760
`
`K. Gr-:nzoN, E. V. Iinuururms, R. L. BnrN1>Lm, F. J. l\IARSHALL, AND M. A. Roor
`
`VOL 6
`
`The Adamantyl Group in Medicinal Agents.
`1. Hypoglycemic N-Arylsulfonyl-N’-adamantylureus
`
`I(or.nr GERZON, Enrzcs V. Knommnns, RICHARD L. BnrN1)Lr., FREDERICK J. MAIYSHALL,
`AND MARY A. Itoor
`
`Illa Lilly Research Laboralmiea, Indianapolis 3. Indiana
`
`Received April 25. 1903
`
`In order to evaluate the phurmacodynamic potential of the symmetrical, lipoplrilic adnmantyl group. a limited
`number of N-arylsulfonyl-N’-adsmantylureas were prepared for evaluation as hypoglycemic agents. N-p-
`Tolyaulfonyl-N’-l—adamantylurca—tlie adamantyl analog of tolbuta.mide——wus lound to be one of the most
`potent oral agents synthesized thus far.
`
`The pronounced lipophilic nature associated with the
`compact, highly symmetrical architecture of tlie ada-
`mantane molecule‘ invites a study of its influence on
`characteristics and biological potential of compounds
`which contain this unique hydrocarbon moiety.
`Such a study has now become possible as a result of
`Schleyer's startling discovery of a direct synthesis’
`of adamantane and of Stetter’s extensive exploration‘
`of its functional derivatives.
`As a first situation in which to assess the possible
`pharmacodynamic effects of the adamantyl group we
`selected the complex structure—activity relationships
`existing within the class of orally active hypoglycemic
`sulionylureas.‘
`In the series of N-arylsulfonyl-N'-
`alkylureas, according to previous experience in our
`laboratories,
`the alkyl group may be varied widely
`with maintenance of activity and the inclusion of cyclo-
`hexyl and cycloheptyl radicals frequently has produced
`agents of maximum efficacy.’
`If the influence of the
`adamantyl group were indeed to be a beneficial one, the
`synthesis and pharmacological evaluation of N-p-
`tolylsulfonyl-N'-I-adamantylurea and closely related
`analogs would provide an initial test of this possibility.
`5
`
`crr.—©_ so.r~u-iconrr Q).1
`‘
`3
`
`The analogs studied were primarily designed tn as-
`sess the cfl’r-ct of (Sr) aubstituents on the plu.-nyl ring,
`(b) substitucnts on the adalnantyl
`radical. and (c)
`the position, on a secondary or tcrtiary carbon, of the
`urcido group on the adanwlltanic skclcl.o:1.
`The synthesis of these analogs (see Table I) involved
`the previously described condensation‘ of
`the ap-
`propriately
`substituted ethyl N-nrylsulfonylcarlwr
`mates‘ with the desired aminoadamantanes. Ada-
`mantyl-l-arnine" and dl-adamantyl-2-amine“ have been
`reported.’ Reduction of adamantane-1-carboxamide’
`(1) S. Lands. V. Mnchncek. and I. Mmurelt. Clmn. bialy, I1, 415, 443
`(1933).
`(2) P. VOII R. Sclileya and M. M. Donaldson. J. Am. Chem. Soc.. us, 4645
`(1060).
`(3) H. Stctlar, Ange-4. Ohm-n.. H, 801 (I902).
`(4) L. J. P. Duncan and J. D. Baird. Pkannaeol. Ram. ll. 91 (1960),
`(5) F. J. Manhall. M. V. Sign]. In. H. R. Sullivan, C. Cecnik. and M. A.
`Rout. J. Med. Clicvm. I, 00 (1903).
`(6) F. J. Marshall and M. v. Sinl. .h.. J. 0.... cm... 31,927 (rose).
`(7) H. Stoltr. J. Mayer. M. Schwlrs. and K. Wulff. Clint. Bth, 98. 226
`(1000).
`(R1 (.3 W Rmitlr nnrl H.
`I‘: Wlllnrrl-u. 1 film o'_m,,.__ gg_ ggm uunn_
`un 11... slnrlrng Ilxal-ufill mluiml rm um ‘um-,..n;.¢,n up ,.|...,,,.,,l_,.H._
`nrnina. n.||nel.:v' ndamurtnnur-.s {l.‘. we R. Br.-hleyar null R. D. NIc|:¢lnn_ J‘. 4.._
`Chin. .'l'ar.. 83.
`IR! (1061)! Ivan iillnlly prnvnrod for us by Dr. Donald 1,,
`Haywood. Union Carbide Chemical: Co.. South {.‘l.u.r|outan. Wen \|'ir;1.;|;_
`
`with lithium aluminum hydride gave l-aminomethyl-
`adamantane which was used for the preparation of the
`compounds XIX and XX with a methylene bridge
`between the N’-atom and the adarnantyl function.
`ii-.li’I(3tlI_}'.l£l.(ll1rI'JllJ1l.yl'l-8.l'fll|'Ic
`(for XVII) and 3,5-
`cliIrict.l'lyln.d:ln1n.rrtyl—l«shrine (for XVIII) were prepared
`from l—moLhyl-and l.Ihlimctlrylndurrisntsnc.‘° respec-
`tively, according to Stotter‘u procedure’-" for ada-
`mantyl-l-amine. This procedure involves as s first
`step the conversion of the hydrocarbon to the tertiary
`bromide with excess bromine.
`In the latter case the
`tertiary nature of the bromide and the absence of
`skeletal rearrangements in this and subsequent conver-
`sions tu the amine has been well established.
`By analogy, a similar bromiruitiou of l—mr~tl:yl~ and
`1,3-dirnetlrylsrlsruantulrc may be cxpcclctl to giuc the
`tertiary dcrivstiw.-s also, and the r11.lclca.r magnetic
`resonance spectra of the respective bromides were found
`to support this structure] :ucsigI1rnuI'rl'... The luytlmgcna
`of the methyl groups all appear as single peaks with the
`expected frequency {r -=- 9.17. relative to l;ctrn.rncth_rl~
`silane). The remaining protons were accounted for in
`"“l1l»ll3lL'l-8 at nhout r 8 and the sbsnncc of peaks all r
`5.8. typical for a proton in the l'uncl.icn—l.‘JllBr— lt‘.‘r"«'1°'
`hcxyl bromide),
`is further evidence for the tertiary
`nature of the bromides.
`For the preparation of adamsntyl-1-amine on B
`larger scale the use of bromine as a solvent in the fore-
`Efllfll.-’. Dmcr-durc proved impractical.
`instead.
`13 mix‘
`ture of mlarrranlsnc sud Hrutyl chloride was treated
`“M1 CW9-Iytic amounts of aluminum chloride (593
`Exnnrhucnu-1)
`to give a high yield of aduumntJr'l'1
`chloride which, without further puriiication, was cm!"
`vcrtcrl
`to the amino tinrougln the ucutaanidu inter-
`lI1[.‘l'llE.l-I1.
`
`<
`
`‘l
`
`llP"t" CroHrs-1—Br flr C..,H.;v1-NHC0Cl’l1
`M01
`H290. /
`1 0“.
`CIol'lrs~l.—Cl -—/
`C|ol‘lrrl.~ NH:
`
`The I.-'fl.t'ilT|ll5 srylsulforiylalkylumm were plfltluflfd
`without dificulty by carrying out the condensation Ol
`carbamatos and nmines in but toluene. Occasinrlflllln
`l‘°“"-"W51". as observed previously,‘ the product olIl3.l"°"l
`lucked stability in hot nthanol, used for recr5’st3]1l"'
`“'7' "- Wm B» S¢l'l0)'er and n. D. Nicholas, r..mr.¢dm. L¢lurI.N°-"
`306 (1961).
`(11) (I) H. Butter. M. Salmon. and A. Hi:-sclrhorn, Axons. CM--"'
`439 (1959):
`(b) H. sum.-. M. Schwarl. and A. Hirachhorn. Ohm. Bn-. 9‘-
`l399 (I059).
`
`'
`
`Page 1 of 4
`
`AstraZeneca Exhibit 2029
`
`Mylan v. Astraleneca
`IPR2015-01340
`
`

`
`November. 1953
`
`ADAMANTYL Mnorcm111,3,
`
`1
`
`761
`
`S
`
`R
`
`n-Butylv.
`A damantyl-1
`Adcyclohexylb
`
`t 1-1
`
`1
`
`_
`
`Aryl
`°“b't-
`h
`1
`4_cii.:ny
`Im
`4—CH
`I
`‘LOB:
`1“
`4-C.H
`MXH:
`IV
`4-CH
`$111 Hm:
`VIII
`4-01-
`IX
`4—Cl—
`X
`4_Cl_
`XI
`4-1'—C;H1-
`xii
`4-CH.O0-
`XIII
`4-CH.CO—
`XIV
`4-CHa,3-NHr
`xv
`4—CHa.3-NHz-
`ll
`4-CHr'
`XVI
`4—CHa-
`XVII
`4-CH.-
`
`XVIII
`
`4—CHr-
`
`150—151
`
`C H CIN 0
`.1
`ll
`. as
`190-192 C:0HuNOS
`163-165 C..HuNi0:s
`
`55
`
`175 dec.
`
`C.HzsN 0:5
`'
`'
`
`59.48 6.93
`
`59
`' 8‘ 7'02
`
`200-208 C..H..N.o,S
`184-186 CnHi.N.0.s
`
`02.04 0.94 8.04 0219 7.04 7.71
`02.95 7.23 7.73 6280 7.17 7.81
`
`0
`
`166-168
`
`C,.,H,.N,0,S
`
`7,14
`
`7 _30
`
`Tiuau I
`U”m”’E° N"““"5““'°NWm=As. ArS0.NHCoNHn
`Relafivo
`Mp
`,‘ "
`F°"”""
`mi“
`0'
`15 _5
`CIBHMNIOJS
`12.8
`172-174
`_3
`C1DH1|Nl0:S
`4” 153-I55
`,
`3 :1
`155-158 C..H..N.0.s.
`2. 1
`5.1
`5,6
`2.9
`1.0
`4 ,0
`0
`5.0
`15 .4
`4.0
`2.8
`
`r——7 Cn.lcd.-—‘ ,-*7 1.‘ 4?
`C
`0 H
`N
`0
`° ii”
`N
`02.04 0.94 8.04 01.90 0.72 7.84
`62.95 7.23 7.73 03.13 7.39 7.31
`50.31 0.30 7.30 50.78 5.87 7.28
`
`.35 5.74 7.54 55.89 0.04 7.37
`63 80
`7 50
`63 (11
`7
`'
`
`7_44
`
`'02 7 71
`'
`
`Ad
`t 1-1
`aJ'_';‘1‘:h:’“,,
`n—l’rui:ri
`Adamautyl-1
`Cyclohexyl,
`Adamantyl~1
`Adamantyl-1
`Cyclohexyl‘
`Adamantyl-I
`cycioiiexyif
`Adsmantyl-1"
`Adamantlyl-2
`3—Mei.hyladaman-
`tyl-1
`3,5-Dimethyladir
`mantyl-I
`14 .8
`Adamantyl-1'
`4-C;Hi-
`IV
`0 2
`Adamantyl-1-CH.—
`4-C.H.-
`XIX
`1 .6
`Adamantyl-1'
`4-CH:C0-
`XII
`6 _97
`7. 17
`CmI:lsoNiO.S
`204-200
`0
`A.dsmantyl-1-CHg-
`4—CH;C0-
`XX
`‘ Tolbutamide (ref. 14).
`‘ See ref. 5; XIII is
`ilel Villsr, Metabolism, 10, 221 (1961).
`‘ Tolcyclamide: J. J. Paullada and J. L.
`Icetohexamide.
`‘ See ref. 6; VII is thiohexsmide, VIII is ehlorpropamide.
`' British Patent 808,073; Chem. Abstr. 53, l2241a (1959).
`I Meiahexamide, C. F. Boehringer and Soehne, Mannheim, Waldhol, Germany.
`' II, IV, and XII are repeated for ease of comparison
`with the N’-analogs.
`‘ II, IV, XVI, XVII, XVIII, and XIX were recrystallized from chloroform—Skelly B (petroleum ether, b.p. 60-
`71°); VI, IX, XI, XII, XIV, and XX from methanol.
`
`203—205
`
`C..H,,N:O.S
`
`03.80 7.50 7.44 63.87 7.50 7.56
`
`tion. The reformed amine, resulting from a. partial
`breakdown, combined with the remaining sulfonylurea
`to form an insoluble salt.
`
`This problem required special attention in the case of
`preparations of N-p—tolylsulfonyl~N’-lauiarnsntyliiiea
`(II) on a larger scale.
`In an effort to find a suitable
`solvent for the recrystallization of II,
`toluene proved
`impractical because of extensive solvation which re-
`quired prolonged heating at 120° be remove last traces
`of
`solvent. Recrystallization from e}1loiofom3*P0'
`troleum ether (b.p. 60-71“) was carried out successfully
`0111)’ after it was discovered that
`traces of
`fllcflllfll
`Dhzsent
`in chloroform must be removed by shaking
`with alumina,
`hypoglycemic
`Pharmacological Evaluation. The
`activities of the new sulfonylureas are listed in terms Of
`relative potency in Table I together with some reference
`°°mlJounds reported previously.‘
`All compounds were tested in normal male rats of a
`“min derived from Wistar stock. The rats were
`lasted 18 hr. and the compounds were sdniiiiistercd ii)’
`sloinach tuhe as a suspension in a 5% solution of acacia-
`Facli rat was used only once. Blood EIUCUW ‘3°“°°“'
`‘lmtivcs were determined i.n
`the autuanalJ'1"”‘" 9"‘
`mlplcii of blood obtained from the tail veins before and
`all 1, 2, 3, 5, and 7 hr. after drug administration. Each
`Wmptmnd was tested at 3 or 4 doses between 5 and 100
`’”3=/l‘8- and each dose was administered to from 6 to 18
`rats. The relative hypoglycemic potency of the com-
`l’°‘_111dS was calculated by the method previously de‘
`Embed-" This method for calculating relative hypo’
`(H) Technlcon Instruments Corp.. Chauncey. N- Y-
`mm) M. A. am. M. v. Sisal Jr
`and R. c. Anderson. D-‘ohm 3: 7
`50).
`‘
`"
`
`Page 2 of4
`
`glycemic potency includes the degree as well as the
`duration of
`the activity produced.
`Therefore,
`in-
`creased potency as expremed here may be due to a.
`greater fall in blood glucose, to a more prolonged fall,
`or to a combination of both parameters. The value for
`relative potency given has been expresed in relation
`to the hypoglycemic activity of
`tolbutamide" (I)
`which has been assigned the potency of 1.0.
`An examination of the relative potcncies listed in
`Table I reveals that N-p-tolylsulfonyl—N’-1-adamanty1—
`nrcs (II) and the gmetliylphoiiyl analog IV are 1111130-"i‘
`irnntely 15 times as active as tolbutsmide (1, N-;.-;»-
`tolylsulfonyl-N’-ii-liutyiurca) on a weight basis. Both
`compounds are also soincwhat more, potent. 1.2 and 1.6
`times, respectively, than their N’-cyclohcxyl aniilogs”
`III and V wliii-h, thus far, are airioin: the most active
`liypoglyccriiic agents of this type.
`_
`It is of interest to note the time course (Fig. 1) of
`glucose levels for the pair II and II]. During the
`first 3 hi‘. after drug administration the decrease
`in blood gluooesa level attained with N-p-tolylsuIfonyl-
`N’-cyclohcxyliirea (III) is actually greater than that
`attained by the N’-adainaatyl compound II, ‘tint the
`prolonged hypoglyceriiie activity of II reverses this rela-
`tion dui-lug the final 3 hr. of the observation period.
`A striking feature is the constancy of glucose levels
`attained with a single 405° 01' the adamantyl compound
`11, These levels vary less than 10 ms-/100 over n_6~
`hr. period while the cyelohexyl c0mI3°U“d In “T193
`over a range of 35 1118-.’ 100-
`_
`It is further noted that changes in the structure of
`[1, 1,9 it in the nature of the phenyl sulistitutinn or in
`(14) H Franks and J. Fuchs. Deal. and. Waelucln-.. 80, 1440 (I955).
`
`

`
`762
`
`K. Gnuzon, E. V. KnUMKALNs, R. L. Barnum, F. J. MARSHALL, AND M. A. Roor
`
`Vol. 6
`
`6
`
`ix’:c:
`
`J:-.3
`
`
`
`
`
`BLOODGLUCOSECHANGEINmg.-/._Li.
`
`
`
`is ca
`
`‘.3
`
`1
`
`2
`
`4
`3
`HOURS.
`
`5
`
`6
`
`7
`
`Fig. l.—Iiypoglycernic activity at a dose orally of 25 mg./kg.
`for tolbutamide (I), N-p-tolylsulfonyl-N'-adamantylurea (II), and
`N-4p-tolylsulfonyl-N'-cyclohexylurea ( III). The individual points
`show the mean glucose levels at the time indicated, while the bars
`reprwent the standard errors of these mean values.
`
`in lowered
`invariably result
`the adamantyl group,
`potency. Thus,
`replacement of
`the p-methyl sub-
`stituent of II by CHzS- (VI), Cl- (IX),
`i-CaH7- (XI),
`and CII;CO- (XII) leads to compounds of progressively
`lower
`activity, while
`the 4—methyl-3-aminophenyl
`analog XIV is without noticeable activity at the highest
`dose level tested (100 mg./kg.).
`Also, what would appear to be minor changes in the
`adamantyl moiety do cause a sharp reduction in po-
`tency. For example,
`the introduction of a single
`methyl substituent, as in XVII, reduces the potency
`drastically. Two methyl
`substituents
`(in XVIII)
`virtually abolish activity. A great reduction in potency
`results from the insertion of a methylene bridge between
`the N ’-atom and the adamantane fragment as in XIX
`and inXX.
`As adamantyl—2-amine (in XVI) differs from the
`1-isomer merely in the orientation of the O—N bond
`relative to the “spherical” carbon skeleton, the strongly
`reduced activity of XVI—-about 25% of II——is sur-
`prising indccd.
`the activity profile in the rat
`It is obvious that
`observed for the adamantane-containing compounds is
`a composite of (a) their absorption characteristics, (b)
`their metabolic disposition, and (c) the precision with
`which they fit at the receptor site. Which of these
`factors is primarily responsible for the favorable activity
`of the N’-1-adamantyl compound II can only be de-
`cided on the basis of
`future experimentation.
`It
`seems of interest to study the pharmacodynamic in-
`fluence of the 1—adamantyl group in other selected
`cases. Work now in progress in our laboratories to
`verify this assumption will be the subject of subsequent
`publications.
`Toxicological and Clinical 0bservations.—In view
`of the favorable hypoglycemic activity observed in rats
`with N-p-tolylsulfonyl-N’-l-adamantylurea (II) toxi-
`cological studies" were undertaken in anticipation of
`clinical investigation" of this agent.
`(15) We are indebted to Dr. R. C. Anderson Ind H. M. Worth, Division
`of Toxicology oi The Lilly Rueurch Laboratories. lor the report on acute
`and chmnio toxicity.
`
`Page 3 of 4
`
`A single oral dose of 2.0 g./kg. given '00 35 normal
`mice of both sexes did not kill any of the animals either
`immediately or during the 7 days following drug ad.
`ministration. At no time did these animals show
`any toxic effects from the drug. Larger doses were
`not administered.
`Groups of six normal male and six normal female
`rats fed for one month on a standard diet containing
`this drug at a concentration such that the daily intake
`of drug averaged 1 g./kg. gained weight slightly less
`rapidly than did the rats in control groups not receiving
`the drug. At the end of the month of treatment all
`animals were killed and the organs and tissues were
`examined for pathological changes. No changes were
`noted except for a slight degranulation of the B cells of
`the pancreatic islets. All of the hypoglycemic sulfonyl-
`urea compounds which have been studied extensively
`produce B cell degranulation.
`Dogs were treated for 232 days by the oral route with
`daily doses as high as 100 mg./kg. Aside from a slight
`elevation of the serum alkaline phosphatase levels in the
`dogs given the h’ghest dose, no unusual changes were
`observed throughout
`the experiment. At necropsy
`there were no abnormalities in the organs or tissues
`that could be attributed to the administered drug.
`At the time of the preparation of this manuscript,
`information on preliminary clinical studies of II was
`available.
`In one phase of
`these studies” thirty
`adult diabetics were managed with the drug and ob-
`served for periods varying from 8 to 12 weeks. The
`patients were grouped according to their prior therapy,
`if any, in order that a comparison with existing hypo-
`glycemic agents could be made.
`The data obtained thus far indicate II to be a most
`satisfactory, potent. oral hypoglycemic agent with an
`eflbctivc average dose, single or divided, of 400 mg. /day.
`Equal to chlorproparnide‘ on a weight basis,
`the drug
`[I possesses about five times the potency of tollnrt-
`arnirle." The activity of II is rapid in onset with a
`tentative duration of 4-{i hr., indicating that the drug is
`rapidly absorbed and utilized by the body.
`
`Experimental
`
`Because of the tendency of most sdarnantene derivatives to
`sublrrne, on-_lt'rng points were commonly taken in sen.lr:cl, sub-
`fllflfgfld ‘>1!-P3llM,)'
`tubes. Generally spe.u.l:in|;, melting imlnl
`delr~rmin:ntions were less mnniusixe than the compnrisonofx-r.1-3'
`dlilrnution patterns and vapor-phase chromatographic belmvior.
`_ Adamanryl Amines
`1-Amlnoruolhyiudsrnontane."—-A solu-
`Wm ‘ll 9 l{- (0.05 mole) of nda.msnLana-l—nnrbo.1mrnide" in 200 ml.
`0f d|'.'r' °l»l'|9r was II-dLlt'.(l dmpwisfi to 11 well stirred suspension oi ll]
`IL (0.25 mole) of lithium aluminum hydride in 500 ml. of dry
`Other. The reubtitln tms carried out in a three-necked, round-
`b“”"’“" “Wk "Q1-‘iPi”-‘Cl with n meciranicni stirrer in a close-fitting
`socket and Inn eiiieiant trait.-r-cooled condenser. After the addi-
`"°“ I'M hm“ """|Pl¢l-ell. the reaction mixture was heated under
`rllflur far 4 hr. The well agitated mixture was then cooled to
`—='3°- “-3101 l0‘rIll. uf water was added drupwiaz, followed by 3|) ml.
`of at 10% Mfllum lzydroxirl-s snlulion, and, firmily, 10 ml. of water
`Tl": PH‘-lfiilllttlted solids were removed by filtration and washer]
`With 500 ml. of other. The cmnbincd other layers were driui
`mu" ‘”"‘~‘F'd"“”3 militnrsium sulfate and concentrated to drynfifl
`
`tn} At The “UV
`us) The ':‘”“|"] "‘"'fi” "01 Dr-rformm! in hm parts:
`Lllilofllaricn under the direction ui William IL Kirlley. M.D.. D-
`'s“";;';l:;'"""1‘\'["!" cl"“l“‘-l R‘-‘lflmll. I-Dd {bi unrl-or the riireutinn of Rob!“
`DI.
`. 3.. al
`lh M ii II
`I
`'
`sue“. “mama. TH”.
`I
`at: o a Research Foumlnlion. M15 THV“
`(17) After our work was concluded the preparation of thin urnine was 19'
`P°"'-‘d by 1*- Smut and P. Gocbcl. Chem. Ban. on, 550 (ms).
`
`

`
`November, woo
`
`ADAMANTYL Mnnrcmans.
`
`I
`
`733
`
`ll, 9.219; N, 39:1,
`
`ufl.Lll.'-|' reduced. pressure. The residue was taken up in 50 ml. of
`aryether, filtered from a small smount of insolublc material, and
`mud with dry hydrogen chloride gas. The precipitated hydro-
`:l:luriL|s 371.11. was l'E1'-‘-l'JI"l“llEli'.I3d from ethanol to give 7 g. (70%)
`at x|1itc|':r0d1IGl« ""-P- 320 - _‘
`__
`Ami. Cslcd.
`for Cg.llmLlN: C,
`lrofill;
`p,,,,,,;; c.o5.35; II, 1o.c1; N,6.83.
`;.uechyladnmsnlyl—l-amine. 3-Msthyladsmanlyl 1-Bromide.
`—Thn lsrmninntion of I-!'l'|l3‘l.l‘|_Vl&l!l.I1.'l1‘ll.l.l'll.«8l.'l£'.“' was mrricrl out by
`me procedure rtrported for odumantyl 1-bromide“ and gave the
`Fuduct as s disullsblc oil, b.p. 65-67‘ ((1.05 mm), inayicld ol
`flffiml, Calcd. for Cullnlir: C, 57.65; H, 7.48; Br, 111.37.
`Found: B, 57.35; H, 7.61;
`l.lr,35.2?.
`crud:-. umidc, pre-
`1-Acel.IlnltIIJ-3-rueI.Iryla¢lamnl1I.Irle.—-'I'l1c
`from the bromide by the CHrCN“HrS0| procedure,’ was
`p{|J'lFIitl by sublimation at 9D—l00° (0.05 mm.). The nrnids
`ncllml at 108-100".
`l-’rm:1d:N,5.B3.
`ylllfll. L‘-slncl.l'or(l..1-l-_oNl.l: N,6.7fl.
`3.fl{e|',l'|_y'Iadan‘I3I1lyl-I-&fl'llI‘l€
`Hydrochloride.——De-ncctylstlrm
`by Patnssiurn liydmxide in diothylonc glycol‘ and other uxtrlwtlon
`gm :1 mlutjon of the amino which by infrared spectral analysis
`as found to contain approximately h% of uncliarigccl c_I.arl.mg
`snide. The hydrochloride, prepared in ether solution with dry
`mmgen chloride gas, was olatamed in 87% yield and melted
`as 2El5~3lll]°.
`'I‘he ow;-.r—a1I yield from l~T|'IBl.llylI|£lBIl)n.11lall1‘lfl was
`817.
`Aonal. Calcd. for C1|HuClN§ Cl, 17.62; N, 6.94. Found:
`Cl 17.77‘ N 6.78.
`3,5-Dirnethyladamantyl l_-
`5,5-Diinetllyladamantyl-1-amine.
`ll'0l:.lt{:d was preprd,7r7185‘];revi01\:lsly desH<:gi'}i:ed,“f'rom.l1,3—¢!i‘1-
`mely
`amantane
`in
`.oy1e ssa.
`yeowoi no
`1.5173, b.p. e7—c9° (0.03 mm.).
`'
`Anal. Calcd. for C.,H,.Br: C, 59.25; H, 7.30; N, 6.33.
`Frrilnd: C 59.39; H 3.lll; N 32.38.
`1-Accuinirlo-3,5-(llmelhylsllnmsnlsne waslgrtépartild, asdpre-
`rinuslydsscrrihed, from the bromide in 96% yie
`0 cm apro uct.
`Purification of a sample by sublimation gave the amide, melting
`al80-82°.
`
`-
`
`H,
`
`l0.47; N, 6.33.
`
`for C14l"[uNOI C,
`Found: C 75.54‘ H 10.49‘ N 6.41.
`3,5-Dhdethyladanisnlyl-l-sriiine was obtained by alkaline
`layairulysis from the crude nmidc and was isolated as the hydro-
`chloride salt, mp. 290-295“,
`in It yield of 37%. The over-oll
`yield hosed on 1.3-dimetliylsdnmnntauc nrnounted to 63%.
`Anal. Cnlcd.lor C|9lI2:ClN: N,6.4G. Found: N, 6.51.‘
`lliiununlyl-1-aniine via Adnnunlyl 1-Chloride-.—A solution of
`l'|1lJ‘g. (0.74 mole) of sdurnsntane‘ and It'll) ml. (85 g., 0.92 mole]
`mutyl chloride in -100 ml. of anhgtgrous cyealolttextitflgdww $0-
`ln a 1-1.,
`1.}
`eclrcd om - ottom as
`'
`wi
`It
`Ilia-rrnnmcter, meclirneriii.-Isl stirie: xirith close-fitting socket, and K33
`E'.l'l:|‘II.lSl. lube lending to n bubblor submerged in water. The
`‘*”'15'fil-. Illuminurn chloride (total -l.ll 1;., 0.00 mole), was added
`in lunches of 0.5 g. at regular intervals over is period of 3 hr-
`Wirrss of the reaction was followccl conveniently by the rate of
`”“1Pl'1Kisobut.snsgss. Upon completion of the rcsction; W0 “I'-
`nl N hydrochloric. acid solution was arldcd with vigorous stirring.
`followed by 50¢"! ml. of other-. The organic layer was separated.
`if extracts-d with 50 ml. of cold water, than with 50 ml. of a
`-.- sodium la"
`b
`. to
`l
`t.'
`d 13
`ll
`d ‘ed with the aid oi
`ME)"-lruus rnGi:lilon'adel. ulillltzlii-iremnolivnlly ofnthe solvents under
`Wllliteii pressure there remained 115 g. (93%) of crlldfl PT0‘l'-‘ct
`
`melting at 152-156” flit.‘ mp. 365“). Vapor chromatographic
`analysis of this rnstcriul re.-vculod in composition of 90-95% of
`adsrnsntyl 1-chloride and 5-10% of adamrmtsne. Recrystalliza-
`tion of a sample of this rnstoriul from ethanol at -50” gave pure
`adamantyl l-dilorirlc which was found to be identical with s.n
`authentic sample’ by mixture melting point determination nnd by
`X-ray diffraction patterns.
`Anal. Calcd. for C..I1..c1: c, 70.37; u, 8.36; CI, 20.76.
`Found: C,70.22', 1-1, 8.96; Cl, 20.09.
`The crude product was convertsd. without further purification,
`by the occtonitrile—sul.lur'ic scirl procedure to l-a.cet.amidoada-
`rnnntnnofi melting at I-H~-1-16° (lit. mp. 149“).
`l.l£|L'l‘)fBi.l:tllli*‘.l’|.-
`tron from sthsnol gavc the pure omirlc, mp. 147-149 °, identical
`with an u.u'l‘.ltcnl.iu sample by mixture melting point and X-my
`dllimction pattern. The crude amide (108 3., 83%), again with-
`out prior pilriliusiion, was Baporlifiodl and pure sdommitylamine
`(m.p. 16()—200°, reported 180—190°) was isolated in an over-all
`yield of 60% (51 g.) based on admnantane.
`the
`N-Aryl-N’-adamantylsulfonylureas.—The preparation of
`new ureas reported followed the published procedure‘ and will be
`exemplified in detail for compound II.
`N-p-'l‘olylsulfonyl-N’-1-adamantylurea (II).—A solution of
`302.5 g. (2 moles) of 1-aminosdamanfane and 535 g. (2.2 moles)
`of ethyl N-(4-methylplienylsulfonyl) carbsms.1e' in 6 1. of dry
`toluene was heated under reflux for 5 hr. The reaction mixture
`was allowed to cool to room temperature, and the crystalline
`product was collected by filtration and then dissolved without the
`application of heat in about 2 l. of chloroform which had pre-
`viously been shaken with 50 g. of alumina to remove traces
`(0.54%) of ethanol. The chloroform solution was washed with a.
`total of 1600 ml. of cold 5% hydrochloric acid solution, then with
`water until neutral, and dried with the aid of anhydrous magne-
`sium sulfate. The chloroform solution was concentrated under
`nrduocd pressure to about one-lLs.ll' its volume, warmed to about
`50°, and hot Skelly B {petmleurw-ether, l.'I.p. [i0«71°) was added
`In stnrt crystallisation. After uhiiling the mixture overnight. the
`crystals were isolated by filtration to give -100 g. of product
`mailing at 175-179“.
`'I‘wo further racryslsllicntions from puri-
`fioil cl:loml'orm—Slrsll_v B gave 356 g. (51%) of final procluct ll,
`melting at 178—179°.
`Anal. Calcd. for CoHuNa0a’3l C. 62-04: H. 3-94: N. 3.04;
`mol. wt., 348.5. Found: C, 61.96; ‘H, 6.72; N, 7.84; mol. wt.
`(electmmetric titration in 66% dimethylformamide, pK.’ 7.98),
`350.
`
`Acknowledgnu-nt.~—Tl1c authors are grateful to W.
`R. Kirtlcy, M. D., and to R. S. Radding, M. D.,for the
`clinical data;
`to Dr. R. C. Anderson and 11. Worth
`for the report on toxicological studies; to W.
`Brown,
`G. M. Munich, 11. L. Iluntcr, and their associates, for
`|_'ni{;roa]']alySeS,‘
`to Dr. I]. E. Boss, P. Lundis, and D. 0.
`Woolf for physicochemicsl data; and fn‘Lfi.wreT1ce A.
`White and Don L. Kim for fine assistance in lzhs prepara-
`tion of the material for clinical trial.
`The helpful interest and advice of Dr. Jack Mills in
`the execution of these studies is worthy of special
`mention.
`_
`The generous help of Dr. Donald L. IIeywood in
`supplying adamantanone is gratefully remembered.
`
`Page 4 of4