Synthesis and Antiviral Activity Evaluation of Some New

2), thymidine kinase-deficient (TK-) HSV-1, vaccinia, vesicular stomatitis, polio 1, Coxsackie. B4, Sindbis, Semliki forest, Reo 1, varicella-zoster v...
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J. Med. Chem. 1996, 39, 3307-3318

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Synthesis and Antiviral Activity Evaluation of Some New Aminoadamantane Derivatives. 2 Nicolas Kolocouris,*,† Antonios Kolocouris,† George B. Foscolos,† George Fytas,† Johan Neyts,‡ Elisabeth Padalko,‡ Jan Balzarini,‡ Robert Snoeck,‡ Graciela Andrei,‡ and Erik De Clercq‡ Department of Pharmacy, Division of Pharmaceutical Chemistry, University of Athens, Panepistimioupoli-Zografou GR-15771, Athens, Greece, and Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium Received December 6, 1995X

The synthesis of some new aminoadamantane derivatives is described. The new compounds were evaluated against a wide range of viruses [influenza A H1N1, influenza A H2N2, influenza A H3N2, influenza B, parainfluenza 3, herpes simplex virus type 1 (HSV-1) and type 2 (HSV2), thymidine kinase-deficient (TK-) HSV-1, vaccinia, vesicular stomatitis, polio 1, Coxsackie B4, Sindbis, Semliki forest, Reo 1, varicella-zoster virus (VZV), TK- VZV, human cytomegalovirus (HCMV), and human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2)]. Some of them proved markedly active against the influenza A H2N2 (compounds 4a,b, 5a, 6a, and 7a), H3N2 (compounds 5a, 6a, and 7a), and H1N1 (compounds 4b,c and 6d). Since compounds 5a, 6a, and 7a, amantadine, and rimantadine showed the same comparative pattern of potency against influenza strains H2N2, H3N2, and B, it may postulated that they act according to a similar mechanism, with regard to their “amine” effect, on the M2 ion channel of influenza A (H1N1, H2N2, or H3N2). In general, no significant activity was noted with any of the new compounds against any of the other viruses tested, making their activity against influenza virus more specific and striking. Borderline activity was noted with some of the compounds (4b,c, 5a-c, and 8a) against HIV-1. Introduction Amantadine (1-adamantanamine) has been established as effective in the prophylaxis and treatment of influenza A virus infections.1-4 Although initially licensed in 1966, the clinical use of amantadine has been limited by central nervous system (CNS) side effects.5,6 On the other hand, the structural analog of amantadine, rimantadine (R-methyl-1-adamantanemethanamine), has been reported to be more active against influenza A virus in vitro in laboratory experiments, in animals, and also in human beings. Rimantadine has been considered to possess fewer side effects and appears to be the drug of choice for the chemoprophylaxis and therapy of influenza A.4,7,8 It has recently been demonstrated that the target of this selective, strain-specific antiviral activity is the hydrophobic, membrane-spanning domain of the small M2 protein and that the adamantanamines inhibit virus replication by blocking the M2 protein ion channel function and subsequently its ability to modulate the pH of the intracellular compartment in virus-infected cells. This may account for the lack of activity of amantadine and rimantadine against influenza B virus, which does not possess this protein.9-14 We have recently reported the synthesis and antiviral evaluation of some aminoadamantane derivatives:15 spiro[pyrrolidine-2,2′-adamantane]s 1 and spiro[cyclopropane-1,2′-adamantan]-2-amines and methanamines 2 (Figure 1). The antiviral activity assays revealed that some of them exhibited potent antiviral activity against influenza A virus accompanied by low cytotoxicity. Particularly striking was the potency and selectivity of † ‡ X

University of Athens. Katholieke Universiteit Leuven. Abstract published in Advance ACS Abstracts, July 1, 1996.

S0022-2623(95)00891-0 CCC: $12.00

the N-methyl derivative 1 (R ) CH3) which inhibited influenza A virus-induced cytopathicity at a concentration of 0.56 µg/mL while not being toxic to the host cells at a concentration as high as 400 µg/mL. Furthermore, some spiro[pyrrolidine-3,2′-adamantane]s 3 showed potent activity against influenza A virus, parainfluenza virus (Sendai), rhinovirus, and Coxsackie A21 viruses.16,17 In regard to the potency of the N-methyl analogs 1 and 3 (R ) CH3), derivative 1 with the pyrrolidine nitrogen closer to the adamantane spiro system is 200 times more active in vitro than its counterpart 3. Furthermore, compound 1 exhibits selectivity against influenza A virus. As a continuation of our efforts to explore the stereoelectronic requirements for optimal antiviral activity of spiro adamantane derivatives, we now report on the synthesis and biological evaluation of several new spiro[piperidine-2,2′-adamantane]s 4 and spiro[morpholine3,2′-adamantane]s 5 bearing a 6-membered heterocyclic ring. In contrast with analogs 1, 4, and 5, the two nuclei of the new molecules 6 are allowed to rotate freely with respect to each other. It is also noteworthy that the latter contain the rimantadine skeleton which is also present in the amines 7. In addition, following the observation that 1-(1-adamantyl)pyrrolidine showed antiviral action18 and aiming at investigating some new structure-antiviral activity relationships of this skeleton, we have synthesized the pyrrolidines 8 and 9. Chemistry The synthetic route followed for the synthesis of the spiro[piperidine-2,2′-adamanantane]s 4 is presented in Scheme 1. The Michael condensation of 2-nitroadamantane anion (10) with acrylic ethyl ester afforded the corresponding ethyl ester as a crude oil.15 This was © 1996 American Chemical Society

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Figure 1.

Scheme 1a

a Reagents: (a) CH dCHCO Et, Triton B, t-BuOH, 55 °C; (b) NaOH, EtOH-H O, reflux; (c) gas HCl, MeOH, room temperature; (d) 2 2 2 NaBH4, dioxane-H2O (1:1), room temperature; (e) SOCl2, toluene, 90 °C; (f) KCN, 18-crown-6, acetonitrile, reflux; (g) gas HCl, CH3OH, reflux, then H2O, reflux; (h) i. H2/Ni, EtOH, 50 °C, ii. EtOH, reflux; (i) LiAlH4, DME, reflux; (j) R′COCl, Et3N, ether, room temperature; (k) LiAlH4, THF, reflux.

purified by saponification, and the intermediate carboxylic acid was then esterified to the methyl ester 11. Selective reduction of the methyl ester 11 with NaBH4 in dioxane-water19 gave the 2-nitro-2-adamantanepropanol (12). Attempts at the direct conversion of alcohol 12 to nitrile 14 via known procedures which

have been shown to proceed by activation of the alcohol function as the trimethylsilyl derivative20 or via the corresponding trifluoroacetate21 failed to succeed. Thus, the above nitro alcohol 12 was converted to its chloride 13 upon treatment with SOCl2 at 90 °C. The nitrile 14 was obtained from the reaction of 13 with KCN in

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Journal of Medicinal Chemistry, 1996, Vol. 39, No. 17 3309

Scheme 2a

a Reagents: (a) CH O, NaOH, dioxane, reflux; (b) H /Ni, EtOH, 50 °C; (c) BrCH COCl, KOH, H O, dichloromethane; (d) KOH, H O, 2 2 2 2 2 dioxane, reflux; (e) LiAlH4, THF, reflux; (f) R′COCl, Et3N, ether, room temperature.

Scheme 3a

a Reagents: (a) 1-AdCOCl, THF, reflux; (b) CaO, ∆; (c) NaBH , MeOH-AcOH (3:1), -30 °C; (d) CH O, NaCNBH , acetonitrile, room 4 2 3 temperature; (e) R′COCl, Et3N, ether, room temperature; (f) LiALH4, THF, reflux.

acetonitrile in the presence of 18-crown-6.22 Methanolysis of the nitrile 14 and hydrogenation of the intermediate nitro ester 15 over Raney nickel catalyst afforded the spiro[piperidine-2,2′-adamantan]-6-one (16) after δ-lactamization in boiling ethanol. Reduction of the δ-lactam 16 with LiAlH4 in DME led to the parent spiro[piperidine-2,2′-adamantane] 4a. N-Acylation of the latter followed by reduction of the intermediate amides 17a,b gave the N-methyl (4b) and N-ethyl (4c) derivatives. The synthesis of the spiro[morpholine-3,2′-adamantane]s 5 is illustrated in Scheme 2. Hydroxymethylation of the 2-nitroadamantane (10) afforded the 2-nitro2-adamantanemethanol (18). Catalytic reduction of the nitro alcohol 18 resulted in the 2-amino-2-adamantanemethanol (19), which was treated with bromoacetyl chloride to give the N-bromoacetamide 20 along with traces of the N,O-bis(bromoacetylated) product. The bromoacetamide 20 was then cyclized in alkaline medium to afford the spiro[morpholine-3,2′-adamantan]5-one (21), which was converted to the parent morpholine 5a by means of LiAlH4 reduction. The amines 5b,c were prepared by reduction of the intermediate amides

22a,b, respectively. N-Methylation of the morpholine 5a according to Borch and Hassid23 (NaCNBH3, CH2O, CH3CN) or Charles et al.24 (NaBH4, CH2O, CH3OH) afforded a mixture of the N-methyl derivatives 5b,a in a 9:1 ratio. The synthesis of 2-(1-adamantyl)pyrrolidines is shown in Scheme 3. 1-(1-Adamantylcarbonyl)-2-pyrrolidinone (24) was obtained from the reaction of 1-adamantanecarbonyl chloride with 1-(trimethylsilyl)-2-pyrrolidinone (23).25 Dry distillation of the N-acylpyrrolidinone 24 in the presence of CaO26-28 led to the 2-(1-adamantanyl)1-pyrroline (25). Reduction of pyrroline 25 with NaBH4 resulted in the 2-(1-adamantanyl)pyrrolidine (6a), which was converted to the desired N-substituted derivatives 6b-d via suitable alkylations. 2-Pyrrolidinemethanamine 8a was synthesized as illustrated in Scheme 4. The reaction of methyl pyroglutamate (27) with 1-bromoadamantane in the presence of Ag2SO418 gave the methyl ester 28, which was saponified to the 1-(1-adamantyl)pyroglutamic acid (29). Acid 29 was converted into the amide 30, which was then reduced with LiAlH4 to the amine 8a.

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Scheme 4a

a Reagents: (a) 1-BrAd, Ag SO , 100 °C; (b) NaOH, EtOH-H O, room temperature; (c) i. SOCl , 55 °C, ii. Me NH, THF, room temperature; 2 4 2 2 2 (d) LiAlH4, THF, reflux.

Scheme 5a

a

Reagents: (a) CH2dC(CO2H)CH2CO2H, 185 °C; (b) i. SOCl2, 65 °C, ii. Me2NH, THF, room temperature; (c) LiAlH4, THF, reflux.

Scheme 6a

Scheme 7a

a Reagents: (a) 1-AdCOCl, Et N, ether, room temperature; (b) 3 LiAlH4, THF, reflux.

a Reagents: (a) succinic anhydride, xylene, reflux; (b) i. SOCl , 2 65 °C, ii. Me2NH, THF, room temperature; (c) LiAlH4, THF, reflux.

Michael condensation of 1-adamantanamine (31) with itaconic acid29 gave the 1-(1-adamantyl)-5-oxo-3-pyrrolidinecarboxylic acid (32) (Scheme 5). The latter was converted into the amide 33, which upon treatment with LiAlH4 afforded the amine 8b. The reaction of aldimine 34 with succinic anhydride30 in refluxing xylene gave a diastereomeric mixture of the acids 35 and 36 (Scheme 6). Since the 1H NMR signals of the methoxycarbonyl protons of this cis methyl ester appear 0.5 ppm upfield with respect to the corresponding protons of the trans isomer, it was possible to estimate the relative yields of the diastereomeric acids by integration of the 1H NMR spectra of the mixture of the methyl esters which were obtained upon Me2SO4 treatment of the crude carboxylic acid product. The ratio of the acids 35 to 36 was estimated to be 7(trans): 1(cis). Treatment of the diastereomeric mixture with hot methanol led to the isolation of the acids 35 and 36 in pure form. Compounds 35 and 36 were in turn converted into the amides 37 and 38 which were then reduced with LiAlH4 to the pyrrolidines 8c,d. The desired pyrrolidines 9a-d were prepared from the corresponding carboxamides 43-46, upon reduction with LiAlH4 (Scheme 7). The target compounds and their intermediates were obtained in high yields, except for pyrroline 25 which was afforded in 34% yield.

Results and Discussion The aminoadamantane derivatives prepared were evaluated according to previously reported methods34-39 against the following viruses: influenza A, influenza B, parainfluenza 3, herpes simplex virus type 1 (HSV-1), thymidine kinase-deficient (TK-) HSV-1, herpes simplex virus type 2 (HSV-2), vaccinia, vesicular stomatitis, polio 1, Coxsackie B4, Sindbis, Semliki forest, Reo 1, varicellazoster virus (VZV), TK- VZV, human cytomegalovirus (HCMV), and human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2). The IC50 values obtained against influenza A for the new compounds 4a-c, 5a, 6a,d, and 7a were comparable to and in some cases lower than those of the reference compounds amantadine and rimantadine. In general, these aminoadamantane derivatives did not exhibit any significant activity against any of the other viruses examined. This fact makes the activity of 4ac, 5a, 6a,d, and 7a against influenza A virus even more specific and striking. Compounds 4b,c and 6d proved at least as active, if not more active, than rimantadine and amantadine against influenza A H1N1. In addition, compounds 4a,b, 5a, 6a, and 7a were markedly active against influenza A H2N2 virus, a strain with exquisite sensitivity to amantadine and rimantadine. The same compounds that were found active against influenza A H2N2 virus, in particular compounds 5a, 6a, and 7a, were also active against influenza A H3N2 virus and influenza B virus, albeit at higher concentrations. Also

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Table 1. Antiviral Activity and Cytotoxicity of Various Aminoadamantane Derivatives virusa

cellb

influenza A, H1N1 H2N2 H3N2 influenza B parainfluenza 3 HSV-1 TK- HSV-1 HSV-2 vaccinia vesicular stomatitis polio 1 Coxsackie B4

MDCK MDCK MDCK MDCK Vero HEF HEF HEF HEF HEF HeLa HeLa HeLa Vero Vero Vero Vero HEL HEL HEL CEM CEM

Sindbis Semliki forest Reo 1 TK+ VZV TK- VZV HCMV HIV-1 HIV-2 morphology

proliferation viability

influenza A, H1N1 H2N2 H3N2 influenza B parainfluenza 3 HSV-1 TK- HSV-1 HSV-2 vaccinia vesicular stomatitis polio 1 Coxsackie B4 Sindbis Semliki forest Reo 1 TK+ VZV TK- VZV HCMV HIV-1 HIV-2 morphology

proliferation viability

MIC50c (µg/mL) 4a

4b

6a

6b

6c

6d

>35 0.24 43 60 >400 100 >200 >200 >200 >200 >400 >400 >400 >400 >400 >400 >400 >50 >50 >50 >40 >40

6.2 0.58 45 60 >400 >200 >200 >200 >200 >200 >400 >400 >400 >400 >400 >400 >400 >50 >50 >50 115 >200

4.4 29 22 >10 31 1.7 4.3 10.5 g65 13 53 g57 g80 20 60 g80 >400 >400 >400 >400 >200 >200 >400 >400 >200 >200 >400 >400 >200 >200 >400 >400 >200 >200 >400 >400 >200 >200 >400 >400 >400 >400 >400 >400 >400 >400 >400 >400 >400 >400 >400 >400 >400 >400 >400 >400 >400 >400 >400 >400 >400 >400 >400 >400 >400 >400 >400 >400 >50 >50 >50 >50 >50 >50 >50 >50 >50 >50 >50 >50 200 158 ( 60 158 ( 60 158 ( 60 >200 >200 >200 >200

15.8 0.6 12.4 12 >200 >40 >40 >40 >40 >40 >100 >100 >100 >200 >200 >200 >200 >50 >50 >50 >40 >40

>34 16.5 60 60 >400 >100 >100 >100 >100 >100 >400 >400 >400 >400 >400 >400 >400 >50 >50 >50 >40 >40

>34 g14 58 60 >400 >100 >100 >100 >100 >100 >400 >400 >400 >400 >400 >400 >400 >50 >50 >50 >40 >40

4 44.5 g100 g80 >100 >40 >40 >40 >40 >40 >100 >100 >100 >100 >100 >100 >100 >50 >20 >50 >40 >40

>250 >400 100 >400 >50 >200

>250 >400 100 >400 >50 >200

250 250 400 >400 100 200 g200 >400 >50 >50 56 ( 12 120

MDCK >250 Vero >400 HEF 400 HeLa >400 HEL >50 CEM 93 ( 5.7

4c

8a

8b

8c

MDCK MDCK MDCK MDCK Vero HEF HEF HEF HEF HEF HeLa HeLa HeLa Vero Vero Vero Vero HEL HEL HEL CEM CEM

>70 32.5 73 60 >400 >200 >200 >200 >200 >200 >400 >400 >400 >400 >400 >400 >400 >50 >50 >50 115 >200

>36 16.1 >100 >100 >100 >10 >10 >10 >10 >10 >200 >200 >200 >100 >100 >100 >100 >20 >50 >20 g23 g40

>36 20.5 g100 g60 >100 >10 >10 >10 >10 >10 >100 >100 >100 >100 >100 >100 >100 >20 >20 >5 >40 >40

MDCK Vero HEF HeLa HEL CEM

>250 >400 g400 >400 >50 >200

5a

5b

>250 >400 >200 >400 >50 >200 8d >34 >100 >100 >100 >100 >10 >10 >10 >10 >10 >100 >100 >100 >100 >100 >100 >100 >20 >20 >20 >40 >40

5c

>250 >400 g400 >400 >50 >200

>250 >400 >400 >400 >50 >200

9a

9b

9c

9d

>150 35 g87 >100 >200 >40 >40 >40 >40 >40 100 >200 >200 >200 >200 >200 >200 >50 >50 >50 >40 >40

>150 >60 >47 >100 >100 >40 >40 >40 >40 >40 >100 >100 >100 >100 >100 >100 >100 32 20 >50 >40 >40

>150 >100 >100 >100 >100 >40 >40 >40 >40 >40 100 >100 >100 >100 >100 >100 >100 30 20 >50 >20 >20

>104 >100 >100 >100 >200 >100 >100 >100 >100 >100 >100 >100 >100 >200 >200 >200 >200 35 20 >50 >40 >40

7a >64 2.5 6 20 >10 >10 >10 >10 >10 >10 >40 >40 >40 >10 >10 >10 >10 >20 >20 >20 >8 >8

7b

7c

59 9 >60 g80 >100 >10 >10 >10 >10 >10 >40 >40 >40 >100 >100 >100 >100 >20 >20 >20 >8 >8

>80 19.7 >100 >100 >400 >40 >40 >40 >40 >40 >100 >100 >100 >400 >400 >400 >400 30 30 40 >40 >40

250 250 >250 >250 >250 >400 g200 >400 >400 >400 200 100 40 40 100 >400 200 100 g100 200 >50 >50 >50 >50 >50 115 ( 7.1 74 ( 9.2 18 ( 0.7 49 70 ( 8.5

amant rimant 48 >28 0.8 e0.14 g12 g20 -

250 250 250 >250 >250 >250 >250 >250 >400 >400 400 >400 >400 g200 400 40 40 40 100 100 100 200 400 200 200 g400 200 200 200 >50 >50 >50 >50 >50 >50 >50 79 ( 8.5 79 ( 7.8 82 ( 26 99 ( 0.7 59 ( 3.5 33 ( 0.7 72 ( 4.2 -

250 -

ribav

BVDU

ganciclovir

19 48.7 5.6 2.4 150 >200 >200 >200 20 20 20 20 10 >400 >400 >400 70 -

>400 0.007 100 >200 0.7 >200 >400 >400 >400 >400 >400 >400 >400 0.0037 15 -

>200 0.02 0.002 >100 >100 0.7

>250 >400 400 g400 -

>400 400 >400 >200 -

>100 -

a Abbreviations and virus strains: amant, amantadine; rimant, rimantadine; ribav, ribavirin; influenza A H1N1 (A/Taiwan/1/86); influenza A H2N2 (A2/Japan/305/57); influenza A H3N2 (X31); influenza B (Hong Kong/5/72); RSV, respiratory syncytial virus (Long); HSV-1, herpes simplex virus type 1 (KOS); TK- HSV-1, thymidine kinase-deficient HSV-1 (B2006); HSV-2, herpes simplex virus type 2 (G); VZV, varicella-zoster virus; TK+ VZV, thymidine kinase-deficient VZV (YS); TK- VZV, thymidine kinase-deficient VZV (YS/R); HCMV, human cytomegalovirus (AD-169); HIV-1, human immunodeficiency virus type 1 (IIIB/LAl); HIV-2, human immunodeficiency virus type 2 (ROD). b Abbreviations: MDCK, Madin-Darby canine kidney; HEF, human embryonic fibroblasts [either embryonic lung (for cell proliferation studies and antiviral studies) or embryonic skin-muscle (for cell morphology studies and antiviral studies)]. Vero, HeLa, HEL, and MT-4 represent African green monkey kidney cells, human epithelial cells, human embryonic lung cells, and human T-lymphocytes, respectively. c Minimum inhibitory concentration required to reduce virus-induced cytopathicity by 50%, to cause a microscopically detectable alteration of normal cell morphology, or to reduce cell proliferation or cell viability by 50%. All data represent average values for at least two separate experiments.

rimantadine was less active against influenza A H3N2 virus and influenza B virus than against influenza A H2N2 virus. Based on their comparative pattern of potency against the three influenza virus strains (H2N2,

H3N2, and B), it may be postulated that compounds 5a, 6a, and 7a act according to a similar mechanism as amantadine and rimantadine. Rimantadine, like amantadine, is assumed to block influenza A virus replication

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by blocking the ion channel of the small virus membrane protein M2.9-14 It is also noteworthy that analogs 4b,c, 5a-c, and 8a exhibited borderline anti-HIV-1 activity. Furthermore, these compounds were not active against HIV-2. It should also be pointed out that the anti-HIV-1 activity is exhibited only by the spiro 6-membered analogs 4 and 5 but not by the spiro 5-membered analogs 1.15 These aminoadamantane derivatives may merit further study as potential leads for the development of new anti-HIV-1 agents. In conclusion, it seems that the presence of 5- or 6-membered amino heterocycles and adamantane in one frame greatly enhances the antiviral activity against influenza A virus. This effect becomes more pronounced when the nitrogen atom is closer to the adamantane moiety. Also the size of the amino heterocycle seems to be critical for antiviral activity. In particular the antiviral activity and specificity against influenza A virus is enhanced in the 5-membered spiro analog 1 relative to the 6-membered analogs 4 and 5. Furthermore, it appears that the size of the N-alkyl group contributes in a different manner to the activity of the compounds against the different influenza A strains.

mmol) in EtOH/H2O (10 ml/3 mL). The mixture was heated to 50 °C for 2 h. After removal of the solvent, water was added and the mixture was extracted with ether. The organic phase was washed with water and brine and dried (Na2SO4). Concentration in vacuo afforded the nitro alcohol 12 (310 mg, 87%): mp 93 °C (Et2O-pentane); IR (Nujol) ν(NO2) 1536, ν(OH) 3270 cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.20-2.10 (complex m, 17H, 4,5,6,7,8,9,10-H, CH2CH2CH2OH), 2.53 (s, 2H, 1,3-H), 3.60 (t, 2H, J ∼ 6 Hz, CH2CH2OH). Anal. (C13H21NO3) C, H, N. 2-(3-Chloropropyl)-2-nitrotricyclo[3.3.1.13,7]decane (13). A mixture of the alcohol 12 (300 mg, 1.26 mmol), toluene (4 mL), and SOCl2 (930 mg, 8 mmol) was heated at 95 °C for 45 min. After removal of the solvent, ether was added and the organic solution was washed with water, NaHCO3 (10%), and then water. The ether extracts were dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was chromatographed on neutral aluminum oxide (100-125 mesh) with ether-hexane (1:1) as the eluent to give chloride 13 (310 mg, 96%): mp 58 °C (n-pentane); 1H NMR (CDCl3, 200 MHz) δ 1.56-2.01 (complex m, 14H, 4,5,6,7,8,9,10-H, CH2CH2CH2Cl), 2.04-2.16 (complex m, 2H, CH2CH2CH2Cl), 2.53 (s, 2H, 1,3-H), 3.48 (t, 2H, J ∼ 6 Hz, CH2CH2Cl). Anal. (C13H20ClNO2) C, H, N. 2-Nitro-2-tricyclo[3.3.1.13,7]decanebutanenitrile (14). To a solution of the chloride 13 (240 mg, 0.93 mmol) and 18crown-6 (100 mg, 0.38 mmol) in dry acetonitrile (5 mL) was added anhydrous KCN (182 mg, 2.79 mmol) at room temperature. The mixture was then refluxed with vigorous stirring for 2 h. After evaporation of the solvent, water was added and the mixture was extracted with ether. The ether layer was washed with water and brine and dried (Na2SO4). Evaporation of the solvent afforded the nitrile 14 (228 mg, 99%): mp 117 °C (n-pentane); IR (Nujol) ν(NO2) 1527, ν(CN) 2244 cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.45-1.63 (complex m, 2H, CH2CH2CH2CN), 1.66-2.23 (m, 12H, 4,5,6,7,8,9,10-H), 2.01-2.23 (m, 2H, CH2CH2CH2CN), 2.33 (t, 2H, J ∼ 7 Hz, CH2CH2CN), 2.53 (s, 2H, 1,3-H). Anal. (C14H20N2O2) C, H, N. Methyl 2-Nitro-2-tricyclo[3.3.1.13,7]decanebutanoate (15). A solution of the nitrile 14 (220 mg, 0.89 mmol) in dry MeOH (2.5 mL) was treated with a saturated methanolic solution of gaseous HCl (5 mL). The resulting mixture was refluxed for 90 min. A drop of water was added, and refluxing was continued for 30 min. After evaporation of the solvent, water was added, and the mixture was extracted with ether. The ether layer was washed with NaHCO3 (10%), water, and brine, dried (Na2SO4), and evaporated to give the methyl ester 15 (229 mg, 92%): mp 54 °C (n-pentane); IR (Nujol) ν(CdO) 1734, ν(NO2) 1533 cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.381.60 (complex m, 2H, CH2CH2CH2CO), 1.61-2.10 (m, 14H, 4,5,6,7,8,9,10-H, CH2CH2CH2CO), 2.26 (t, 2H, J ∼ 7 Hz, CH2CH2CO), 2.53 (s, 2H, 1,3-H), 3.64 (s, 3H, CH3). Spiro[piperidine-2,2′-tricyclo[3.3.1.13,7]decan]-6-one (16). A solution of the nitro ester 15 (440 mg, 1.56 mmol) in ethanol (20 mL) was hydrogenated in the presence of Raney nickel catalyst under a pressure of 45 psi, at 50 °C, for 8 h. The suspension was filtered to remove the catalyst, and the filtrate was refluxed for 5 h. The solvent was evaporated, and the residue was chromatographed on neutral alumina (100-125 mesh) with 1:1 chloroform-n-hexane as the eluent to afford the δ-lactam 16 (334 mg, 97.4%): mp 165-166 °C (n-pentane); IR (Nujol) ν(NH) 3290, 3250, ν(CdO) 1653 cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.49-2.13 (m, 18H, adamantane H, 3,4H), 2.28 (t, 2H, J ∼ 7 Hz, 5-H), 6.39 (br s, 1H, 1-H); 13C NMR (CDCl3, 50 MHz) δ 16.2 (4-C), 26.6 (7′-C), 27.0 (5′-C), 30.4 (3C), 30.8 (5-C), 32.1 (4′-C, 9′-C), 33.6 (8′-C, 10′-C), 37.0 (1′-C, 3′-C), 38.4 (6′-C), 57.8 (2,2′-C), 172.1 (6-C). Anal. (C14H21NO) C, H, N. Spiro[piperidine-2,2′-tricyclo[3.3.1.13,7]decane] (4a). To a stirred suspension of LiAlH4 (443 mg, 11.7 mmol) in dry DME (20 mL) was added dropwise a solution of the lactam 16 (320 mg, 1.46 mmol) in dry DME (10 mL). The reaction mixture was refluxed for 36 h and then hydrolyzed with water and NaOH (10%) under ice cooling. The inorganic precipitate was filtered off and washed with DME, and the filtrate was

Experimental Section Melting points were determined using a Buchi capillary apparatus and are uncorrected. IR spectra were recorded on a Perkin-Elmer 833 spectrometer. 1H NMR spectra were recorded on Bruker AC200 and AC300 spectrometers at 200 and 300 MHz, respectively, using CDCl3 as solvent and TMS as internal standard. 13C NMR spectra were recorded on a Brucker AC200 spectrometer at 50 MHz using CDCl3 as solvent and TMS as internal standard. Carbon multiplicities were established by DEPT experiments. The 2D NMR techniques (XHCORR and COSY) were used for the elucidation of the structures of some derivatives. Microanalyses were carried out by the Service Central de Microanalyse (CNRS), France, and the results obtained had a maximum deviation of (0.4% from the theoretical value. 2-Nitroadamantane (10) was prepared from the oxime of 2-adamantanone.15 1-(Trimethylsilyl)-2-pyrrolidinone (23) was prepared in 85.5% yield from the reaction of 2-pyrrolidinone with Me3SiCl in the presence of Et3N in refluxing toluene:25 bp 102-104 °C (25 mmHg). The crystallization of hydrochlorides 5b,c and 6d proved to be tedious and required totally anhydrous conditions. Aldimine (34) and methyl pyroglutamate (27) were prepared using known procedures.18,25 The pyrrolidines 39-41 were synthesized by reducing the corresponding lactams with LiAlH4.31,32 The pyrrolidine 42 was prepared upon reduction of 2-tert-butyl-1-pyrroline28 with NaBH4. The synthesis of (1-adamantyl)-1-cyclopentanamines 7 has previously been reported.33 Methyl 2-Nitro-2-tricyclo[3.3.1.13,7]decanepropanoate (11). 2-Nitro-2-adamantanepropanoic acid15 (8.1 g, 32 mmol) was esterified in a methanolic solution of gaseous HCl to give the methyl ester 11 as an oil which was crystallized on cooling: yield 8.25 g (97%); mp 61 °C (n-pentane); IR (Nujol) ν(CdO) 1735, ν(NO2) 1530 cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.56-2.05 (m, 12H, 4,5,6,7,8,9,10-H), 2.10-2.40 (m, 4H, CH2CH2CO), 2.51 (s, 2H, 1,3-H), 3.63 (s, 3H, CH3). 2-Nitro-2-tricyclo[3.3.1.13,7]decanepropanol (12). To a stirred suspension of the nitro ester 11 (410 mg, 1.54 mmol) in dioxane-H2O (1:1, 10 mL) was added NaBH4 (580 mg, 15.4 mmol) in small portions, and stirring was continued for 22 h, at room temperature. The mixture was acidified with HCl (18%) under ice cooling and extracted with ether. The combined ether extracts were washed with water and brine. The solvent was removed under reduced pressure, and the residue was treated with a solution of NaOH (62 mg, 1.54

New Aminoadamantane Derivatives

Journal of Medicinal Chemistry, 1996, Vol. 39, No. 17 3313

concentrated in vacuo. The residue was dissolved in ether and extracted with HCl (5%). The aqueous layer was made alkaline with solid Na2CO3 and extracted with ether. The combined ether extracts were washed with water and brine and dried (Na2SO4). After evaporation of the solvent, the residue was chromatographed on neutral aluminum oxide (100-125 mesh) with 1:1 ether-hexane as an eluent to give the piperidine 4a (256 mg, 85.4%): mp 34 °C (n-pentane); IR (film) ν(NH) 3295 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.112.02 (complex m, 21H, adamantane H, 1,3,4,5-H), 2.73 (t, 2H, J ∼ 5 Hz, 6-H); 13C NMR (CDCl3, 50 MHz) δ 19.8 (4-C), 26.6 (5-C), 27.5 (7′-C), 28.0 (5′-C), 32.0 (4′-C, 9′-C), 33.2 (3-C), 33.3 (8′-C, 10′-C), 33.9 (1′-C, 3′-C), 38.9 (6′-C), 39.8 (6-C), 54.2 (2,2′C). Hydrochloride: mp >260 °C (EtOH-Et2O). Picrate: mp >260 °C (MeOH-Et2O). Anal. (C20H26N4O7) C, H. 1-(Ethoxycarbonyl)spiro[piperidine-2,2′-tricyclo[3.3.1.13,7]decane] (17a). Ethyl chloroformate (390 mg, 3.61 mmol) in dry ether (10 mL) was added dropwise under ice cooling to a stirred solution of the piperidine 4a (370 mg, 1.8 mmol) and triethylamine (640 mg, 6.30 mmol) in dry ether (10 mL). The mixture was stirred at room temperature for 25 h. The precipitated triethylamine hydrochloride was filtered off, and the filtrate was washed with water, cold HCl (2%), water, and dried (Na2SO4). The solvent was evaporated, and the residue was filtered through neutral alumina (100125 mesh) with ether as the eluent. After removal of the solvent, the carbamate 17a (IR film ν(CdO) 1695 cm-1) was obtained as an oil (320 mg, 64%) which was used without further purification for the preparation of the derivative 4b. 1-Methylspiro[piperidine-2,2′-tricyclo[3.3.1.1 3,7 ]decane] (4b). A solution of the carbamate 17a (320 mg, 1.22 mmol) in dry THF (10 mL) was added to a stirred suspension of LiAlH4 (250 mg, 6.59 mmol) in dry THF (30 mL). The reaction mixture was refluxed for 25 h and then hydrolyzed with water and NaOH (10%) under ice cooling. The inorganic precipitate was filtered off, and the filtrate was evaporated under vacuum. The residue was chromatographed on neutral aluminum oxide (100-125 mesh) with 1:4 AcOCH3-hexane as the eluent to afford the piperidine 4b (200 mg, 80%): mp 55 °C; 1H NMR (CDCl3, 200 MHz) δ 0.98-2.02 (m, 15H, 3′,5′,6′,7′,8′,10′-H, 3,4,5-H), 1.38 (br d, 2H, J ∼ 12 Hz, 4′,9′H), 2.04-2.73, (br m, 4H, 1′-H 4′,9′-H, 6-H), 2.32 (s, 3H, CH3), 3.16 (∼t, 1H, J ∼ 12 Hz, 6-H); 13C NMR (CDCl3, 50 MHz) δ 18.4 (5-C), 19.7 (4-C), 22.4 (3-C), 27.3 (7′-C), 27.7 (5′-C), 29.1 (1′-C), 31.7 (4′-C), 32.0 (9′-C), 33.2 (8′-C, 10′-C), 34.0 (CH3), 35.1 (3′-C), 38.9 (6′-C), 47.6 (6-C), 57.9 (2,2′-C). Hydrochloride: mp 242 °C dec (EtOH-Et2O). Picrate: mp 236 °C (MeOH-Et2O). Anal. (C21H28N4O7) C, H, N. 1-Acetylspiro[piperidine-2,2′-tricyclo[3.3.1.1 3,7 ]decane] (17b). Compound 17b was prepared by the procedure followed for 17a, by the reaction of acetyl chloride with the piperidine 4a in the presence of triethylamine: yield 85.4%; mp 129 °C (Et2O-n-pentane); IR (Nujol) ν(CdO) 1645 cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.15-2.23 (m, 18H, 3′,4′,5′,6′,7′,8′,9′,10′-H, 3,4,5-H), 2.11 (s, 3H, CH3), 2.44 (br s, 1H, 1′-H), 3.27-3.53 (m, 2H, 6-H). Anal. (C16H25NO) C, H, N. 1-Ethylspiro[piperidine-2,2′-tricyclo[3.3.1.1 3 , 7 ]decane] (4c). Compound 4c was prepared upon reduction of the amide 17b with LiAlH4 by the procedure followed for the synthesis of 4b. The crude oily product was chromatographed on neutral aluminum oxide (100-125 mesh) with AcOCH3hexane (1:10) as the eluent: yield 77%; 1H NMR (CDCl3, 200 MHz) δ 0.95-1.96 (m, 16H, 3′,5′,6′,7′,8′,10′-H, 3,4,5-H), 1.01 (t, 3H, A3X2, JAX ∼ 7 Hz, CH3CH2), 1.30 (br d, 2H, J ∼ 12 Hz, 4′,9′-H), 2.0-2.93 (br m, 5H, 1′-H 4′,9′-H, 6-H), 2.53 (q, 2H, A3X2, JAX ∼ 7 Hz, CH3CH2); 13C NMR (CDCl3, 50 MHz) δ 14.3 (CH3), 17.5 (5-C), 19.5 (4-C), 24.5 (3-C), 27.4 (7′-C), 27.9 (5′C), 29.2 (1′-C), 31.6 (4′-C, 9′-C), 33.0 (10′-C), 33.5 (8′-C), 35.2 (CH2N, 3′-C), 38.8 (6′-C), 39.3 (6-C), 58.3 (2,2′-C). Hydrochloride: mp 209 °C dec (EtOH-Et2O). Picrate: mp 176 °C (MeOH-Et2O). Anal. (C22H30N4O7) C, H. 2-Nitro-2-tricyclo[3.3.1.13,7]decanemethanol (18). To a solution of 2-nitroadamantane (10) (1.85 g, 10.3 mmol) in dioxane (5 mL) were added an aqueous 37% formaldehyde solution (1.85 mL) and NaOH (60 mg, 1.5 mmol) in 95%

ethanol (10 mL). After refluxing for 4 h, the solvent was removed and water was added. The mixture was extracted with ether, and the ether layer was washed with water and dried (Na2SO4). The solvent was evaporated almost to dryness, petroleum ether was added, and the mixture was cooled to -15 °C for several hours until the product crystallized out. Filtration of the mixture afforded the nitro alcohol 15 as needles which were washed with cold pentane. The filtrate was chromatographed on silica gel (70-230 mesh) with etherhexane (2:1) as the eluent to give an additional amount of the compound 18: yield 1.4 g (60%); mp 196 °C (Et2O-n-pentane); IR (Nujol) ν(OH) 3180, ν(NO2) 1536 cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.52-1.97 (m, 13H, 4,5,6,7,8,9,10-H, OH), 2.67 (s, 2H, 1,3-H), 3.98 (s, 2H, CH2O). Anal. (C11H17NO3) C, H, N. 2-Amino-2-tricyclo[3.3.1.13,7]decanemethanol (19). Nitro alcohol 18 (3 g, 14.2 mmol) in ethanol (30 mL) was hydrogenated in the presence of Raney nickel catalyst under a pressure of 45 psi, at 50 °C, for 5 h. Filtration and removal of the solvent under reduced pressure gave the amino alcohol 19 (2.52 g, 99%): mp 214 °C (Et2O-n-pentane); IR (Nujol) ν(NH) 3376, 3317, ν(OH) 3100 cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.42-2.21 (m, 16H, adamantane H, NH2), 3.55 (s, 2H, CH2O), 3.83 (br s, 1H, OH). Anal. (C11H19NO) C, H, N. 2-Bromacetamido-2-tricyclo[3.3.1.1 3 , 7 ]decanemethanol (20). A solution of KOH (1.68 g, 30 mmol) in water (50 mL) was added to a solution of the amino alcohol 19 (2.55 g, 14.1 mmol) in dichloromethane (150 mL). Bromacetyl chloride (2.42 g, 15.4 mmol) in dichloromethane (50 mL) was then added under ice cooling and vigorous stirring. Stirring was continued for 2 h under cooling, and the aqueous layer was decanted. The organic phase was washed with water, HCl (3%), and water and dried (Na2SO4). The solvent was removed under reduced pressure to afford 4.15 g (98%) of the bromacetamide 20. The IR spectrum of this derivative showed a strong peak at 1660 cm-1 (CdO amide) and a very weak peak at 1738 cm-1 (CdO ester). This compound was used without further purification for the preparation of the morpholinone 21: mp 163 °C (Et2O); IR (Nujol) ν(NH), ν(OH) 3373, 3284, ν(CdO) 1660 cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.49 (2H, dd, J ∼ 12, 1.1 Hz, 4,9-H), 1.53-2.10 (m, 11H, 5,6,7,8,10-H, 4,9-H, OH), 2.23 (s, 2H, 1,3-H), 3.90 (s, 2H, CH2Br), 3.98 (s, 2H, CH2O), 6.66 (br s, 1H, NH). Spiro[morpholine-3,2′-tricyclo[3.3.1.13,7]decan]-5-one (21). A solution of KOH (6 g, 107 mmol) in water (8 mL) was added to a solution of the bromacetamide 20 (3 g, 9.9 mmol) in dioxane (50 mL). The resulting mixture was heated at reflux for 2 h. After evaporation of the solvent, water was added and the precipitated morpholinone 18 was filtered off, washed with water, and dried: yield 3.08 g (98% from the amino alcohol 19); mp 214-215 °C (MeOH-Et2O); IR (Nujol) ν(NH) 3458, 3262, ν(CdO) 1644 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.60-1.98 (m, 14H, adamantane H), 3.85 (s, 2H, 2-H), 4.13 (s, 2H, 6-H), 6.64 (br s, 1H, NH); 13C NMR (CDCl3, 50 MHz) δ 26.6 (7′-C), 27.0 (5′-C), 31.8 (4′,9′-C), 33.7 (8′,10′-C), 34.4 (1′,3′-C), 38.1 (6′-C), 57.7 (3,2′-C), 67.5 (2-C), 70.0 (6-C), 168.9 (5-C). Anal. (C13H19NO2) C, H, N. Spiro[morpholine-3,2′-tricyclo[3.3.1.13,7]decane (5a). A solution of the morpholinone 21 (1.21 g, 5.48 mmol) in dry THF (30 mL) was added to a stirred suspension of LiAlH4 (1.8 g, 47.5 mmol) in dry THF (60 mL). The reaction mixture was refluxed for 25 h and then hydrolyzed with water and NaOH (10%) under ice cooling. The inorganic precipitate was filtered off and washed with THF, and the filtrate was evaporated under vacuum. The residue was dissolved in ether and extracted with HCl (5%). The aqueous layer was washed with ether, made alkaline with solid Na2CO3, and extracted with ether. The ether phase was washed with water and brine, dried (Na2CO3), and evaporated under vacuum to give 1.12 g (98%) of the morpholine 5a as an oil: 1H NMR (CDCl3, 300 MHz) δ 1.51 (d, 2H, J ∼ 13 Hz, 4′,9′-H), 1.57-1.94 (m, 11H, 1′,3′,5′,6′,7′,8′,10′-H, NH), 2.0 (d, 2H, J ∼ 13 Hz, 4′,9′-H), 2.84 (t, 2H, A2X2, A part of the system, JAX ) 4.9 Hz, 5-H), 3.60 (t, 2H, X part of the system, A2X2, JAX ) 4.9 Hz, 6-H), 3.70 (s, 2H, 2-H); 13C NMR (CDCl3, 50 MHz) δ 27.5 (7′-C), 27.8 (5′-C), 31.7 (4′-C, 9′-C), 31.8 (1′-C, 3′-C), 33.2 (8′-C, 10′-C), 38.6 (6′-

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C), 39.9 (5-C), 53.7 (3,2′-C), 68.0 (6-C), 73.7 (2-C). Hydrochloride: mp >280 °C (EtOH-Et2O). Picrate: mp 273-274 °C (MeOH). Anal. (C19H24N4O8) C, H, N. 4-(Ethoxycarbonyl)spiro[morpholine-3,2′-tricyclo[3.3.1.13,7]decane] (22a). The oily carbamate 22a was prepared in 64% yield using the procedure for the preparation of 17a, by the reaction of ethyl chloroformate with the morpholine 5a in the presence of triethylamine, and used without further purification for the preparation of compound 5b: IR (film) ν(CdO) 1690 cm-1. 4-Methylspiro[morpholine-3,2′-tricyclo[3.3.1.1 3,7 ]decane] (5b). Method A: Using morpholine 5a (300 mg, 1.45 mmol) as starting material and following the procedure of Borch and Hassid23 or Charles et al.,24 ∼290 mg of an oily product was afforded which was a mixture of the N-methyl derivative 5b and the starting material 5a in a 9:1 ratio. The nonmethylated morpholine 5a was removed by the following procedure: To a stirred solution of the above mixture and triethylamine (293 mg, 2.9 mmol) in dry ether (5 mL) was added a solution of ethyl chloroformate (157 mg, 1.45 mmol) in dry ether (10 mL), and the mixture was stirred at room temperature for 24 h. Then water was added, and the mixture was extracted with ether. The combined ether extracts were washed with water and extracted with cold HCl (2%). The aqueous layer was washed with ether, made alkaline with solid Na2CO3 and extracted with ether. The ether layer was dried over Na2SO4 and evaporated to give the morpholine 5b as an oil (260 mg, 82%): 1H NMR (CDCl3, 200 MHz) δ 1.29-1.49 (br d, 2H, J ) 11 Hz, 4′,9′-H), 1.52-1.93 (m, 9H, 3′,5′,6′,7′,8′,10′H), 1.95-2.71 (br m, 4H, 1′-H, 4′,9′-H, 5-H), 2.40 (s, 3H, CH3), 3.20-4.30 (br m, 5H, 2,6-H, 5-H); 13C NMR (CDCl3, 50 MHz) δ 27.2 (5′-C, 7′-C), 27.6 (1′-C, 3′-C), 31.7 (4′-C, 9′-C), 33.1 (8′C, 10′-C), 33.6 (CH3), 38.5 (6′-C), 47.9 (5-C), 57.5 (3,2′-C), 60.1 (6-C), 63.2 (2-C). Hydrochloride mp 231 °C dec (EtOH-Et2O). Picrate: mp 239-241 °C (MeOH). Anal. (C20H26N4O8) C, H, N. Method B: A solution of the carbamate 22a (260 mg, 0.93 mmol) in dry THF (10 mL) was added to a stirred suspension of LiAlH4 (260 mg, 6.8 mmol) in dry THF (20 mL), and the reaction mixture was refluxed for 25 h. The mixture was worked up as for 5a to give the morpholine 5b (190 mg, 92%) as an oil. 4-Acetylspiro[morpholine-3,2′-tricyclo[3.3.1.1 3,7 ]decane] (22b). Compound 22b was prepared by the procedure used for 17a, by the reaction of acetyl chloride with the morpholine 5a in the presence of triethylamine: yield 70%; mp 170 °C (Et2O-n-pentane); IR (Nujol) ν(CdO) 1612 cm-1; 1H NMR (CDCl , 200 MHz) δ 1.58 (d, 2H, J ∼ 12 Hz, 4′,9′-H), 3 1.64-2.0 (m, 11H, 3′,5′,6′,7′,8′,10′-H, 4′,9′-H), 2.11 (3H, s, CH3), 2.66 (1H, s, 1′-H), 3.24-3.84 (br m, 4H, 2,5,6-H), 3.85 (d, 1H, J ∼ 11 Hz, 6-H), 4.24 (d, 1H, J ∼ 11 Hz, 2-H). Anal. (C15H23NO2) C, H, N. 4-Ethylspiro[morpholine-3,2′-tricyclo[3.3.1.1 3,7 ]decane] (5c). Compound 5c was obtained upon reduction of the N-acetyl derivative 22b with LiAlH4, using the abovementioned procedure for the preparation of 5b (method B): yield 70%; 1H NMR (CDCl3, 200 MHz) δ 1.02 (t, 3H, A3X2, JAX ∼ 7 Hz, CH3CH2), 1.28-1.43 (br d, 2H, J ∼ 12 Hz, 4′,9′-H), 1.52-1.99 (m, 9H, 3′,5′,6′,7′,8′,10′-H), 2.0-2.70 (m, 4H, 1′-H, 4′,9′-H, 5-H), 2.64 (q, 2H, A3X2, JAX ∼ 7 Hz, CH3CH2), 3.04.10 (br m, 5H, 2,6-H, 5-H); 13C NMR (CDCl3, 50 MHz) δ 14.1 (CH3), 27.3 (5′-C, 7′-C), 27.9 (1′-C, 3′-C), 31.4 (4′-C, 9′-C), 33.2 (8′-C, 10′-C), 35.1 (CH2N), 38.5 (6′-C), 40.4 (5-C), 58.1 (3,2′-C), 59.8 (6-C), 65.4 (2-C). Hydrochloride: mp 260 °C dec (EtOHEt2O). Picrate: mp 155 °C (MeOH). Anal. (C21H28N4O8) C, H, N. 1-(1-Tricyclo[3.3.1.13,7]decylcarbonyl)-2-pyrrolidinone (24). A solution of 1-adamantanecarbonyl chloride (13.2 g, 66.6 mmol) in dry THF (30 mL) was added dropwise at room temperature to a solution of compound 23 (13.6 g, 87 mmol) in dry THF (50 mL). The mixture was refluxed for 7 h, the solvent was evaporated, and the residue was crystallized from methanol at 0 °C to give the lactam 24 (15.4 g, 93.6%): mp 219 °C (MeOH); IR (film) ν(CdO) 1674 (amide), 1738 (lactam) cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.57-1.76 (m, 6H, 4,6,10adamantane H), 1.81-2.29 (m, 11H, 2,3,5,7,8,9-adamantane

H, 4-H), 2.53 (t, 2H, J ) 8.0 Hz, 3-H), 3.77 (t, 2H, J ) 7.6 Hz, 5-H). Anal. (C15H21NO2) C, H, N. 2-(1-Tricyclo[3.3.1.13,7]decyl)-1-pyrroline (25). The Nacyl lactam 24 (6 g, 24.3 mmol) was mixed thoroughly with an equal weight of calcium oxide, and the mixture was placed in a Pyrex tube fitted with a small vigreux column. The mixture was gently heated with a flame until a melt was formed and a vigorous reaction was observed. Reduced pressure (25 mmHg) was then applied, and the heat was continued until the crude product distilled off (above 150 °C). The product was dissolved in ether and extracted with HCl (5%). The aqueous phase was made alkaline with solid Na2CO3 and extracted with ether. The combined ether extracts were washed with brine, dried (Na2SO4), and evaporated. The residue was chromatographed on neutral aluminum oxide (100-125 mesh) with ether-hexane (1:1) as the eluent to give the oily pyrroline 25 (1.7 g, 34.5%): IR (film) ν(CdN) 1632 cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.57-1.88 (m, 2H, 4-H), 1.67 (br s, 4,6,10-adamantane H), 1.75 (br d, 6H, J ) 2.9 Hz, 2,8,9-adamantane H), 1.97 (s, 3H, 3,5,7-adamantane H), 2.44 (tt, 2H, J ) 7.9, 1.8 Hz, 3-H), 3.74 (tt, 2H, J ) 7.3, 1.8 Hz, 5-H); 13C NMR (CDCl3, 50 MHz) δ 22.3 (4-C), 28.2 (3,5,7adamantane C), 32.3 (3-C), 36.8 (4,6,10-adamantane C), 37.8 (2-C, 1-adamantane C), 40.2 (2,8,9-adamantane C), 60.5 (5C). Picrate: mp 200 °C (MeOH). Anal. (C20H24N4O7) C, H, N. 2-(1-Tricyclo[3.3.1.13,7]decyl)pyrrolidine (6a). Sodium borohydride (440 mg, 11.5 mmol) was added portionwise to a stirred solution of pyrrolidine 25 (1 g, 4.93 mmol) in 20 mL of 3:1 methanol-acetic acid cooled to ∼ -30 °C. The mixture was stirred for 4 h at room temperature, and the solvent was evaporated under reduced pressure. The residue was treated with a 30% NaOH solution (30 mL), and the mixture was extracted with dichloromethane. The combined organic extracts were washed with water and extracted with HCl (5%). The aqueous phase was made alkaline with solid Na2CO3 and extracted with dichloromethane, and the organic layer was washed with water and brine and dried (Na2SO4). Removal of the solvent under reduced pressure left the pyrrolidine 6a (840 mg, 83%) as an oil: IR (film) ν(NH) 3313 cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.32-1.80 (m, 17H, 2,4,6,8,9,10-adamantane H, 3,4-H, NH), 1.89 (s, 3H, 3,5,7-adamantane H), 2.51 (t, 1H, J ∼ 8 Hz, 2-H), 2.73 (m, 1H, 5-H), 2.84 (m, 1H, 5-H); 13C NMR (CDCl3, 50 MHz) δ 24.6 (3-C), 25.81 (4-C), 28.4 (3,5,7adamantane C), 34.9 (1-adamantane C), 37.3 (4,6,10-adamantane C), 39.2 (2,8,9-adamantane C), 47.0 (5-C), 68.9 (2-C). Hydrochloride: mp 273 °C dec (EtOH-Et2O). Anal. (C14H24ClN‚1/2C2H5OH) C, H, N. 1-Acetyl-2-(1-tricyclo[3.3.1.13,7)decyl]pyrrolidine (26a). Compound 26a was prepared by the procedure used for 17a, by the reaction of acetyl chloride with the pyrrolidine 6a in the presence of triethylamine. The product was purified by filtration over neutral aluminum oxide (100-125 mesh) with ether as the eluent: yield 99%; mp 129 °C (Et2O-n-pentane); IR (Nujol) ν(CdO) 1653 cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.40-2.03 (m, 19H, adamantane H, 3,4-H), 2.07 (s, 3H, CH3), 3.25-3.40 (complex m, 1H, 5-H), 3.41-3.59 (complex m, 1H, 5-H), 3.98 (d, 1H, J ∼ 8.5 Hz, 2-H). Anal. (C16H25NO) C, H, N. 1-Butanoyl-2-(1-tricyclo[3.3.1.13,7]decyl)pyrrolidine (26b). Compound 26b was prepared by the procedure used for 17a, by the reaction of butanoyl chloride with the pyrrolidine 6a in the presence of triethylamine. The product was purified by filtration over neutral aluminum oxide (100-125 mesh) with ether as the eluent: yield 98%; mp 75-77 °C (npentane); IR (Nujol) ν(CdO) 1650 cm-1; 1H NMR (CDCl3, 200 MHz) δ 0.93 (t, 3H, J ∼ 7 Hz, CH3), 1.40-2.0 (m, 21H, adamantane H, 3,4-H, COCH2CH2), 2.28 (t, 2H, J ∼ 7 Hz, COCH2CH2), 3.21-3.40 (complex m, 1H, 5-H), 3.45-3.61 (complex m, 1H, 5-H), 4.30 (d, 1H, J ∼ 8.5 Hz, 2-H). Anal. (C18H29NO) C, H, N. 1-Methyl-2-(1-tricyclo[3.3.1.13,7]decyl)pyrrolidine (6b). Pyrrolidine 6a was methylated according to the procedure of Borch and Hassid23 to give 6b as an oil: yield 83%; 1H NMR (CDCl3, 200 MHz) δ 1.36-1.73 (m, 16H, 2,4,6,8,9,10-adamantane H, 3,4-H), 1.84-2.02 (m, 4H, 3,5,7-adamantane H, 2-H),

New Aminoadamantane Derivatives

Journal of Medicinal Chemistry, 1996, Vol. 39, No. 17 3315

2.37 (s, 3H, CH3), 2.19-2.40 (complex m, 1H, 5-H), 2.83-3.02 (m, 1H, 5-H); 13C NMR (CDCl3, 50 MHz) δ 25.2 (3-C), 26.1 (4C), 28.4 (3,5,7-adamantane C), 37.0 (1-adamantane C), 37.2 (4,6,10-adamantane C), 39.2 (2,8,9-adamantane C), 46.5 (CH3), 58.8 (5-C), 75.6 (2-C). Hydrochloride: mp 244 °C dec (EtOHEt2O). Hyperchlorate: mp 168 °C (MeOH-Et2O). Anal. (C15H26ClNO4) C, H, N. 1-Ethyl-2-(1-tricyclo[3.3.1.13,7]decyl)pyrrolidine (6c). Compound 6c was prepared by the LiAlH4 reduction of the N-acetyl derivative 26a, using the same procedure followed for the preparation of 5c: yield 95%; 1H NMR (CDCl3, 200 MHz) δ 1.05 (t, 3H, J ∼ 7 Hz, CH3CH2), 1.38-1.78 (m, 16H, 2,4,6,8,9,10-adamantane H, 3,4-H), 1.92 (br s, 3H, 3,5,7adamantane H), 2.05-2.18 (m, 1H, 2-H), 2.19-2.50 (m, 2H, CH3CH2), 2.60-2.83 (m, 1H, 5-H), 2.87-3.12 (m, 1H, 5-H); 13C NMR (CDCl3, 50 MHz) δ 14.3 (CH3), 25.5 (3,4-C), 28.5 (3,5,7adamantane C), 37.4 (1,4,6,10-adamantane C), 39.2 (2,8,9adamantane C), 53.3 (5-C), 54.9 (CH2N), 74.0 (2-C). Hydrochloride: mp 273 °C dec (EtOH-Et2O). Anal. (C16H28ClN) C, H, N. 1-Butyl-2-(1-tricyclo[3.3.1.13,7]decyl)pyrrolidine (6d). Compound 6d was prepared by the LiAlH4 reduction of the N-butanoyl derivative 26b, using the procedure followed for the preparation of 5c. The product was purified by column chromatography on neutral aluminum oxide (100-125 mesh) using a mixture of ether-hexane (1:14) as the eluent: yield 61%; 1H NMR (CDCl3, 200 MHz) δ 0.99 (t, 3H, J ∼ 7 Hz, CH3CH2), 1.13-1.72 (m, 20H, 2,4,6,8,9,10-adamantane H, 3,4-H, CH3CH2CH2), 1.92 (br s, 3H, 3,5,7-adamantane H), 2.02-2.17 (m, 1H, 2-H), 2.19-2.49 (m, 2H, CH2N), 2.54-2.73 (m, 1H, 5-H), 2.84-3.02 (m, 1H, 5-H); 13C-NMR (CDCl3, 50 MHz) δ 14.3 (CH3), 20.7 (CH2CH3), 25.4 (3-C), 25.5 (4-C), 28.5 (3,5,7adamantane C), 31.8 (1-adamantane C), 37.4 (4,6,10-adamantane C, CH2CH2CH3), 39.3 (2,8,9-adamantane C), 55.4 (5-C), 59.8 (CH2N), 74.3 (2-C). Hydrochloride: mp 191 °C (EtOHEt2O). Anal. (C18H32ClN) C, H, N. Methyl 5-Oxo-1-(1-tricyclo[3.3.1.13,7]decyl)-2-pyrrolidinecarboxylate (28). A mixture of 1-bromoadamantane (8.29 g, 38.5 mmol), Ag2SO4 (12 g, 38.5 mmol), and methyl pyroglutamate (27) (19.3 g, 135 mmol) was stirred and heated slowly to 80 °C when an exothermic reaction was observed. Stirring was continued for 1 h at 100 °C. The mixture was then cooled to room temperature and treated with dichloromethane. The inorganic precipitate was filtered off, and the filtrate was washed several times with water, dried (Na2SO4), and evaporated under reduced pressure to give an oily residue which was crystallized by the addition of water. The precipitated methyl ester 28 was filtered, washed exhaustively with water, and dried: yield 9.54 g (89.5%); mp 154 °C (Et2O); IR (Nujol) ν(CdO) 1733 (ester), 1665 (lactam) cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.50-1.68 (m, 6H, 4,6,10-adamantane H), 1.79-2.31 (complex m, 12H, 2,3,5,7,8,9-adamantane H, 3,4H), 2.38-2.67 (complex m, 1H, 4-H), 3.73 (s, 3H, CH3), 4.36 (d, 1H, J ) 8.4 Hz, 2-H). Anal. (C16H23NO3) C, H, N. 5-Oxo-1-(1-tricyclo[3.3.1.13,7]decyl)-2-pyrrolidinecarboxylic Acid (29). The methyl ester 28 (4.5 g, 16.2 mmol) was saponified with KOH (1.38 g, 24.4 mmol) in an aqueous ethanolic solution (25 mL of ethanol/5 mL of water) at room temperature for 15 h. Most of the ethanol was removed under vacuum, and the residue was diluted with water and extracted with ether. The aqueous layer was acidified under ice cooling with HCl (18%), and the precipitated acid 29 was filtered, washed with water, and dried: yield 4.2 g (98.5%); mp >283 °C (MeOH); IR (Nujol) ν(CdO) 1718 (acid), 1615 (lactam) cm-1; 1H NMR (DMSO, 200 MHz) δ 1.58 (br s, 6H, 4,6,10-adamantane H), 1.75-1.87 (m, 1H, 4-H), 1.88-2.03 (m, 6H, 2,8,9adamantane H), 2.04-2.22 (m, 2H, 3-H), 2.12 (br s, 3H, 3,5,7adamantane H), 2.23-2.37 (m, 1H, 4-H), 4.35 (∼d, 1H, J ) 8.4 Hz, 2-H), 12.75 (br s, 1H, CO2H). Anal. (C15H21NO3) C, H, N. N,N-Dimethyl-5-oxo-1-(1-tricyclo[3.3.1.13,7]decyl)-2-pyrrolidinecarboxamide (30). A mixture of the acid 29 (2.97 g, 11.3 mmol) and thionyl chloride (3.3 mL, 45.5 mmol) was heated at 55 °C for 1 h. The excess thionyl chloride was removed under vacuum, and the resulting solid chloride was dissolved in dry THF (30 mL). The resulting solution was

saturated with dimethylamine under ice cooling and stirred at room temperature for 5 h. The precipitate was filtered off and washed with THF, and the filtrate was concentrated in vacuo. The solid residue was treated with ether at 0 °C and filtered to give the dimethylamide 30 (2.5 g, 76%), which was used without further purification for the preparation of the derivative 8a: mp 225-227 °C (THF-n-pentane); IR (Nujol) ν(CdO) 1673 (lactam), 1645 (amide) cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.50-1.85 (m, 7H, 4,6,10-adamantane H, 4-H), 1.93-2.08 (m, 6H, 2,8,9-adamantane H), 2.10-2.29 (m, 2H, 3-H), 2.11 (s, 3H, 3,5,7-adamantane H), 2.42-2.70 (complex m, 1H, 4-H), 2.96 (s, 3H, CH3), 3.02 (s, 3H, CH3), 4.69 (d, 1H, J ) 8.35 Hz, 2-H). Anal. (C17H26N2O2) C, H, N. N,N-Dimethyl-1-(1-tricyclo[3.3.1.1 3,7 ]decyl)-2-pyrrolidinemethanamine (8a). A solution of the amide 30 (2.16 g, 7.45 mmol) in dry THF (30 mL) was added to a stirred suspension of LiAlH4 (2.26 g, 59.6 mmol) in dry THF (60 mL), and the reaction mixture was refluxed for 20 h. Pyrrolidinemethanamine 8a was isolated following the procedure used for compound 5a: yield almost quantitative; mp 68-70 °C (n-pentane); 1H NMR (CDCl3, 200 MHz) δ 1.37-1.85 (m, 16H, 2,4,6,8,9,10-adamantane H, 3,4-H), 1.87-2.06 (m, 1H, CH2N), 2.03 (s, 3H, 3,5,7-adamantane H), 2.11-2.26 (m, 1H, CH2N), 2.20 (s, 6H, 2 × CH3), 2.37-2.84 (m, 1H, 5-H), 2.722.84 (m, 1H, 5-H), 3.01-3.17 (m, 1H, 2-H); 13C NMR (CDCl3, 50 MHz) δ 23.9 (4-C), 29.4 (3,5,7-adamantane C), 29.9 (3-C), 36.8 (4,6,10-adamantane C), 39.7 (2,8,9-adamantane C), 45.9 (5-C), 46.2 (2 × CH3), 53.0 (2-C), 54.0 (1-adamantane C), 67.9 (CH2N). Dihydrochloride: mp 235 °C dec (EtOH-Et2O). Fumarate: mp 196 °C dec (EtOH-Et2O). Anal. (C21H34N2O4) C, H, N. 5-Oxo-1-(1-tricyclo[3.3.1.13,7]decyl)-3-pyrrolidinecarboxylic Acid (32). A mixture of 1-adamantanamine (31) (6.98 g, 46.1 mmol), itaconic acid (6 g, 46.1 mmol), and water was refluxed for 45 min. Water was removed under vacuum, and the solid residue was heated at 185 °C for 40 min. The mixture was cooled to room temperature, treated with ether, and filtered to give the carboxylic acid 32 (9.6 g, 79%): mp 218219 °C (THF-n-pentane); IR (Nujol) ν(CdO) 1727 (acid), 1622 (lactam) cm-1; 1H NMR (DMSO, 200 MHz) δ 1.60 (br s, 6H, 4,6,10-adamantane H), 2.03 (m, 9H, 2,3,5,7,8,9-adamantane H), 2.35 (dd, 1H, J ) 7.8, 16.6 Hz, 4-H), 2.45 (dd, 1H, J ) 9.0, 16.6 Hz, 4-H), 2.93-3.15 (m, 1H, 3-H), 3.35-3.70 (complex m, 2H, 2-H). Anal. (C15H21NO3) C, H, N. N,N-Dimethyl-5-oxo-1-(1-tricyclo[3.3.1.13,7]decyl)-3-pyrrolidinecarboxamide (33). Following the procedure used for the preparation of 30, amide 33 was initially afforded as an oil. This oily product was then worked up with 1:1 ethern-pentane, under ice cooling, to give the dimethylamide 33 as a crystalline solid: yield 93%; mp 111-113 °C (Et2O); IR (Nujol) ν(CdO) 1674 (lactam), 1643 (amide) cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.50-1.78 (m, 6H, 4,6,10-adamantane H), 1.87-2.26 (m, 9H, 2,3,5,7,8,9-adamantane H), 2.49 (dd, 1H, J ) 9.6, 16.5 Hz, 4-H), 2.60 (dd, 1H, J ) 8.8, 16.5 Hz, 4-H), 2.93 (s, 3H, CH3), 3.0 (s, 3H, CH3), 3.26 (quint, 1H, J ) 7.0 Hz, 3-H), 3.53 (t, 1H, J ∼ 9 Hz, 2-H), 3.75 (dd, 1H, J ) 7.5, 9.5 Hz, 2-H). Anal. (C17H26N2O2) C, H, N. N,N-Dimethyl-1-(1-tricyclo[3.3.1.1 3,7 ]decyl)-3-pyrrolidinemethanamine (8b). Compound 8b was prepared by the LiAlH4 reduction of the amide 33, using the procedure followed for the preparation of 8a: yield 90%; 1H NMR (CDCl3, 200 MHz) δ 1.10-1.41 (m, 2H, 3,4-H), 1.45-1.73 (m, 12H, 2,4,6,8,9,10-adamantane H), 1.82-2.02 (m, 1H, 4-H), 2.03 (br s, 3H, 3,5,7-adamantane H), 2.12-2.35 (m, 3H, 2-H, CH2N), 2.18 (br s, 6H, 2 × CH3), 2.55-2.80 (m, 2H, 5-H), 2.88-3.07 (m, 1H, 2-H); 13C NMR (CDCl3, 50 MHz) δ 29.2 (4-C), 29.4 (3,5,7-adamantane C), 35.3 (3-C), 36.9 (4,6,10-adamantane C), 38.8 (2,8,9-adamantane C), 43.5 (5-C), 45.7 (2 × CH3), 49.3 (2-C), 52.6 (1-adamantane C), 65.0 (CH2N). Difumarate: mp 131 °C dec (EtOH-Et2O). Dipicrate: mp 234 °C dec (EtOH). Anal. (C29H36N8O14) C, H, N. trans- and cis-5-Oxo-2-phenyl-1-(1-tricyclo[3.3.1.13,7]decyl)-3-pyrrolidinecarboxylic Acid (35 and 36). A mixture of N-benzylidene-1-adamantanamine (34) (4.39 g, 18.3 mmol), succinic anhydride (1.83 g, 18.3 mmol), and xylene (20 mL) was refluxed for 15 h. After removal of the solvent, the

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solid residue was treated with NaHCO3 (6%) to alkaline pH. The mixture was washed with ether, and the aqueous phase was acidified under ice cooling with HCl (18%). The precipitated mixture of acids 35 and 36 was filtered, washed with water, and dried: yield 4.46 g (72%). The above mixture was treated with 30 mL of hot methanol, and the resulting solid residue was filtered to give 430 mg of the cis acid 36: mp 283 °C (MeOH); IR (Nujol) ν(CdO) 1731 (acid), 1631 (lactam) cm-1; 1H NMR (DMSO, 200 MHz) δ 1.351.58 (m, 6H, 4,6,10-adamantane H), 1.80-2.12 (m, 9H, 2,3,5,7,8,9-adamantane H), 2.23 (dd, 1H, J ) 8.7, 16.6 Hz, 4-H), 2.79 (dd, 1H, J ) 12.1, 16.6 Hz, 4-H), 3.43-3.63 (m, 1H, 3-H), 5.19 (d, 1H, J ) 8.7 Hz, 2-H), 7.10-7.39 (m, 5H, aromatic H). Anal. (C21H25NO3) C, H, N. The filtrate obtained above was evaporated to dryness, and the solid residue was treated with hot methanol (15 mL). The resulting solid was filtered off, and the remaining liquors were evaporated to dryness to yield 3 g of the trans acid 35: mp 222 °C (MeOH); IR (Nujol) ν(CdO) 1731 (acid), 1637 (lactam) cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.45-1.62 (m, 6H, 4,6,10adamantane H), 1.97 (s, 3H, 3,5,7-adamantane H), 1.98-2.11 (m, 6H, 2,8,9-adamantane H), 2.63-3.02 (m, 3H, 3,4-H), 5.37 (s, 1H, 2-H), 7.21-7.42 (m, 5H, aromatic H). Anal. (C21H25NO3) C, H, N. Procedure for the Determination of the Ratio of Acids 35 and 36. A mixture of the crude acid (300 mg, 0.88 mmol), anhydrous K2CO3 (122 mg, 0.88 mmol), dimethyl sulfate (223 mg, 1.77 mmol), and acetone (10 mL) was stirred for 16 h. The inorganic precipitate was filtered off, and the filtrate was evaporated to dryness. The ratio of the diastereomeric methyl esters was then determined by NMR integration of the corresponding methyl signals. trans-N,N-Dimethyl-5-oxo-2-phenyl-1-(1-tricyclo[3.3.1.13,7]decyl)-3-pyrrolidinecarboxamide (37). Following the procedure used for the preparation of 30, amide 37 was afforded with the following data: yield 91%; mp 215217 °C (THF-n-pentane); IR (Nujol) ν(CdO) 1682 (lactam), 1651 (amide) cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.47-1.63 (m, 6H, 4,6,10-adamantane H), 1.94 (br s, 3H, 3,5,7-adamantane H), 2.0-2.13 (m, 6H, 2,8,9-adamantane H), 2.30 (dd, 1H, J ) 15.9, 1.2 Hz, 4-H), 2.78-3.03 (m, 2H, 3,4-H), 2.83 (s, 3H, CH3), 2.95 (s, 3H, CH3), 5.37 (s, 1H, 2-H), 7.18-7.39 (m, 5H, aromatic H). Anal. (C23H30N2O2) C, H, N. trans-N,N-Dimethyl-2-phenyl-1-(1-tricyclo[3.3.1.13,7]decyl)-3-pyrrolidinemethanamine (8c). Compound 8c was prepared by the LiAlH4 reduction of the amide 37, using the procedure for the preparation of 8a: yield 90%; 1H NMR (CDCl3, 200 MHz) δ 1.41-1.68 (m, 12H, 2,4,6,8,9,10-adamantane H), 1.84-2.29 (m, 8H, 3,5,7-adamantane H, 3,4-H, CH2N), 2.21 (s, 6H, 2 × CH3), 2.87-3.13 (complex m, 2H, 5-H), 4.07 (s, 1H, 2-H), 7.08-7.31 (m, 3H, aromatic H), 7.39-7.49 (m, 2H, aromatic H); 13C NMR (CDCl3, 50 MHz) δ 27.3 (4-C), 29.8 (3,5,7-adamantane C), 37.2 (4,6,10-adamantane C), 40.4 (2,8,9adamantane C), 44.6 (5-C), 46.1 (2 × CH3), 47.1 (3-C), 53.5 (1-adamantane C), 63.0 (2-C), 63.3 (CH2N), 125.8, 126.7, 128.0 (5 tertiary aromatic C), 151.2 (quaternary aromatic C). Difumarate: mp 177 °C dec (EtOH-acetone). Anal. (C31H42N2O8) C, H, N. cis-N,N-Dimethyl-5-oxo-2-phenyl-1-(1-tricyclo[3.3.1.13,7]decyl)-3-pyrrolidinecarboxamide (38). Following the procedure used for the preparation of 30, amide 38 was afforded with the following data: yield 97%; mp 198-199 °C (THFn-pentane); IR (Nujol) ν(CdO) 1675 (amide), 1648 (lactam) cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.53 (br s, 6H, 4,6,10adamantane H), 1.82-2.13 (m, 2,3,5,7,8,9-adamantane H), 2.28 (dd, 1H, J ) 8.4, 16.8 Hz, 4-H), 3.40 (dd, 1H, J ) 11.6, 16.8 Hz, 4-H), 3.59-3.71 (m, 1H, 3-H), 5.06 (d, 1H, J ) 8.8 Hz, 2-H), 7.02-7.14 (m, 2H, aromatic H), 7.22-7.34 (m, 3H, aromatic H). Anal. (C23H30N2O2) C, H, N. cis-N,N-Dimethyl-2-phenyl-1-(1-tricyclo[3.3.1.13,7]decyl)3-pyrrolidinemethanamine (8d). Compound 8d was prepared by the reduction of the amide 38, using the same procedure as for the preparation of 8a: yield 81%; 1H NMR (CDCl3, 200 MHz) δ 1.38-1.90 (m, 15H, 2,4,6,8,9,10-adamantane H, 3,4-H), 1.95 (br s, 3H, 3,5,7-adamantane H), 2.06 (s, 6H, 2 × CH3), 2.05-2.25 (m, 2H, CH2N), 2.80-2.95 (m, 1H,

5-H), 3.11 (t, 1H, J ) 7.4 Hz, 5-H), 4.23 (d, 1H, J ) 8.8 Hz, 2-H), 7.09-7.26 (m, 3H, aromatic H), 7.31-7.40 (m, 2H, aromatic H); 13C NMR (CDCl3, 50 MHz) δ 28.8 (4-C), 29.4 (3,5,7-adamantane C), 36.9 (4,6,10-adamantane C), 39.8 (2,8,9adamantane C), 42.7 (3-C), 44.8 (5-C), 45.9 (2 × CH3), 53.5 (1-adamantane C), 60.7 (2-C), 61.3 (CH2N), 125.8, 127.1, 128.3 (5 tertiary aromatic C), 146.9 (quarernary aromatic C). Difumarate: mp 126 °C (EtOH-acetone). Anal. (C31H42N2O8) C, H, N. General Procedure for the Preparation of 1-(1-Tricyclo[3.3.1.13,7]decylcarbonyl)pyrrolidines 43-46. A solution of 1-adamantanecarbonyl chloride (13.5 mmol) in dry THF (10 mL) was added dropwise under ice cooling to a stirred solution of pyrrolidines 39-42 (11.1 mmol) and triethylamine (38.9 mmol) in dry THF (15 mL), and the mixture was stirred at room temperature for 8 h. The precipitated triethylamine hydrochloride was filtered off and washed with THF, and the filtrate was washed with HCl (2%) and water, dried (Na2SO4), and evaporated. The residue was filtered through neutral aluminum oxide (100-125 mesh) with ether as the eluent. 2,2-Dimethyl-1-(1-tricyclo[3.3.1.13,7]decylcarbonyl)pyrrolidine (43): yield 57.3%; mp 107-109 °C (acetone-H2O); IR (Nujol) ν(CdO) 1616 cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.57 (br s, 6H, 2 × CH3), 1.71-2.04 (m, 4H, 3,4-H), 1.85 (s, 6H, 4,6,10-adamantane H), 2.12 (br s, 9H, 2,3,5,7,8,9-adamantane H), 3.87 (t, 2H, J ) 6.0 Hz, 5-H). Anal. (C17H27NO) C, H, N. 1-(1-Tricyclo[3.3.1.13,7]decylcarbonyl)-1-azaspiro[4.4]nonane (44): yield 54.3%; mp 124-125 °C (acetone-H2O); IR (Nujol) ν(CdO) 1611 cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.201.33 (m, 2H, cyclopentane H), 1.35-1.55 (m, 2H, cyclopentane H), 1.60-1.79 (m, 4H, 3,4-H), 1.67 (br s, 6H, 4,6,10-adamantane H), 1.80-2.03 (m, 2H, cyclopentane H), 1.96 (br s, 9H, 2,3,5,7,8,9-adamantane H), 2.22-2.40 (m, 2H, cyclopentane H), 3.69 (t, 2H, J ) 6.2 Hz, 2-H). Anal. (C19H29NO) C, H, N. 1-(1-Tricyclo[3.3.1.13,7]decylcarbonyl)-1-azaspiro[4.5]decane (45): yield 54%; mp 140 °C (acetone-H2O); IR (Nujol) ν(CdO) 1605 cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.05-1.38 (m, 6H, cyclohexane H), 1.40-1.75 (m, 6H, cyclohexane H, 3,4H), 1.67 (br s, 6H, 4,6,10-adamantane H), 1.95 (s, 9H, 2,3,5,7,8,9-adamantane H), 2.62-2.83 (m, 2H, cyclohexane H), 3.69 (t, 2H, J ) 6.3 Hz, 2-H). Anal. (C20H31NO) C, H, N. 2-(1,1-Dimethylethyl)-1-(1-tricyclo[3.3.1.13,7 ]decylcarbonyl)pyrrolidine (46): yield 64.3%; mp 113-115 °C (acetone-H2O); IR (Nujol) ν(CdO) 1626 cm-1; 1H NMR (CDCl3, 200 MHz) δ 0.81 (s, 9H, 3 × CH3), 1.44-2.10 (complex m, 4H, 3,4-H), 1.70 (br s, 6H, 4,6,10-adamantane H), 1.92-2.10 (m, 9H, 2,3,5,7,8,9-adamantane H), 3.10-3.29 (m, 1H, 5-H), 3.964.14 (m, 1H, 5-H), 4.45 (dd, J ) 6.0, 8.9 Hz, 1H, 2-H). Anal. (C19H31NO) C, H, N. General Procedure for the Preparation of 1-(1-Tricyclo[3.3.1.13,7]decylmethyl)pyrrolidines 9a-d. A solution of the amides 43-46 (4.6 mmol) in dry THF (15 mL) was added to a stirred suspension of LiAlH4 (18.4 mmol) in dry THF (30 mL). The reaction mixture was refluxed for 25 h and then hydrolyzed with water and NaOH (10%) under ice cooling. The inorganic precipitate was filtered off and washed with THF, and the filtrate was concentrated in vacuo. The residue was dissolved in ether and extracted with HCl (5%). The aqueous phase was made alkaline with solid Na2CO3, and the oil formed was extracted with ether. The ether extracts were washed with water and brine, dried (Na2SO4), and evaporated to give the amines 9a-d as oily products. 2,2-Dimethyl-1-(1-tricyclo[3.3.1.1 3,7 ]decylmethyl)pyrrolidine (9a): yield 84%; 1H NMR (CDCl3, 200 MHz) δ 0.88 (s, 6H, 2 × CH3), 1.35-1.77 (m, 10H, 4,6,10-adamantane H, 3,4-H), 1.45 (d, 6H, J ) 2.3 Hz, 2,8,9-adamantane H), 1.91 (br s, 3H, 3,5,7-adamantane H), 1.96 (s, 2H, CH2N), 2.77 (t, 2H, J ∼ 7 Hz, 5-H); 13C NMR (CDCl3, 50 MHz) δ 20.9 (4-C), 23.1 (2 × CH3), 28.7 (3,5,7-adamantane C), 34.2 (1-adamantane C), 37.3 (4,6,10-adamantane C), 39.6 (3-C), 41.7 (2,8,9-adamantane C), 55.4 (5-C), 60.8 (2-C), 63.1 (CH2N). Hydrochloride: mp 285-287 °C dec (EtOH-Et2O). Anal. (C17H30ClN) C, H, N. 1-(1-Tricyclo[3.3.1.13,7]decylmethyl)-1-azaspiro[4.4]nonane (9b): yield 96%; 1H NMR (CDCl3, 200 MHz) δ 1.17-

New Aminoadamantane Derivatives 1.78 (m, 18H, 4,6,10-adamantane H, 3,4,6,7,8,9-H), 1.45 (d, 6H, J ) 2.5 Hz, 2,8,9-adamantane H), 1.91 (br s, 3H, 3,5,7adamantane H), 1.99 (s, 2H, CH2N), 2.72 (t, 2H, J ∼ 7 Hz, 2-H); 13C NMR (CDCl3, 50 MHz) δ 21.2 (3-C), 24.0 (7,8-C), 28.7 (3,5,7-adamantane C), 32.1 (6,9-C), 34.4 (1-adamantane C), 37.3 (4,6,10-adamantane C), 39.0 (4-C), 41.7 (2,8,9-adamantane C), 56.3 (2-C), 63.1 (CH2N), 73.2 (5-C). Hydrochloride: mp 269 °C dec (EtOH-Et2O). Anal. (C19H32ClN) C, H, N. 1-(1-Tricyclo[3.3.1.13,7]decylmethyl)-1-azaspiro[4.5]decane (9c): yield 83%; 1H NMR (CDCl3, 200 MHz) δ 1.121.37 (m, 6H, 6,10,7eq,9eq-H), 1.45 (d, 6H, J ) 2.2 Hz, 2,8,9adamantane H), 1.51-1.77 (m, 14H, 4,6,10-adamantane H, 3,4,7ax,8,9ax-H), 1.91 (br s, 3H, 3,5,7-adamantane H), 2.03 (s, 2H, CH2N), 2.80 (t, 2H, J ∼ 7 Hz, 2-H); 13C NMR (CDCl3, 50 MHz) δ 21.14 (3-C), 24.5 (7,9-C), 26.4 (8-C), 28.7 (3,5,7adamantane C), 32.2 (6,10-C), 33.7 (4-C), 34.4 (1-adamantane C), 37.3 (4,6,10-adamantane C), 41.7 (2,8,9-adamantane C), 54.7 (2-C), 62.0 (CH2N), 63.8 (5-C). Hydrochloride: mp 282 °C dec (EtOH-Et2O). Anal. (C20H34ClN) C, H, N. 2-(1,1-Dimethylethyl)-1-(1-tricyclo[3.3.1.13,7 ]decylmethyl)pyrrolidine (9d): yield 95%; 1H NMR (CDCl3, 200 MHz) δ 0.83 (s, 9H, 3 × CH3), 1.38-1.76 (m, 16H, 2,4,6,8,9,10adamantane H, 3,4-H), 1.93 (s, 3H, 3,5,7-adamantane H), 2.28-2.46 (m, 2H, 5-H), 2.2 (dd, 2H, AB, JAB ) 13.0 Hz, CH2N), 2.88-3.05 (m, 1H, 2-H); 13C NMR (CDCl3, 50 MHz) δ 25.5 (4C), 27.0 (3 × CH3), 28.7 (3,5,7-adamantane C), 35.3 (1adamantane C), 37.2 (4,6,10-adamantane C), 42.3 (3-C, 2,8,9adamantane C), 58.6 (5-C), 74.5 (CH2N), 76.9 (2-C). Hydrochloride: mp 289-291 °C dec (EtOH-Et2O). Anal. (C19H34ClN) C, H, N.

Acknowledgment. These investigations were partially supported by a research grant from the University of Athens, the Biomedical Research Programme of the European Commision, and grants from the Belgian Nationaal Fonds voor Wetenschappelijk Onderzoek, the Belgian Fonds voor Geneeskundig Wetenschappelijk Onderzoek, and the Belgian Geconcerteede Onderzoeksacties. J. Neyts is a postdoctoral research assistant from the Belgian National Fonds voor Wetenschappelijk Onderzoek. We thank Anita Van Lierde, Frieda De Meyer, Anita Camps, Ann Absillis, and Ria Van Berwaer for excellent technical assistance.

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