环氧合酶-2抑制剂的设计，合成与活性评估
摘要
环氧合酶—2(COX-2)的发现为寻找低毒副作用的非甾体抗炎药提供了新的靶酶，由于这类药物有很大的临床需求，因而COX-2选择性抑制剂成为研究的重点。
本论文在总结前人工作的基础上，根据已有的构效关系，设计合成了以下五类化合物：
1．利用酰胺键中存在p-π共轭且具有部分双键的特性，以及N-烷基氢与苯环氢的位阻效应，用酰胺键连接两个芳环呈顺式构象的苯甲酰苯胺类化合物(Ⅰ)。
2．为了提高化合物的疏水性以及考虑到苯并咪唑衍生物有抗炎作用，合成N-苯甲酰苯并眯唑类化合物(Ⅱ)。
3．建立了新的合成1，2—二取代苯基苯并咪唑化合物(Ⅲ)方法，该方法与现有文献报道的方法相比，反应温和，操作简单，收率较高。
4．2，3—二取代苯基吲哚类化合物(Ⅳ)，它们是Ⅲ类的(N，CH)电子等排体。
5．α，β-不饱和γ内酰胺化合物(Ⅴ)。
根据论文研究的需要还合成了阳性对照样品MK—966等化合物。
本论文在合成以上五种结构类型(甲磺酰基或氨磺酰基取代的N-甲基-N-芳基-芳甲酰胺；2-烷基-N-芳甲酰基苯并咪唑；1，2-二芳基-苯并咪唑；2，3-二芳基吲哚；N-烷基-3，4-二芳基-1，5-二氢吡咯-2-酮)的过程中共合成150个化合物，目标化合物73个，其中新化合物68个，全部化合物经过NMR和MS鉴定。对其中两个具有代表性的化合物进行了X—线单晶结构测定，比较了晶体结构的特征。
综合核磁共振氢谱，紫外光谱和单晶X—光衍射分析结果，证明N-甲基-N-芳基-苯甲酰胺的二个芳基在溶液状态和在晶体状态下是“顺式”构象，并与1-(4-甲磺酰基)-2-(4-甲基苯基)-苯并咪唑的晶体结构进行了比较。
实验结果表明，Ⅰ、Ⅱ类化合物未见活性；Ⅲ、Ⅳ、Ⅴ类化合物呈现程度不同的活性(IC_(50)：10~(-6)-10~(-11)M)，并且每一类都有高活性的化合物，表明中间环可以允许较大程度的变换，而环的特征和取代基变换对活性影响较大。在活性化合物中，选出对COX—2活性较高的5个化合物(IC50＜10~(-9) M)评价对COX—1的抑制活性，它们在10~(-5)M浓度下，有微弱活性。表明这些化合物对于COX—2有较高的选择性抑制作用。
构效关系研究表明，在苯并咪唑和吲哚类中含有磺酰基苯环的位置对于活性有相似的影响，苯基连在苯并咪唑的2-位有较好的影响，连在1-位较差；连在吲哚的2-位有利；3-位不利。这反映了杂环并合的苯基与SO_2之间距离对活性的影响，距离过近对抑制作用有不利趋势，可能是位阻影响所致。此外，氨磺酰基的抑制活性比相应的甲磺酰基抑制剂要高。
在具有COX—2活性和选择性(IC_(50)：10~(-6)-10~(-11)M)三种结构类型的化合物中化合物No51、56、57、60、61、62、63、67活性很高(IC_(50)10~(-9)-10~(-11)M)，有深入研究的价值。
The discovery of cyclooxygenase-2 (COX-2 ) provides a novel target for developing more effective NSAIDs with fewer side effects. On the basis of results of the structure-activity relationships (SAR) of selective COX-2 inhibitors, five groups of compounds with different structure scaffolds were synthesized as follow:1 Taking advantage of amids linkage , which possesses partial double bond owing to p-πconjugation , and the steric hindrance between hydrogen atoms on N-alkyl group and phenyl ring , which makes the two aromatic rings Z conformation , substituted benzoic anilides (I) were designed and synthesized.2 N-Benzoyl benzimidazoles (II) with elevating hydrophobic property were prepared for the potentially anti-inflammatory activity .3 1,2-Disubstituted phenyl benzimidazoles (III) were prepared by a new synthetic route which is characterized by the smooth reaction condition , easy operation and good yield , compared to the methods described in literatures.4 2,3-Disubstitued phenylindolies (IV) , the bioisosters of III (N,CH) were synthesized.5α,β-unsaturated-γ-lactam derivatives (V) were produced.In the synthesis of the above five series of compounds 150 chemical substances were prepared , in which 73 compounds are the target molecules, and 68 compounds are novel. All the compounds were identified by the methods of NMR and MS. X-ray crystal graph of two typical molecules were studied. The features of their crystalline structures were investigated.The Z-conformation of N-methyl-N-phenyl benzanilide both in liquid and in crystalline states was documented by integrating the spectra of NMR ,UV and X-ray crystallography , which was compared with that of l-(4-bromophenyl)-2-(4-methanesulfonylphenyl)-benzimidazole.The biological experiments showed that compounds of groups I and II are devoid of inhibitory activity for COX-2 ; compounds of III, IV, and V exhibit inhibition to a different extent (IC50 10~(-6) --10~(-11) M) .Compounds with high activity are included in each of the three groups. The results suggested that the central ring linkages are able to tolerate a wide alteration in structures while maintaining the activity. Meantime, the character of the central ring linkage and the substituent conveys an effect on the inhibition. Five compounds were selected from the active molecules to be t the evaluated for COX-1 activity. they showed weak activity at the concentration of 10~(-5)M, Indicating that the compounds have high selectivity for COX-2.
Study on SAR indicated that the location of sulfonylphenyl group on the benzimidazole or indole skeleton gave a similar tendency to affect the activity. The activity of 2—sulfonylphenylibenzzimidazole is higher than that of 1-position; 2- sulfonylphenylindole is advantageous over the corresponding 3-substitution. This presumable suggested that the distance between phenyl ring fusing heterocycle and sulfonyl group is of importance, a shorter distance may not be beneficial, owing to a steric hindrance.
SAR also showed that the inhibitory activity of the aminosulfonyl series is more potent than that of the methylsulfonyl ones.
Compounds No 51、56、57、60、61、62、63 and 67 with high activity and selectivity for COX-2 in the three groups (IC_(50) 10~(-9)—10~(-11)M) are worthy to be further investigated.
本论文在总结前人工作的基础上，根据已有的构效关系，设计合成了以下五类化合物：
1．利用酰胺键中存在p-π共轭且具有部分双键的特性，以及N-烷基氢与苯环氢的位阻效应，用酰胺键连接两个芳环呈顺式构象的苯甲酰苯胺类化合物(Ⅰ)。
2．为了提高化合物的疏水性以及考虑到苯并咪唑衍生物有抗炎作用，合成N-苯甲酰苯并眯唑类化合物(Ⅱ)。
3．建立了新的合成1，2—二取代苯基苯并咪唑化合物(Ⅲ)方法，该方法与现有文献报道的方法相比，反应温和，操作简单，收率较高。
4．2，3—二取代苯基吲哚类化合物(Ⅳ)，它们是Ⅲ类的(N，CH)电子等排体。
5．α，β-不饱和γ内酰胺化合物(Ⅴ)。
根据论文研究的需要还合成了阳性对照样品MK—966等化合物。
本论文在合成以上五种结构类型(甲磺酰基或氨磺酰基取代的N-甲基-N-芳基-芳甲酰胺；2-烷基-N-芳甲酰基苯并咪唑；1，2-二芳基-苯并咪唑；2，3-二芳基吲哚；N-烷基-3，4-二芳基-1，5-二氢吡咯-2-酮)的过程中共合成150个化合物，目标化合物73个，其中新化合物68个，全部化合物经过NMR和MS鉴定。对其中两个具有代表性的化合物进行了X—线单晶结构测定，比较了晶体结构的特征。
综合核磁共振氢谱，紫外光谱和单晶X—光衍射分析结果，证明N-甲基-N-芳基-苯甲酰胺的二个芳基在溶液状态和在晶体状态下是“顺式”构象，并与1-(4-甲磺酰基)-2-(4-甲基苯基)-苯并咪唑的晶体结构进行了比较。
实验结果表明，Ⅰ、Ⅱ类化合物未见活性；Ⅲ、Ⅳ、Ⅴ类化合物呈现程度不同的活性(IC_(50)：10~(-6)-10~(-11)M)，并且每一类都有高活性的化合物，表明中间环可以允许较大程度的变换，而环的特征和取代基变换对活性影响较大。在活性化合物中，选出对COX—2活性较高的5个化合物(IC50＜10~(-9) M)评价对COX—1的抑制活性，它们在10~(-5)M浓度下，有微弱活性。表明这些化合物对于COX—2有较高的选择性抑制作用。
构效关系研究表明，在苯并咪唑和吲哚类中含有磺酰基苯环的位置对于活性有相似的影响，苯基连在苯并咪唑的2-位有较好的影响，连在1-位较差；连在吲哚的2-位有利；3-位不利。这反映了杂环并合的苯基与SO_2之间距离对活性的影响，距离过近对抑制作用有不利趋势，可能是位阻影响所致。此外，氨磺酰基的抑制活性比相应的甲磺酰基抑制剂要高。
在具有COX—2活性和选择性(IC_(50)：10~(-6)-10~(-11)M)三种结构类型的化合物中化合物No51、56、57、60、61、62、63、67活性很高(IC_(50)10~(-9)-10~(-11)M)，有深入研究的价值。
The discovery of cyclooxygenase-2 (COX-2 ) provides a novel target for developing more effective NSAIDs with fewer side effects. On the basis of results of the structure-activity relationships (SAR) of selective COX-2 inhibitors, five groups of compounds with different structure scaffolds were synthesized as follow:1 Taking advantage of amids linkage , which possesses partial double bond owing to p-πconjugation , and the steric hindrance between hydrogen atoms on N-alkyl group and phenyl ring , which makes the two aromatic rings Z conformation , substituted benzoic anilides (I) were designed and synthesized.2 N-Benzoyl benzimidazoles (II) with elevating hydrophobic property were prepared for the potentially anti-inflammatory activity .3 1,2-Disubstituted phenyl benzimidazoles (III) were prepared by a new synthetic route which is characterized by the smooth reaction condition , easy operation and good yield , compared to the methods described in literatures.4 2,3-Disubstitued phenylindolies (IV) , the bioisosters of III (N,CH) were synthesized.5α,β-unsaturated-γ-lactam derivatives (V) were produced.In the synthesis of the above five series of compounds 150 chemical substances were prepared , in which 73 compounds are the target molecules, and 68 compounds are novel. All the compounds were identified by the methods of NMR and MS. X-ray crystal graph of two typical molecules were studied. The features of their crystalline structures were investigated.The Z-conformation of N-methyl-N-phenyl benzanilide both in liquid and in crystalline states was documented by integrating the spectra of NMR ,UV and X-ray crystallography , which was compared with that of l-(4-bromophenyl)-2-(4-methanesulfonylphenyl)-benzimidazole.The biological experiments showed that compounds of groups I and II are devoid of inhibitory activity for COX-2 ; compounds of III, IV, and V exhibit inhibition to a different extent (IC50 10~(-6) --10~(-11) M) .Compounds with high activity are included in each of the three groups. The results suggested that the central ring linkages are able to tolerate a wide alteration in structures while maintaining the activity. Meantime, the character of the central ring linkage and the substituent conveys an effect on the inhibition. Five compounds were selected from the active molecules to be t the evaluated for COX-1 activity. they showed weak activity at the concentration of 10~(-5)M, Indicating that the compounds have high selectivity for COX-2.
Study on SAR indicated that the location of sulfonylphenyl group on the benzimidazole or indole skeleton gave a similar tendency to affect the activity. The activity of 2—sulfonylphenylibenzzimidazole is higher than that of 1-position; 2- sulfonylphenylindole is advantageous over the corresponding 3-substitution. This presumable suggested that the distance between phenyl ring fusing heterocycle and sulfonyl group is of importance, a shorter distance may not be beneficial, owing to a steric hindrance.
SAR also showed that the inhibitory activity of the aminosulfonyl series is more potent than that of the methylsulfonyl ones.
Compounds No 51、56、57、60、61、62、63 and 67 with high activity and selectivity for COX-2 in the three groups (IC_(50) 10~(-9)—10~(-11)M) are worthy to be further investigated.
引文
(1) J.R. Vane, Nature, 1971, 321, 232-235.
(2) a. D. A. Kujubu;B.S. Fletcher;B. C. Varnum;et al J. Biol. Chem. 1991,266, 12866-12872. b. W. Xie;J.G. Chipman;D.L. Robertson;et al Proc. Natl. icad. Sci. USA, 1991,88, 2692-2696 c.M.K.O' Banion;H.B. Sadowski;V. Winn; et al J. Biol. Chem. 1991,266, 23261-23267 d.D.L. DeWitt;W.L. Smith, Proc. Natl. Acad. Sci. USi, 1988,85,1412-1416.
(3) a.M.lecomite;O. Laneuville;C.,Ji;et al, J. Biol. Chem. 1994,269(18), 13207-13215
b. D. Bhattacharyya;R. M. Garavito;W. L. Smith 1996,271 (4),2179-2184
(4) a. D. Picot;P. J. Loll; R. M. Garavito, Nature 1994, 367 (20), 243.
b. D. Picot; P. J. Loll; R. M. Garavito, Nature Struct. Biol. 1996, 3(11), 897-901.
c. P. J. Loll, D. Picot, R. M. Garavito, Biochem. 1996, 35 (23), 7330-7340.
e. R. G. Kurumbail, T. D. Penning, J. M. Miyashiro, Nature 1996, 384(19/26), 644-648.
(5). P. M. Engelhart : Fundamental Clinical harmacology . 1996,10(1)1-15
(6) a. Special Issue, Med. Chem. Res. 1995, 5.
b. D. E. Griswold, J. L. Adams, Med. Res. Rev. 1996, 16 (2), 181-206.
c. Ann. Rep. in Med. Chem., 1995, 36 (chapt. 19), 179.
(7) a. K. R. Gans, W. Galbraaith, R. T. Romam, et al, J. Pharmacol. Exp. Ther. 1990, 254, 180- 187
b. N. Futaki, K. Yoshikawa, I. Arai, et al, Gen. Pharmac. 1993, 24, 105-110.
c. CA125(3):P33646t WO9603388.
(8) a. J. K. Gierse, S. D. Hauser, K. Seibeit, Biochem. J. 1995, 305, 479-484.
b. N. Futaki, I. Arai, S. Otomo, Prostaglandins. 1994, 42, 55-59
c. CA:128(12)P140614q.WO9803484
(9) a. W. W. Wilkerson, W. Galbraith, M. Grubb, et al, J. Med. Chem, 1994, 37, 988-998.
b. W. W. Wilkerson, R. A. Copeland, M. Covington, et al, J. Med. Chem, 1995,38, 3895-3901.
c. I. K. Khanna, R. M. Weiser, P. C. Isakson, et al, J. Med. Chem, 1997, 40, 1619-1633.
(10) a. D.B. Reitz,J.J. Li, K. Seibert,et al, J. Med. Chem, 1994, 37, 3878-3881.
b. D. B. Reitz, J. J. Li, M. B. Norton, et al, Med. Chem. Res, 1995, 5, 351-363.
c. J. J. Li, G. D. Anderson, D. B. Reitz, et al, J. Med. Chem, 1995, 38, 4570-4578.
d. Indian. J. Chem. Sect. B, 1997, 36B (12), 1164-1168
e. D. B. David, H-C. Huang, J. J. Li, Bioorg. Med. Chem. Lett. 1995, 5 (8), 867- 872.
(11) H. C. Huang, J. J. Li, D. B. Reitz, J. Med. Chem. 1996, 39, 253-266.
(12) J. J. Li,M. B.Norton, D.B. Reitz, et al, J. Med. Chem. 1996, 39, 1846-1856.
(13) a. Y. Leblanc, J. Y. Gauthier, D. Ethier, Bioorg. Med. cChem. Lett. 1995, 5(18),2123-2128
b. CA: 126 (14): 152396s. Bioorg. Med. Chem. Lett. 1996, 6 (24), 2907-2912.
(14) a. T. D. Penning, J. J. Talley, P. C. Isakson, et al, J. Med. Chem. 1997, 40,1347-1365.
b. K. Seibert, Y. Zhang, P. C. Isakson, Proc. Naatl. Acad. Sci. USA. 1994, 91,12013-12017.
c. J. D. Penning, K. Seibert, P. C. Isakson, Bioorg. Med. Chem. Lett. , 1997, 7 (16),2121-2124
d.CA:123(25):p340112h, WO9515316
e. CA:123(25):p313952a, WO0915318.
(15) a. I.K. Khanna,R.M.Weier.P.C.Isakson, et al J. Med. Chem. 1997,40,1634-1647.
b. T. E. Barta, M. A. Stealey, R. M. Weier, Bioorg, Med. Chem. Lett. 1998, 8, 3443-3448.
c. CA:127(14):pl90737g, WO9727181.
(16) a. R..M. Weier, L.F. Lee, R.A. Partis, et al,WO9624584
b. L. F. WO9624585.
c. R. W. Friesen, C. Brideau, C. C. Chan, et al, Bioorg. Med. Chem. Lett. 1998,2777-2782
d. CA:125(19):p247624h, WO9624584.
(17)a. M. Therien, C. Brideau, C. C. Chan, et al, Bioorg. Med. Chem. Lett. 1997, 7(1),47-52.
b. L.A. Trimble, N. Leblanc, R. G. Ball, et al, ibid, 1997, 7(1), 53-56.
c. P. Roy, Y. Leblanc,R.G. Ball, 1997, 7(1), 57-62.
d. CA:125(15):pl95659b, WO9621667.
(18)a.CA:125(7):p86474s, WO9608482
b. CA:125(3):p33628p, WO9603392.
c. CA:125(9):p114604e, WO9609293
d.CA:125(9):p114294d, WO9613483.
e. CA:125(13):p167967g, WO9619462.
f. CA:125(13):pl67971d, WO9619463.
g. CA:126(1):p8117j, WO963150.
h. CA:126(7) :p89250X, WO9636623.
i. CA:125(19):p247800n, WO9625405.
j. CA:125(11):p142530w,WO9619469
k. CA:126(14):p142539w,WO9619469.
l. CA:126(8):p104081p, WO9638442
m. CA:126(8)p104079u, WO9638418.
n. CA:127(3)p34112u, WO9716435;CA:127(15)p205356h, WO9728120;CA:127(16):p220465m, WO9728121.
o. CA:127(5):p65756m, US5633272.
p. CA:127 (22):p307375f, WO9734882.
q. CA:127(24):p331281t,WO9736863.
r. CA:128(16):pl92645v,US5719163.
s. CA:125(3):p300608j, WO9626921.
(19)a. C. Rufer, F. Bahnlmann, E. Schroder, et al, Eur. J. Med. Chem. 1982, 17, 173-189.
b. A. Schweizer, J. A. Green, K. Miller,, et al,Agents Action.
c. T.Klein, R.M. Musing, V.Ullrich, et al, Biochem. Pharmacol. 1994, 48,1605-1610.
(20) a. C. S. Li, C. C. Chan, P. Praist, et al, J. Med. Chem. 1995, 38, 4897-4905.
b. P. Brain, Pet-piboon, J.Philip, et al, W09413635.
c. CA:125(15):p195438d,CA2164559.
(21)a.CA:125(17):p221839g,WO9623786.
b.CA:125(11):p132769s,JP08157361.
c. CA:126(15):p199339r,W09703953.
(22) a. W. C. Black, C. C. Chan, P. Praist, et al, Bioorg. Med. Chem. Lett. 1996, 6 (6),725-730
b. ibid, 1996, 6(6), 731-736.
c. ibid, 1996, 6(6), 737-742.
d. CA:123(25) :p227989, GB228374s.
e. CA: 126(7) :p89260a, W09637469.
f.CA:126(7):p89261b, W09637467.
g. CA:127(13):pl76343u,W09730030.
(23)a. E. S. Laser, C. K. Miao, G. Trummlitz, et al, J. Med. Chem., 1997, 40, 980-989.
b. E. S. Laser, R. Sorcek, C. L. Cywin, et al, Bioorg. Med/Chem. 1998, 8, 1181-1186.
c. CA:125(11):pl42754x, US5527796.
(24) a. A. S. Kalgutka, C. Garner, K. Seibert, et al, Science, 1998, 28 (22), 1268-1270.
b. D. K. Bhattacharyya, M. Lecomte, J. Dunn, et al Arch. Biochem. Biophys. 1995,317, 19.
c. A. S. Kalgutkar, K. R. Kozak, L. J. Marnett, et al, Med. Chem. 1998, 41 (24),4800-4818
(25) a. J. M. Janusz, P. A. Young, M. W. Scherz, J. Med. Chem. 1998, 41 (7), 1112-1123.
b. J. M. Janusz, P. A. Young, M. W. Scherz, J. Med. Chem. 1998, 41 (7), 1124-1137.
(26) a. C. I. Bayly, W. C. Black, S. Leger, et al, Bioorg. Med. Chem. Lett. 1999, 9, 307-312.
(27) K D. Stewart, S. Loren, L. Frey, et al, Bioorg. Med. Chem. Lett. 1998, 8,529-534.
(28) CA:127(1):pl3453r, JP9777664.
(29)a. CA:128(7):p75294, W0976524.
b. CA:128(22):p270440r, W09815528.
c. CA:129(12):pl48830y, DE19803003.
d. CA: 129(12):pl48904a, US5783597
e. CA:129(6) :p67772d, EP846689.
f. CA:129(10):pl22569v,US5776967CA:129(2):p16046n, WO9821195 g. CA:129(2):pl6046n, W09821195
(30)a.D.Evans,TA Hicks,WRN Williamson, etal, Eur. J. Med. Chera. 1996,31,635-642.
b. J. B. Hendrickson, Md. S. Hussoin, J. Org. Chera. 1987, 52, 4137-4139.
c. A. Alberti, P. Carloni, L. Greci, etal, J. Chem. Soc. Perkin TransII, 1991, 7,1019.
(31). M. R. DeLuca, S. M. Kerwin,Tetrahedron, 1997, 53 (2), 457-464.
(32). P. Babu, TR Balasubramanian, Indian J. Chem. 1987, 26B, 63.
(2) a. D. A. Kujubu;B.S. Fletcher;B. C. Varnum;et al J. Biol. Chem. 1991,266, 12866-12872. b. W. Xie;J.G. Chipman;D.L. Robertson;et al Proc. Natl. icad. Sci. USA, 1991,88, 2692-2696 c.M.K.O' Banion;H.B. Sadowski;V. Winn; et al J. Biol. Chem. 1991,266, 23261-23267 d.D.L. DeWitt;W.L. Smith, Proc. Natl. Acad. Sci. USi, 1988,85,1412-1416.
(3) a.M.lecomite;O. Laneuville;C.,Ji;et al, J. Biol. Chem. 1994,269(18), 13207-13215
b. D. Bhattacharyya;R. M. Garavito;W. L. Smith 1996,271 (4),2179-2184
(4) a. D. Picot;P. J. Loll; R. M. Garavito, Nature 1994, 367 (20), 243.
b. D. Picot; P. J. Loll; R. M. Garavito, Nature Struct. Biol. 1996, 3(11), 897-901.
c. P. J. Loll, D. Picot, R. M. Garavito, Biochem. 1996, 35 (23), 7330-7340.
e. R. G. Kurumbail, T. D. Penning, J. M. Miyashiro, Nature 1996, 384(19/26), 644-648.
(5). P. M. Engelhart : Fundamental Clinical harmacology . 1996,10(1)1-15
(6) a. Special Issue, Med. Chem. Res. 1995, 5.
b. D. E. Griswold, J. L. Adams, Med. Res. Rev. 1996, 16 (2), 181-206.
c. Ann. Rep. in Med. Chem., 1995, 36 (chapt. 19), 179.
(7) a. K. R. Gans, W. Galbraaith, R. T. Romam, et al, J. Pharmacol. Exp. Ther. 1990, 254, 180- 187
b. N. Futaki, K. Yoshikawa, I. Arai, et al, Gen. Pharmac. 1993, 24, 105-110.
c. CA125(3):P33646t WO9603388.
(8) a. J. K. Gierse, S. D. Hauser, K. Seibeit, Biochem. J. 1995, 305, 479-484.
b. N. Futaki, I. Arai, S. Otomo, Prostaglandins. 1994, 42, 55-59
c. CA:128(12)P140614q.WO9803484
(9) a. W. W. Wilkerson, W. Galbraith, M. Grubb, et al, J. Med. Chem, 1994, 37, 988-998.
b. W. W. Wilkerson, R. A. Copeland, M. Covington, et al, J. Med. Chem, 1995,38, 3895-3901.
c. I. K. Khanna, R. M. Weiser, P. C. Isakson, et al, J. Med. Chem, 1997, 40, 1619-1633.
(10) a. D.B. Reitz,J.J. Li, K. Seibert,et al, J. Med. Chem, 1994, 37, 3878-3881.
b. D. B. Reitz, J. J. Li, M. B. Norton, et al, Med. Chem. Res, 1995, 5, 351-363.
c. J. J. Li, G. D. Anderson, D. B. Reitz, et al, J. Med. Chem, 1995, 38, 4570-4578.
d. Indian. J. Chem. Sect. B, 1997, 36B (12), 1164-1168
e. D. B. David, H-C. Huang, J. J. Li, Bioorg. Med. Chem. Lett. 1995, 5 (8), 867- 872.
(11) H. C. Huang, J. J. Li, D. B. Reitz, J. Med. Chem. 1996, 39, 253-266.
(12) J. J. Li,M. B.Norton, D.B. Reitz, et al, J. Med. Chem. 1996, 39, 1846-1856.
(13) a. Y. Leblanc, J. Y. Gauthier, D. Ethier, Bioorg. Med. cChem. Lett. 1995, 5(18),2123-2128
b. CA: 126 (14): 152396s. Bioorg. Med. Chem. Lett. 1996, 6 (24), 2907-2912.
(14) a. T. D. Penning, J. J. Talley, P. C. Isakson, et al, J. Med. Chem. 1997, 40,1347-1365.
b. K. Seibert, Y. Zhang, P. C. Isakson, Proc. Naatl. Acad. Sci. USA. 1994, 91,12013-12017.
c. J. D. Penning, K. Seibert, P. C. Isakson, Bioorg. Med. Chem. Lett. , 1997, 7 (16),2121-2124
d.CA:123(25):p340112h, WO9515316
e. CA:123(25):p313952a, WO0915318.
(15) a. I.K. Khanna,R.M.Weier.P.C.Isakson, et al J. Med. Chem. 1997,40,1634-1647.
b. T. E. Barta, M. A. Stealey, R. M. Weier, Bioorg, Med. Chem. Lett. 1998, 8, 3443-3448.
c. CA:127(14):pl90737g, WO9727181.
(16) a. R..M. Weier, L.F. Lee, R.A. Partis, et al,WO9624584
b. L. F. WO9624585.
c. R. W. Friesen, C. Brideau, C. C. Chan, et al, Bioorg. Med. Chem. Lett. 1998,2777-2782
d. CA:125(19):p247624h, WO9624584.
(17)a. M. Therien, C. Brideau, C. C. Chan, et al, Bioorg. Med. Chem. Lett. 1997, 7(1),47-52.
b. L.A. Trimble, N. Leblanc, R. G. Ball, et al, ibid, 1997, 7(1), 53-56.
c. P. Roy, Y. Leblanc,R.G. Ball, 1997, 7(1), 57-62.
d. CA:125(15):pl95659b, WO9621667.
(18)a.CA:125(7):p86474s, WO9608482
b. CA:125(3):p33628p, WO9603392.
c. CA:125(9):p114604e, WO9609293
d.CA:125(9):p114294d, WO9613483.
e. CA:125(13):p167967g, WO9619462.
f. CA:125(13):pl67971d, WO9619463.
g. CA:126(1):p8117j, WO963150.
h. CA:126(7) :p89250X, WO9636623.
i. CA:125(19):p247800n, WO9625405.
j. CA:125(11):p142530w,WO9619469
k. CA:126(14):p142539w,WO9619469.
l. CA:126(8):p104081p, WO9638442
m. CA:126(8)p104079u, WO9638418.
n. CA:127(3)p34112u, WO9716435;CA:127(15)p205356h, WO9728120;CA:127(16):p220465m, WO9728121.
o. CA:127(5):p65756m, US5633272.
p. CA:127 (22):p307375f, WO9734882.
q. CA:127(24):p331281t,WO9736863.
r. CA:128(16):pl92645v,US5719163.
s. CA:125(3):p300608j, WO9626921.
(19)a. C. Rufer, F. Bahnlmann, E. Schroder, et al, Eur. J. Med. Chem. 1982, 17, 173-189.
b. A. Schweizer, J. A. Green, K. Miller,, et al,Agents Action.
c. T.Klein, R.M. Musing, V.Ullrich, et al, Biochem. Pharmacol. 1994, 48,1605-1610.
(20) a. C. S. Li, C. C. Chan, P. Praist, et al, J. Med. Chem. 1995, 38, 4897-4905.
b. P. Brain, Pet-piboon, J.Philip, et al, W09413635.
c. CA:125(15):p195438d,CA2164559.
(21)a.CA:125(17):p221839g,WO9623786.
b.CA:125(11):p132769s,JP08157361.
c. CA:126(15):p199339r,W09703953.
(22) a. W. C. Black, C. C. Chan, P. Praist, et al, Bioorg. Med. Chem. Lett. 1996, 6 (6),725-730
b. ibid, 1996, 6(6), 731-736.
c. ibid, 1996, 6(6), 737-742.
d. CA:123(25) :p227989, GB228374s.
e. CA: 126(7) :p89260a, W09637469.
f.CA:126(7):p89261b, W09637467.
g. CA:127(13):pl76343u,W09730030.
(23)a. E. S. Laser, C. K. Miao, G. Trummlitz, et al, J. Med. Chem., 1997, 40, 980-989.
b. E. S. Laser, R. Sorcek, C. L. Cywin, et al, Bioorg. Med/Chem. 1998, 8, 1181-1186.
c. CA:125(11):pl42754x, US5527796.
(24) a. A. S. Kalgutka, C. Garner, K. Seibert, et al, Science, 1998, 28 (22), 1268-1270.
b. D. K. Bhattacharyya, M. Lecomte, J. Dunn, et al Arch. Biochem. Biophys. 1995,317, 19.
c. A. S. Kalgutkar, K. R. Kozak, L. J. Marnett, et al, Med. Chem. 1998, 41 (24),4800-4818
(25) a. J. M. Janusz, P. A. Young, M. W. Scherz, J. Med. Chem. 1998, 41 (7), 1112-1123.
b. J. M. Janusz, P. A. Young, M. W. Scherz, J. Med. Chem. 1998, 41 (7), 1124-1137.
(26) a. C. I. Bayly, W. C. Black, S. Leger, et al, Bioorg. Med. Chem. Lett. 1999, 9, 307-312.
(27) K D. Stewart, S. Loren, L. Frey, et al, Bioorg. Med. Chem. Lett. 1998, 8,529-534.
(28) CA:127(1):pl3453r, JP9777664.
(29)a. CA:128(7):p75294, W0976524.
b. CA:128(22):p270440r, W09815528.
c. CA:129(12):pl48830y, DE19803003.
d. CA: 129(12):pl48904a, US5783597
e. CA:129(6) :p67772d, EP846689.
f. CA:129(10):pl22569v,US5776967CA:129(2):p16046n, WO9821195 g. CA:129(2):pl6046n, W09821195
(30)a.D.Evans,TA Hicks,WRN Williamson, etal, Eur. J. Med. Chera. 1996,31,635-642.
b. J. B. Hendrickson, Md. S. Hussoin, J. Org. Chera. 1987, 52, 4137-4139.
c. A. Alberti, P. Carloni, L. Greci, etal, J. Chem. Soc. Perkin TransII, 1991, 7,1019.
(31). M. R. DeLuca, S. M. Kerwin,Tetrahedron, 1997, 53 (2), 457-464.
(32). P. Babu, TR Balasubramanian, Indian J. Chem. 1987, 26B, 63.