Letters in Peptide Science, 2 (1995) 135-140 (cid:9)
`ESCOM
`
`LIPS 075
`
`135
`
`New peptidomimetics in the chemistry of fibrinogen
`receptor antagonists
`
`J. Gante*, H. Juraszyk, P. Raddatz, H. Wurziger, S. Bernotat-Danielowski, G. Melzer
`and E Rippmann
`
`Merck KGaA, Preclinical Pharmaceutical Research Department, Frankfurter Strasse 250, D-64271 Darmstadt, Germany
`
`Received 8 September 1995
`Accepted 2 November 1995
`
`Keywords: RGD; Antithrombotics; GP IIb/IIIa
`
`SUMMARY
`
`RGD-peptidomimetics are currently being investigated as a class of potential antithrombotics that antagonize
`the fibrinogen receptor, GP IIb/IIIa, on the surface of platelets. These mimetics are expected to have decisive
`advantages — such as higher activity and specificity, oral bioavailability and longer duration of action — over known
`antithrombotics. For further optimization in this respect, novel peptidomimetic GP IIb/IIIa antagonists with an
`oxazolidinonemethyl central building block were synthesized. This building block proved to be very versatile as an
``anchor' for structurally different C-termini and was the starting point for highly efficient and orally active com-
`pounds.
`
`Letters in Peptide Science, 2 (1995) 135-140 135 ESCOM LIPS 075 New peptidomimetics in the chemistry of fibrinogen receptor antagonists J. Gante*, H. Juraszyk, P. Raddatz, H. Wurziger, S. Bernotat-Danielowski, G. Melzer and E Rippmann Merck KGaA, Preclinical Pharmaceutical Research Department, Frankfurter Strasse 250, D-64271 Darmstadt, Germany Received 8 September 1995 Accepted 2 November 1995 Keywords." RGD; Antithrombotics; GP IIb/IIIa SUMMARY RGD-peptidomimetics are currently being investigated as a class of potential antithrombotics that antagonize the fibrinogen receptor, GP IIb/IIIa, on the surface of platelets. These mimetics are expected to have decisive advantages - such as higher activity and specificity, oral bioavailability and longer duration of action - over known antithrombotics. For further optimization in this respect, novel peptidomimetic GP IIb/IIIa antagonists with an oxazolidinonemethyl central building block were synthesized. This building block proved to be very versatile as an 'anchor' for structurally different C-termini and was the starting point for highly efficient and orally active com- pounds. INTRODUCTION Analogues of the RGD sequence in certain bioactive peptides or proteins are, as so-called 'adhesion receptor antagonists', very important candidates as antithrombotics [1]. These potential pharmaceuticals are aimed to antagonize adhesion receptors of the GP IIb/IIIa type on blood platelets. These receptors are glyco- proteins of the large family of 'integrins', which undergo binding to the blood protein fibrinogen as an essential step during the coagulation process. Blocking them by bioactive substances should interfere with and ameliorate pathological condi- tions such as thrombosis, unstable angina, acute myocardial infarction, thrombotic stroke and peripheral arterial occlusion [2]. The receptors are located on the surface of blood platelets (- 50 000 per platelet), which play an important role in the coagulation process. The GP IIb/IIIa receptor is a transmembrane heterodimer with binding sites for the attachment of fibrinogen. Fibrinogen itself has binding sites for the attachment to the platelet receptor, which are characterized by R-G-D (Arg-Gly-Asp) se- quences within the protein chain. The multiple occurrence of the 'binding points' on both sides implies the formation of a tight platelet/fibrinogen network during the clotting process. For the development of nonpeptidic adhesion *To whom correspondence should be addressed. 0929-5666l$ 6.00 + 1.00 © 1995 ESCOM Science Publishers B.V.
`
`Analogues of the RGD sequence in certain
`bioactive peptides or proteins are, as so-called
``adhesion receptor antagonists', very important
`candidates as antithrombotics [1].
`These potential pharmaceuticals are aimed to
`antagonize adhesion receptors of the GP IIb/IIIa
`type on blood platelets. These receptors are glyco-
`proteins of the large family of Integrins', which
`undergo binding to the blood protein fibrinogen as
`an essential step during the coagulation process.
`Blocking them by bioactive substances should
`interfere with and ameliorate pathological condi-
`tions such as thrombosis, unstable angina, acute
`
`INTRODUCTION
`
`*To whom correspondence should be addressed.
`
`0929-5666/$ 6.00 + 1.00 (cid:9)
`
`1995 ESCOM Science Publishers B.V.
`
`myocardial infarction, thrombotic stroke and
`peripheral arterial occlusion [2]. The receptors are
`located on the surface of blood platelets 50 000
`per platelet), which play an important role in the
`coagulation process.
`The GP IIb/IIIa receptor is a transmembrane
`heterodimer with binding sites for the attachment
`of fibrinogen. Fibrinogen itself has binding sites
`for the attachment to the platelet receptor, which
`are characterized by R-G-D (Arg-Gly-Asp) se-
`quences within the protein chain. The multiple
`occurrence of the 'binding points' on both sides
`implies the formation of a tight platelet/fibrinogen
`network during the clotting process.
`For the development of nonpeptidic adhesion
`
`MYLAN - EXHIBIT 1018
`
`

`
`136
`
`NH
`
`H2N
`
`HN
`
`H2N
`
`H2N
`
`R
`
`G — D
`
`— AA
`
`— AA
`
`— AA
`
`COOH
`
`H (cid:9)
`O
`
`I
`
`Scheme 1. Mimetization sequence from peptide to nonpeptide.
`
`receptor antagonists, the binding RGD sequence
`of the fibrinogen is taken as a motif for low-mol-
`ecular-weight inhibitors that should bind more
`strongly to the receptor in order to prevent fi-
`brinogen itself from binding [3], thus inhibiting
`platelet aggregation. The inhibitors should also be
`specific for this integrin and, if possible, orally
`active for chronic treatment. Therefore, in the
`development of such compounds, there is a trend
`from fibrinogen-derived peptides via 'semi-mime-
`tics' to low-molecular-weight 'complete' nonpep-
`tides [1,4]. This can be demonstrated by a struc-
`tural `mimetization sequence' with an assembly of
`structures synthesized at different laboratories as
`an example (see Scheme 1).
`
`As a first logical step, arginine and glycine of
`the fibrinogen -Arg-Gly-Asp- sequence are mod-
`ified, so that only the arginine guanidino group
`and the glycine carbonyl group remain, with a
`simple aliphatic chain as 'spacer'.
`The next step on the way to 'less peptidic'
`compounds is the change from guanidino-alkyl to
`amidino-phenyl, which introduces a rigidizing
`element into the molecule and considerably en-
`hances the binding strength. Then the aspartate
`residue is replaced with an unnatural 13-amino
`acid residue. This leads to oral activity, which can
`be enhanced by further rigidization and introduc-
`tion of an acetylenic 13-amino acid, as shown in
`Scheme 1.
`We want to report here the design, synthesis
`and biological activity of a new system with a
`rigidizing central oxazolidinonemethyl building
`block. This cardiovascularly active system is for-
`mally generated by a simple exchange of func-
`tional groups from a proven CNS-active (neuro-
`leptic) Merck substance [5] (Scheme 2). Theoreti-
`cal and computer modelling considerations, dis-
`closing suitable conformational parameters of this
`building block, had encouraged us in this effort.
`
`136 R -- G D NH O 0 HN f..COOH O . COOH H2 N" ~ H~ Scheme 1, Mimetization sequence from peptide to nonpeptide. receptor antagonists, the binding RGD sequence of the fibrinogen is taken as a motif for low-mol- ecular-weight inhibitors that should bind more strongly to the receptor in order to prevent fi- brinogen itself from binding 3, thus inhibiting platelet aggregation. The inhibitors should also be specific for this integrin and, if possible, orally active for chronic treatment. Therefore, in the development of such compounds, there is a trend from fibrinogen-derived peptides via 'semi-mime- tics' to low-molecular-weight 'complete' nonpep- tides 1,4. This can be demonstrated by a struc- tural 'mimetization sequence' with an assembly of structures synthesized at different laboratories as an example (see Scheme 1). As a first logical step, arginine and glycine of the fibrinogen -Arg-Gly-Asp- sequence are mod- ified, so that only the arginine guanidino group and the glycine carbonyl group remain, with a simple aliphatic chain as 'spacer'. The next step on the way to 'less peptidic' compounds is the change from guanidino-alkyl to amidino-phenyl, which introduces a rigidizing element into the molecule and considerably en- hances the binding strength. Then the aspartate residue is replaced with an unnatural I-amino acid residue. This leads to oral activity, which can be enhanced by further rigidization and introduc- tion of an acetylenic 3-amino acid, as shown in Scheme 1. We want to report here the design, synthesis and biological activity of a new system with a rigidizing central oxazolidinonemethyl building block. This cardiovascularly active system is for- mally generated by a simple exchange of func- tional groups from a proven CNS-active (neuro- leptic) Merck substance 5 (Scheme 2). Theoreti- cal and computer modelling considerations, dis- closing suitable conformational parameters of this building block, had encouraged us in this effort. CH O 3 ~ ".,11 / central II nervous o system l ...... ~ N/'~ COOH '% O ... cardio- vascular system Scheme 2. From the central nervous system to the cardio- vascular system by functional group exchange.
`
`CH,0
`
`central
`nervous
`system
`
`cardio-
`vascular
`system
`
`Scheme 2. From the central nervous system to the cardio-
`vascular system by functional group exchange.
`
`

`
`TABLE 1
`STRUCTURE—ACTIVITY RELATIONSHIPS FOR A SERIES OF SUBSTITUTED PIPERIDINES
`
`137
`
`Piperidine
`
`NH
`
`H,N
`
`N`s 0
`
`COOH
`
`I-12N
`
`NH
`
`H21,1
`
`H2N
`
`NH
`
`HzN
`
`COOH
`
`COON
`
`/-( N
`N 0
`
`O
`
`(S)
`
`r-rNaCOOH
`COOH
`0 (cid:9)
`
`XOI
`
`(Disodium salt)
`
`TABLE 1 STRUCTURE-ACTIVITY RELATIONSHIPS FOR A SERIES OF SUBSTITUTED PIPERIDINES 137 Piperidine IC5o (gM) Fibrinogen binding test Collagen-induced platelet aggregation (PAT) NH O NH H.N Ny f'o NO 'coo" o NH /~,~-.,.@N O~COOH .2N "yo ,=, o .2.- ' _-R=7-=y ° o ~ ~/- y o (Disodium salt) 0.0076 0.122 0.168 0.036 4.21 0.5 5.0 0.5 >10 >10 The substitution on this piperidine building block proved to be variable over a wide range, giving highly active compounds. In Table 1 the structure-activity relationships of a series of sub- stituted piperidines are listed. As can be seen, the binding strength is diminished with elongation of the chain, whereas a hydroxy group, but not an additional carboxy group, enhances the biological activity. On average, the antiaggregatory activity (PAT) of these molecules is moderate. Exchanging piperidine by piperazine substitu- ents gives another group of compounds with high biological activity (see Table 2). As can be seen, the optimum of the binding strength and anti- platelet aggregatory activity is found with the propionic acid, whereas further chain elongation gives a less active product. An interesting feature is the fact that in the acetic acid series the (R)- stereoisomer is the most active compound, where- as in the propionic acid series it is the (S)-isomer. The synthesis of the new system is demonstrated with the example of a piperazine compound (see Scheme 3). Glycidol is reacted with 4-aminoben- zonitrile to give the diol. This reacts with diethyl- carbonate with ring closure to give the hetero- cyclic alcohol. Mesylation and reaction with the piperazino carboxylic acid derivative affords the basic system from which the functional groups of the final product are generated by successive reaction with hydroxylamine and hydrogenation. Modification of the N-terminus to the corre- sponding aminomethyl and guanidinomethyl com- pounds by hydrogenation of the cyano group and successive guanylation of the amino groups led to compounds with decreased biological activity com- pared to the corresponding amidines (Table 3). We also prepared compounds with piperidine and guanyl-piperidine functionalities instead of amidinophenyl. Here a strong increase in activity in the transition from the piperidine to the corre-
`
`The substitution on this piperidine building
`block proved to be variable over a wide range,
`giving highly active compounds. In Table 1 the
`structure—activity relationships of a series of sub-
`stituted piperidines are listed. As can be seen, the
`binding strength is diminished with elongation of
`the chain, whereas a hydroxy group, but not an
`additional carboxy group, enhances the biological
`activity. On average, the antiaggregatory activity
`(PAT) of these molecules is moderate.
`Exchanging piperidine by piperazine substitu-
`ents gives another group of compounds with high
`biological activity (see Table 2). As can be seen,
`the optimum of the binding strength and anti-
`platelet aggregatory activity is found with the
`propionic acid, whereas further chain elongation
`gives a less active product. An interesting feature
`is the fact that in the acetic acid series the (R)-
`stereoisomer is the most active compound, where-
`as in the propionic acid series it is the (S)-isomer.
`
`ICS (uM)
`
`Fibrinogen binding test (cid:9)
`
`Collagen-induced platelet
`aggregation (PAT)
`
`0.0076
`
`0.122
`
`0.168
`
`0.036
`
`4.21
`
`0.5
`
`5.0
`
`0.5
`
`>10
`
`>10
`
`The synthesis of the new system is demonstrated
`with the example of a piperazine compound (see
`Scheme 3). Glycidol is reacted with 4-aminoben-
`zonitrile to give the diol. This reacts with diethyl-
`carbonate with ring closure to give the hetero-
`cyclic alcohol. Mesylation and reaction with the
`piperazino carboxylic acid derivative affords the
`basic system from which the functional groups of
`the final product are generated by successive
`reaction with hydroxylamine and hydrogenation.
`Modification of the N-terminus to the corre-
`sponding aminomethyl and guanidinomethyl com-
`pounds by hydrogenation of the cyano group and
`successive guanylation of the amino groups led to
`compounds with decreased biological activity com-
`pared to the corresponding amidines (Table 3).
`We also prepared compounds with piperidine
`and guanyl-piperidine functionalities instead of
`amidinophenyl. Here a strong increase in activity
`in the transition from the piperidine to the corre-
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`138
`
`TABLE 2
`STRUCTURE—ACTIVITY RELATIONSHIPS FOR A SERIES OF SUBSTITUTED PIPERAZINES
`
`IC50 (gm)
`Fibrinogen binding test
`
`Collagen-induced platelet
`aggregation (PAT)
`
`Piperazine
`
`NH
`
`H,N
`
`NH
`
`H,N
`
`NH
`
`H,N
`
`NH
`
`H N
`
`NH
`
`112N
`
`NH
`
`H,N
`
`*/".. N (cid:9)
`N
`0 (cid:9)
`\-/
`
`N (cid:9)
`
`COOH
`
`O
`
`IXoI
`
`N (cid:9)
`
`0 (cid:9)
`
`\-/
`
`Ny
`
`O
`
`O
`
`COOH
`COOH
`
`\
`N
`
`0
`
`N
`
`N (cid:9)
`
`0
`
`O
`
`/-4
`r-rN
`N (cid:9)
`0
`
`O
`
`COOH
`
`138 TABLE 2 STRUCTURE ACTIVITY RELATIONSHIPS FOR A SERIES OF SUBSTITUTED PIPERAZINES Piperazine IC5o (~tM) Fibrinogen binding test Collagen-induced platelet aggregation (PAT) NH ./~. /~k /~. 0.124 (RS) ~Ntt~O N N COOH H2N ~ 0.044 (R) 0.248 (S) O NH */'~/~COOH ~J~ ~ Ntf~o N N 0.0042 (RS) H~N" ~ y 0.008 (R) o 0.0009 (S) NH /~.~A A II ~N N" v -COOH H2N NyO O 1.18 COOH NH A N/~N .,,~ COOH H2N ~ .~ 0.0077 O O H~N..-~ s,T],, o ~ 0.05 0 0 NH /~ /~ @COOH O 0.1 0.1 0.5 0.05 0.5 0.1 0.05 0.05 0.05 0.05 sponding guanidine was observed (Table 3). The starting materials are 1-benzyl-4-aminopiperidine and glycidol in a reaction sequence analogous to the synthesis of the amidinophenyl derivatives. The guanylation was performed with N-guanyl- pyrrazole [6]. That the heterocyclic mesylate is a versatile intermediate in the synthesis of potent GP IIb/ IIIa antagonists could be shown by reaction with other nucleophiles, for instance with the sodium salts of the o-, m- and p-substituted hydroxyphen- yl acetic acid esters to give (performing the usual reactions) the corresponding amidino carboxylic acids. The biological activities of these com- pounds are shown in Table 4. Interestingly, the para and ortho derivatives show high receptor affinities, while the meta compound is nearly inactive. The PAT value for the o-acetic acid is significantly higher than for the other two. Most of the amidino compounds are orally active (in guinea pig) in the low mg/kg range. The most active compounds in this respect belong to the piperidine and piperazine series. DISCUSSION AND CONCLUSIONS The structure-activity relationships within the new system are as follows. In the piperidine series, the strongest receptor inhibition is shown by the 4- piperidine carboxylic acid derivative. With the pi- perazines, a slight enhancement of activity can be achieved. In this series the 4-piperazine propionic
`
`sponding guanidine was observed (Table 3). The
`starting materials are 1-benzy1-4-aminopiperidine
`and glycidol in a reaction sequence analogous to
`the synthesis of the amidinophenyl derivatives.
`The guanylation was performed with N-guanyl-
`pyrrazole [6].
`That the heterocyclic mesylate is a versatile
`intermediate in the synthesis of potent GP IIb/
`Ma antagonists could be shown by reaction with
`other nucleophiles, for instance with the sodium
`salts of the o-, m- and p-substituted hydroxyphen-
`yl acetic acid esters to give (performing the usual
`reactions) the corresponding amidino carboxylic
`acids. The biological activities of these com-
`pounds are shown in Table 4. Interestingly, the
`para and ortho derivatives show high receptor
`
`0.124 (RS)
`0.044 (R)
`0.248 (S)
`
`0.0042 (RS)
`0.008 (cid:9)
`(R)
`0.0009 (S)
`
`1.18
`
`0.0077
`
`0.05
`
`0.0022
`
`0.1
`0.1
`0.5
`
`0.05
`0.5
`0.1
`
`0.05
`
`0.05
`
`0.05
`
`0.05
`
`affinities, while the meta compound is nearly
`inactive. The PAT value for the o-acetic acid is
`significantly higher than for the other two.
`Most of the amidino compounds are orally
`active (in guinea pig) in the low mg/kg range. The
`most active compounds in this respect belong to
`the piperidine and piperazine series.
`
`DISCUSSION AND CONCLUSIONS
`
`The structure—activity relationships within the
`new system are as follows. In the piperidine series,
`the strongest receptor inhibition is shown by the 4-
`piperidine carboxylic acid derivative. With the pi-
`perazines, a slight enhancement of activity can be
`achieved. In this series the 4-piperazine propionic
`
`

`
`139
`
`Collagen-induced platelet
`aggregation (PAT)
`
`1.0
`
`10.0
`
`0.5
`
`1.0
`
`0.5
`
`0.5
`
`TABLE 3
`STRUCTURE—ACTIVITY RELATIONSHIPS FOR COMPOUNDS WITH A MODIFIED N-TERMINUS
`Ic„ (vm)
`Fibrinogen binding test (cid:9)
`
`139 TABLE 3 STRUCTURE-ACTIVITY RELATIONSHIPS FOR COMPOUNDS WITH A MODIFIED N-TERMINUS Variation of the N-terminus IC5o (I-tM) Fibrinogen binding test Collagen-induced platelet aggregation (PAT) ~/- y 0 0 COOH ~" ~---~ N ~0 N__/N H2N" "~y O C~ NH ~J'-,. N/~N ~'-,.,/- COOH 0 r~N/~N ~(]OOH )--Ny' 'o 0 NH , AN~ ~COOH 0 0.151 1.0 0.062 10.0 1.0 0.5 1.37 1.0 3.65 0.5 0.18 0.5 TABLE 4 STRUCTURE-ACTIVITY RELATIONSHIPS FOR VARIOUS PHENYLACETIC ACIDS Phenylacetic acid ICs0 (gM) Fibrinogen binding test Collagen-induced platelet aggregation (PAT) NH 0 COOH 0 ,.,- -%5~,yO ~,~ooo. o 0.044 183 0.034 10.0 >10 1.0
`
`Variation of the N-terminus
`
`H2N
`
`NH
`
`O
`
`,
`
`Nr—c N (cid:9)
`
`COON
`
`COON
`
`O
`
`COON
`
`H,N
`
`NI0
`
`COON
`
`H,N;
`
`HN
`
`NH (cid:9)
`
`O
`
`cZNN/—"" N
`
`N 0 \
`
`0
`
`Ny 0 (cid:9)
`
`O
`
`COON
`
`0.151 (cid:9)
`
`0.062 (cid:9)
`
`1.0 (cid:9)
`
`1.37 (cid:9)
`
`3.65 (cid:9)
`
`0.18 (cid:9)
`
`TABLE 4
`STRUCTURE—ACTIVITY RELATIONSHIPS FOR VARIOUS PHENYLACETIC ACIDS
`
`Phenylacetic acid
`
`IC„ (u.M)
`
`Fibrinogen binding test (cid:9)
`
`Collagen-induced platelet
`aggregation (PAT)
`
`H21,1
`
`HzN
`
`COOH
`
`0.044 (cid:9)
`
`COON
`
`183 (cid:9)
`
`0.034 (cid:9)
`
`10.0
`
`>10
`
`1.0
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`140
`
`LrOH (cid:9)
`
`
`0
`
`NH,
`
`NC
`
`a)
`
`b)
`
`OH
`
`OH
`
`NC
`
`CO(0E42/K-tBu
`
`Mes-CI
`
`c)
`
`NC
`
`OMes
`
`0
`
`d)
`•
`
`HN N CO,Bz/K,CO/KI
`
`NC
`
`N
` N CO2Bz
`\
`
`O
`
`e) I H2NOH
`
`NOH
`
`H2N
`
`--\
`N CO2Bz
`\---/
`
`140 "0 OH NC-~ NH2 a) h) CO(OEt)2/K-tBu No '_-L=2-Nyo 0 Mes-CI c) OH /~ OMes , 0 7--k~ d) 2Bz/%CO#m ~ ~-~ N N i C02Bz 0 e) ~ H2NOH NOH - II ,----, /---'~ N N ~'~C02Bz 0 f) ~ H2/Pd-C 5 % NH - /---k II ~-~ /~N N~COOH H2N~NyO 0 Scheme 3. Synthesis of the new system. (a) 2:1, MeOH, 20 h refl. 50-60%; (b) 1:6:0.05, 2 h at 100 °C, 70-80%; (c) 1:1, pyridine, 10 h at 5-20 °C, 90%; (d) 1:1:1:1, acetonitril, 10 h refl., 70%; (e) 1: 3, i-propanol, 3 h refl., 75-80%; and (f) glacial acetic acid/acetic anhydride, 85-90%. acid derivative is the most active compound. Com- paring both systems, the same tendency is seen in the platelet aggregation test (PAT). The phenyl acetic acids are slightly less active in the two tests than both the piperidines and piperazines. Vari- ation of the N-terminus does not improve the biological activities. Good oral activity in guinea pig is found in the piperidine and piperazine series. REFERENCES 1 a. Ojima, 3., Chakravarty, S. and Dong, Q., Bioorg. Med. Chem., 3 (1995) 337. b. Zablocky, J.A., Nicholson, N.S. and Feigen, L.E, Exp. Opin. Invest. Drugs, 3 (1994) 437. c. Weller, T., Alig, L., Hiirzeler-Mfiller, M., Kouns, W.C. and Steiner, B., Drugs Future, 19 (1994) 461. 2 Scharf, R.E. and Harker, L.A., Blut, 55 (1987) 131. 3 Plow, E.E, d'Souza, S.E. and Ginberg, M.H., Semin. Thromb. Hemost., 18 (1992) 324. 4 Gante, J., Angew. Chem., Int. Ed. Engl., 33 (1994) 1699. 5 Priicher, H., Gottschlich, R., Haase, A., Stohrer, M. and Seyfried, C., Bioorg. Med. Chem. Lett., 2 (1992) 165. 6 Bernatowics, M.S., Wu, Y. and Matsueda, G.R., J. Org. Chem., 57 (1992) 2497.
`
`acid derivative is the most active compound. Com-
`paring both systems, the same tendency is seen in
`the platelet aggregation test (PAT). The phenyl
`acetic acids are slightly less active in the two tests
`than both the piperidines and piperazines. Vari-
`ation of the N-terminus does not improve the
`biological activities. Good oral activity in guinea
`pig is found in the piperidine and piperazine series.
`
`I
`
`0
`
`f) I H2/Pd-C 5 %
`
`Scheme 3. Synthesis of the new system. (a) 2:1, Me0H, 20 h refl. 50-60%; (b) 1: 6 : 0.05, 2 hat 100 °C, 70-80%; (c) 1:1, pyridine,
`10 hat 5-20 °C, 90%; (d) 1:1:1:1, acetonitril, 10 h refl., 70%; (e) 1: 3, i-propanol, 3 h refl., 75-80%; and (1) glacial acetic acid/acetic
`anhydride, 85-90%.
`
`Chem., 3 (1995) 337.
`b. Zablocky, J.A., Nicholson, N.S. and Feigen, L.P., Exp.
`Opin. Invest. Drugs, 3 (1994) 437.
`c. Weller, T., Alig, L., Htirzeler-Mtiller, M., Kouns, W.C.
`and Steiner, B., Drugs Future, 19 (1994) 461.
`2 Scharf, R.E. and Harker, L.A., Blut, 55 (1987) 131.
`3 Plow, E.F., d'Souza, S.E. and Ginberg, M.H., Semin.
`Thromb. Hemost., 18 (1992) 324.
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