English:
[0001] Glucokinase (GK) is one of four hexokinases that are found in mammals [Colowick, S.P., in The Enzymes, Vol. 9 (P. Boyer, ed.) Academic Press, New York, NY, pages 1-48, 1973]. The hexokinases catalyze the first step in the metabolism of glucose, i.e., the conversion of glucose to glucose-6-phosphate. Glucokinase has a limited cellular distribution, being found principally in pancreatic β-cells and liver parenchymal cells. In addition, GK is a rate-controlling enzyme for glucose metabolism in these two cell types that are known to play critical roles in whole-body glucose homeostasis [Chipkin, S.R., Kelly, K.L., and Ruderman, N.B. in Joslin 's Diabetes (C.R. Khan and G.C. Wier, eds.), Lea and Febiger, Philadelphia, PA, pages 97-115, 1994]. The concentration of glucose at which GK demonstrates half-maximal activity is approximately 8 mM. The other three hexokinases are saturated with glucose at much lower concentrations (<1 mM). Therefore, the flux of glucose through the GK pathway rises as the concentration of glucose in the blood increases from fasting (5 mM) to postprandial (∞10-15 mM) levels following a carbohydrate-containing meal [Printz, R.G., Magnuson, M.A., and Granner, D.K. in Ann. Rev. Nutrition Vol. 13 (R.E. Olson, D.M. Bier, and D.B. McCormick, eds.), Annual Review, Inc., Palo Alto, CA, pages 463-496, 1993]. These findings contributed over a decade ago to the hypothesis that GK functions as a glucose sensor in β-cells and hepatocytes (Meglasson, M.D. and Matschinsky, F.M. Amer. J. Physiol. 246, E1-E13, 1984). In recent years, studies in transgenic animals have confirmed that GK does indeed play a critical role in whole-body glucose homeostasis. Animals that do not express GK die within days of birth with severe diabetes while animals overexpressing GK have improved glucose tolerance (Grape, A., Hultgren, B., Ryan, A. et al., Cell 83, 69-78, 1995; Ferrie, T., Riu, E., Bosch, F. et al., FASEB J, 10, 1213-1218, 1996). An increase in glucose exposure is coupled through GK in β-cells to increased insulin secretion and in hepatocytes to increased glycogen deposition and perhaps decreased glucose production.
[0002] The finding that type II maturity-onset diabetes of the young (MODY-2) is caused by loss of function mutations in the GK gene suggests that GK also functions as a glucose sensor in humans (Liang, Y., Kesavan, P., Wang, L. et al., Biochem. J. 309, 167-173, 1995). Additional evidence supporting an important role for GK in the regulation of glucose metabolism in humans was provided by the identification of patients that express a mutant form of GK with increased enzymatic activity. These patients exhibit a fasting hypoglycemia associated with an inappropriately elevated level of plasma insulin (Glaser, B., Kesavan, P., Heyman, M. et al, New England J. Med. 338, 226-230, 1998). While mutations of the GK gene are not found in the majority of patients with type II diabetes, compounds that activate GK, and thereby increase the sensitivity of the GK sensor system, will still be useful in the treatment of the hyperglycemia characteristic of all type II diabetes. Glucokinase activators will increase the flux of glucose metabolism in β- cells and hepatocytes, which will be coupled to increased insulin secretion. Such agents would be useful for treating type II diabetes.
[0005] -(CH2)n-Q, wherein Q is a 5-membered saturated, substituted, heterocyclic ring connected by a ring carbon atom, said heterocyclic ring containing two heteroatoms selected from nitrogen, sulfur and oxygen, and substituted at each of two ring carbons with an oxo group, and optionally substituted at the connecting ring carbon with a substituent which is methyl or amino;
[0008] or an unsubstituted or mono-substituted six-membered aryl ring connected by a ring carbon atom, said mono-substituted aryl ring being mono-substituted at a position on a ring carbon atom other than the said connecting carbon atom with a substituent selected from the group consisting of cyano, halo, nitro, amino, methyl, methoxy, and hydroxy;
[00043] In a more preferable embodiment, compounds in accordance with the present invention are selected from:
[00048] If it is desired to produce compounds of formula V where R2 is hydrogen and R20 is lower alkyl sulfonyl, the known 4-(mercapto)phenylacetic acid can be used as a starting material. The compound of formula V where R2 is hydrogen and R20 is mercapto can be alkylated by conventional methods (for example, with a lower alkyl halide) to the conesponding lower alkyl thio compounds of formula V. The lower alkyl thio compounds can then be converted to the conesponding lower alkyl sulfonyl compounds of formula V by oxidation. Any conventional method of oxidizing an alkyl thio substituent to the conesponding sulfone group can be utilized to effect this conversion.
[00050] On the other hand, if it is desired to produce the compounds of formula N where R2 is bromo and R20 is lower alkyl sulfonyl, the compounds wherein R2 is hydrogen and R20 is lower alkyl thio, compounds produced as described above, can also be used as starting materials. The phenyl acetic acid derivatives of formula V wherein R is hydrogen and R20 is lower alkyl thio can be brominated. Any conventional method of aromatic bromination can be utilized to effect this conversion (J. Med. Chem. 1989, 32, 2493-2500). Once the compounds of formula V where R2 is bromo and R20 is lower alkyl thio are available, they can be converted to the conesponding compounds of formula V where R2 is bromo and R20 is lower alkyl sulfonyl by oxidation. Any conventional method of oxidizing an alkyl thio substituent to the conesponding sulfone group can be utilized to effect this conversion.
[00053] If it is desired to produce the compounds of formula V where R2 is fluoro and R20 is lower alkyl sulfonyl, these compounds can be alternatively prepared from the aforementioned compounds where R2 is nitro and R20 is lower alkyl sulfonyl. The aromatic nitro substituent is first converted to the aromatic amino group. Any conventional method for the reduction of a nitro group to an amino group can be utilized to effect this conversion. The amino group can then be converted to the fluorine group to produce the compounds of formula V where R2 is fluoro and R20 is lower alkyl sulfonyl. Any conventional method for converting an aromatic amino group to an aromatic fluorine can be utilized to effect this conversion (Synthetic Commun. 1992, 22, 73-82; J. Fluorine Chem. 1991, 51, 299-304).
[00054] On the other hand, if it is desired to produce the compounds of formula V where R2 is trifluoromethyl and R20 is lower alkyl sulfonyl, the known 4-fluoro-3- (trifluoromethyl)phenyl acetic acid can be used as a starting material. In this reaction, any conventional method for the nucleophilic displacement of an aromatic fluorine group with a lower alkyl thiol can be utilized to effect this conversion (J. Org. Chem. 1995, 60, 6592-6594; J. Org. Chem. 1982, 47, 4341-4344). Once the compounds of formula N where R2 is trifluoromethyl and R20 is lower alkyl thio are available, they can be converted to the conesponding compounds of formula V where R2 is trifluoromethyl and R20 is lower alkyl sulfonyl using conventional oxidation procedures.
[00055] If it is desired to produce compounds of formula V where R2 is methyl and R20 is lower alkyl sulfonyl, the commercially available 2-methylthiophenol can be used as starting material. In this reaction sequence, the mercapto group may be alkylated by conventional methods (for example, with a lower alkyl halide) to the conesponding 2- methyl-1 -lower alkyl thio benzenes. These compounds can then be converted to the conesponding 3-methyl-4-(lower alkyl thio)-phenyl acetic acids. First, the 2-methyl-l- lower alkyl thio benzenes can be acylated with a (lower alkyl)oxalyl chloride (such as methyloxalyl chloride or ethyloxalyl chloride) via a Friedel-Crafts acylation to produce the alpha-keto carboxylic ester in the position para to the lower alkyl thio functional group. The alpha-keto carboxylic ester can then be hydrolyzed by any conventional method for converting an alpha-keto carboxylic ester to an alpha-keto carboxylic acid. Wolff-Kishner reduction of the resulting alpha-keto carboxylic acid will produce the compounds of formula V where R2 is methyl and R20 is lower alkyl thio. The lower alkyl thio compounds can then be converted to the conesponding lower alkyl sulfonyl compounds of formula V by oxidation. Any conventional method of oxidizing an alkyl thio substituent to the conesponding sulfone group can be utilized to effect this conversion.
[00056] If it is desired to produce the compounds of formula V wherein R2 is methoxy and R20 is lower alkyl sulfonyl, these compounds can also be prepared as described hereinbefore from compounds wherein R2 is halo and R20 is lower alkyl sulfonyl. In this reaction, any conventional method for the nucleophilic displacement of an aromatic halo group with sodium methoxide can be utilized to effect this conversion. Once the compounds of formula V wherein R2 is methoxy and R20 is lower alkyl sulfonyl are available, they can be converted to the conesponding compounds of formula V wherein R2 is hydroxy and R20 is lower alkyl sulfonyl. Any conventional method for the demethylation of an aromatic methoxy group to an aromatic hydroxy group can be utilized to effect this conversion. This compound of formula N wherein R2 is hydroxy and R is lower alkyl sulfonyl would have to be protected throughout the remaining reaction scheme. The aromatic hydroxy group may be protected via a conventional hydrolyzable ether protecting group. At the end of the reaction scheme, the ether protecting group can then be removed to produce the respective hydroxy group conesponding to the desired compound of formula I wherein R2 is hydroxy. Alternatively, once the compound of formula I wherein R2 is methoxy is made following the reaction scheme, this compound can be converted to the desired compound of formula I wherein R2 is hydroxy. Any conventional method for the demethylation of an aromatic methoxy group to an aromatic hydroxy group can be utilized to effect this conversion
[00060] The amino heteroaromatic compounds of formula X are known in the chemical literature or can be prepared from those skilled in the art by using adaptations of standard synthetic transformations reported in the chemical literature. To produce the compounds of formula I, the synthetic conversions described herein to produce the desired R4 substituents can take place either before or after the compounds of formula X are converted to the compounds of formula I.
[00061] For example, if it is desired to produce the amino heteroaromatic compounds of formula X wherein R4 is methylthio, the known amino heteroaromatic compounds of formula X wherein R4 is bromo can be used as starting materials (if Y=CH, then the compound of formula X is the commercially available 2-amino-5- bromopyridine; if Y=N, then the compound of formula X is the known 2-amino-5- bromopyrazine which can be prepared according to Tetrahedron 1988, 44, 2977-2983). In this reaction sequence, the bromo substituent can be converted to the compounds of formula X wherein R4 is a methylthio substituent. Any conventional method for the nucleophilic displacement of an aromatic bromo substituent with sodium thiomethoxide can be utilized to effect this conversion (Tetrahedron 2002, 58, 1125-1129). The resulting compounds of formula X wherein R4 is methylthio can then be condensed with the compounds of formula IX via conventional peptide coupling to produce the desired compounds of formula I wherein R4 is methylthio. In canying out this reaction, any conventional method of condensing a primary amine with a carboxylic acid can be utilized to effect this conversion.
[00062] Once the compounds of formula I wherein R4 is methylthio are available, they can be converted to the conesponding compounds of formula I wherein R4 is methylsulfmyl. Any conventional method of oxidizing a methylthio substituent to a methylsulfmyl substituent (sulfoxide) can be utilized to effect this conversion. On the other hand, if it is desired to produce compounds of formula I wherein R4 is methylsulfonyl, the compounds of formula I wherein R4 is methylthio can also be used as starting materials. Any conventional method of oxidizing a methylthio substituent to a methylsulfone substituent can be utilized to effect this conversion.
[00064] Once the compounds of formula I wherein R4 is (methylthio)methyl are available, they can be converted to the conesponding compounds of formula I wherein R4 is (methylsulfmyl)methyl. Any conventional method of oxidizing a methylthio substituent to a methylsulfmyl substituent (sulfoxide) can be utilized to effect this conversion. On the other hand, if it is desired to produce compounds of formula I wherein R4 is (methylsulfonyl)methyl, the compounds of formula I wherein R is (methylthio)methyl can also be used as starting materials. Any conventional method of oxidizing a methylthio substituent to a methylsulfone substituent can be utilized to effect this conversion.
[00066] On the other hand, if it is desired to produce the compounds of formula I wherein R4 is a 5-amino-[l,2,4]oxadiazole ring, the aforementioned compounds of formula I wherein R4 is an N-(hydroxy)-carboximidamide substituent can be used as starting materials. The compounds of formula I wherein R4 is an N-(hydroxy)- carboximidamide substituent can be treated with N-cyanopiperidine to afford the compounds of formula I wherein R4 is a 5-amino-[l,2,4]oxadiazole ring (Nippon Kagάku Kaishi 1987, 10, 1807-1812).
[00067] If it is desired to produce the compounds of formula I wherein R4 is a 5- methyl-[l,2,4]oxadiazole ring, the aforementioned compounds of formula I wherein R4 is an N-(hydroxy)-carboximidamide substituent can also be used as starting materials. The compounds of formula I wherein R4 is an N-(hydroxy)-carboximidamide substituent can be treated with acetic anhydride to afford the compounds of formula I wherein R4 is a 5- methyl-[l,2,4]oxadiazole ring. (J. Med. Chem. 1991, 34, 2726-2735).
[00070] If it is desired to produce the compounds of formula I wherein R4 is a 3- substituted-1-propyne substituent or a 4-substituted-l-butyne substituent, -C≡C-(CH2)P-R8, and R8 is hydroxy, methoxy, or dimethylamine and p is 1 or 2, the aforementioned compounds of formula I wherein R4 is bromo can be used as starting materials. The bromo substituent in the compounds of formula I can be directly converted to the compounds of formula I wherein R4 is a 3 -substituted- 1-propyne substituent or a 4-substituted-l-butyne substituent, -C≡C-(CH2)P-R8, and R8 is hydroxy, methoxy, or dimethylamine and p is 1 or 2. Any conventional method for the catalytic substitution of an acetylenic hydrogen (for example, propargyl alcohol and 3-butyn-l-ol) with an aryl bromide, such as the Sonogashira reaction, can be utilized to effect this conversion (for a general review, see Campbell, I. B. Organocopper Reagents 1994, 217- 235).
[00072] Once the compounds of formula I wherein R4 is a 4- ethynyltetrahydropyran-4-ol substituent are available, they can be converted to the conesponding compounds of formula I wherein R4 is a 4-ethyltetrahydropyran-4-ol substituent. The heteroaromatic 4-ethynyltetrahydropyran-4-ol substituent can be reduced to produce the corresponding heteroaromatic 4-ethyltetrahydropyran-4-ol substituent. Any conventional method for the reduction of an alkyne to a saturated hydrocarbon can be utilized to effect this conversion.
[00073] On the other hand, if it is desired to produce the compounds of formula I wherein R4 is a -C≡C-C(CH3)2-OH substituent, the aforementioned compounds of formula I wherein R4 is bromo can also be used as starting materials. The compounds of formula I wherein R4 is bromo can be reacted with 2-methyl-3-butyn-2-ol to produce the compounds of formula I wherein R4 is a -C≡C-C(CH3)2-OH substituent. Any conventional method for the catalytic substitution of an acetylenic hydrogen with an aryl bromide, such as the Sonogashira reaction, can be utilized to effect this conversion.
[00074] If it is desired to produce the compounds of formula I wherein R4 is a N- methyl sulfonamide substituent or a NN-dimethyl sulfonamide substituent, the aforementioned compounds of formula I wherein R4 is methylsulfmyl (methyl sulfoxide) can be used as starting materials. The compounds of formula I wherein R4 is methylsulfmyl can then be converted to the compounds of formula I wherein R4 is thiol. A two-step procedure which involves a Pummerer methyl sulfoxide reanangement using trifluoroacetic anhydride followed by hydrolysis of the Pummerer reanangement intermediate with triethylamine and methanol can be utilized to effect this conversion. Once the compounds of formula I wherein R4 is thiol are available, these compounds can be converted to the compounds of formula I wherein R4 is sulfonyl chloride. Any conventional method of oxidizing a thiol substituent to a sulfonyl chloride substituent can be utilized to effect this conversion. Finally, the resulting compounds of formula I wherein R4 is sulfonyl chloride can then be converted to the desired compounds of formula I wherein R4 is a N-methyl sulfonamide substituent or a NN-dimethyl sulfonamide substituent. Any conventional method of reacting a sulfonyl chloride substituent with methylamine to produce a N-methyl sulfonamide substituent or with dimethylamine to produce a NN-dimethyl sulfonamide substituent can be utilized to effect this conversion.
[00095] If it is desired to produce the compounds of formula I wherein R4 is a (2,4- dioxo-thiazolidin-5-ylmethyl) substituent, the aforementioned compounds of formula I wherein R4 is a formyl substituent can be used as starting materials. In this reaction sequence, the formyl substituent can be reacted with 2,4-thiazolidinedione to afford the conesponding compounds of formula I wherein R4 is a (2,4-dioxo-thiazolidin-5- ylidenemethyl) substituent (J. Med. Chem. 1998, 41, 1619-1630; PCT Intl. Appl. 9743283, 20 Nov. 1997). The compounds of formula I wherein R4 is a (2,4-dioxo- thiazolidin-5-ylidenemethyl) substituent can then be converted into the desired compounds of formula I wherein R4 is a (2,4-dioxo-thiazolidin-5-ylmethyl) substituent by reduction of the carbon-carbon double bond using 2,6-dimethyl-l,4-dihydro-pyridine-3,5- dicarboxylic acid diethyl ester and silica gel in toluene.
[00096] If it is desired to produce the compounds of formula I wherein R4 is a (2,5- dioxo-imidazolidin-4-ylmethyl) substituent, the aforementioned compounds of formula I wherein R4 is a formyl substituent can also be used as starting materials. In this reaction sequence, the formyl substituent can be reacted with hydantoin to afford the conesponding compounds of formula I wherein R4 is a (2,5-dioxo-imidazolidin-4- ylidenemethyl) substituent (Egyptian Journal of Chemistry 1987, 30, 281-294). The compounds of formula I wherein R4 is a (2,5-dioxo-imidazolidin-4-ylidenemethyl) substituent can then be converted into the desired compounds of formula I wherein R4 is a (2,5-dioxo-imidazolidin-4-ylmethyl) substituent by catalytic hydrogenation of the carbon- carbon double bond.

中文:
[0001]葡糖激酶(GK)是哺乳动物体内发现的四种己糖激酶之一[Colowick,S.P.,TheEnzymes,第9卷(P.Boyer编辑)AcademicPress,NewYork,NY,第1-48页,1973]。己糖激酶催化葡萄糖代谢的第一步,即将葡萄糖转化为葡萄糖-6-磷酸。葡糖激酶在细胞中分布有限,发现主要存在于胰β-细胞和肝实质细胞。另外,GK是这两类细胞中葡萄糖代谢的限速酶,在全身葡萄糖动态平衡中发挥重要作用[Chipkin,S.R.,Kelly,K.L.,和Ruderman,N.B.Joslin′sDiabetes(C.R.Khan和G.C.Wier,编辑),Lea和Febiger,Philadelphia,PA,P.97-115,1994]。GK表现半数最大活性的葡萄糖浓度约为8mM。另外三种己糖激酶在葡萄糖相对很低的浓度下(<1mM)就达饱和。因此,随着血糖浓度从禁食状态(5mM)增加到含碳水化合物食物的餐后状态(≈10-15mM),通过GK途径的葡萄糖流量也随之增加[Printz,R.G.,Magnuson,M.A.,和Granner,D.K.Ann.Rev.Nutrition第13卷(R.E.Olson,D.M.Bier,和D.B.McCormick编辑),AnnualReview,Inc.,PaloAlto,CA,P.463-496,1993]。这些结论在十年前形成这样一个假说,即GK在β-细胞和肝实质细胞中发挥葡萄糖传感器的功能(Meglasson,M.D.和Matschinsky,F.M.,Amer.J.Physiol.246,E1-E13,1984)。近些年在转基因动物中的研究证实GK在全身葡萄糖动态平衡中的确发挥关键作用。不表达GK的动物在出生后数天内因严重糖尿病死亡,而过量表达GK的动物表现改善的糖耐量(Grupe,A.,Hultgren,B.,Ryan,A.等,Cell83,69-78,1995;Ferrie,T.,Riu,E.,Bosch,F.等,FASERJ.,10,1213-1218,1996)。在β-细胞中葡萄糖暴露的增加通过GK导致胰岛素分泌增加,在肝细胞中葡萄糖的增加通过GK导致糖原沉积增加并可能导致葡萄糖产生降低。
[0002]青年人的II型成年糖尿病(MODY-2)是由于GK基因突变引起功能丧失所致这一结论表明,GK在人体中同样发挥葡萄糖传感器的功能(Liang,Y.,Kesavan,P.,Wang,L.等,Biochem.J.309,167-173,1995)。支持GK在人体葡萄糖代谢的调节中具有重要作用的另外一个证据是鉴定出了表达具有增加的酶活性的GK突变型的患者。这些患者表现血浆胰岛素水平过高所致的禁食低血糖(Glaser,B.,Kesavan,P.,Heyman,M.等,NewEnglandJ.Med.338,226-230,1998)。大多数II型糖尿病患者中未发现有GK基因突变,激活GK并由此增加GK传感器系统灵敏度的化合物在治疗所有II糖尿病的高血糖症状中仍然有用。葡糖激酶激活剂将增加β-细胞和肝实质细胞中葡萄糖代谢的流量,这将导致胰岛素分泌的增加。这些物质将会在治疗II型糖尿病中发挥作用。
[0005]-(CH2)n-Q,其中Q是5-元饱和的、取代的通过环碳原子连接的杂环,所述杂环含有两个选自氮、硫和氧的杂原子,并且在两个环碳的每个上被氧代基团取代,且任选地在连接的环碳上被取代基取代,该取代基是甲基或氨基;
[0008]或未取代的或单取代的通过环碳原子连接的六元芳环,所述单取代的芳环在除了所述连接的碳原子以外的环碳原子的位置上被取代基单取代,该取代基选自氰基,卤素,硝基,氨基,甲基,甲氧基,和羟基;
[00043]在一个更优选的实施方案中,按照本发明的化合物选自:
[00048]如果期望生产其中R2是氢和R20是低级烷基磺酰基的式V的化合物,已知的4-(巯基)苯基乙酸可以用作原材料。其中R2是氢和R20是巯基的式V的化合物可以通过常规方法烷基化(例如用低级烷基卤)成相应的式V的低级烷硫基化合物。低级烷硫基化合物然后可以通过氧化转化为相应的式V的低级烷基磺酰基化合物。任何常规的将烷硫基取代基氧化成相应的砜基团的方法可以用于实施该转化。
[00050]在另一方面,当期望生产其中R2是溴和R20是低级烷基磺酰基的式V的化合物时,其中R2是氢和R20是低级烷硫基的化合物,如上所述生产的化合物,也可以用作原材料。其中R2是氢和R20是低级烷硫基的式V的苯基乙酸衍生物可以被溴化。任何常规的芳族溴化的方法可以用于实施该转化(J.Med.Chem.1989,32,2493-2500)。一旦其中R2是溴和R20是低级烷硫基的式V的化合物可获得,它们可以通过氧化转化为相应的其中R2是溴和R20是低级烷基磺酰基的式V的化合物。任何常规的将烷硫基取代基转化为相应的砜基团的方法可以用于实施该转化。
[00053]如果期望生产其中R2是氟和R20是低级烷基磺酰基的式V的化合物,这些化合物可以备选地从其中R2是硝基和R20是低级烷基磺酰基的上述化合物制备。芳族硝基取代基首先转化为芳族氨基。任何常规的将硝基还原成氨基的方法可以用于实施该转化。氨基然后可以转化为氟基团,以生产其中R2是氟和R20是低级烷基磺酰基的式V的化合物。任何常规的将芳族氨基转化为芳族氟的方法可以用于实施该转化(SyntheticCommun.1992,22,73-82;J.FluorineChem.1991,51,299-304)。
[00054]在另一方面,如果期望生产其中R2是三氟甲基和R20是低级烷基磺酰基的式V的化合物,已知的4-氟-3-(三氟甲基)苯基乙酸可以用作原材料。在该反应中,任何常规的用低级烷基硫醇亲核置换芳族氟基团的方法可以用于实施该转化(J.Org.Chem.1995,60,6592-6594;J.Org.Chem.1982,47,4341-4344)。一旦其中R2是三氟甲基和R20是低级烷硫基的式V的化合物可以获得,它们可以使用常规氧化方法转化为相应的其中R2是三氟甲基和R20是低级烷基磺酰基的式V的化合物。
[00055]如果期望生产其中R2是甲基和R20是低级烷基磺酰基的式V的化合物,可以将可商购的2-甲基苯硫酚用作原材料。在该反应顺序中,巯基可以通过常规方法烷基化(例如用低级烷基卤)成相应的2-甲基-1-低级烷基硫代苯。这些化合物然后可以转化为相应的3-甲基-4-(低级烷硫基)-苯基乙酸。首先,2-甲基-1-低级烷基硫代苯可以用(低级烷基)草酰氯(如甲基草酰氯或乙基草酰氯)通过弗瑞德-克来福特酰化反应酰化,在所述低级烷硫基官能团的对位产生α-酮羧酸酯。α-酮羧酸酯然后可以通过任何常规方法水解,将α-酮羧酸酯转化为α-酮羧酸。获得的α-酮羧酸的Wolff-Kishner还原将产生式V的化合物,其中R2是甲基和R20是低级烷硫基。低级烷硫基化合物然后可以通过氧化转化为相应的式V的低级烷基磺酰基化合物。任何常规的将烷硫基取代基氧化成相应的砜基团的方法可以用于实施本转化。
[00056]如果期望生产其中R2是甲氧基和R20是低级烷基磺酰基的式V的化合物,这些化合物也可以如上所述由其中R2是卤素和R20是低级烷基磺酰基的化合物制备。在该反应中,任何常规的用甲醇钠亲核置换芳族卤素基团的方法可以用于实施该转化。一旦其中R2是甲氧基和R20是低级烷基磺酰基的式V的化合物可以获得,它们可以转化为相应的其中R2是羟基和R20是低级烷基磺酰基的式V的化合物。任何常规的将芳族甲氧基脱甲基为芳族羟基的方法可以用于实施该转化。这种R2是羟基和R20是低级烷基磺酰基的式V的化合物必须在剩余的反应路线中保护。芳族羟基可以通过常规的可水解的醚保护基来保护。在反应路线结束时,醚保护基然后可以去除以生产对应于期望的其中R2是羟基的式I的化合物的各自羟基。备选地,一旦根据反应路线制备其中R2是甲氧基的式I的化合物,该化合物然后可以转化为期望的其中R2是羟基的式I的化合物。任何常规的将芳族甲氧基脱甲基化为芳族羟基的方法可以用于实施该转化。
[00060]式X的氨基杂芳族化合物在化学文献中已知或者可以由本领域技术人员通过使用在化学文献中报道的标准合成转化的改进制备。为了生产式I的化合物,本文所述的合成转化以生产期望的R4取代基可以发生在式X的化合物转化为式I的化合物之前或之后。
[00061]例如,如果期望生产其中R4是甲硫基的式X的氨基杂芳族化合物,已知的其中R4是溴的式X的氨基杂芳族化合物可以用作原材料(如果Y=CH,那么式X的化合物是可商购的2-氨基-5-溴吡啶;如果Y=N,那么式X的化合物是已知的2-氨基-5-溴吡嗪,其可以根据Tetrahedron1988,44,2977-2983制备)。在该反应步骤中,溴取代基可以转化为其中R4是甲硫基取代基的式X的化合物。任何常规的用硫代甲醇钠亲核置换芳族溴取代基的方法可以用于实施该转化(Tetrahedron2002,58,1125-1129)。产生的其中R4是甲硫基的式X的化合物然后可以与式IX的化合物通过常规的肽偶联缩合,生产期望的其中R4是甲硫基的式I的化合物。在进行该反应中,任何将伯胺与羧酸缩合的常规方法可以用于实施该转化。
[00062]一旦其中R4是甲硫基的式I的化合物可以获得,它们可以转化为相应的其中R4是甲基亚磺酰基的式I的化合物。任何将甲硫基取代基氧化为甲基亚磺酰基取代基(亚砜)的常规方法可以用于实施该转化。在另一方面,如果期望生产其中R4是甲磺酰基的式I的化合物,其中R4是甲硫基的式I的化合物也可以用作原材料。任何常规的将甲硫基取代基氧化为二甲亚砜取代基方法可以用于实施该转化。
[00064]一旦其中R4是(甲硫基)甲基的式I的化合物可以获得,它们可以转化为相应的其中R4是(甲基亚磺酰基)甲基的式I的化合物。任何常规的将甲硫基取代基氧化为甲基亚磺酰基取代基(亚砜)的方法可以用于实施该转化。在另一方面,如果期望生产其中R4是(甲磺酰基)甲基的式I的化合物,其中R4是(甲硫基)甲基的式I的化合物也可以用作原材料。任何常规的将甲硫基取代基氧化为二甲亚砜取代基的方法可以用于实施该转化。
[00066]在另一方面,如果期望生产其中R4是5-氨基-[1,2,4]噁二唑环的式I的化合物,其中R4是N-(羟基)-亚氨酰胺取代基的上述式I的化合物可以用作原材料。其中R4是N-(羟基)-亚氨酰胺取代基的式I的化合物可以用N-氰基哌啶处理,以提供其中R4是5-氨基-[1,2,4]噁二唑环的式I的化合物(NipponKagakuKaishi1987,10,1807-1812)。
[00067]如果期望生产其中R4是5-甲基-[1,2,4]噁二唑环的式I的化合物,其中R4是N-(羟基)-亚氨酰胺取代基的上述式I的化合物也可以用作原材料。其中R4是N-(羟基)-亚氨酰胺取代基的式I的化合物可以用乙酐处理以提供其中R4是5-甲基-[1,2,4]噁二唑环的式I的化合物,(J.Med.Chem.1991,34,2726-2735)。
[00070]如果期望生成其中R4是3-取代-1-丙炔取代基或4-取代-1-丁炔取代基,-C≡C-(CH2)p-R8的式I的化合物,其中R8是羟基、甲氧基或二甲胺和p为1或2,其中R4是溴的上述式I的化合物可以用作原材料。式I的化合物中的溴取代基可以直接转化为其中R4是3-取代-1-丙炔取代基或4-取代-1-丁炔取代基,-C≡C-(CH2)p-R8的式I的化合物,其中R8是羟基、甲氧基或二甲胺和p为1或2。任何常规的用芳基溴催化取代乙炔氢的方法(例如炔丙醇和3-丁炔-1-醇),如Sonogashira反应,可以用于实施该转化(关于综述,参见Campbell,I.B.OrganocopperReagents1994,217-235)。
[00072]一旦其中R4是4-乙炔基四氢吡喃-4-醇取代基的式I的化合物可以获得,它们可以转化为相应的其中R4是4-乙基四氢吡喃-4-醇取代基的式I的化合物。杂芳环4-乙炔基四氢吡喃-4-醇取代基可以还原以产生相应的杂芳环4-乙基四氢吡喃-4-醇取代基。任何常规的将炔烃还原成饱和烃的方法可以用于实施该转化。
[00073]在另一方面,如果期望生成其中R4是-C≡C-C(CH3)2-OH取代基的式I的化合物,其中R4是溴的上述式I的化合物也可以用作原材料。其中R4是溴的式I的化合物可以与2-甲基-3-丁炔-2-醇反应生成其中R4是-C≡C-C(CH3)2-OH取代基的式I的化合物。任何常规的用芳基溴催化置换乙炔氢的方法,如Sonogashira反应,可以用于实施该转化。
[00074]如果期望生成其中R4是N-甲磺酰胺取代基或N,N-二甲磺酰胺的式I的化合物,其中R4是甲基亚磺酰基(二甲亚砜)的上述式I的化合物可以用作原材料。其中R4是甲基亚磺酰基的式I的化合物然后可以转化为其中R4是硫醇的式I的化合物。一种两步方法可以用于实施该转化,在该两步方法中涉及使用三氟乙酐的Pummerer二甲亚砜重排,接着用三乙胺和甲醇水解Pummerer重排的中间体。一旦其中R4是硫醇的式I的化合物可以获得,这些化合物可以转化为其中R4是磺酰氯的式I的化合物。任何常规的将硫醇取代基氧化为磺酰氯取代基的方法可以用于实施该转化。最终,产生的其中R4是磺酰氯的式I的化合物然后可以转化为期望的其中R4是N-甲磺酰胺取代基或N,N-二甲磺酰胺取代基的式I的化合物。任何常规的将磺酰氯取代基与甲胺反应生成N-甲磺酰胺取代基或与二甲胺反应生成N,N-二甲磺酰胺取代基的方法可以用于实施该转化。
[00095]如果期望生成其中R4是(2,4-二氧代-噻唑烷-5-基甲基)取代基的式I的化合物,其中R4是甲酰基取代基的上述式I的化合物可以用作原材料。在该反应顺序中,甲酰基取代基可以与2,4-噻唑烷二酮反应,提供相应的其中R4是(2,4-二氧代-噻唑烷-5-亚基甲基)取代基的式I的化合物(J.Med.Chem.1998,41,1619-1630;PCTIntl.Appl.9743283,20Nov.1997)。其中R4是(2,4-二氧代-噻唑烷-5-亚基甲基)取代基的式I的化合物然后可以通过使用甲苯中的2,6-二甲基-1,4-二氢-吡啶-3,5-二羧酸二乙酯和硅胶还原碳-碳双键,转化为期望的其中R4是(2,4-二氧代-噻唑烷-5-基甲基)取代基的式I的化合物。
[00096]如果期望生成其中R4是(2,5-二氧代-咪唑烷-4-基甲基)取代基的式I的化合物,其中R4是甲酰基取代基的上述式I的化合物也可以用作原材料。在该反应顺序中,甲酰基取代基可以与乙内酰脲反应以提供相应其中R4是(2,5-二氧代-咪唑烷-4-亚基甲基)取代基的式I的化合物(EgyptianJournalofChemistry1987,30,281-294)。其中R4是(2,5-二氧代-咪唑烷-4-亚基甲基)取代基的式I的化合物然后可以通过催化氢化碳-碳双键,转化为期望的其中R4是(2,5-二氧代-咪唑烷-4-基甲基)取代基的式I的化合物。