May, l9G4
289
o-HYDROXYPHENETHYLA44MTN0 DERIVATIVES
Synthetic approaches to the Y-(P-hydroxyphenethylamino)heterocycles listed in Table I11 generally paralleled those employed ear1ier.l Most of the compounds were prepared by one of the following methods: (1) lithium aluminum hydride reduction of the corresponding K-substituted mandelamide (VIII, XI, XII, and XX) ; (2) reaction of an aminoheterocycle with styrene oxide (IX, XXI) ; or ( 3 ) aminolysis of the appropriate chloroheterocycle with /3-hydroxyphenethylamine (X, XIII, XIT', XT', XT'II, and XIX).
viding thermodynamically more stable products acyls ated on the exocyclic nitrogen under basic ~onditions.~ Lithium aluminum hydride reduction of I11 to give 2(6-hydroxyphenethylamino) thiazole (XX) in 707, yield confirms the structural assignment. The amide VI1 appeared to be a stronger acid (soluble in dilute potassium carbonate) than I11 (soluble only in dilute sodium hydroxide) and showed a higher frequency carbonyl band in the infrared (Table I). This accords with the TABLE I
Het-n"C(0)CH(OR)C6H5 7,
(1)
CARBONYL STRETCHIKG FREQUEXCIES, INFRARED~
I.iA1Hc
+ CHs-CHCsHs -+
Het-NHCH&HOHCsHs (2)
t
Het-C1
Amide
Ester
NaNH2
Het-NHn
ern.-'-
---vmBx
+ H2NCH2CHOHCsHs 1
(3)
The S-substituted mandelamides (Table 11) were obtained in 36 (V,T'I) to 717,(IT') yield by acylation of an aminoheterocycle with (+)-mandelic acid in refluxing xylene with azeotropic removal of water, or under milder conditions and in better yield (83-92%; I, 11, 111, and VII) by reaction with (+)-0-acetylmandelyl chloride in ether (or tetrahydrofuran)triethylamine, or in cold pyridine. 4-Mandelamido1,2,4-triazole (V) and 4-mandelamido-3,5-dimethyl1,2,4-triazole (TI), were fairly strong acids as shown by their pK,' iralues (Table 11) and by their ready solubility in dilute sodium bicarbonate. In contrast, 3-mandelamido-l,2,4-triazole(IV) was insoluble in bicarbonate but soluble in dilute sodium hydroxide. The stronger acidity of T' and TI in comparison with IV reflects the powerful inductire influence of the nitrogen in the 4-position of the electronegative 1,2,4triazole ring in stabilizing the anionic charge (compare -4and B). [It should be noted that it has not actually been established that in the formation of the anion of IT' the amide nitrogen loses a proton (to give B) rather than a ring nitrogen.] The higher frequency of the
I*
1700 I1 1685 IV ... 1685 V ... 1715 I11 1743 1698 IIIC 1750 1700 T'IIc 1740 li10 a Spectra were measured on the solids in KBr disks with a Beckman IR-5 infrared spectrophotometer. * Hydrochloride salt. c Compound in chloroform. 1720 1755
more electronegative character of the heterocyclic ring of T711 owing t o the presence of the additional nitrogen. In general, increases in acidity of the secondary N-substituted mandelamides paralleled increases in carbonyl stretching frequency (see Table I), both of which properties may be useful indices of the electron-withdrawing power of the S-attached heterocyclic ring. That the acylation of 2-amino-3-hydroxypyridine and of 3-amino-2-hydroxypyridine by ( + )-0-acetylmandelyl chloride gave the amides I and I1 rather than the isomeric esters was shown by their ready solubility in cold dilute aqueous sodium hydroxide, their amide absorption in the infrared (Table I), and by their reduction to suhstituted amines.
aoH :: YR N
I,
X
NH-C-CHC6HS
=
0; R
XII, X = Hz; R
= -COCH3
H
x
N
OR
C-CH II I CeHs
UNHOH
11, S = 0 ; R = -COCHI XI, X = Hz; R = H
A
amide carbonyl stretching absorption in the infrared spectrum of V in comparison with that of IV (Table I) also indicates the relative effects of these electron withdrawing ring system^.^ The structural assignment of IV as 3-mandelamido- rather than a ring ?\'-substituted mandelyltriazole derivative is based on the conditions of amide formation (refluxing xylene), t'he posit'ion of the carbonyl absorption in the infrared and the stability of the compound to hydrolysis.6 The structures assigned to 2-mandelamidothiazole (111)and 2-mandelamido-1,3,4-thiadiazole (VII) follow from the known behavior of the parent amines in pro( ~ ? )See H. A. Staab, i l n g e i c . Chem. I n t e r n . E d . Enol., 1, 351 (1962), and
-4. P. ICatritzky and .4. P. .4tnbler, i n "Physical Methods in Heterocyclic Chemistry," Vol. 11, A . P. Katritakg-, Ed., .4cadewic Press, Inr , N e a York, N. Y . , 196.7, pp. 308-309, 327-329. (6) C'jL 13. A . Staab and 0 . Srel, Chpm. B c Y . ,92, 1302 (1959).
Lithium aluminum hydride reduction of these amides gave the corresponding hydroxyamino derivatives XI1 and X I in poor yield accompanied by large amounts of dark by-products that appeared to form during workup of the reactions and may have arisen from air oxidation of the o-hydroxyamine products. (- )-2-(P-Hydroxyphenethylamino)pyridine (VIII) was obtained by the reaction of 2-aminopyridine with (+)-0-acetylmandelyl chloride in ether-triethylamine followed by reduction of the resultant optically active 2-(0-acetylmandelamido)pyridine with lithium aluminum hydride in ether. (7) I. A . Kaye and C. L. Parris, ,J. Org. Chsm., 16, 1761 (1951): I. Ts. Posotovskii and I. B. Lundina, Z h . Ohshch. Kirirn., 29, 608 (1959); Chrm. d h s t r . , 5 4 , 1499 (1960). (8) E. Testa, G. G. Gallo, and F.Fava, Gam. Chim. I l d . , 88, 1 2 i 2 (19.58); Chrm. d b s t r . , 53, 21904 11959); F. Ueda. T. Ueda, and S. Toyosliinta, Ynkiignlci, Znssiii, 79, 920 ( l % W ) : Chrm. . I h s / ~ .63, , 21888 (1959).
\-()I, 7
200 ?I
!+I1
2 8 6 , :> '
28;
24ii,.'
,.l!)) appeals nioi'e t o rr~cm1)lr the aniinop~~idine iii it. p h i m i cological proiilc IT liereas the :~-1iic~tliyl-2-pyl.asiti(~ aiialog (XT'II, pTCz = 3.14+) follows a patter11 mort1 ieininiscc>nt of the aminopyrimidine. This is in accord with previous observation^.^ It is of particular notc that the pyrimidine derivative seems to stand alone iii being (at higher doses) an effective geiieral depressat it of the central nwvous system as well as a powrful interneuronal hlocking agent. 11) It s l ~ o u l dl i t IioteJ t h j t pri3.i i o i i ~d i - c u w u n s h:tx P heen 1 II d.it ~r oht%incrl o n t h e d r r ~ ritixi.. In fin'; :qIIpoIii I -
a-HYDROXYPHENETHYLAMISO DERIVATIVES
May, 1964
29 1
TABLE I11 N-SUBSTITUTED ~HYDROXYPHENETHYLAMINES, Het-SHCH2CHOHC6HS --Carbon, 70-Hydrogen, 3 ' %- -Nitrogen, M.P., Het VI11
Salt
2-Pyridyld HC1
IX
3-Pyridyl
X
5-Carbam yl-Z-pyridyl
XI
2-Hydroxy-3-pyridyl
XI1 XI11
3- Hydroxy-2-pyridyl 5-Chloro-2-pyrimidyl
HCI HCle
XI\' XV
4-hlethoxy-2-pyrimidyl 6-Chloro-3-pyridazyl
HC1 HC1 HCl HC1 HC1
XVI
3-Pyridazyl
XVII
3-Methyl-2-pyrazyl
XVIII XIX
Z-(a-Triazyl) 4,6-Dianiino-2- (8-triazyl)
xx
2-Thiazolyl
XXI
4 4 1,2,4-Triazolyl)
HCI HC1
IlCl HC1
oC.c 102-105 124-126 87-89 125-126 188-190 90-95 167-168 160-162 198-199 123-124 178-179 130-132 149-150 185-186 141-142 122-124 Q lll-113h 211-212 176-178 231-232 96-97 161-162 137-141
Formula
Calcd.
Found
CiaHi&"O CiaHisClNzO 62.27 62.89 CiaHi4NzO 62.27 62.45 CiaHisCINzO CuHisNaOz CiaHieC1NoOz.a 56.87 56.86 CiaHi4NzOz CiaHisClNzOz 58.54 58.39 CisHiaCINtOz 58.54 59.04 CnHizClNaO 50.35 50.42 CizHisC12NaO 55.43 56.12 CiaHi6ClNaOz CizHizCINaO 50.35 50.67 CizHiaClzNsO CizHiaNa0 57.25 57.53 CizHiaClNsO CiaHisNaO C ~ ~ . K H ? Q C ~ 58.80 N ~ ~ ~ . S59.22 61.10 61.46 CiiHizN10 53.64 51.00 CUHUN~O CiiHirClNaO Ci I H i z N z 0S 51.43 52.18 CiiHisClNzOS 58.82 58.84 CioHirN~0
Calcd.
Found
6.03
6.19
6.03 6.05
4.58 5.72
4.63 6.20
4.58
4.65
5.10 5.93
6.54
6.56
5.44
5.27
6.08
5.82
-Chlorine, 7ObCalcd. Found
6.27 5.54 5.75
6.82 5.60 5.73
Found 6.49
5.90
5.67 5.67
5.60
70"-
Calcd. 6.54
5.62
5.11
5.62
5.51
6.51
6.50
6.11
6.06
6.48 5.69
6.45 5.60
6.36
6.32
6.86
6.80
5.50 6.77 5.88 5.83
5.35 6.05
14.14
14.10
14.14
14.15
11.20
10.78
13.30 13.30 14.20 12.38 12.58
13.27 12.94 14.181 12.21 12.37
12.39
12.37
14.09
14.08
12.00
32.36
12.54
12.49
13.80
13.74
5 Basic nitrogen by acetous-perchloric titration. * Potentiometric determination of ionic chlorine. c Hydrochloride salts melt with ~ (c 2.0, ethanol). e Formulated as hemiethanolate on the decomposition. d ( - ) Isomer; hydrochloride salt showed [ c Y ] D ~-64.8" Base was an oil, b.p. 195-201' (0.5 mm.). Loses hydrogen chloride basis of analysis. f Total chlorine by Schoniger method. when dried in uucuo a t higher than room temperature; formulated as hemiisopropyl alcoholate.
TABLEIV RELATIVE PHARMACOLOGICAL ACTIVITIESOF SELECTED V-SUBSTITUTED 6-HYDROXYPHENETHYLAMINES N-Substituent
P Kaa
Analgesicb
Interneuronal blockingC
General central depressiond
AntiinflammatoryC
2-Pyridylf 6.86 3+ 2+ 0 0 2-Pyridylk 3+ 3-Pyridyl 5.98 I+ 1+ 0 2-PyrimidyP 3.54 I f 4+ 4+ 2+ 1+ 0 1+ XVI 3-Pyridaeyl 5.19 XVII 3-Methyl-2-pyraz yl 3.14h 1& 4+ XVIII 2-( s-Triaryl) 2.9( 0 2+ 0 I+ XIX 4,6-Diamino-2-(s-Triazyl) 5 .0' 0 0 4+ xx 2-Thiazolyl 5.39 =k 2+ 0 a The listed dissociation constant's atre of the parent aminoheterocycle measured in water as reported by A. Albert, R. Goldacre, and J. In mice, see ref. lb-3. I n dogs, see ref. lb-4. An over-all evaluation used by the PharmaPhillips [ J . Chem. Sac., 2240 (1948)l. cology Section of these laboratories; based on a spectrum of tests including the effect of the compound on voluntary and amphetaminestimulated motor activity of mice (mouse run), and on the behavior of unanesthetized dogs; see also ref. 2 and 4. e Based on % reduction in mustard-induced edema of the rat's paw effected by the compound administered subcutaneously; on this scale cortisone is rated This value is for the desmethyl base. The pK, of the methyl derivative could be up to 0.5 units 4+. f See ref. 1. g See ref. 3. higher; see ref. lb. 2 Determined spectrophotometrically [R. C. Hirt, R. G. Schmitt, H. L. Strauss, and J. G. Koren, J . Chem. Eng. Datu, 6, 610 (1961). jJ. K. Dixon, N. T. Woodberry, and G. W.Costa, J. Am. Chem. Sac., 69, 599 (1947). ( - ) Isomer. VI11 IX
+
*
Antiinflammatory activity, as measured by the per cent reduction in the mustard-induced edema of the rat's paw, appears to require a pK, about 5 or below. This is supported by the fact that the mandelamidopyridine derivatives reported earlier (pKa values ca. 3)'b are, almost without exception, effective antiinflammatory agents. In fact, this property is evidenced quite generally by the amide relatives of the present compounds as well. The exceptional efficacy of XIX, however, could well be more complexly dependent on its additional amino substituents. Basicity has been exploited in this discussion as a conveniently measured parameter but certainly other, not independent, factors are involved. As basicity is reduced the proportion of the agent in free base form increases and thereby the lipoid solubility and ability to penetrate biological membranes. At a pK, of 5 or below, however, essentially all of the compound is in the form of free base a t physiological pH values and further
reduction in basicity by the insertion of additional heteroatoms can only serve to have the counter effect of reducing lipoid solubility. On this basis (and in this series) interneuronal blocking properties might be inferred to be associated optimally with weakly basic (or nonbasic) compounds with a moderately high lipophilic to hydrophilic balance. Only analgesic activity may require that a significant amount of the protonated cation of the agent be p r e ~ e n t . ' ~
Experimental
+
Interrnediate~.-2,PDichloropyrimidine,~( )-0-acetylmandelyl chloride,' 2,5-di~hloropyrimidine,~~ m.p. 54-56", 2-chloro-4(14) See also A . P. Gray, Prosram of the Eighth National Medicinal Chemistry Symposium of the American Chemical Society, University of Colorado, June, 1962, p. l l a . (15) Microanalyses were performed b y the Clark Microanalytical Laboratories, Urbana, Ill., the Micro-Tech. Laboratories, Skokie. Ill., and the Galbraith Laboratories, Knoxville. Tenn. Aleltinp points are corrected and were determined witli a modified Hershberg melting point apparatus using h1.C.A. thermometers.
IIay, 196.2
h N T I T U S S I V E 1,2-DIAZ24BICYCLO [2.2.2]OCTAXES
The hydrochloride salt was recrystallized from ethanol, m.p. 185-186". 3-(P-Hydroxyphenethylamino)pyridazine(XVI).-A stirred mixture of 15.0 g. (0.06 mole) of XV, 2 g. of lOy0palladium-oncarbon, 25 ml. of 64y0 hydrazine, and 200 ml. of ethanol was boiled on the steam bath for 1.5 hr. The cooled mixture was filtered and the filtrate concentrated to a tan solid residue that was washed with water and crystallized from isopropyl alcoholwater to yield 8.8 g. (68%) of XS'I, m.p. 141-142". The hydrochloride salt of XVI, crystallized from isopropyl alcohol, melted a t 122-124'. 2-(p-Hydroxyphenethylamino)-3-methylpyrazine (XVII).-A mixture of 18.0 g. (0.14 mole) of 2-chloro-3-methylpyrazine, 18.0 g. (0.13 mole) of 0-hydroxyphenethylamine, 23.2 g. (0.14 mole) of potassium carbonate, and 0.5 g. of copper powder was heated in an oil bath maintained a t 160" for 7 hr. The mixture was triturated with benzene and the solution filtered and concentrated to a dark oil that was vacuum distilled to yield 8.3 g. (287,) of product, b.p. 195-201' (0.5 mm.). The hydrochloride salt \vas crystallized from isopropyl alcoholethyl acetate to give tan crystals, m.p. 111-113". 2-( P-Hydroxyphenethy1amino)-s-triazine(XVIII).-A solution of 13 8 g. (0.05 mole) of P-hydroxyphenethylguanidinehydro-
293
bromide3 and 4.2 g. (0.05 mole) of s-triazine in 25 ml. of dry ethanol was heated on the steam bath for 20 hr. The precipitated solid was rollected and crystallized from methanol t o give 4.3 g. (40% yield) of XT?II, m.p. 211-212'. 2-(~-Hydroxyphenethylamino)-4,6-diamino-s-triazine (XIX). -To a slurry of 72.8 g. (0.5 mole) of 2,4-diamino-6-chloro-striazine and 71.3 g. (0.52 mole) of 6-hydroxyphenethylamine in 500 ml. of water was added, dropwise a t steam-bath temperature, a solution of 74.4 g. (0.6 mole) of sodium carbonate monohydrate in 160 ml. of warm water. The addition required approximately 1 hr. after which the mixture was heated for an additional 3 hr. and then cooled and filtered. The water-washed precipitate mas re(-rystallized from ethanol to yield 66.7 g. (54cc) of white crystals, m.p. 176-1 78 '. 2-(~-Hydroxyphenethylamino)-4,6-diamino-~-triazine hydrochloride,recrystallized from ethanol, showed m.p. 231-232".
Acknowledgment.-The authors are grateful to nlr. D. F. Cortright and to Miss RI. Unroe for the basic nitrogen, ionic halogen, and other analytical determinations and to AIiss Yorma Frick for technical assistance.
Synthesis and Antitussive Activity of a New Heterocyclic Ring System. Some 1,2-Diazabicyclo[2.2.2]octanes P. AI. CAR ABATE AS,^ A. R.SURREY, AND L.
s. HARRIS
Sterling-Tt'inthrop Research Instatute, Rensselaer, ,Yetit York Receized Noaember 29, 1963 Two routes to the previously unknown 1,2-diazabicyclo [2.2.21octane ring system have been developed. The parent heterocycle, 1,2-diazabicyclo[2.2.2]octane, as well as a number of substituted derivatives, has been synthesized. The most effective compound is similar to codeine in antitussive potency and is devoid of analgesic activity.
The use of 4-acyl-4-phenylpiperidines for the preparation of the corresponding 1-alkyl derivatives has been reported previously. The same intermediates are suitable starting materials for the synthesis of the previously unknown3 1,2-diazabicyclo[2.2.2]octanering system. The preparation of the parent compound, 1,2-diazahicyrlo[2.2.21octan~, as rye11 as a wriw of 2-
K'-
SCHEME
1
HONO
N H 1 R
-
(1) This paper is taken in part from tlie thesis of Philip XI. Carabateas, submitted t o Rensselaer Polytechnic Institute, Troy, N. Y., i n partial fulfillment of tlie requirements for t h e Ph.D. degree. (2) B. Elprrn, P. 11. Carabateas, a n d 1.. Grrimhsrli, .I. 0i.g. C h ~ m . 26, , 4728 (1061).
and 3-substituted derivatives has now been acconiplished. The 3-alkyl-4-phenyl-l ,2-diazabicyclo [2.2.2]octanes (Y)listed in Table I1 were prepared as shown in Scheme I. Addition of a slight excess of aqueous sodium nitrite to aqueous solutions of the hydrochlorides of the amino ketones (I) gave verv good vields of the corresponding l-nitrosop&ridines- (YI) . !These are listed in Table I. In all cases, the products as obtained froin the reaction mixture were analytically pure and were used directly in the next step. Any attempts a t recrystallization or distillation resulted in partial decomposition. Reduction of the nitroso ketones (11) with zinc dust and acetic acid a t 15-20' gave basic materials which proved to be the 3-alkyl3-phenyl-1,2-diazabicyclo[2.2.2]octanes (Y). S o other products could be isolated. Apparently, cyclization of the 1-amino derivatives (111) occurs to yield what are probably the cyclic hydrazones (IV). Under the conditions of the reaction, these are further reduced to the saturated heterocycle (V). The method of synthesis, elemental analyses, and the infrared and n.m.r. spectra of representative compounds are all consistent with the bicyclic structure assigned for the products (V). The infrared spectrum of 4-phenyl-3-propyl-l,2-diazabicyclo [2.2.2]octane (V, R = CsH,; R ' = hydrochloride, a typical compound in this series, shows a broad absorption band a t 4.204.32 p , which is indicative of a disubstituted >NH+ function. The carbonyl band at 5.92 I.( (3) The literature records examples of 1,3-,1.4-, 2,%, and 2,6-diazabicyclo[2.2.2loctanes; C. Harries, A m . , 294, 362 (1897); 0. Hromatka and 0 . Kraup, .Wonatsh.. 82, 880 (1951); .J. Pirsch and .J. Jorgl, Ber., 68B, 1324 (1935); E:. Piper and G. F. JTriglit, .I. A m . C h ~ m S. o c . , 72, 1669 (19.50).
n.
