417
J. Med. Chem. 1993,36, 417-420
Communications to the Editor Dibenz[ b,e]oxepin Derivatives: Novel Antiallergic Agents Possessing Thromboxane A2 and Histamine HI Dual Antagonizing Activity. 1
Chart I S-2' m
C
O
O
H
&Y-COOH
0
Etsuo Ohshima, Hitoshi Takami, Hiroyuki Harakawa, Hideyuki Sato, Hiroyuki Obase,' Ichiro Miki, Akio Ishii, Hidee Ishii, Yasuo Sasaki, Kenji Ohmori, Akira Karasawa, and Kazuhiro Kubo
X2 e
Y
-N
p Ar
,NHSOzPh
Thromboxane A2 (TXAz), a short-lived metabolite of arachidonic acid (AA),is a powerful inducer of platelet aggregation and of vascular smooth muscle contraction.' In addition, TXAz has been implicated in the pathophysiological conditions of asthma, since it has been shown to produce bronchoconstriction2and contribute to airway hyperresp~nsiveness,~~ a key feature of asthma.8 Therefore, intensive efforts have been made to discover TXAz synthase inhibitors (TXS-I) and TXAZreceptor antagonists (TXRA),and presently severalof TXS-Is and TXRAs are undergoing clinical evaluations as new antiasthmatic agents? Sincemultiple mediatorsare involved in asthma? an agent which inhibits other mediator@)in addition to TXAz should be clinically more effective than selective TXS-I or TXRA. We have recently reported antiallergic and histamine HI receptor antagonizing activities of KW4994 (1)'Oand 21' (Chart I). Moreover, dibenz[b,eloxepin derivatives 312and 413were found to be potent TXRAs. Thus we attempted to synthesize an antiallergic agent possessing TXAz and histamine HI dual antagonizing activity. Taking the compatibilitybetween the structureactivity relationships of 1-4, we designed the general structure 5. The tertiary amino group in the side chain of 6 was expected to be an equivalent of the benzimidazole moiety that was crucial for the enhanced TXRA activity of 4. In this paper, we will describe the synthesis and structure-activity relationships of a new series of 6,ll-dihydrodibenz[b,eloxepinderivatives(5). Sulotroban (6),14-16 one of the representative non-prostanoid TXRAS,'~-~~ was used as a reference compound during our series of experiments.
-
C
O
O
H
'
0 5 X'-X2 = SCHZCHp or CHCHz Y =bond or spacer
Received J u l y 6, 1992
0022-2623J93J1836-0417$04.00/0
2: R' = NMe2,Y = CH, 4: R' = I-benzimidazolyl, Y = bond
X''
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka-ken, 41 1 J a p a n
Chemistry Compounds 7-17, listed in Table I, were obtained by the alkalinesaponificationof the corresponding esters 2232,which were prepared from 18 as depicted in Scheme I. Compounds 18 were treated with trifluoroacetic anhydride and subsequentlywith 2-mercaptoethanolto provide 19>OJ2which were converted into iodides 21 by consecutive treatments with MsCVLiCVDMF and NaVCHsCN. However, since the iodides 21b-d were unstable, the chlorides 20b-d were used in the next reaction. Compounds 20b-d and 21a were allowed to react with a secondary amine (HNR2R3)in refluxing EtOH to afford 22-32. Resolution
0
1: R' = NMe, HCI 3: R' = NHSOzPh
OACOOH
6, sulotroban
Scheme I a ?H
a
Y
.
C
O
O
M
e
a
m
Y
C
O
O
M
e
(7695%)
-
l e a : Y-bond b: Y .CHr C: Y = -CHzCH,d: Y -C(Me)z-
-
-
- my-cm 7
20b-d, 218
d
R2R3
7-17
(s€-92%)
(4140%)
22-32
(a) (i) (CF&0)20, CH2C12; (ii) 2-mercaptoethanol, CH2Cl2; (b) MeCl, LiCl, 2,4,6-collidine, DMF; (c) NaI, acetonitrile; (d) HNR2R3, EtOH; (e) NaOH, H20, MeOH. a
Scheme I1 a
36
35
(a) 1-(4-fluorophenyl)piperazine, EtOH; (b) NaOH, HzO, MeOH.
Scheme I11 a
5 3,E
&--
4 R & " ' 37
(52%)
--
0
38: R'
E34: 'R
CH&OCM
CHzCOOH
(a) (HCHO),, 4-benzylpiperidine, CFBCOOH,AcOH, dichloroethane; (b) NaOH, Hz0, MeOH; (c) fumaric acid; (d) fractional crystallization. a
of racemic 12, one of the most promising examples in this study, was accomplished by HPLC separation of the precursor (f)-27 on a ChiralcelOD column and subsequent saponification. Compounds 33 and 34 (Table 11)were prepared by the methods depicted in Schemes I1 and 111, respectively. A dibenzoxepin derivative possessing an (E)-2-chloroethylidene substituent (38)'' was treated with l-(Cfluo@ 1993 American Chemical Society
Communications to the Editor
418 Journal of Medicinal Chemistry, 1993, Vol. 36, No.3 Table I. New Dibenz[b,e]oxepin Derivatives S/\/NRZR3 I
no.
NR2R3
1, KW-4994 NMe2 3 NHSO2Ph 6, sulotroban 7' morpholino 8/ 4-Ph-piperazino 9 FPP 101 4-Bn-piperazino 1l h 4-Ph-piperidino (f)-12hJ 4-Bn-piperidino (+)-12/J 4-Bn-piperidino (-)-12f,k 4-Bn-piperidino 13 4-Bn-piperidino 14 4-Bn-piperidino 15 4-Bn-piperidino 16' THIQ 17" OBIP
'Ph, phenyl; Bn,benzyl; FPP,
R4
precursor
TXAdPGH2 receptor binding HI receptor binding (guinea pig washed platelet) (guinea pig cerebellum) Ki,' nM Ki: nM
mp, OC (solvent)
*
COOH COOH 22 220-224 (IPA-MA) COOH COOH 23 244-246 dec (ACY COOH 24 165-166 dec (1PA)I 25 112-115 dec (1PE)g COOH 26 182-184 dec (IPA) COOH (f)-27 78-80 dec (IPA-W) COONa (+)-27 79-81 dec (IPA-W) COONa (-)-27 79-81 dec (IPA-W) COONa 28 157-158 (TLP CHzCOOH 29 163-165 (EA) C(Me)&OOH CH2CHpCOOH 30 141-142 ( P A ) 31 139-141 (IPE) COOH 32 185-188 (AN-IPA) COOH
~ 3 o F : THIO,N
4 ; OBIP,
18%a t 1 pMd 32 f 1.4 (3) 1300 f 140 (3) 1900 f 62 (3) 210 f 20 (3) 400 f 52 (3) 490 f 48 (3) 990 f 60 (3) 140 f 3 (3) 14000 f 1100 (3) 42 f 3.8 (3) 430 f 52 (3) 1600 f 78 (3) 340 f 67 (3) 240 f 51 (3) 130 f 14 (3)
9.0 f 1.6 (3) 0% a t 1pMd 0% a t 1pMd 42 f 6.7 (3) 47 f 5.6 (3) 41 f 5.4 (3) 14 f 2.2 (3) 20 f 1.0 (3) 18 f 3.8 (3) 9.9 0.29 (3) 740 f 69 (3) 10 f 1.1 (1) 17 f 3.2 (3) 12 f 1.4 (3) 6.9 f 0.25 (3) 500 f 31 (3)
0
* P A , 2-propanol;MA, methanol; AC, acetone; IPE,
0
inopropyl ether; W, water; "I,,toluene; EA, ethyl acetate; AN, acetonitrile.'Values are mean f SEM of numbers indicated in parentheses. dPercent inhibition,n I2. 'HCI salt. /Monohydrate.# Wturation solvent. hmihydrate. 'KW-4099.'299.6% ee; [al~ +84.1" (c = 1, MeOH). '299.6% ee; [ab-B6.8D( E = 1, MeOH). 'Dihydrate. '"0.26-Hydrate.
ropheny1)piperazineto furnish 36,which was saponified to provide 33. No detectable isomerization of the double bond occurredduring the conversion. Olefin 37was treated with 4-benzylpiperidine under Mannich reaction conditions to provide 38 (E/Z = 3.2/1).11 Compound 38 was saponified and subsequently purified by fractional crystallization to afford the E-isomer (34E). Concentration of the mother liquor of the crystallization of the crude 34E yielded 2-rich 34,which was esterified, converted to the corresponding oxalate, and purified by crystallization to afford 382 that was the precursor of 342.
of the correspondingpiperazine derivative8. Replacement of the phenyl group of 11 with benzyl group to afford (a)12 increased the affmity for TXAdPGHz receptor (Ki= 140 nM). Moreover, the results of 16 indicated that the substitution with tetrahydroisoquinoline,a benzene-fused piperidine, was tolerable and enhanced the affinity for H1 receptor. On the other hand, compound 17,possessing a benzimidazolone-substitutedpiperidine, was much less active than (&)-12 in the H1binding m y , while it retained the TXRA activity (Ki= 130 nM). Insertion of a spacer in the acidic moiety (i.e., Y in 5) caused a decrease in TXRA activity, while ita influence was negligible on affinity for H1 receptor. Compounds Results and Discussion with a straight alkylene spacer (13and 15)exhibited 2-3fold weaker affinities for TXAdPGHz receptor than (i)The compounds synthesized were tested for their inhibitory effects both on the specific binding of [3HlU12. Insertion of dimethylmethylenegroup,which provided 46619 to guinea pig plateleta TXAdPGHz r e ~ e p t o r s l ~ . ~ ~14,resulted in a considerablereduction in TXRA activity. This observation suggestedthat a steric hindrance around and on the specific binding of PHIpyrilamine to guinea pig cerebellum histamine HI receptors.11*2sResults are the carboxyl group might affect the interaction between the acidic group and a putative proton-accepting moiety represented by Ki values (Tables I and 11). of TXAdPGHz receptor protein.27 Most of the compounds,listed in Table I, exhibited both TXAz and HI antagonizing activities.26 The terminal Although compound (*)-12 (KW-4099) was seemingly structure on the side chain (i.e., NRzR3) proved to be one of the most promising TXAdH1 dual antagonists in important tomodulate the biologicalactivities. Compound this series,the two modes of actions of (&I-12were divided with 4-phenylpiperazine and ita derivatives (8-10) posinto the optical isomers. Compound (-1.12 inhibited the sewed significant TXRA activities in addition to potent specific receptor binding of [3HlU-46619concentrationHI antagonizing activities, whereas 1 and ita morpholine dependently with a Ki value of 42 nM and ita potency was analogue 7 failed to exhibit potent TXRA activity. These 30-fold more potent than that of sulotroban (61,a pure data confirmed that the presence of an aromatic ring TXRA. In addition, (3-12 possessed a moderate HI moiety (i.e., Ar in 5) was crucial for good TXRA activity. receptor binding affinity (Ki= 740 nM). On the other Similarly, a compound with 4-phenylpiperidine (1 1) was hand, (+)-12 proved to be a potent and selective HI potent in both receptor asaaye, although ita TXRA activity antagonist (Ki= 9.9 nM). Therefore, the configuration at (Ki= 990 nM) was approximately4-fold weaker than that the 11-position of the molecule was crucial on the ligand
Journal of Medicinal Chemistry, 1993, Vol. 36, No.3 419
Communications to the Editor Table 11. New Dibenz[ b,e)oxepin Derivatives
no.
NRZR3
R4
2 4 33eJ 34EhJ 34Zhvk
NMez 1-benzimidazolyl
CHzCOOH COONa COOH CHzCOOH CHzCOOH
FPP 4-Bn-piperidino 4-Bn-piperidino
mp, OC (solvent)
*
236-238 (IPA) 187-188 (ET)) 120 dec (IPA)
TXAdPGHz receptor binding (guinea pig washed platelet) Ki: nM
HI receptor binding (guinea pig cerebellum) Ki: nM
>loo0 (1) 15 2.3 (4) 2300 f 130 740 f 44 (3) 2600 (1)
11f 0.9 (3) NTd 3% at 1pMg 20 f 0.8 (3) 15 1.6 (3)
~~
~
"Bn, benzyl; FPP. N ~ N + F bIPA, 2-pmpanol; ET, ethanol. Values are mean f SEM of numbers indicated i n parentheses dNot tested I hlonohydrate. 'Scheme 11. qercent inhhhon, n = 2. 'Fumarate half salt. 'Scheme 111 'Trituration solvent "Possessing Z- geometry
recognition of each receptor which was recently cloned and shown to possess a similar transmembrane topology to that of r h o d o p ~ i n . ~X-ray ~ , ~ ~crystallographic data relative to absolute configuration determination will be reported ~eparately.~~ The enhanced TXRA activity of 4 encouraged us to synthesize some derivatives which possess an ethylidene connecting group. The preliminary results are shown in Table 11. Replacement of the benzimidazole moiety of 4 with 4-(4-fluorophenyl)piperazineto provide 33 resulted in a remarkable reduction of TXRA activity. Moreover, 33 was devoid of HI-receptor binding activity. Interestingly, compound 34Eexhibited both of TXA2 antagonizing (Ki= 740nM) and HI antagonizing (Ki= 20 nM) activities. The geometry of the double bond at the 11-position affected the TXRA activity more significantly than the H1 antagonizing activity. Compound 34E was approximately 3-fold more potent than 342 as a TXRA, whereas it was slightly less active than 342 as an H1 antagonist. Selectivityof 34E was also assessed. It showed negligible activities at concentration of 10 pM in the following receptor binding assays: a1 and a2 adrenergic,muscarinic 1,H2 histamine, serotonin, dopamine, platelet-activating factor, PGE2, and PGI2. Compound 34E showed potent inhibitory effect on 48 h homologous passive cutaneous anaphylaxis (PCA) in rats (ED50 = 0.73 mg/kg, po).I1 In this model, antihistamines 1,2, and ketotifen30exhibited inhibitory effects with ED50 values of 0.92, 0.077, and 4.8 mg/kg, PO, respectively, while sulotroban (6) and 4 did not show any efficacy in this model. Histamine- and U-46619-induced bronchoconstrictions in guinea pigs were prevented by the oral pretreatment of 34E (0.3 mg/kg and 10 mg/kg, re~pectively).~~ In addition to the good oral activities described above, 34E has a great safety margin to effect both of receptor antagonizing activities (e.g.,LDM> lo00 mg/kg, PO, rats).32 In conclusion, we have demonstrated the successful modifications of the structures of TXRAs and HI antagonists possessing a dibenzoxepin ring system to obtain a TXAdHl dual receptor antagonist. (E)-ll-[2-(4-Benzylpiperidino)ethylidenel-6,11-dihydrodibenz[b,eloxepin2-acetic acid fumarate half salt (34E) represents the first of the antiallergic agents to combine TXA2/H1 dual antagonism in one molecule. Compound 34E (KF15766) is selected for the new lead of further modifications to
obtain a better-balanced TXAdH1 dual antagonist. The results of this endeavor will be addressed in future publications.
Acknowledgment. We are grateful to A. Nakamura, T. Yasuzawa, and K. Yamaguchi for spectral data, and especially to Drs. N. Hirayama, T. Kumazawa, and K. Suzuki for their continuous support and pertinent discussion. Appreciation is expressed for excellent technical assistance by T. Watanabe. S u p p l e m e n t a r y Material Available: Experimental procedures for the synthesisof 22-38, procedures for the histamine-1 receptor and TXAdPGHzreceptor binding ways, and elemental analyses (8 pages). Ordering information is given on any current
masthead page.
References Hamberg, M.; Svensson, J.; Samuelsson, B. Thromboxanes: a New Group of Biologically Active Compounds Derived from Proetaglandin Endoperoxides. Proc. Nat. Acad. Sci. U.S.A. 1976, 72, 2994-2998. Svensson, J.; Strangberg, K.; Tuvemo, T.; Hamberg, M. Thromboxane AP: Effecta on Airway and Vascular Smooth Muscle. Prostaglandins 1977, 14, 425-436. Chung, K.F.; Aizawa, H.; Becker, A. B.; Frick, 0.;Gold, W. M.; Nadel, J. A. Inhibition of antigen-induced airway hyperreaponsiveness by a thromboxane synthetase inhibitor (OKY-046) in allergic dogs. Am. Rev. Respir. Die. 1986, 134, 25f5-261. Aizawa, H.; Chung, K. F.; Leikauf, G. D.; Ueki, I. F.; Bethel, R. A.; OBpne, P. M.; Hirose, T.; Nadel, Jay A. Significance of thromboxane generation in ozone-induced airway hyperresponsiveneea. J.AppL Physiol. 1986,59, 1936-1940.
Fujimura,M.;Sakai,F.;Nakatumi,Y.;Hifumi,S.;Taga,K.;Mifune, J.; Tanaka, T.; Matsuda, T. Effects of a thromboxane synthetase inhibitor (OKY-046) and a lipoxygenme inhibitor (AA-861) on bronchial responsiveness of acetylcholine in asthmatic subjects. Thorax 1986,41,955-959. Taylor, I. K.; Ward, P. S.; OShaughnessy, K. M.; Dollery, C. T.; Black, P.; Barrow, S. E.; Taylor, G. W.; Fuller, R. W. Thromboxane A2 biosynthesis in acute asthma and after antigen challenge. Am. Reu. Respir. Dis. 1991, 143, 119-125. Barnes, P. J. New Concepts in the Pathogenesis of Bronchial Hyperresponsiveneeaand Asthma. J.Allergy. Clin.Immunol. 1989, 83, 1013-1026. Juniper,E. F.;Frith,P. A.;Hargreave,F.E. Airway Responsiveneaa to Histamine and Methacholine: Relationship to Minimum Treatment to Control Symptoms of Asthma. Thorax 1981,36,575-579. For a recent review of TXA2 synthetase inhibitors and TXAz receptor antagonists, see: Collington, E. W.; Finch, H. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Academic: New York, 1990; Vol. 25, pp 99-108. Ohshima, E.; Kumazawa, T.; Takizawa, H.; Harakawa, H.; Sato, H.; Obase, H.; Oiji, Y.; Ishii, A.; Ishii, H.; Ohmori, K.A New Seriea of Antiallergic Agenta. 1. Synthesis and Activity of 1142Aminoethyl)thio-6,1l-dihy&odibenz[b,eloxepin Derivatives Chem. Pharm. Bull. 1991,39, 2724-2728.
420 Journal of Medicinal Chemistry, 1993, Vol. 36, No.3
Communications to the Editor
(22) Shiraishi, M.; Kato, K.; Terao, S.; Aahida, Y.; Teraehita, 2.;Kito, A,; Ishii, H.; Ohmori, K.; Hirayama, N. Synthesis and Antiallergic G. Quinones. 4. Novel Eicoaanoid Antagonists: Synthesis and Activity of ll-(Aminoalkylidene)-6,ll-dihydrodibenz[ b,eloxepin Pharmacological Evaluation. J.Med. Chem. 1989,32,2214-2221. Derivatives. J. Med. Chem. 1992, 35, 2074-2084. The methods (23) Tomiyama, T.; Wakabayashi, S.; Koaakai, K.; Yokota, M. Azulene and references of the homologous PCA test and the experimental Derivatives: New Non-Prostanoid Thromboxnne A:! Receptor bronchoconstriction were cited therein. Antagonists. J. Med. Chem. 1990,33, 2323-2326. (12) Ohshima, E.; Takami, H.; Sato, H.; Obase, H.; Miki, I.; Ishii, A.; (24) Miki, I.; Kishibayashi, N.; Nonaka, H.; Ohshima, E.; Takami, H.; Karasawa,A,;Kubo, K. Non-prostanoid Thromboxane A:! Receptor Obase, H.; Ishii, A. Effects of KW-3635, a Novel Dibenzoxepin Antagonists with a Dibenzoxepin Ring System. 1. J. Med. Chem. Derivative of a Selective Thromboxane A2 Antagonist, on Human, 1992,35, 3394-3402. Guinea Pig and Rat Platelets. Jpn. J. Pharmacol. 1992,59,357(13) Ohshima, E.; Takami, H.; Sato, H.; Mohri, S.; Obase, H.; Miki, I.; 364. Ishii, A.; Shirakura, S.; Karasawa, A.; Kubo, K. Non-proetanoid (25) Chang, R. S. L.; Tran, V. T.; Snyder, S. H. Characteristics of Thromboxane A:! Receptor Antagonists with a Dibenzoxepin Ring Histamine H1-Receptors in Peripheral Tissues Labeled with ["HISystem. 2. J. Med. Chem. 1992,35,3402-3413. Mepyramine. J. Pharmacol. Exp. Ther. 1979,209,437-442. (14) Patacheke, H.; Stegmeier, K. Investigations on a Selective Non(26) Compound (+)-12, an example poeseeeing a potent HI receptor prostanoic Thromboxane Antagonist, BM 13.177, in Human binding affinity demonstrated significant inhibitory effect on Platelets. Thrombosis Res. 1984,33, 277-288. histamine-induced contraction of guinea pig tracheal preparation (15) Stegmeier,K.;Pill, J.;Mtiller-Beckmann, BjSchmidt, F. H.; Witte, EX.; Wolff, H.-P.; Patscheke, H. The Pharmacological Profile of (pA2 = 8.57). In addition, (-)-12, possessing an affinity for TXAd the Thromboxane AI Antagonist BM 13,177. A New Anti-platelet PGHz receptor-inhibited U-46619-induced contraction of t h e m e and Anti-thrombotic Drug. Thrombosis Res. 1984, 35, 379-395. tracheal preparation (PA:! = 7.22). Any agonistic effect of the (16) Seeger,W.; E r e t , Ch.; Waimrath,D.; Neuhof, H.; Roka, L. Influence compounds was not observed in the experiments. of the Thromboxane Antagonist BM 13,177 on the Arachidonic (27) Hirata, M.; Hayashi, Y.; Ushikubi, F.; Yokota, Y.; Kageyama, R.; Acid-induced Increase in Pulmonary Vascular Resistance and Nakanishi, S.; Narumiya, S. Cloning and Expression of cDNA for Permeability in Rabbit Lungs. Thrombosis Res. 1985, 40, 793a Human Thromboxane A:! Receptor. Nature 1991,349,617-620. 805. (28) Yamashita, M.;Fukui,H.;Sugama,K.;Horio,Y.; Ito,S.;Mizuguchi, (17) Carrer,R.; Cragoe,E. J.;Ethier,D.;Ford-Hutchinson,A. W.;Girard, H.; Wada, H. Expression Cloning of a cDNA Encoding the Bovine Y.; Hall, R. A.; Hamel, P.; Rokach, J.; Share, N. N.; Stone, C. A.; Histamine HIReceptor. Proc. Natl. Acad. Sci. U.S.A. 1991,88, Yusko, P. Studies on L-640,035: a Novel Antagonist of Contractile 11515-11519. Prostanoids in the Lung. Br. J. Pharmacol. 1984,82, 389-395. (29) Hirayama, N.; Sugaya, T.; Tomioka, 5.; Ohshima, E.; Obase, H. (18) Hall, R. A.; Gillard, J.; Guindon, Y .;Letts, G.; Champion, E.; Ethier, Methyl 11R-ll-~2-(4-benzylpiperidino)ethyllthio-6,ll-dihydroD.; Evans, J.; Ford-Hutchinson, A. W.; Fortin, R.; Jones, T. R.; dibenz[b,eloxepin-2-carboxylate. Acta Crystallogr., Sect. C, in Lord, A.; Morton, H. E.; Rokach, J.; Yoakim, C. Pharmacology of press. L-655,240 (3-[l-(4-chlorobenyl)-5-fluoro-3-methyl-indol-2-y1]-2,2dimethylpropanoic acid); a Potent, Selective, Thromboxane/ (30) Ketotifen, an antiallergic agent possessing a similar tricyclic ProstaglandinEndoperoxideAntagonist. Eur. J.Pharmacol. 1987, skeleton, was used as a reference compound. 135,193-201. (31) Male Hartley guinea pigs (400-600 g) were pretreated with 34E (19) Mais, D. E.; Yoakim, C.; Guidon, Y.; Gillard, J. W.; Rokach, J.; (PO) and propranolol (3 mg/kg, ip) 1hand 30 min before spasmogen Haluahka, P. V. Photoaffinity Labelling of the Human Platelet injection, respectively. Bronchoconstriction induced by histamine Thromboxane AdProstaglandin HI Receptor. Biochem. Biophys. (50 pg/ccp/k;g, iv) or U-46619 (1.05 p g / k g , iv) was measured by the Acta 1989, 1012, 184-190. method of Konzett and Rbsler: Konzett, H.; Rbeeler, R. Naunyn(20) Mais, D. E.; Bowling, N. L.; True, T. A.; Naka, M.; Morinelli, T. Schmiedebergs Arch. Exp. Pathol. Phurmakol. 1940,195,71-74. A.: Oatis. J. E.: Hamanaka. N.: Halushka. P. V. Novel Svnthesis Compound34Eshowed83.5% (n= 7)and98.0% (n=6)inhibitioe andBiochemi&lPropertiesof& [12SI]-LabeledPhotoaffinityProbe a t 0.3 and 1 mg/kg po, respectively, on the histamine-induced for Thromboxane AJProataglandin HZReceptors. J.Med. Chern. bronchoconstriction, while34Eexhibited 71.3% (n= 7) and87.4% 1991,34, 1511-1514. ( n= 7) a t 10and 30 mg/kg PO,respectively, on the U-46619-induced (21) Rosentreter, U.; Bbhagen, H.; Seuter, F.; Perzborn, E.; Fiedler, V. bronchoconstriction. B. Svnthesis and Absolute Confiwation of the New Thromboxane Ankonist ( 3 R ) - 3 - ( 4 - F l u o r o p h e l a ~ o n ~ d e ) - 1 , 2 , 3 , ~ t e ~ ~ y ~(32) o - Effeds of 34E on other experimental modela as well as advantages of the dual antagonist over a pure TXRA or an HI antagonist will 9-carbazolepropanoic Acid and Comparison with its Enantiomer. Arzneirn.-Forsch. 1989,39, 1519-1521. be reported in a separate paper. (11) Ohshima, E.; Otaki, S.; Sato, H.; Kumazawa, T.; Obase, H.; Ishii,
~~
