butyl Ethyl Ethyl1061 NO 4 Butyl Ethyl Propyl1062 NO 4 Butyl Ethyl Butyl1063 NO 4 Butyl Propyl Propyl1064 NO 4 Butyl Propyl Butyl1065 NO 4 Butyl Butyl Butyl1066 NO 4 Methyl H H1067 NO 4 Methyl H Methyl1068 NO 4 Methyl H Ethyl1069 NO 4 Methyl H Propyl1070 NO 4 Methyl H Butyl1071 NO 4 Methyl Methyl Methyl1072 NO 4 Methyl Methyl Ethyl1073 NO 4 Methyl Methyl Propyl1074 NO 4 Methyl Methyl Butyl1075 NO 4 Methyl Ethyl Ethyl1076 NO 4 Methyl Ethyl Propyl1077 NO 4 Methyl Ethyl Butyl1078 NO 4 Methyl Propyl Propyl1079 NO 4 Methyl Propyl Butyl1080 NO 4 Methyl Butyl Butyl1081 NO 2 Butyl H H1082 NO 2 Butyl H Methyl1083 NO 2 Butyl H Ethyl1084 NO 2 Butyl H Propyl1085 NO 2 Butyl H Butyl1086 NO 2 Butyl Methyl Methyl1087 NO 2 Butyl Methyl Ethyl1088 NO 2 Butyl Methyl Propyl1089 NO 2 Butyl Methyl Butyl1090 NO 2 Butyl Ethyl Ethyl1091 NO 2 Butyl Ethyl Propyl1092 NO 2 Butyl Ethyl Butyl1093 NO 2 Butyl Propyl Propyl1094 NO 2 Butyl Propyl Butyl1095 NO 2 Butyl Butyl Butyl1096 NO 1 Ethyl H H1097 NO 1 Ethyl H Methyl1098 NO 1 Ethyl H Ethyl1099 NO 1 Ethyl H Propyl1100 NO 1 Ethyl H Butyl1101 NO 1 Ethyl Methyl Methyl1102 NO 1 Ethyl Methyl Ethyl1103 NO 1 Ethyl Methyl Propyl1104 NO 1 Ethyl Methyl Butyl1105 NO 1 Ethyl Ethyl Ethyl1106 NO 1 Ethyl Ethyl Propyl1107 NO 1 Ethyl Ethyl Butyl1108 NO 1 Ethyl Propyl Propyl1109 NO 1 Ethyl Propyl Butyl1110 NO 1 Ethyl Butyl Butyl1111 NO 3 Ethyl H H1112 NO 3 Propyl H Methyl1113 NO 3 Propyl H Ethyl1114 NO 3 Propyl H Propyl1115 NO 3 Propyl H Butyl1116 NO 3 Propyl Methyl Methyl1117 NO 3 Propyl Methyl Ethyl1118 NO 3 Propyl Methyl Propyl1119 NO 3 Propyl Methyl Butyl1120 NO 3 Propyl Ethyl Ethyl1121 NO 3 Propyl Ethyl Propyl1122 NO 3 Propyl Ethyl Butyl1123 NO 3 Propyl Propyl Propyl1124 NO 3 Propyl Propyl Butyl1125 NO 3 Propyl Butyl Butyl__________________________________________________________________________

Claims

1. A compound of the formula ##STR645## wherein X is ##STR646## 55 or .dbd.N--O--, in which R.sub.4 is hydrogen or halogen, R.sub.1, R.sub.2, and R.sub.3 independently represent hydrogen or a C.sub.1-4 alkyl group, and n is an integer having a value of zero to four inclusive and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein R.sub.1, R.sub.2 and R.sub.3 independently represent hydrogen or a methyl group and pharmaceutically acceptable salts thereof.

3. The compound of claim 1 wherein n has a value of zero to two and pharmaceutically acceptable salts thereof.

4. The compound of claim 1 wherein X is ##STR647## in which R.sub.4 is hydrogen or halogen and pharmaceutically acceptable salts thereof.

5. The compound of claim 1 wherein X is .dbd.H--O-- and pharmaceutically acceptable salts thereof.

6. A pharmaceutical composition comprising an effective amount of the compound or salt of claim 1 admixed with a pharmaceutically acceptable carrier.

7. A method to block N-methyl-D-aspartate receptors comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 6.

8. A method to treat pathosis or diseases having a relation with N-methyl-D-aspartate receptors comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 6.

9. A method to treat cerebral ischemia, cerebral hypoglycemia, epilepsy, anxiety or convulsion comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 6.