Abstract:
A novel series of 2-amino-5-spiro substituted oxazolin-4-ones and intermediates for making said compounds. These compounds are prepared by first converting the appropriately substituted cycloketone to the corresponding cyclocyanohydrin; converting this compounds to the corresponding hydroxy acid; esterifying the hydroxy acid, and finally cyclizing the hydroester to form the 2-amino-5-spiro substituted oxazolin-4-one. These compounds exhibit central nervous system activity and are active as either stimulants or depressants, and some are useful as performance enhancers.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This is a division, of application Ser. No. 170,652 filed Aug. 10, 1971, now U.S. Pat. No. 3,720,681 which in turn is a continuation-in-part of co-pending application Ser. No. 27,120, filed Apr. 9, 1970, now abandoned, which was a continuation-in-part of application Ser. No. 689,356, filed Dec. 11, 1967, now abandoned. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     This invention is directed to a new series of chemical compounds consisting of 2-amino-5-spiro substituted oxazolin-4-ones. More specifically, this series of compounds includes those compounds having alicyclic spiro substituents at the 5-position of the oxazole ring as well as compounds having heterocyclic spiro substituents at the 5-position. All of the compounds of this invention exhibit central nervous system activity. Some of the compounds are CNS depressants. Others are stimulants. 
     The compounds of this invention are represented by structural Formula I: ##SPC1## 
     wherein Z is a member selected from the group consisting of C 4  to C 8  cycloalkyl, lower alkyl-substituted C 4  to C 8  cycloalkyl, 4-piperidyl, lower alkyl-substituted 4-piperidyl and phenloweralkyl substituted 4-piperidyl. 
     The term &#34;lower alkyl&#34; as used herein refers to C 1  -C 4  straight, branched and cycloalkyl including methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, iso-butyl, t-butyl and cyclobutyl. 
     The stimulants of this invention are compounds of Formula II: ##SPC2## 
     wherein Z is 3,5-dimethylcyclohexyl, 3,3,5-trimethylcyclohexyl, or 4-(N-methylpiperidyl). The stimulants of Formula II are administered to animal in dosages of from 0.1 to 50 mg./kg. of body weight daily, preferably in divided doses. 
     The central nervous system depressants are represented by Formula III: ##SPC3## 
     wherein Z is C 4  to C 8  cycloalkyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 3,4,5-trimethylcyclohexyl, 4-piperidyl, 1,2,6-trimethy-4-piperidyl, N-isopropyl-4-piperidyl, or N-(2-phenethyl)-4-piperidyl. The compounds are administered to animals in need of tranquilization or sedation in dosages of from 20 to 500 mg./kg. daily, preferably in divided doses. 
     These compounds are prepared by first reacting an appropriately substituted cycloketone with a cyanide salt of an alkali metal to form the corresponding cyclocyanohydrin. This compounds is then converted to the hydroxy acid by reaction with a strong acid, such as concentrated hydrochloric acid. The hydroxy acid derivative is then esterified by reaction with the appropriate alcohol to form an alkyl ester. This compound is then reacted with guanidine hydrochloride to form the spiro derivative. 
     The reactions leading to the intermediate compounds are standard reactions well known in the art, as are the intermediate compounds formed by these reactions. Thus, the cycloketones, cyclocyanohydrins, hydroxy acids and hydroxyesters are structurally familiar compounds. The 5-spiro substituted derivatives are prepared by reacting the hydroxyester derivative with guanidine in a suitable alcoholic solvent, such as methanol, ethanol, propanol and the like. 
     In order to better illustrate the invention disclosed herein, reference is made to the following examples which are presented to illustrate a few specific embodiments of this invention and not to limit same thereby. 
    
    
     EXAMPLE 1 
     1-Hydroxy-3,5-Dimethyl-Cyclohexane Carboxylic Acid Ethyl Ester 
     Part I - Cyanohydrin Derivative 
     A solution of 106.8 grams of sodium bisulphite in 130 ml. of water is added dropwise with stirring over 30 minutes to a stirred mixture of 100 grams of 3,5-dimethylcyclohexanone, 67.0 grams of potassium cyanide and 170 ml. of water. The reaction mixture is kept below 40° C. by means of a cold water bath. The reaction mixture is stirred for an additional 2 hours, the organic layer separated and the aqueous layer extracted with 250 ml. of ether three times. The combined organic layer and ether solutions are dried over magnesium sulfate and concentrated at reduced pressure to yield 40.3 grams of 1-hydroxy-3,5-dimethyl-cyclohexanecarbonitrile. 
     PART II -- HYDROXY ACID 
     This product is then refluxed with stirring, with 300 ml. concentrated hydrochloric acid for 3 hours. The reaction mixture is concentrated at reduced pressure and the residue taken up in 250 ml. of chloroform and filtered to remove ammonium chloride. The filtrate is dried over magnesium sulfate and concentrated at reduced pressure. A syrup is obtained which upon trituration with 500 ml. of petroleum spirit and refrigeration at 50° overnight yields the crude hydroxy acid as white crystals. The crystals are filtered, dried and recrystallized from petroleum spirit to yield 9.50 grams of the pure 1-hydroxy-3,4-dimethylcyclohexane carboxylic acid. 
     PART III -- HYDROXY ESTER 
     The hydroxy acid is heated under reflux with 100 ml. of ethanol and 0.05 grams of p-toluene sulphonic acid for 8 hours. The solution is concentrated at reduced pressure, the residue dissolved in 100 ml. of ether and washed with 20 ml. of 10 percent sodium carbonate and 20 ml. water. The ether solution is dried over magnesium sulfate and concentrated at reduced pressure to yield 9.43 grams of the pure 1-hydroxy-3,5-dimethylcyclohexane carboxylic acid ethyl ester. 
     Following the procedure of Parts I, II and III in Example 1 above, various other hydroxy acids and their corresponding alkyl esters may be prepared. Table I below lists a representative series of the hydroxy acids prepared and their accompanying physical characteristics; while Table II below lists esters prepared from the corresponding acids prepared according to the description in Part III of Example 1. 
     
                                           TABLE I__________________________________________________________________________                 Analysis             I.R.AbsorptionEx.   Compound      Empirical                 Calc. % Found % M.P.inOH cm.sup..sup.-1                                 C=O cm.sup..sup.-1                                                   % yield            Formula                 C   H   C   H   °C                                      stretch.                                             stretch.                                                   from__________________________________________________________________________                                                   ketone2                C.sub.5 H.sub.8 O.sub.3                 51.7                     6.9 51.8                             7.0 63-5 3500(b)                                             1700  18.73                C.sub.9 H.sub.16 O.sub.3                 62.8                     9.4 62.8                             9.4 84-6 3530(b)                                             1700  24.14                C.sub.8 H.sub.14 O.sub.3                 60.8                     8.9 60.8                             8.8 67-86                                      3530(b)                                             1700  34.85                C.sub.8 H.sub.14 O.sub.3                 60.8                     8.9 60.9                             8.9  95-100                                      3520(b)                                             1710   9.66                C.sub.10 H.sub.18 O.sub.3                 64.5                     9.7 64.7                             9.5 134-6                                      3530(b)                                             1700  33.37                C.sub.11 H.sub.19 O.sub.3                 66.0                     10.1                         66.2                             10.0                                 126.9                                      3530   1700  33.18                C.sub.11 H.sub.16 O.sub.3                 66.2                     9.2 66.6                             9.0 124-50                                      3540(b)                                             1700  23.6                                 isomers9                C.sub.8 H.sub.12 O.sub.3                 61.5                     7.8 61.7                             7.7 123-6                                      3530(b)                                             1700  27.5                                 isomers10               C.sub.10 H.sub.18 O.sub.3                 64.5                     9.7 64.4                             9.7 131-3                                      3520(b)                                             1695  10.5__________________________________________________________________________ 
    
     Other hydroxy acids which may be synthesized include 1-hydroxycyclopentane carboxylic acid, 1-hydroxycyclohexane carboxylic acid and 1-hydroxycycloheptane carboxylic acid, among others. 
     
                       TABLE II______________________________________HYDROXY ESTERSEx.   Compound            % yield from acid______________________________________11                    71.912                    76.313                    58.414                    24.515                    54.916                    49.317                    57.418                    85.419                    68.520                    58.421                    63.522                    69.123                    89.4______________________________________ 
    
     The spiro compounds are prepared from the corresponding hydroxyesters prepared according to Example 1. Example 24 below describes the conversion of 1-hydroxy-3,5-dimethyl cyclohexane carboxylic acid ethyl ester of Example 1 to the spiro derivative. 
     EXAMPLE 24 
     2-Amino-7,9-Dimethyl-1-Oxa-3-Aza-Spiro[4,5]Dec-2-En-4-One ##SPC4## 
     A mixture of 9.43 grams of 1-hydroxy-3,5-dimethylcyclohexane carboxylic acid ethyl ester with 4.38 grams of guanidine hydrochloride and 2.59 grams of potassium hydroxide pellets in 52 ml of ethanol is refluxed for 1 hour. The solution is cooled, diluted with 172 ml of water and brought to pH 7 with glacial acetic acid resulting in a white precipitate being formed. After refrigeration at 5° C for 3 hours, the crystals are filtered, washed with water and ether, and dried yielding 3.20 grams of 2-amino-7,9-dimethyl-1-oxa-3-aza-spiro[4,5]dec-2-en-4-one, having a melting point of 276°-81° C. 
     Elemental analysis calculated for C 10  H 16  N 2  O 2:  C=61.2; H=8.2;N=14.3 Found: C=61.2;H=8.3; N=14.3 
     Following the procedure of Example 24, other hydroxy esters, such as those described in Table II, may similarly be converted to the corresponding spiro derivatives. Table III below lists a representative series of such spiro derivatives prepared from the hydroxy esters listed in Table II and their accompanying physical characteristics. 
     
                                           TABLE III__________________________________________________________________________                   Analysis               I.R.Absorption                                                   % yield from             Empirical                   Calc. %  Found %       Bands in                                                   hydroxyEx.   Compound       Formula                   C  H  N  C  H  N  MP in°C                                          1800 cm.sup..sup.-1                                          region   ester__________________________________________________________________________25                C.sub.6 H.sub.8 N.sub.2 O.sub.2                   51.4                      5.8                         20.0                            51.5                               5.8                                  20.0                                     188-93                                          1660, 1740                                                   15.026                C.sub.7 H.sub.10 N.sub.2 O.sub.2                   54.5                      6.5                         18.2                            54.3                               6.5                                  18.2                                     215-20                                          1660, 1720                                                   16.227                C.sub.8 H.sub.12 N.sub.2 O.sub.2                   57.1                      7.2                         16.7                            56.9                               7.2                                  16.9                                     220-5                                          1660, 1720                                                   16.028                C.sub.9 H.sub.14 N.sub.2 O.sub.2                   59.3                      7.7                         15.4                            59.1                               7.8                                  15.4                                     248-53                                          1660, 1720                                                   21.329                C.sub.10 H.sub.16 N.sub.2 O.sub.2                   61.2                      8.2                         14.3                            61.2                               8.2                                  14.2                                     262-6                                          1660, 1720                                                   31.230                C.sub.9 H.sub.14 N.sub.2 O.sub.2                   59.3                      7.7                         15.4                            59.3                               7.6                                  15.3                                     272-7                                          1660, 1720                                                   11.331                C.sub.9 H.sub.14 N.sub.2 O.sub.2                   59.3                      7.7                         15.4                            59.6                               7.6                                  15.5                                     249-52                                          1660, 1720                                                   30.732                C.sub.11 H.sub.18 N.sub.2 O.sub.2                   62.8                      8.6                         13.3                            62.7                               8.6                                  13.5                                     273-6                                          1665, 1730                                                   14.733                C.sub.12 H.sub.20 N.sub.2 O.sub.2                   64.3                      9.0                         12.5                            64.6                               9.0                                  12.3                                     318-20                                          1660, 1725                                                   27.834                C.sub.12 H.sub.18 N.sub.2 O.sub.2                   64.8                      8.2                         12.6                            65.1                               8.2                                  12.7                                     248-68                                          1660, 1720                                                   13.335                C.sub.9 H.sub.12 N.sub.2 O.sub.2                   60.0                      6.7                         15.6                            59.8                               6.6                                  15.7                                     284-9                                          1665, 1725                                                   31.436                C.sub.11 H.sub.18 N.sub.2 O.sub.2                   62.8                      8.6                         13.3                            62.9                               8.5                                  13.3                                     296- 1630, 1710                                                   36.4                                     302__________________________________________________________________________ 
    
     The foregoing examples describe the various alicyclic spiro derivatives which form a part of this invention. The heterocyclic spiro substituents are prepared in a similar manner to that previously described herein, but for a clear understanding of this invention, the following examples are presented to further describe this novel series of compounds. 
     EXAMPLE 37 
     1-Methyl-4-Hydroxy-4-Carboethoxy Piperidine ##SPC5## 
     A solution of 38.5 grams of sodium bisulphite in 100 ml of water is added dropwise over 30 minutes to a stirred mixture of 32.3 grams of 1-methyl-4-piperidone, 24.1 grams of potassium cyanide and 100 ml of water. The reaction mixture is kept below 40° C by means of a cold water bath and stirred for 2 hours during which time a white crystalline precipitate is formed. The precipitate is filtered, washed with 50 ml of water and dried in vacuo yielding 26.3 grams of 1-methyl-4-piperidone cyanohydrin. 
     The cyanohydrin is refluxed with stirring, with 100 ml concentrated hydrochloric acid for 3 hours. The solution is then concentrated at reduced pressure and the residue taken up in boiling alcohol, filtered hot, and the filtrate concentrated at reduced pressure to a white solid yielding 35.9 grams of 1-methyl-4-hydroxy-4-carboxy-piperidine hydrochloride. 
     The hydroxy acid hydrochloride is heated under reflux with 300 ml of ethanol and 0.15 grams of p-toluene sulphonic acid for 16 hours. The solution is concentrated at reduced pressure and the residue treated with 200 ml of 10 percent sodium carbonate solution, then extracted with 250 ml of chloroform three times. The chloroform solution is washed with 100 ml water, dried over magnesium sulfate and concentrated at reduced pressure. The clear liquid obtained is distilled and on cooling, solidifies to a white crystalline material yielding 16.5 grams of 1-methyl-4-hydroxy-4-carboethoxy piperidine having a boiling point of 93°-95° at 1.2 mm of pressure. Elemental analysis for C 9  H 17  NO 3  :Calculated: C=57.7; H=9.2; N=7.5 Found: C=57.5; H=9.2; N=7.6 
     In Table IV below are listed a representative number of other such hydroxy acid esters prepared in accordance with the procedure of Example 37, and their characteristic physical properties. 
     
                                           TABLE IV__________________________________________________________________________                    Analysis               IR Absorption                                                     % yield                    Calc. %  Found %       chloroform                                                     from              Empirical                    C  H  N  C  H  NOH                                                   C=O  ketoneEx.   Compound        Formula                 BP °C                                           stretch.                                                stretch.__________________________________________________________________________38                 C.sub.16 H.sub.23 NO.sub.3                    69.3                       8.4                          5.1 69.4                                8.5                                   5.3                                      160-4 at                                           3520 1720 58.3                                      0.8 mm39                 C.sub.15 H.sub.21 NO.sub.3                    68.4                       8.0                          5.3 68.7                                8.1                                   5.3                                      142-8 at                                           3510 1710 66.4                                      0.2 mm40                 C.sub.11 H.sub.21 NO.sub.3                    61.4                       9.8                          6.5 61.4                                10.1                                   6.6                                      111-5 at                                           3575 1720 62.1                                      4.0 mm41                 C.sub.10 H.sub.19 NO.sub.3                    59.7                       9.5                          7.0 59.6                                9.5                                   6.9                                      77-80 at                                           3510 1710 51.7                                      0.5 mm42                 C.sub.11 H.sub. 21 NO.sub.3                    61.4                       9.8                          6.5 61.5                                9.8                                   6.4                                      87-103 at                                           3515 1710 30.2                                      1.0 mm__________________________________________________________________________ 
    
     The heterocyclic spiro substituents are generally prepared in the same manner as previously described for the alicyclic spiro compounds; that is, the hydroxy ester is reacted with guanidine hydrochloride in an alcoholic solvent and the product removed. Example 43 following below shows the preparation of one such heterocyclic spiro compound. 
     EXAMPLE 43 
     2-Amino-8-Methyl-3,8-Diaza-Spiro[4,5]Dec-2-En-One ##SPC6## 
     A solution consisting of 43.5 grams of sodium methoxide in 1,320 ml of ethanol is added to a solution containing 78.0 grams of guanidine hydrochloride in 330 ml of ethanol and the mixture stirred thoroughly. Sodium chloride precipitates out of solution and is removed by filtration. A solution of 150.3 grams of 1-methyl-4-hydroxy-4-carboethoxy-piperidine in 375 ml of ethanol is then added to the filtrate and the resulting solution is refluxed with stirring for 1 hour. One liter of ethanol is removed by distillation at reduced pressure and the remaining solution cooled. On cooling a crystalline precipitate forms which is filtered and dried. The filtrate is then completely evaporated at reduced pressure and the residue obtained taken up in 100 ml of fresh ethanol, cooled and additional precipitate is obtained. This procedure is repeated twice more until a total of 74.3 grams of crude product is obtained. The crude product is recrystallized from ethanol, filtered and dried, yielding 56.3 grams of 2-amino-8-methyl-3,8-diaza-spiro[4,5]dec-2-en- 4-one having a melting point of 257°-261° C. Elemental analysis for C 8  H 13  N 3  O 2  : Calculated: C=52.4; H=7.2; N=22.9 Found: C=52.2; H=7.3; N=23.0 
     The procedure of Example 43 may be followed to prepare other heterocyclic spiro compounds. In Table V below is listed those spiro substituents prepared from the corresponding hydroxy esters according to the procedure of Example 43 including the identifying physical characteristics of each. 
     
                                           TABLE V__________________________________________________________________________                     Analysis                IR Absorption                                                      % yield               Empirical                     Calc. %  Found %        bands in                                                      from-Ex.   Compound         Formula                     C  H  N  C  H  N  MP in °C                                             1800 cm.sup..sup.-1                                             reg.     ester__________________________________________________________________________44                  C.sub.7 H.sub.11 N.sub.3 O.sub.2                     49.7                        6.6                           24.8                              49.8                                 6.6                                    24.8                                       313-7 1625,                                                      32.445                  C.sub.15 H.sub.19 N.sub.3 O.sub.2                     65.9                        7.0                           15.4                              65.6                                 7.1                                    15.6                                       253-8 1660,                                                      47.746                  C.sub.14 H.sub.17 N.sub.3 O.sub.2                     64.8                        6.6                           16.2                              64.7                                 6.4                                    16.0                                       225-9 1660,                                                      50.347                  C.sub.10 H.sub.17 N.sub.3 O.sub.2                     56.8                        8.1                           19.9                              57.0                                 8.3                                    19.8                                       293-8 1650,                                                       4.548                  C.sub.9 H.sub.15 N.sub.3 O.sub.2                     54.8                        7.7                           21.3                              54.7                                 7.7                                    21.5                                       246-50                                             1680,                                                      37.149                  C.sub.10 H.sub.17 N.sub.3 O.sub.2                     56.8                        8.1                           19.9                              56.9                                 8.2                                    20.1                                       237-44                                             1640,                                                      35.5__________________________________________________________________________ 
    
     The foregoing 2-amino-5-substituted spiro oxazolin-4-one compounds exhibit central nervous system activity; more specifically, most of these novel compounds are central nervous system depressants. A few of the compounds disclosed herein appear to exhibit stimulant activity, rather than depressant activity. 
     When these compounds are administered to a group of test mice in dosages ranging up to 500 milligrams per kilogram of body weight, the mice exhibit a general decrease in activity being withdrawn and lethargic. Table VI below details the activity of the various species of this series along with the dosages utilized expressed in mg/kg of body weight and the lethal dosage at which 50 percent of the animals expire ( LD  50) for each of the compounds. Unless otherwise indicated, the dosage and the  LD  50 were administered by intraperitoneal injection. It is to be understood, of course, that the particular route of administration is not critical to the manifestation of biological effects. 
     
                                           TABLE VI__________________________________________________________________________                  Dose in                       LD.sub.50 inCompound         Activity                  mg/kg                       mg/kg__________________________________________________________________________6-amino-5-oxa-7-azaspiro[3,4]            depressant                  200  &gt;500oct-6-en-8-one2-amino-1-oxa-3-azaspiro[4,4]            depressant                  500  &gt;1000non-2-en-4-one2-amino-1-oxa-3-azaspiro[4,5]            depressant                  200  &gt;1000dec-2-en-4-one2-amino-1-oxa-3-azaspiro[4,6]            depressant                  500  &gt;1000undec-2-en-4-one2-amino-1-oxa-3-azaspiro[4,7]            depressant                  500  &gt;1000dodec-2-en-4-one2-amino-8-methyl-1-oxa-2-aza-            depressant                  500  &gt;1000spiro[4,5]dec-2-en-4-one2-amino-7-methyl-1-oxa-3-aza-            depressant                  200  ˜750spiro[4,5]dec-2-en-4-one2-amino-7,9-dimethyl-1-oxa-            stimulant                  1    ˜3003-azaspiro[4,5]dec-2-en-4-one2-amino-7,8,9-trimethyl-1-oxa-3-azaspiro[4,5]dec-2-en-4-one            depressant                  200  &gt;10002-amino-7,7,9-trimethyl-1-            stimulant                  0.1  &gt;750oxa-3-azaspiro[4,5]dec-2-en-4-one2&#39;-aminospiro[norbornane-2,            depressant                  500  &gt;10005&#39;-[2]oxazolin]-4&#39;-one2&#39;-amino-octahydrospiro            depressant                  500  &gt;1000[naphthalene-2(1H),5&#39;-[2]oxazolin]-4&#39;-one2-amino-1-oxa-3,8-diazaspiro            depressant                  50   &gt;1000[4,5]dec-2-en-4-one2-amino-8-methyl-1-oxa-3,8-            stimulant                  10   &gt;1000diazaspiro[4,5]dec-2-en-4-one2-amino-8-benzyl-1-oxa-3,8-diazaspiro[4,5]dec-2-en-4-one            depressant                  200  &gt;10002-amino-7,8,9-trimethyl-1-oxa-            depressant                  20   &gt;5003,8-diazaspiro[4,5]-2-en-4-one2-amino-8-isopropyl-1-oxa-3,8-            depressant                  100  1000diazaspiro-[4,5]dec-2-en-4-one2-amino-8-phenethyl-1-oxa-            depressant                  200  &gt;10003,8-diazaspiro-[4,5]dec-2-en-4-one__________________________________________________________________________ 
    
     In addition to the foregoing activity, the administration of some of these novel compounds to warm-blooded animals results in an increased rate of learning by the animal coupled with a prolonged period of retention of the learned behavior. 
     The behavioral effects resulting from the administration of these compounds to rats were evaluated on a modified Cook-Weidley apparatus (L. Cook and E. Weidley, Ann. N.Y. Acad. Sci., 66, 790, 1957). The apparatus consists of a chamber with a grid flooring and an escape platform outside the chamber. The electric shock to the grid floor was controlled by a rheostat mechanism and scrambler. Rats were divided into 2 groups for each test trial. One group was administered saline as the control and the other group the test compound about 1/2 hour prior to electroconvulsive shock. It is known that electroconvulsive shock induces a state of proactive amnesia or an impaired learning rate (Deutsch, J.A., 1962, Ann. Rev. Psychol., 24, 259). Then, 15 minutes after electroconvulsive shock, the rats were given 10 acquisition trials on the jump out test to measure learning rates. Each acquisition trial consisted of 15 seconds in the chamber without any stimulation followed by 10 seconds of buzzer stimulation and culminated by 5 seconds of buzzer-plus-shock stimulation. The time from entrance into the apparatus until the rat jumps out is recorded as the escape time. Retention of the learned behavioral pattern was tested by repeating the test one hour after the last acquisition trial. The test sequence for each trial was terminated upon successful completion of the task, e.g., jumping out of the chamber.EFFECT OF 2-AMINO-8-METHYL-1-OXA-3,8-DIAZASPIRO[4,5]DEC-2-EN-4-ONEINTRAPERITONEAL ADMINISTRATION  Mean Escape Time -- Sec.Trial    Test Cpd. -- 10 mg/kg                    Control______________________________________1        29.8 ± 0.3   30.0 ± 0.02        29.5 ± 0.5   29.3 ± 0.83        13.8 ± 1.7   26.0 ± 2.44        12.0 ± 2.1   22.0 ± 3.65         7.0 ± 1.6   22.3 ± 3.86         7.8 ± 1.5   18.5 ± 1.97         6.5 ± 1.6   18.0 ± 2.38         7.0 ± 2.2   13.0 ± 2.99        10.8 ± 3.0   15.6 ± 2.110        9.0 ± 1.2   13.9 ± 1.7Retention Trial -- 1 hour after last Acquisition Trial:  13.8 ± 1.4 15.8 ± 3.3EFFECT OF 2-AMINO-7,7,9-TRIMETHYL-1-OXA-3-AZASPIRO[4,5]DEC-2-EN-4-ONEINTRAPERITONEAL ADMINISTRATION  Mean Escape Time -- Sec.Trial    Test Cpd. 20 mg/kg                    Control______________________________________1        30.0 ± 0.0   30.0 ± 0.02        29.0 ± 0.4   29.5 ± 0.23        21.2 ± 3.0   19.7 ± 5.24        17.7 ± 5.4   20.2 ± 5.35        14.7 ± 1.8   18.0 ± 2.76        18.0 ± 3.9   18.5 ± 3.67        10.0 ± 2.1   20.2 ± 4.78         5.5 ± 1.8   16.5 ± 3.89         6.7 ± 2.5   18.7 ± 5.010        7.2 ± 2.8   13.7 ± 4.4Retention Trial -- 1 hour after last Acquisition Trial:   8.0 ± 2.6 20.2 ± 3.3EFFECT OF 2-AMINO-7,9-DIMETHYL-1-OXA-3-AZASPIRO[4,5]DEC-2-EN-4-ONEORAL ADMINISTRATION  Mean Escape Time -- Sec.Trial    Test Cpd. -- 20 mg/kg                    Control______________________________________1        30.0 ± 0.0   30.0 ± 0.02        29.2 ± 0.4   29.7 ± 0.23        20.0 ± 4.3   27.2 ± 1.84         7.5 ± 2.9   19.7 ± 2.45         4.7 ± 0.8   16.0 ± 3.26         7.2 ± 2.0   14.7 ± 3.67         8.0 ± 1.6   18.7 ± 4.58        10.5 ± 3.7   11.0 ± 2.69         7.0 ± 1.2   13.0 ± 3.210        7.5 ± 2.1   15.5 ± 4.1Retention Trial -- 1 hour after last Acquisition Trial:   6.7 ± 1.4 15.7 ± 5.0______________________________________