Welcome to Scribd, the world's digital library. Read, publish, and share books and documents. See more
Download
Standard view
Full view
of .
Look up keyword
Like this
1Activity
0 of .
Results for:
No results containing your search query
P. 1
4 Amino 4 Aryl Cyclohexanones - 1. Modification of the Aryl Ring

4 Amino 4 Aryl Cyclohexanones - 1. Modification of the Aryl Ring

Ratings: (0)|Views: 44 |Likes:
Published by borohydride
Daniel Lednicer cyclohexanone part 1- aromatic substitution
Daniel Lednicer cyclohexanone part 1- aromatic substitution

More info:

Published by: borohydride on Oct 01, 2011
Copyright:Attribution Non-commercial

Availability:

Read on Scribd mobile: iPhone, iPad and Android.
download as PDF, TXT or read online from Scribd
See more
See less

10/01/2011

pdf

text

original

 
424
J.
Med. Chem
1980,
23,
424-430
white solid
(98%):
mp 139-140
"C;
[uIz5~
1.2'
(c 1.2,
CH,OH).Anal. (CI6Hz2N2O7)
,
H, N.
Acknowledgment.
We acknowledge the Food andDrug Administration (Grant FD
00590)
for their supportof this investigation. M.K. thanks the Mitsubishi-KaseiInstitute of Life Sciences for enabling him to perform thiswork. We also thank Constance Mullin for her help inpreparing this manuscript.
L-Aspartyl-L-m,p-dimethoxyphenylalanine
ethyl Ester(20).
The coupling reaction followed general procedure
B.
The
residue obtained from removal
of
the
solvent
under reducedpressure
was
crystallized
from
isopropyl
alcohol
to
give
N-(ben-zyloxycarbony1)-P-
enzyl-L-aspartyl-L-m,p-dimethoxyphenyl-
alanine methyl ester
as
a
white solid
(61%):
mp 154-155
"C;
[0IED
$41.4"
(c
1.0, CHC13). Anal. (C31H34N209)
,
H,
N.
The deprotection reaction followed general procedure
D.
Removal
of
the
solvent
under reduced pressure yielded
20
as
a
4-Amino-4-arylcyclohexanones and Their Derivatives, a Novel Class
of
Analgesics.
1.
Modification of the Aryl Ring
Daniel Lednicer,' Philip
F.
VonVoigtlander,* and
D.
Edward Emmert
The
Upjohn
Company, Research Laboratories, Kalamazoo, Michigan
49001.
Received August 7, 1979
Investigation
of
central nervous system activity
of
phenylcyclohexylamines
was
continued by preparation
of
"reversed"analogues. Following the unexpected finding
of
analgesic
activity
with 1-(dimethylamino)-1-phenylcyclohexylamine,the SAR
of
the series
was
investigated. Synthesis starts by double Michael reaction
of
acrylate on arylacetonitriles.Following cyclization, decarboxylation,
ketalization,
and saponification, he
geminally
substituted acid
is
rearranged
to
the isocyanate by means
of
(C6H50)2PON3.socyanates were then converted
to
the
title
compounds. Analgesic
activity
is
very
sensitive
to
he
nature
and position
of
the
substitutent on the aromatic
ring.
The most potent compoundsin this
series
(p-CH3,
p-Br) showed 50% the
potency
of
morphine. Deletion
of
the ring
oxygen
abolishes activity.Compounds related to 4-phenylcyclohexylamine haveproven a fruitful nucleus for the preparation of biologicallyactive compounds. Suitable modifications of this moietyhave provided several series of compounds which showneuroleptic activity;' substitution of
a
carbon onto the ringatom bearing aryl leads to hypotensive agent^.^ One ofthe more interesting of the earlier series was that in whichthat same carbon bore an oxygen substituent.2 It was thusof some interest to ascertain the effect on biological activityof placing a nitrogen atom on that apparently importantposition. Specifically, we undertook the preparation of
4-phenyl-4-(dimethylamino)cyclohexanone
1
.
Random
o3
6H5
/tu\
CH3 CcI3
1
screening surprisingly showed this compound to exhibitnarcotic-like analgesic activity. This was particularly un-anticipated because the molecule departs
so
radically fromthe various SAR correlations proposed for centrally actinganalgesic^.^ We thus undertook the systematic investi-gation of the SAR in this series. The present report dealswith the effect on activity of modification of the aromaticmoiety.
Chemistry.
Our initial approach to these deceptivelysimple compounds relied heavily on the scheme we haddevised in connection with the earlier work for constructionof the substituted carboxylic acids
(7)
(Scheme
I).3
Thisroute offered the advantage that most of the requiredarylacetonitriles are commercially available (the
p-tert-
butylnitrile was obtained in a straightforward manner fromthe benzyl alcohol). The key to the sequence was the
(1)
Address:
Mead
Johnson
&
Co.,
Evansville, Indiana
47721.
(2)
See,
tor
example,
D.
Lednicer,
D.
E.
Emmert,
R. A.
Lahti,
and
A.
D.
Rudzik,
J.
Med. Chem.,
16,
1251
(1973).
(3)
D.
Lednicer,
D.E.
Emmert,
A.
D.
Rudzik, and
B.
E.
Graham,
J.
Med.
Chem.
18,
593
(1975).
(4)
(a)
0.
Schauman.
Pharrnazie,
4,364
(1949);
(b)
A.
H.
Beckett
and
A.
F.
Cases,
J. Pharm. Pharrnacol.,
6,
986
(1954);
(c)
P.
S.
ortoghese,
J. Pharm
Sci.,
55.
865
(1966).
0022-2623/80/1823-0424$01.00/0
Scheme
I
COzCH3ArCHZCN
-
r<
-
r
2
COzCH3
4,
R'
=
CO,CH,;
R2
0
5,
R'
=
H;
R2
0
3
2-
6,
R'
=
H;
R2
=
(
/N\
Do
r70:I
14NCH3
-
r7Q:I
CH3
CH3
7,
R3
=
CO,H
9,
R4
=
H
11
10,
4
=
CH,
8,
RJ
=
NCO
recently developed modification of the Curtius reactionwhich allows this transformation to be carried out in thepresence of acid-labile
group^.^
We modified this proce-dure yet further in that we substituted an inert high-boilingsolvent (anisole) for the alcohols used in the original work.It is a tribute to the extreme steric hindrance about thequaternary carbon that the isocyanates
(8)
obtained by thisreaction sequence are usually stable to chromatographyon silica gel-the routine isolation procedure. For reasonswhich are not immediately apparent, the product from theacid containing the 2-thienyl group as the aromatic
sub-
stituent showed the expected isocyanate reactivity; in thiscase, the reaction was run in ethanol to afford the corre-sponding carbamate. Reduction of
8
by means
of
LiAlH,afforded the secondary amine
(9).
This was then meth-ylated by means of
CHzO
and NaBHd6 the hindered na-ture of the amine again manifested itself in the observationthat at least one recycle was required to assure complete
(5)
T.
Shioivi, K.
Ninomiya,
and
S.
Yamada,
J.
Am.
Chem.
SOC.,
94,
6204
(1972).
(6)
R.
L.
Sondergam,
J.
Hentchoya,
H.
Charle,
and
G.
Charles,
Tetrahedron Lett.,
261
(1973).
C
1980
American
Chemical
Society
 
4-Amino-4-arylcyclohexanones
Table
I.
Analeesic Activitv
Journal
of
Medicinal Chemistry,
1980,
Vol.
23,
No.
4
425
0.
/N\CH3 CH3
analgesic act.:=
ED,,,
mglkgb
no.
Ar
X flick pinch screen writhe antag
1
a10allb
10b
llc
1
clld10d
1
e
10ellf10f
Ilk!
logllhlli
1
Oi
llj
lOj
Ilk10k111
101
llm10mlln10n
110
1001lP19P11q
loa
C6H5
C6HS2-thienyl2-thienyl1-naphthyl
1
naphthyl
o
-CH C, H,
o
-CII C
,
,
m-CH,C,H,m-CH,C,H,
p-CH3C6H4p-CH3C6H4
m-(CH30)C,H,
m-(
CH,O)C,H,p-(CH30)C6H43,4-(CH30)2C6H3
3,4-(CH30)2C6H3
P-FC,H,
p-FC6H4
o-ClC,H,0-ClC,H,m-ClC,H,p-ClC,H,p-ClC,H,m-ClC,H,p-BrC,H,
p-
Br C, H,
3>4-(C1)2C6H3
3,4-(Cl),C,H,2,4-(Cl),C,H,
0
OCH,CH,O
0
OCH,CH,O
0
OCH,CH,O
0
OCH,CH,O
0
OCH,CH,O
0
OCH,CH,O
0
OCH,CH,
0
0
0
OCH,CH,
00
OCH,CH,O
0
OCH,CH,O
0
OCH,CH,O
0
OCH,CH,
0
0
OCH,CH,
0
0
OCH,CH,O
0
71
>
100
63
24
>
100
>
100
63
>
100
71
>
100
1
3
>
100
81
19
>25
8744
35
22
71
>
100
>loo
8
44
3
63
>
100
>
100
66
>
100
63
47
>
100
>
100
63
>loo
79
>
100
4
2
71
2920
>
257144
13
35
71
>
100
>
100
93
5
3
63
>
100
>
100
>
100
>
100
>
100
>
100
>
100
>
100
>
100
>
100
>
100
>
100
>
50
>
25
>
100
>
100
>
25>25
>
100
>
50>25
>
100
>
100
>
100
>loo
>
25
>
25
>
100
>
100
>
100
>
100
>
10044
>
100
3222
>
100
>
100
63
22
56
>
100
3
24717
19
>
25
71
10
15
2071
>
10071
3
4
2
1
>loo
>
10071
>
100
>
100
>
100
>
100
>
100
>
100
>
100
>
100
>
100
>
100
>
50
>
25
>
100
>
100
>25>25
>
100
>
50>25
>
100
>
100
>
100
>
100
>25>25
>
100
>
100
>
100
>
100
>
100
2;4-(Clj;C,H; OCH,CH,
0
2525
>
10010
>
100
p-[(CH3)3ClC6H4
0
>loo
>
100
>loo
>
100
>loo
p-[(CH3),CIC,H, OCH,CH,
0
>
100
>
100
>
100
>
100
>
100meperidine hydrochloride
22 29
>loo
15
>
100
morphine sulfate
1.5
1.6
>
100
0.6
>
100pentazocine lactate7 6
>
50
4
>
50
The upper and lower
95%
confidence intervals (ref
10)
were not more than
2
and 0.5 times the
ED,,
respectively.See Experimental Section and ref
8
for description of methods.
reaction). Finally, prolonged exposure to acid gave the freeketals. It is of interest in this connection that the fearedelmination of the tertiary benzylic amine was never ob-served under the admittedly mild conditions used.In order to ascertain the role of the oxygen at the
4
position, the deoxy counterpart
(13)
of the lead compoundwas prepared in a straightforward manner by displacementof the cyano group from the P-aminonitrile of cyclo-hexanone
(12)
by means of phenylmagnesium bromide(Scheme
II).7
The necessity for the aromatic portion wastested by replacing this group with a cyclopentyl ring.Thus, alkylation of the anion from
14
(LDA)
with cyclo-pentyl bromide gave
15
in workable yield. The ester wasthen saponified and the acid taken on to the dimethyl-amine analogue
20
by the same sequence as that used inthe main series.
Results
The
EDh0
values for these compounds are recorded inTable
I.
The ketals and ketone analogues were of similarpotency. Substitution on the aromatic ring has a pro-nounced effect on activity in this series.
A
substantialenhancement of potency is seen by inclusion of a sub-
(7)
C.
R.Hauser and D. Lednicer,
J.
Org.
Chern.,
24,
46
(1954).
Scheme
I1
Me2
NcD
-
c6H5>0
e2N
15,
R
=
C,H,16,
R=
14
0
yo(]-
Yo0
N\
17.
R
=
NCO
CH3 CH3
20
8;
R
=
NHCH,19,
R
=
N(CH,),
stituent in the para position. Ortho and meta substitutiongive agents with moderate activity. At first sight, the rankorder of activity (CH3
y
Br
>
C1
>
CH,O
>
F
>
H)
issuggestive of some steric effect; it is of note in this con-nection that the p-tert-butyl compound is inert in this
 
426
Journal
of
Medicinal Chemistry,
1980,
Vol.
23,
No.
4
Lednicer, VonVoigtlander,
Ernrnert
Table
11.
Dimethyl
4-Aryl-4-cyanopimelates'
E,,?
jj
c
r
dine
1
Figure
1.
assay at the top screening dose. It is of note, too, that allcompounds reported in Table
I
are devoid of sedative(screen) as well as morphine antagonistic (antag) activity.Two compounds
(13
and
20)
not listed in Table
I
wereinactive on all five of the end points.Further work on selected analogues shows these agents
to
be classical opioids.R Effects of these compounds can,for example, be reversed by administration of naloxone.We consider this at least presumptive evidence that theseinteract with the same receptors as do classical narcotics.This observation is at first sight surprising, since thecompounds in question differ markedly from the connec-tivity posited by Beckett and Casey. Closer examination,however, shows topological similarity to the prototypenarcotic meperidine. Comparison of Dreiding models of
1
and meperidine, wherein the phenyl groups are axiallydisp~sed,~llows direct superposition
of
carbonyl oxygensand nitrogen
(N
o
0
distance is
5
8,
n each compound).
It
is of note that the aromatic rings will then occupy thesame plane with about
0.5
8,
eparation (Figure
1).
While
it
is tempting to adduce physical significance to this ob-servation, more detailed data is needed regarding themolecular pharmacology of these compounds. The topo-logical coincidence does, however, serve to rationalize theactivity of the above agents.
Experimental Section
All melting points are uncorrected and reported as observedon a Thomas-Hoover melting point apparatus. The authors areindebted to the Department of Physical and Analytical Researchof The Upjohn Co. for spectral and elemental analyses. Analyticalresults indicated by element symbols were within f0.4% of theory.
p-tert-Butylphenylacetonitrile.
A
solution
of
5 mL ofthionyl chloride in 10 mL of benzene was added to
10.0
g
(0.061
mol) of p-tert-butylbenzyl alcohol in 85 mL of benzene. Following30 min of stirring at room temperature, the mixture was heatedto reflux for 4 h. The mixture was allowed
to
cool, and the solventwas removed under vacuum. The residue was distilled at 0.05mm to afford 10.14 g (92%) of product, bp 62-65 "C.
A
mixture
of
9.64 g (0.053 mol) of the benzyl chloride obtainedabove, 10.13 g of potassium cyanide, and 0.10 g of potassium iodidein 71 mL
of
water and 150 mL of methanol was heated at refluxfor
1
h. The bulk of the methanol was removed under vacuumand the residue extracted with ether. The organic layer waswashed with water and brine and taken to dryness. Distillation
of
the residual oil at 0.03 mm afforded 6.38 g
(70%)
of product.bp
7S84
"C. Anal. (C12H21N)
,
N;
C: calcd, 83.19; found, 82.56.Dimethyl 4-Aryl-4-cyanopimelates Table
11).
A
mixtureof 0.10 mol of the appropriate arylacetonitrile,
47
mL
of
methylacrylate, and
60
mL of tert-butyl alcohol was brought to reflux.The sourceofheat was removed and there was added quickly 15.2mL
of
Triton
B
in 23 mL of tert-butyl alcohol. Following
4
h
ofheating at reflux, the mixture was allowed to cool and diluted withwater and benzene. The organic layer was separated, washed withwater and brine, and taken to dryness. The residue was distilledfirst at 40 mm
to
remove excess reagent; the pressure was thenreduced and the product allowed
to
distill over. These esters were
(8)
D. Lednicer and
P.
F. VonVoigtlander,
J.
Med.
Chern..
22,
1157 (1979).
(9)
The phenyl ring
in a
closely
related compound has been de-termined by
NMR
and X-ray diffraction
to
occupy
the axialposition.
D.
Lednicer and
D.
J.
DuChamp,
J.
Org.
Chern..
39,
2311
(1974).
____
COzCH3
COZCY3
yield,no. Ar
%
bp (mmHg), "C
3b
2-thienyl
73 162-180
(0.05)
3d
o-CH,C,H,
37 168-175 (0.03)
3e
rn-CH,C,H,
66
165-174 (0.04)
3f
p-CH,C,H,
73 170-180 (0.07)3g
m-(CH,O)C,H,
56 180-187
(0.08)
3k
o-ClC,H,
73 170-183
0.08)
31
m-CIC,H,
64
175-181
0.04)
3n
p-BrC,H, 70
183-193 (0.04)30 3,4-(
l), C,
H,
70 187-196 (0.04)3P
2 144Cl),
c,
H,
66 183-184 (0.04)3q
p-[(CH,),C]C,H,
70 180-199 (0.05)
a
All products were viscous oils; none were subjected
to
combustion analyses.characteristically very viscous oils and were, as a rule, notcharacterized further.
4-Aryl-4-cyano-2-carbomethoxycyclohexanones
Table
111).
Solid potassium tert-butoxide (22.5 g,
0.20
mol) was addedto a solution of 0.10 mol of the cyanopimelate in
700
mL of
THF.
The mixture was heated at reflux for 5 h, cooled in ice, and treatedwith 170 mL of 2.5
N
acetic acid. The organic layer was separated,diluted with benzene, and washed in turn with aqueous sodiumbicarbonate, water, and brine. The solid which remained whenthe organic solution was taken
to
dryness was recrystallized. Inthose cases where the product failed to crystallize, it was useddirectly in the next step.4-Aryl-4-cyanocyclohexanones (Table
IV).
A mixture of0.100 mol of the
carbomethoxycyclohexanone,
310 mL of 10%aqueous sulfuric acid, and 720 mL of acetic acid was stirred ona steam bath for
24
h. The mixture was then allowed to cool,diluted with water, and extracted thoroughly with ether. Theorganic layer was washed with water, aqueous sodium bicarbonate,and brine. The solid which remained when the extract was takento dryness was then recrystallized.In several cases the product crystallized on dilution of thereaction mixture. The solid was then collected on a filter andrecrystallized.4-Aryl-4-cyanocyclohexanone Ethylene Ketals (Table
V).
A
mixture of 0.050 mol of the cyano ketone, 3.6 mL of ethyleneglycol, and 0.16 g
of
p-toluenesulfonic acid in
140
mL
of
benzenewas stirred at reflux under a Dean-Stark trap for
6
h. The solutionwas allowed to cool, washed with aqueous sodium bicarbonate,and taken to dryness. The residual solid was then recrystallized.
4-Aryl-4-carboxycyclohexanones
thylene Ketals (Table
VI).
A
mixture of 0.070 mol of the cyano ketal and 15.0 g (0.38mol) of sodium hydroxide in 150 mL of ethylene glycol was stirredat reflux for 18 h. The mixture was allowed to cool, diluted withice-water, and covered with ether. Hydrochloric acid was thenadded slowly with continuous stirring until the aqueous layer wasstrongly acidic. The organic layer was separated, washed withwater and brine, and taken to dryness. The residual solid waspurified by recrystallization.
4-Aryl-4-isocyanatocyclohexanone
thylene Ketals (Table
VII).
To a mixture
of
0.040 mol
of
the appropriate 4-aryl-4-carboxycyclohexanone ethylene ketal and 5.6 g
of
triethylaminein
100
mL of anisole was added 11.17 g of diphenyl phosphonicazide. The mixture was then warmed to
90
"C
in an ice bath(effervescence was noted at
80
"C).
At
the end of
2
h the solventwas removed by means
of
a mechanical vacuum pump. The
total
residue was chromatographed as quickly as possible on silica gel.The isocyanate
(urn=
2250-2270 cm-') thus obtained was recrys-tallized when a solid. When an oil, the product was reducedwithout further purification.

You're Reading a Free Preview

Download
scribd
/*********** DO NOT ALTER ANYTHING BELOW THIS LINE ! ************/ var s_code=s.t();if(s_code)document.write(s_code)//-->