Journal of Medicinal Chemistry, 2979, Vol. 22, No. 3 295
2-Mercaptoacetamidines and the solvent was evaporated. This was layered on a column of silica gel (100 g) and eluted with a solvent system of CBHGEtOAc (101). After evaporation of the solvent, the first fraction gave crystals (480 mg), which were recrystallized from EtOAcn-hexane to give colorless needles of 27 mp 122-123 “C; ‘H NMR (CDClB) 6 8.70 (1H, s), 8.10 (1H, d, J = 2 Hz), 7.47-7.80 (2 H, m), 5.60 (2 H, s), 3.73 (3 H, s), 2.85 (2 H, q, J = 7 Hz), 1.33 (3 H, t, J = 7 Hz); 13CNMR (CDCl3) 6 173.7 (C-4), 166.1 (C-2’), 158.3 (C-2),154.2 (C-9), 149.7 (C-ll),142.8 (C-6),134.9 (C-7), 123.9 (C-5), 123.2 (C-lo), 118.1 (C-a), 110.9 (C-3),52.7 (C-3’),49.9 (C-l’), 28.2 (C-12), 15.1 (C-13); mass spectrum m / e 314 (M), 227, 201, 200, 184. Anal. (C15H14N404) C, H, N. The second fraction gave crystals (330 mg), which were recrystallized from EtOAc to give colorless crystals of 28: mp 159-160 “C; ‘H NMR (CDCl,) 6 8.83 (1 H, s), 8.15 (1 H , d, J = 2 Hz), 7.37-7.70 (2 H, m), 5.57 (2 H, s), 3.80 (3 H, s), 2.82 (2 H, q, J = 7 Hz), 1.30 (3 H, t, J = 7 Hz); 13C: NMR (CDC13) 6 173.1 (C-4), 165.1 (C-2’), 159.0 (Call), 156.4 (C-2), 153.9 (C-9), 142.0 (C-6), 133.9 (C-7), 124.2 (C-5), 123.9 (C-lo), 117.7 (C-8), 112.9 (C-3), 53.1 (C-l’), 52.9 ((2-39, 28.1 (C-lZ), 15.2 (C-13); mass spectrum mje 315 (M + I), 314 (M), 286 (M - N2), 243, 227, 201, 200, 184. Anal. (C15H14N404) C, H, N. Biological Assay. Male Sprague-Dawley rata, 8 weeks old and weighing about 280 g, were used. Rat antiserum containing homocytotropic antibody was prepared according to the method of Mota.” In brief, the animals were sensitized by intramuscular injections of 1 mg of egg albumin in 1 mL of saline solution concomitantly with an intraperitoneal injection of 2 X 1O’O of sterilized Bordetella pertussis. Serum collected from each animal 12 days after sensitization was pooled and frozen until use. The biological properties of the skin sensitizing antibody contained in these sera satisfy the requirements for a homocytotropic antibody; Le., it fixes homologous skin tissue for a long time and is heat labile. The antisera showed passive cutaneous anaphylaxis (PCA, 72-h latent period) titers of 1:32 to 1:64. Homologous rat PCA response was elicited as follows. Four 0.05-mL aliquots of serum diluted fourfold with physiological saline solutions were injected intradermally into the shaved dorsal skin of the rat. After 72 h, the rat was challenged with an intravenous injection of 1 mL of saline solution containing 5 mg of egg albumin and 10 mg of Evans blue. Drugs to be tested or vehicles (saline or polyethylene glycol 400) were administered intravenously immediately
before antigen challenge. In the case of oral administration, drugs suspended in 3% gum arabicum were administered 5 min before antigen challenge. Rats were sacrificed by bleeding 30 min later, and the area of the dye leakage was measured in square millimeters. The ID50value, i.e., the dose required to cause 50% inhibition of the PCA reaction, was calculated from the relationship between logarithmic dose and area of dye leakage by the method of least squares. Fiducial limits of the IDMvalues were calculated according to Fieller’s theorem.12 Acknowledgment. We express o u r sincere thanks to Drs. E. O h m u r a and K. M o r i t a for their encouragement, t o Messers. H. Asakawa, E. Mizuta, and H. Sugihara and Miss F. Kasahara for measurement and discussions of 13C NMR and mass spectrometry, and to Mr. K. Gomaibashi for his assistance in t h e biological assay.
References and Notes (1) A. Nohara, H. Kuriki, T. Saijo, H. Sugihara, M. Kanno, and Y. Sanno, J . Med. Chem., 20, 141 (1977). (2) (a) M. Kuwayama, K. Itakura, H. Ito, K. Takeda, A. Nohara, and H. Kuriki, unpublished work; (b) Y. Kanai, Y. Nakai, Y. Shirakawa, T. Kobayashi, N. Nakajima, and S. Tanayama, unpublished work. (3) E. Wiberg and H. Michaud, 2.Naturforsch.,B, 9,496 (1954). (4) L. F. Fieser and M. Fieser, “Reagentz for Organic Synthesis”, Wiley, New York, N.Y., 1967, p 142. (5) R. P. Holysz, J. Am. Chem. SOC.,75, 4432 (1953). (6) G. N. Bollenback, J. W. Long, D. G. Benjamin, and J. A. Lindquist, J. Am. Chem. Soc., 77, 3310 (1955). (7) (a) R. N. Butler, Can. J. Chem., 51,2315 (1973); (b) R. N. Butler, T. M. MacFroy, F. L. Scott, and J. C. Tobin, ibid., 55, 1564 (1977). (8) R. N. Butler, Adu. Heterocycl Chem., 21, 338 (1977). (9) D. Buckley and J. Thomas, J. Med. Chem., 14,265 (1971). (10) (a) H. Dharwarkar and R. L. Alimchandai, J. Indian Chem. SOC.,17,416 (1940); (b) Japan Patent, 43-29375 (1968); (c) The melting point was identical with that of the 1iterature.lh (11) I. Mota, Life Sci., 2, 917 (1963). (12) D. J. Finney, “Statistical Method in Biological Assay”, Charles Griffin & Company Ltd., London, 1964, p 27.
2-Mercaptoacetamidines as Gastric Antisecretory Agents William A. Bolhofer,* Charles N. Habecker, Adolph M. Pietruszkiewicz, Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania 19486 M a r y L o u T o r c h i a n a , H e n r y I. Jacoby,’ a n d C l e m e n t A. S t o n e
Merck Institute f o r Therapeutic Research, West Point, Pennsylaania 19486. Received June 12, 1978 A series of N-substituted 2-mercaptoacetamidines was synthesized and evaluated for gastric ant,isecretory activity in dogs stimulated with gastrin tetrapeptide. The most potent analogues showed 80-95% inhibition of acid secretion after an oral dose of 8 mg/kg. Thus, these compounds represent a new structural type having significant antisecretory activity. Disulfides had essentially the same antisecretory potency as the corresponding mercaptoacetamidines, indicating a metabolic interconversion. Alkylation of the mercapto group decreased potency. Higher carboxamidine homologues such as 2- and 3-mercaptopropionamidines had very low activity. Hydroxyacetamidines and mercaptoacetamides also had low potency. Side effects observed with this series of compounds included emesis, tachycardia, and gastric bleeding.
Pharmacological evaluation of the a n t i r a d i a t i o n a g e n t N-(l-adamantylmethyl)-2-mercaptoacetamidine2a~b (3) revealed that i t possesses gastric secretion inhibitory properties. Detailed examination of its gastric effects i n d o g s w i t h secretion i n d u c e d b y g a s t r i n t e t r a p e p t i d e , histamine, and 2-deoxy-D-glucose confirmed antisecretory activity of significant degree, accompanied, however, b y an emetic side effect. Since the compound is structurally unlike that of a n y antisecretory agent reported heretofore, a s y n t h e t i c p r o g r a m was initiated to assess the antisecretory and antiulcer p o t e n t i a l of mercaptoacetamidines and related structures. The objectives of this research were 0022-2623/79/1822-0295$01.00/0
(a) t o d e t e r m i n e the extent of s t r u c t u r a l variation consistent with retention of significant antisecretory activity, (b) to identify the specific s t r u c t u r e s having m a x i m a l potency, and (c) t o eliminate undesirable pharmacologic effects. Compounds chosen for preparation were designed to incorporate features permitting studies of the effect of size and lipophilicity of the a m i d i n e s u b s t i t u e n t , changes i n the structure of the carboxamidine c h a i n , a m i d i n e surrogates, and sulfhydryl g r o u p requirements. Although compounds possessing sulfhydryl groups such as d i t h i o t h r e i t o l and 2,3-dimercaptopropanol c a u s e a protein-losing g a ~ t r o p a t h ythe , ~ mercaptoacetamidine lead
0 1979 American Chemical Society
296 Journal of Medicinal Chemistry, 1979, Vol 22, N o 3
was deemed sufficiently different in structure, lipophilicity, and sulfhydryl acidity to warrant further exploration. Chemistry. Several synthetic methods for the preparation of 2-mtrcaptoacetamidine derivatives have been reported, and these served as the basic preparative procedures foi compounds required in the investigation. In the synthetic route generally used, methyl 2-chloroacetimidate (1) was prepared by the base-catalyzed reaction
r
NH,+Cl-
Nt1,'Cl1
HSCH,CNRR' IT1
of chloroacetonitrile with rnethanoi*J and allowed to react "in situ" with amine hydrochlorides to obtain the 2chloroacetamidine hydrochlorides5 11. Displacement of the halogen with phosphoruthioate anion and subsequent acid hydrolysis produced the 2-mercaptoacetamidine hydrochloridesfi111. 41! the 2-mercaptoacetamidine hydrochlorides shown in Table I (compounds 1-42), including those previously reported by other investigators, were prepared via this pathway. Compounds 43-59, shown in Table 11, are analogues structurally related to the mercaptoacetamidines. The 2-mercaptoacetamides 44-46, 2-mercaptopropionamidine 4 4 , and 4-mercaptobutyramidinr 48 were prepared from their respective halo precursors by the same procedure used to prepare I11 from 11. The 3-mercaptopropionamidine 49 was obtained by tributylphosphine cleargage of the corresponding disulfide7 5 5 . Reaction of the 2chloroacetaniidine 15a with sodium niethylmercaptide and sodium benzylmercaptide gave thioethers 50 and 51, respectively. Mercaptoacetamidine disulfides IV, 52, and 53 were formed from the appropriate mercaptan: 111 by NH;ClI1
IISCH,CNRR 1x1 NI&+CII
(-SCH2CH,COC,H,), V
NH,+CI-
-HZO2
R R"
11
(-SCH,CNRR ) * I\' NH,'Cl /I
+
I _
(-SCH,CH,CNRR' VI
2
mild oxidation with hydrogen peroxide. Mercaptopropionamidine disulfides VI, 54, and 55 were synthesized by reacting amines with diethyl 3,3'-dithiobis(propionimidate) dihydrochloride (V). Reaction of ethyl 2 hydrvxyacetimidate with amines gave the %hydroxyacetamidines .56 and 57. Products 43, 58, and 59 were synthesized as reported in the literature. The 2-chloroacetamidine intermediates for the products shown in Table 1 are listed in Table I11 and numbered correspondingly (la--42a). The preparation of four previously unreported amine precursors to chloroacetamidines 'ia, 14a, 17a, and 19a is described under Experimental Section. All were made by reduction of the corresponding carboxamides. The proton dissociation constants, pK,' for the reaction -CH2SH + -CH2S- + H+ and pK,2 for the reaction -NHC(=NH)- + H+ F= -NHC(=NH2+)-, were determined by potentiometric titration. Values for repre-
Rolhofcr et u /
sentative products are recorded in Table IV. A useful predictive correlation of these physical constants with antisecretory potency for the mercaptoacetamidines could not be established. Except for the aryl derivative 35, the pK,' values for loss of the sulfhydryl proton of monosubstituted mercaptoacetamidines are all within the range of 6.50-6.80. The effects of the amidino group on the sulfhydryl moiety cause it to be considerably more acidic than an isolated sulr3ydryl group of an alkyl mercaptan; e.g., the pK, of ethyl mercaptan is 10.50.8 A5 the length of the carbon chain separating the amidino and mercapto groups increased, the pK, of the latter approached that of an isolated sulfhydryl, as shown by compound 48. The narrow pK,' range of 10.70-11.00 for the gain of a proton by S-alkylated mercaptocarboxamidines is similar to the ph', of the acetamidine 58 and demonstrates the lack of effect of the sulfhydryl group on the basicity of the sin;ciino group. Discussion The original lead, compound 3, inhibits gastric' sec retioil in the dog induced by a gastrin analogue, histamine, 2deoxy-D-glucose, as shown in Table V. Volume and acid concentration were inhibited approximately equillly, regardless of the stimulant. Corresponding data for metiamide,g N-methyl-N'- [ 2- [ (5-methyl-lH-imidazol-4-yl)methylthio]ethyl]thiourea, obtained in the same dog W ~ O T I ~ with gastrin tetrapeptide stimulation are included in the table for comparison. The antisecretory potency of the mercaptoacetamidines and related structures vs. gastrin tetrapeptide stimulations is expressed as inhibition of total acid output in Tables I and 11. Although many of the new compounds are more active inhibitors of gastric secretion than the lead, 3, side effects such as emesis remained a major problem. Polycyclic alkyl derivatives showed some promise of decreased side effects. A homologous group, 1 and 5 8, was prepared to evaluate the effectiveness of greater separation of the polycyclic alkyl and amidino g r o u p Side effects were decreased but not completely eliminated with compound 6, the most potent of the group. Lofiered potency resulted from disubstitution on nitrogen, as shown by a comparison of 21 and 40. Aryl substitution on the amidine group also lowered potency. The disulfide derivatives 52 and 53 have essentially the same antisecretory activity as the corresponding mercapto analogues 21 and 3, indicating a possible metabolic interconversion of the former to the latter. Alkylation of the mercapto group as in the S-methyl (50) and S-benzyl (511 derivatives o f 15 decreases antisecretory activity. Increasing the length ot the carbon chain as in 48 and 49 results in a decreased potency relative to the corresponding mercnptoacetamidines 12 and 21. Branching a t the mercapto cdrbon as in 47 also decreases potency. Acetamidines 58 arid 59, hydroxyacetamidines 56 and 57, and mercaptoacetarnides 44-46 showed a sharply reduced potency. It therefore appears that maximal antisecretory activity resides in the mercaptoacetamidine nucleus, and changes in this part of the structure, except for pxidatiorl to the corresponding disulfide, affect the potency adversely. Side effects, of which emesis, tachycardia, and gastric bleeding were the most common, were associated with actik ity, and total elimination of these undesitable characteristics was not achieved. Side effects were not quantitated and are not included in the tables of data. Experimental Section Melting points were determined with a Thomas-Hoover capillary apparatus and are uncorrected. Infrared spectra were recorded on a Perkin-Elmer 137 spectrophotometer, and NMR
2-Mercaptoacetamidines
0
2
am* Walt-
0 ;
W
2
Journal of Medicinal Chemistry, 1979, Vol. 22, No. 3 297
m
0
2
t-t-rlrlt-a
*awwcD
ow0 m
comwrimt-mtmawuawwaw
a 00
B
0
ua
m
0.1
omoo%**
00.1t-*
wwww
0.1
o t-
o
omw'&
mmmmo wwwm
om*
a
mt(Dm
CJ
SI*
o w 4
ot-a rc
0
c.l
o m
0.1
0.1a
rl(Dri
0.1 (
D
m
0
4
P
0
0
P
a m
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3
I
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n
i N
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Holhofer e f ~ l .
298 Journnl of Medicinal Chernistr),, 1979, Voi. 22, No. 3
Table 11. Gastric Ant.isecretory Screening in t h e Dog. Compounds Related to 2-Mercaptoacetamidines
____
___
_____
inhib of total acid output,b dose in mg/kgc %
compd 43d 44g 4 5:
46'. 41' 48'
49 50
51 5 2d
structure C,H,CH,NHC(S O)CH;SH c-C,Hl1NHC(= O)CH,SH 1-adamantyl-NHC(= O)CH,SH (CH,),CCH,NHC( =NH)CH(CH,)SH (CH,),CCH,NHC( = NH)(CH, ),SH C,H,CH,NHC( =NH)(CH, ),SH endo-2-norbornyl-CH2NHC(=NH)CH,SCH, errdo-2-norbornyl-CH,NHC( = NH)CH,SCH,C,H, [ C,II,CH,NHC( =NH)CH,S-1,
recrystn solvent
yield,
mp. 'C
106.5-108.5 212.5-214 dec 143-145 noncryst
C,H,,CH, EtOH-Et,O CH ,CN-Et ,O
86 20 12
61-62.5
hexane
58
formulaa 4.0 8.0 16.0 C,H,N, S H C l e f 0 C,H.,NOS C~H~;NOS O f 58 CI,Hl,NOS 0 28 C,H 18N2S. HC1 11 C,H,,N,S~HCl 18' Cl,H14N,S~HC1~ 0.25(C4H,),POh 35 Cl,H,"N,S
77-80
hexane
49
C17H24N2S
%
19
84 C1,H,,N,S;2HC1 62 80 C,,H,,N,S; 2HC1 54 21 7 5 C16H34N4S2.2HCln 55 noncryst [ C,H,CH,NHC( = NH)CH,CH,S-1, C,,H,,N,S; 2HC1° 42 56 (CH ),CCH,NHC(= N H K H , OH 22 61 78 C,H,,N,O~€ICl 164-166 i-PrOH-Et,O 57 c,H;CH,NHC(=NH,CH~OH 151-153 i-PrOH-Et, 0 79 C,H,,N,O~HCl 0 58p C,H,CH,NHC( =NH)CH, 19 C,H ,,N;HClq 5 9 c-C,H,,NHC(=NH)CH, 0 C8H16N:q .__See corresponding footnote in Table I. See corresponding footnote in Table I. See corresponding footnote in Table I. Ref 6. 1 0 0 % inhibition a t 2 mg/kg. Mortality in one animal; test abandoned. H. Nishimura and H. German Patent 1 2 5 3 8 6 9 (1967); Chem. Takamatsu, Yukuguhu Zusshi,,84, 944 (1964); Chem. Abstr., 62, 2750f (1965). Abetr., 68, 2 4 5 1 0 ~( 1 9 6 8 ) . ' Precursor N-( 1-adamanty1)chloroacetamidereported in Netherlands Patent 6 509 927 ( 1 9 6 6 ) ; Chern. Abstr., 64, 19450e (1966). Halo precursor described under Experimental Section. NMR spectra and analyses indicate the presence of 0.25 mol of tributylphosphine oxide, the reaction byproduct. Test levels were adjusted accordingly. C: calcd, 54.74; found, 56.25. 42% inhibition at 32 mg/kg. Ref 2b. C: calcd, 45.80; found, 46.85. O C: calcd, 52.213; found, 54.25. L. Baiccchi and G. Palazzo, Ann. Chim. ( R o m e ) ,58, 608 (1968). 4 Not analyzed. 53m
[ l-adamantyl-CH,NHC(=NH)CH,S-l, noncryst [(CH,),CCH,NHC( = NH)CH,CH,S-];-
'
spectra were obtained with a Varian A-60 spectrometer. NMR spectra were obtained for all intermediates and final products and are consistent with the assigned structures. Elemental analyses as indicated by the symbols of the elements were within A 0 . 4 7 ~ of the calculat,ed value, unless stated otherwise. For products listed in Tables I, 11, or 111, yields, recrystallization solvents. physical constants. and analyses are recorded in the tabular form rather than in this section. S y n t h e s i s of 2-Chloroacetamidine Hydrochlorides. General Method. Most of the amine hydrochlorides used in this sj-nthesis were prepared by published procedures or were obtained f m n commercial sources as indicated in Table 111. Syntheses of previmsly undescribed amine hydrochlorides are documented h!er in this section. Chloroai~etonitrile(0.10 mol) was added to a cold solution of MeONa (0.01 mol) in 50 ml; of dry MeOH, and the solution was stirred at ambient temperature for 0.5 to 1 h. Then the amine hydrochlxide (0.1: mol) was added, and stirring was continued at amhient temperature for 1 to 3 h. Secondary and sterically fkdcred amines required a reaction period of up to 16 h. Product was ohtained by filtering the cold mixture to remove precipitated ot?!t. followed by concentration of the filtrate in vacuo. The oily residue usually crystallized upon trituration with Me2C0. Synthesis of Mercaptocarboxamidine Hydrochlorides and Merraptoacetamides. General Method. The chlorocarboxan:idine hydrochloride or chlorc~carboxamide(0.025 mol) was added to a solution of trisodium phosphorothioate"' (0.025 mol) in 35 mL of H 2 0 at room temperature under NZ. The solution was stirred at ambient temperature until the AgNO, test" for phosphorothioate anion was negative (usually 2-10 min). Then IlCi (25 mL) was added, and the solution was heated for 10 rim on a steam bath and concentrated in vacuo. The residue was treated with i-PrOH (25 mL), filtered, and diluted with excess Et$? IO precipitate the product as the HCl salt. N-Benzyl-3-mercaptopropionamidine Hydrochloride (49). 3,3'-Dithiobis(A;-benzylpropionamidine)dihydrochloride (55)(4.3 g, 0.00925mol) was stirred under N2with tributylphosphine (5.66 g. 0.028 mol) in 90 mL of MeOH containing 3 mL of H 2 0 for 48 h. The mixture was concentrated below 40 'C, the residue was suspended in 50 mL of H 2 0 , and 50 mL of CCl, was added dropwisi, with cooling and stirring. The aqueous layer was re-
peatedly extracted with CCll and then lyophilized to obtain a gummy residue of 4 g. The gum was dissolved in z-PrOH, filtered from insoluble matter, and reprecipitated with EtzO. The reprecipitation was repeated several times. The product was dried at 55 "C under high vacuum. NMR confirmed the structure but indicated about a 0.25 mol contamination with tributylphosphine oxide. N - (endo-2-Norbornylmethyl)-2-methylthioacetamidine (50). The reaction was carried out under N2atmosphere. A solution of MeSNa was prepared by bubbling MeSH into 50 mI, of EtOH containing MeONa (0.54 g. 0.01 mol). This solution was added to 50 mL of EtOH containing Ar-(endo-2-norbornylmethyl)-2-chloroacetamidinehydrochloride (15a)(2.37 g, 0.01 mol) and MeONa (0.54 g, 0.01 mol). 'The mixture was stirred at ambient temperature for 1.5 h, filtered, and concentrated in vacuo. Trituration of the residue with hexane gave compound 50. N -(endo-2-Norborn ylmet hyl) 2-benzylthioacetamidine (51). Compound 5 1 was prepared by the procedure for the synthesis of compound 50 by replacing the methyl mercaptan with an equivalent amount of benzyl mercaptan. 3,3'-Dithiobis (N-benzyl propionamidine) Dihydroc hloride (55). Diethyl 3,3'-dithiobis(propionimidate)dihydrochloride'2 (16.9 g, 0.05 mol) was suspended in I00 mI, of absolute EtOH, and benzylamine (10.7 g, 0.1 mol) in 25 mi. of EtOH was added over 10 min with cooling to keep the temperature below 35 "C. After stirring for 24 h at room temperature, the mixture was concentrated under vacuum at 25 "C. On trituration with Et,O, the residue solidified to an amorphous hygroscopic mass. A 3-g portion of the crude product wa? dissolved in 9 mL of EtOH and filtered from insoluble matter; addition of E t 2 0 precipitated the salt. The precipitation was repeated, and the sample was dried at room temperature for 48 h over P,05 under vacuum. NMR indicated solvation. 3,3'-Dithiobis[ N-(2,2-dimethylpropyl)propionamidine] dihydrochloride (54)was prepared in the Fame manner as 55 by replacing the benzylamine with an equimolar amount of 2,2-dimethylpropylamine. N-(2,2-Dimethylpropy1)-2-hydroxyacetamidine Hydrochloride (56). Ethyl 2-hydroxyacetimidate hydr~chloride'~ (9.5 g, 0.068 mol) was suspended in 50 mL of absolute EtOH and cooled to 5 "C 2,2-Dimethylpropylamine (5.65 g, 0.065 mol) was added
Journal of Medicinal Chemistry, 1979, Vol. 22, No. 3 299
2- Mercaptoacetamidines Table 111. 2-Chloroacetamidines, RC(=NH)CH,C1.HCla compd mp, "C recrystn solvent
I
yield, %
formulab
RHC source A A
l~. a 257-258 dec EtOH-i-Pr, 0 C,,H,.CIN,.HC~~ 90 i-PrOH-Et; 0 248-249.5 dec 2a 3af Bh 77 MeOH-Et,O 218-220 4a Bi. 76 EtOH-i-PrOH 255-256 dec 5a I31 76 i-PrOH-Et ,0 219-220 6a C i-PrOH-Et,O 62 196-197.5 7a B' 94 i-PrOH-Et,O 161-163 8a gam 1Oa" A C, H ,,C1N;HCl i-PrOH-Et,O 53 164-166 1l a A C,H,,ClN,~HCl E t OH-E t, 0 74 165-166.5 12a C,H,,ClN,*HCl A i-PrOH-i-Pr,O 77 145-146.5 13a C i-PrOH-Et ,0 77 c,,H,,cIN,~Hc~~ 178-1 8 0 14a A C ,,H ,,ClN,*HCl i-PrOH-i-Pr,O 55 171-173.5 15a Bo C , H,,ClN;HCl 77 249.5-251 dec EtOH-Et,O 16a C c,,H,,cIN,~Hc~~ 92 i-PrOH-Et ,0 227 dec 1la Bp C,,H,,CIN,~HCl 81 MeOH-Et, 0 252-255 dec 18a C i-PrOH-i-Pr,O C,,H,,ClN,~HCl 74 162-164 19a Bq c ,,H ,,c~N,o. noncryst 20a 21a" C,H,,ClN,~2HClr A MeOH-Et, 0 80 202-205 dec 22a 23as Bt 85 noncryst 24a A E tOH-E t 0 60 187-190 2 5a A i-PrOH 74 236-237 dec 26a A 191-193 33 CH,CN 27a 52 A CH,CN 198-200 28a 29aU 30a" 31af A noncryst 56 32a A MeOH-Et,O 172.5-175 82 33a A EtOH-Et,O 222-225 71 34a EtOH-Et,O A 160-163 34 35a 14 A 153 dec 36a Me,CO Me,CO-Et,O 150-153 A 16 31a A 20 noncryst 38a 39a" C,,H,,ClN;HCl 40a 158.5-160.5 CH,CN 45 A C,H,,ClN,O~HCl 41a 162-165 i-PrOH 72 A C,,H,,ClN;HCl EtOH 39 236-238 dec 42a A a Compounds are numbered t o correspond with the mercapto products in Table I. The R structure is shown in that table. All new compounds had analyses within 0.4% for C, H, and N, except as noted otherwise. A, commercial source; B, known, prepared by previously reported method; C, new, described under Experimental Section. Not Ref 2a. C: calcd, 56.32; analyzed, NMR spectra consistent with structure assigned. e H: calcd, 7.66; found, 8.14. I. S. Yankovskaya, I. Mayeika, D. Kruskops, and J. Polis, Zh. Obshch. Khim., 43, 490 (1973); Chem. found, 55.25. Abstr., 79, 31049h,(1973). V. L. Narayanan and J. Bernstein, German Patent 2 1 3 6 7 0 2 (1972); Chem. Abstr., 76, 112796q (1972). J. K. Chakrabarti, M. J. Foulis, T. M. Hotten, S. S. Szinai, and A. Todd, J. Med. Chem., 17, 602 (1974). C: calcd, 61.25; found, 60.70. W. Hoek, H. Wynberg, and J. Strating, R e d . DQU. Chim. PCZ~S-BQS, 85, 1 0 5 4 (1966); Chem. Abstr., 66, 28600%(1967). Ref 5. " L. Bauer and T. L. Welsh, J. Org. Chem., 27, 4382 (1962). O J. G. Whitney, W. A. Gregory, J. C. Kauer, J. R. Roland, J. A. Snyder, R. E. Benson, and C. E. Hermann, J. Med. Chem., 13, 254 British Patent 1 1 0 4 058; Chem. Abstr., 69, 51739e (1968). (1970). L. J. Loeffler, S. F. Britcher, and W. Baumgarten, J. Med. Chem., 13, 9 2 6 (1970). N: calcd, 16.38; found, 15.77. A. P. Parulkar and L. Bauer, J. Heterocycl. Chern., 3, C: calcd, 62.14; found, 61.69. Ref 472 (1966). Japanese Patent, 28 351 (1965); Chem. Abstr., 64, 17480h (1966). 6. C: calcd, 46.85; found, 45.83.
'
'
Table IV. pK,' and pKaZof Selected Mercaptoacetamidines and Related Structures compd pK,la 9 6.78 11 6.70 12 6.50 15 6.65 21 6.50 29 6.80 30 6.70 35 6.40 a Proton lost. EtOH-H, 0 .
pKaZb compd pKaIa 11.00 39 6.30 10.80 41 6.30 10.75 43 6.60 10.75 47 6.70 10.85 48 9.50 11.00
51
10.80 58 10.38 Proton gained.
pKaZb 11.00
11.00 10.70 11.00 10.90 11.ooc 10.60
Determined in 20%
with stirring over 5 min while the temperature rose to 25 "C. After stirring at 25 "C for 3 h, the reaction mixture was filtered from insoluble matter. Addition of 500 mL of EtpOprecipitated crude 56, wt 9.2 g.
N-Benzyl-2-hydroxyacetamidinehydrochloride (57) was prepared analogously to 56 by replacing the 2,2-dimethylpropylamine with an equivalent amount of benzylamine. Bicycle[ 3.2. l l o c t a n e -1-carboxamide. Bicyclo [3.2.l]octane-1-carboxylic acid14(15.5 g, 0.1 mol) was refluxed with 40 mL of SOClz in 50 mL of CCl, for 6 h. The mixture was then concentrated under vacuum and the residue was dissolved in 15 mL of Et,O. Concentrated NH40H (125 mL) was added dropwise with vigorous stirring at 0 "C. After 2 h, the product, 15.8 g (mp 186-188 "C), was filtered and recrystallized from CH3CN to obtain the amide of mp 187-189 "C. Anal. (C9H15NO)C, H, N. The following carboxamides were synthesized by the procedure described for the preparation of bicyclo[3.2.l]octane-l-carboxamide. These carboxamides were reduced to the corresponding amines without further purification. 4-( 1-Adamanty1)butyramide. From 44-adamantyl)butyric acid15 (20.0 g, 0.09 molj was obtained 17.1 g of crude amide, mp 95-100 "C. Several recrystallizations from cyclohexaneestablished
dorirnai of Medicinal ('hemistri,, 1979. Vu/. :k, .Vi) :j
310
Sabi,, .;' ..
-
Effect of Compound 3 and Metiamide on Gastric Secretion in the Dog
-~
-_. .~
Bolhofer et al.
-.
-
- .____
--
.
% inhibitionb
_. .
...
.-
compd
metiamide 'I
gastric stimulant gastrin tetrapeptide gastrin tetrapeptide histamine 2-deoxy-D-glucose 2-deoxy-D-glucose gastrin tetrapeptide gastrin tetrapeptide
... .. .__._._.._____I__
...
R a e weight.
'
dose,u mg/kg PO
vol
-_
8
7
16
Ti
-32
3 6 1 18 31: 13
5 i6 16 32
7 i'i
-
79 + 6 651 6 83 ! 6
titratable acid ~0L 0 91: 5 40 i 18 18 I 8 857 15 5 i 5
70 i 1 4 Average values for compound 3 in three dogs and metiamide in four dogs. . ...
-
the mp of lWlO8.5 "C (yield 47% 1. The structure was cotifirmed by NMR. 'Tricycl0[5.?.1 .0'~6]decane-l-carhoxamide.This amide \\a> vkained in 40% yield from tricyclo[5.2.1.0',6]decane-l-carboxylic acid. After recrystallization from isopropyl ether it had a mp of 120- 126 "C. NMR confirmed the structure. I-Bicyclo~4.2.1]octanemethy1amineHydrochloride. 'l'he reductiori was conducted under N2atmosphere. Red-al" j 70% scdium his(2-methoxyethoxy)ali~inrimhydride in benzene] (86.5 g, 0.3 mol) was dissolved in 300 ml. of dry C6H6and hicyclo. j~i.2.l]octane-i-carboxamide (18.4 g, n.12 mol) W R S added i i i portions over 20 niin. The stirred reaction mixtLue was kept below 50 "C. On Lvmpletion of the addition, the mixture was refluxed for 2 h and then cooled to 5 "C while 200 mL of 5 N NaOH was s:owly added. The layers were separated, and the aqueous layer was extracted with EtzO. The combined organic e x t r w t s wF'r(' washed with brine and dried (blgSO,). Addition of excms 6 K cthanolic HCI precipitated the product h>drochIoride. 16.4 g i 7 ' i % ) , mp 322--324 "C dec. Iiecrystalli7ation from i-PrOH brought the melting point to 325 327 "C dec. Anal I C ,H F.I. N; C: calcd. 61.52; found. 62.02. The following amines were prepared hy r.educ.tion of' the corresponding carboxamides as illustrated in the preparatitm t i t l-bicyclo[~i.2.l]octi~nen~ethylamirie hydrochloride. .4-( I-Adamanty1)butylamine Hydrochloridr. Ilediictio!i ot .~-(l.adamantyl)butyramidei 1 LL g. 0,066mol) t o the amini. ,inti conversicm t o the HC1 salt produced 9.5 g of white solid. hich was recrystallized from EtOH- Et@: nip %8 '771 "(' d e r : \.ield 4 9 % . Anal. /C14H2jN"C1) (I. H. K, yclo[ 5.2.1.0"."]decane-.l-methylarnineHydrochloride. o[5.2.1.02~~]ldecane-4-melh~lamine hydrochloride was iibtaineci in 44% yield by reduction of the corresponding caramide and recrystallized from i-PrOH -i-Pr20,mp 276 ~ 2 7 8 le(,. Anal. (C1,HL9N.HC1) H. N: C: colcd, 65.49; found. 65.06. - N o r b o r n a n e m e t h y l a m i n e Hydrochloride. Norhorn n n ~ --carboxamidel' l (1:3.99 g. 0 , i mol) \vas reduced i o oh1aiti 11.1 g (69%,)of the amine hgd de. Recrystallization i'roni i-PrOH Et& brought the nip t * X I I ~ .((lhHj-,K*H('i! 11. N:C: talcd, 59.43: found. .l-Bromo-N-(2,'?-dimeth y 1)butyramidine Hydrochloride. 2~2-nimethylpropylamine(3.46 g, 17.0t5 mcili was adtied t o R stirred solution of ethyl -~-hrornobut~rimidate hydrochlorirle'~~ .5 g, 0.05 mol) in 100 niI, t)f EtOJI tit 5 "t'. 5tirring t v ~ i i . vbritinued at ambient temperature t S ) i 1 . 75 li. 'l'he s~)iiitio~i +\:3< concentrated in vacuo at room temperntiire arid, o n dilution oi the residue with Me,CO, 5.2 g of white wiid w a s ohtriiried. r i i ~ . , 1:2 -156 O C ' . Recrystalliz n f r o m ('FLC'N raised the mp L U 1*56 1 S7 "C The yield wa 7 Anal ~(.',Ff,,RrN,-HVIi H.U: ('. calcd, riR.79; found, 4( 2 - C hlo r 0.N -(2,2- d i me t h y 1p ropy 1 ) p r o pi on a midi I!e 113 drochloride. Sodium methoxide (0.27 g. 0.005 mol) was added tn a cold solution of 2-chloropropionitrile (4,48g, U.O,? mol! in 50 rnL of MeOH and stirred at ambient temperature for 1.5 h. 'Then a solution of 2.2-dimethylpropylaine (4.35 g. 0.05 in(il1in 20 ml. of MeOH con:ainirig 8.3 ml. of ethanolic HCI (ti N) as added and stirring W ~ Econtinued S for :I h. The mixture was concentrated in vacuo, and the solid residue \\a!; washed with col E:t20. The white ioii 1 2. r n p 238 242 cr,wai from Etrjii Et2(? to pure mnterial. m p W I 82%. Anal. (C,H,,ClN,.HCl) (1. H. S . eterminat,ion of pK,. The "apparent" pK,, talues were ined hi. a rnrthcd i n which the ph', i. ccinslder~rlt i ) b 1 1 ,
1
1
~
.
..
~
-._.._l___._l_._...._.
--
-
total acid o u t p u t 8t8 63-t 15
55 2 42 z 97 i 64 t 90 z
21 12 3
5 5
t o the pI1 at the half neutralization point. (An apparent pK, does not include corrections for ionic strength. For dilute solutions, these corrections are usually less than 0.1 pK unit.18) The sample (0.05 mol) was either dissolved in H 2 0for a direct titration with 0.5 N NaOH or in 30 mL of HzO containing NaOH (0.15mol) for a hack-titration with 0.5 N HC1 using a glass---calomel tem on an expanded p H scale. The pH a t the half 11 point \!as taken from the neutralization curve. €3enzamidir:e under these conditions has a p K , value in water of I i .5 and 11.2 in 5076 EtOH. The corresponding reported values ;ire 11 .GI q and 11.3,*" respectively. Riological Test Methods. Nonanesthetized female beagles weighing 5 9 kg with a chronic gastric fistula were administered teqt compounds directly into the stomach via the gastric cannula j identified herein as oral administration). The compounds were iiistcred in 50 nil, of a 1'7c methylcellulose solution 1 h prior irniilation of gastric secretion. Control animals received vdiic!e alone. Secretion was stimulated with gastrin tetrapeptide ~ 6 .i*g: i kg sc from a 30% Me2S0 solution containing 640 pg/mL), histamin? 164 ug base u.t,'kg sc from a solution of histamine diphi)sphdtc, 6.10 p g base wt,,mL,, in physiological saline), o r "-deo?t!-.i)-glucose (200 mg,'kg sc dissolved in physiological saline). (iastrir o u t p u t was collected for 2 h after stimulation. Total vol\inie \vas iiieasureti. and the acid concentration (titratable acid) \vas determined on ;In aliquot by titration to pH 7 with 0.01 N ' i i i O H iihing a glass calomel electrode. Total acid output was i,alcuiateti
