Abstract:
Compounds of formula I ##STR1## wherein X is ##STR2## or ═N--O--, in which R 4  is hydrogen or halogen, R 1 , R 2 , and R 3  independently represent hydrogen or a C 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 ═N--O--, in which R 4  is hydrogen or halogen, R 1 , R 2 , and R 3  independently represent hydrogen or a C 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 ═N--O-- wherein R 4  is hydrogen or a halo, such as fluoro, chloro, bromo or the like. When R 4  is present, it is preferably hydrogen or fluoro. &#34;n&#34; is an integer. It can be 0, 1, 2, 3, or 4. R 1  is hydrogen or a C 1-4  alkyl. The term &#34;C 1-4  alkyl&#34; means a saturated aliphatic group Of 1, 2, 3 or 4 carbons, either branched or straight chain. &#34;C 1-4  alkyls&#34; include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and tert-butyl groups. 
     R 2  and R 3  are also hydrogen or C 1-4  alkyls R 1 , R 2  and R 3  are selected independently, but usually, for ease of synthesis, R 2  and R 3  are the same. Methyl and hydrogen are preferred as R 2  and R 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 1 ), and salts can be formed of the phosphonic acid (i.e., replacing the R 2  and/or the R 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&#39;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 &#34;olefin&#34; 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 1 , R 2  and R 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 2 ) n  -- chain lengths, these can be attained. A suitably protected carbonyl such as 16 in Scheme 3 can be reacted with a triphenylphosphorane Ph 3  P═CH--(CH 2 ) n  --Z, or a phosphorane ylide generated from (EtO) 2  P(O)--CH 2  (CH 2 ) 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 ═CH--(CH 2 ) 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 3  Et 2  in an aprotic solvent such as DMF at moderate temperatures (50°-100° 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 ═CH(CH 2 ) n  --Z group employed. R 1 , R 2  and R 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. 
     ═X can also be an ##STR7## group, wherein R 4  is a halo instead of H. The R 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 4  halo at the desired position. 
     In a final variation, ═X can be ═N--O--. This functionality can be introduced using well-known chemistry. 
     The reagents H 2  N--O--CH 2  --PO 3  H 2  and H 2  N--O--(CH 2 ) 2  --PO 3  H 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°-100° C., preferably from room temperature to 70° C. in, for example, an appropriate solvent such as water, alcohol, dioxane or THF. This will add the ═N--O--(CH 2 ) n  --PO 3  H 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 1 , R 2  and R 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° C. to about 100° 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° C. to about 50° 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 2  (5 g) at 60 psi H 2  pressure at 60° 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 3  and washed with 4% HCl. The organic phase was dried over MgSO 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° C. for 18 h in a sealed tube to afford, after evaporation of the excess t-butylamine, the desired amide 5  1  H NMR (CDCl 3 , 300 MHz): δ4.91 (m, 1H, 2-H), 4.20 (m, 2H, 6-H 2 ), 3.32 (m, 1H, 4-H), 1.72 [s, 9H, C(CH 3 ) 3  ], 1.51 [s, 9H, C(CH 3 ) 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 2  Cl 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 2  Cl 2 . After stirring at room temperature for 3 h, the reaction mixture was suction-filtered directly through flash chromatography silica gel using CH 2  Cl 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.  1  H NMR (CDCl 3 , 300 MHz): δ4.80 (m, 1H, 2-H), 1.51 [m, 9H, C(CH 3 ) 3  ], 1.32 [m, 9H, C(CH 3 ) 3  ]. HRMS for C 15  H 26  NO 4  ; Calcd. M+H +   299.1971. Found M+H +   299.1979. 
     A solution of ketone 6 (1.37 g, 0.0046 mol) in THF (50 mL) was added at -78° 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° 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 18  H 33  N 2  O 6  P. Calcd. M+H +  404.2154. Found M+H +   404.2174.  1  H NMR (CDCl 3 , 300 MHz) δ5.45 (d, 1H, J=16 Hz HC═C), 4.75 (m, 1H, H-2), 3.69-3.80 (m, 6H, OCH 3 ), 1.49 [s, 9H, C(CH 3 ) 3  ], 1.33 [s, 9H, C(CH 3 ) 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 3   + );  1  H NMR (400 MHz, D 2  O) δ3.80 (dd, J=4, 12 Hz, 1H C 2-H ), 5.75 (d, J=16 Hz, 1H, HC═C) 10: EIMS (m/e) 437 (M.TMS 3   + );  1  H NMR (400 MHz, D 2  O) 3.86 dd, J=4,12 Hz, 1H, C 2H ), 5.78 (d, J=16 Hz, 1H HC═C). NOESY on 10 showed an NOE between the vinylic proton at δ5.78 and C-3H 3  at δ2.8. 
     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&#39;-tert-butyl-N,N-dimethylformamidine (38 g) in toluene (100 mL) at 100° C. for 24 hours afforded the formamidine ketal 11, b.p. 87° 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 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 3 ):3434 (N-H), 1674 cm -1  (amide). EIMS (m/z): 270 (M + ). A solution of the ketal (3.2 g) in AcOH (28 mL) and H 2  O (28 mL) was heated at 80° C. for 2 hours, and the solvent was removed under reduced pressure. Crystallization from CH 2  Cl 2  --EtOAc yielded the ketone 13 (2.05 g, 75% yield). IR (CHCl 3 ): 3395 (N-H), 1725 (ketone), 1681 cm -  1 (amide). EIMS (m/z): 226 (M + ). A solution of ketone 13 (400 mg) in THF (20 mL) was added to the anion at -78° 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 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 3 ): 3342 (N-H), 1679 cm -1  (amide). EIMS (m/z): 332 (M + ). 
     NMR (CDCl 3 , 90 MHz): δ5.06 (dd, J=2 and 5 Hz, 1H, 2-H), 5.51 (d, J=16 Hz. 1H, HC═C). The exocyclic E-isomer 15 was crystallized from EtOAc/hexane; IR (CHCl 3 ): 3339 (N-H), 1678 cm -1  (amide). EIMS (m/z): 332 (M + ). NMR (CDCl 3 , 90 MHz): δ4.99 (dd, J=1 and 5 Hz, 1H, 2-H), 5.60 (d, J=16 Hz, 1H, HC═C). 
     The Z-isomer 14 (55 mg) was heated with 6N HCl/H 2  O (3 mL) at 100° 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 18  reverse-phase flash column chromatography, using water as solvent, gave compound 9 (52 mg, 70% yield). EIMS (m/z): 437 (M+ TMS 3   + ). NMR (D 2  O, 400 MHz): δ3.80 (dd, J=4 and 12 Hz, 1H, 2-H), 5.75 (d, J=16 Hz, 1H, HC═C). 
     The exocyclic E-isomer 15 (65 mg) was similarly treated with 6N HCl/H 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 3   + ). NMR (D 2  O, 400 MHz): δ3.86 (dd, J=4 and 12 Hz, 1H, 2-H), 5.78 (d, J=16 Hz, 1H, HC═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 δ5.78 (d) and the 3H.sub.β  at δ2.8. The assignment of 3-H.sub.β  was confirmed by decoupling the 2-H proton (δ3.86), since the vicinal coupling of 3-H.sub.β  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.β. 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 2  Cl 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.  1  H NMR (90 MHz, CDCl 3 ): δ4.70 (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° 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  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.β. The assignment of 3-H.sub.β  was confirmed by decoupling the 2-H, because the vicinal coupling of 3-H.sub.β  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 2 ) 
       1  H NMR (D 2  O, 400 MHz): δ1.28 (t, 3H, CH 2 ), 2.5 (m, 1H, 6-H.sub.α), 2.65 (bt, 1H, 3-H.sub.α), 2.95 (dd, 1H, 3-H.sub.β), 3.12 (tt, 1H, 5-H.sub.α), 3.30 (dd, 1H, 6-H.sub.β), 3.65 (bt, 1H, 5-H.sub.β), 4.2 (dd, J=4 and 12 MHz, 1H, 2-H), 4.32 (q, 3H, CH 3 ), 5.80 (d, J=16 Hz, 1H, HC═C). 
     In Vitro Binding Assay using [ 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 [ 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×G for 15 minutes. The pellet was resuspended in 20 volumes of distilled water followed by centrifugation at 8000×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×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°  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 μl) were incubated with 10 nM [ 3  H]CGS-19755 (100 μl) and varying concentrations of the test compounds (100 μl) for 15 minutes at 4° 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 [ 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 (μM)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 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 50  values using three or more doses with the eight mice per dose. The ED 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__________________________________________________________________________