SK62003A3 - A combination of FBPase inhibitors and antidiabetic agents useful for the treatment of diabetes - Google Patents

Abstract

A combination therapy of at least one FBPase inhibitor and at least one other antidiabetic agent is disclosed.

Description

Technical field

The invention provides a combination therapy based on the use of at least one FBPase inhibitor and at least one other antidiabetic agent.

BACKGROUND OF THE INVENTION

This application claims the provisional Application No. 60/216,531 entitled Combination of FBPase Inhibitors and Antidiabetic Agents Useful in the Treatment of Diabetes, filed July 6, 2000, which is incorporated herein by reference in its entirety, including the drawings.

Diabetes melitus (also described generally as diabetes) is one of the most widespread diseases of the world today. Patients who have diabetes (i.e., diabetics) are divided into two classes, namely type I, insulin-dependent diabetes mellitus (IDDM) and type II, or non-insulin-dependent diabetes mellitus (NIDDM).

IDDM patients are typically treated with insulin and insulin analogs. However, some of these patients, known as brittle diabetics, do not treat these procedures well.

NIDDM accounts for about 90% of all diabetics and it is estimated that 12 to 14 million people are affected in the United States (6.6% of the US population). The three major metabolic abnormalities associated with NIDDM are: (a) impaired insulin secretion from the pancreas, (b) insulin resistance in peripheral tissues such as muscles and adiposis, and (c) hepatic glucose overproduction (i.e., hepatic glucose output). These abnormalities typically result in hyperglycemia and an exaggerated postprandial increase in plasma glucose concentration.

Diabetes is associated with many long-term complications, including microvascular diseases such as retinopathy, nephropathy and neuropathy, and macrovascular diseases such as coronary heart disease. Numerous animal model studies demonstrate a causal relationship between long-term hyperglycemia and known diabetic complications. The results of the Diabetes Control and Complications Trial (DCCT) and the Stockholm Prospective Study show for the first time this relationship in humans by showing that IDDM diabetics who have more stringent glycemic control have a significantly lower risk of developing and progressing known diabetic complications. Strict glycemic control is expected to also benefit NIDDM patients.

Current therapies used to treat NIDDM patients involve both control of lifestyle risk factors as well as pharmaceutical intervention. First of all, the diet and exercise regimen is typically strictly controlled in NIDDM therapy because a large number of NIDDM patients are overweight or obese (67%) and since weight loss can adjust insulin secretion and / or insulin sensitivity and thus lead to normoglycemia. Normalization of blood glucose occurs in less than 30% of these patients, but due to poor compliance of therapy and poor response to therapy. Patients with hyperglycaemia that is not controlled by diet alone are typically treated with oral hypoglycaemics and / or insulin.

The four main classes of oral agents typically prescribed are insulin secretagogues (e.g. sulfonylureas: glyburide, glimeperide and glipizide), biguanides (e.g. metformin and phenformin), insulin sensitizers (e.g. rosiglitazone and pioglitazone) and α-glucosidase inhibitors (e.g.). Insulin secretagogues affect defects in pancreatic secretion, defects that are typically observed in diabetics. Classical agents of this class, as well as more recent agents such as meglitinides (eg nateglanide and repaglinide), stimulate the release of insulin from the pancreas by binding to adenosine triphosphate (ATP) -supported potassium channel of the pancreatic β cells. Other agents for insulin secretion include glucagon-like peptide (GLP-1), whose primary site of action is also β cells. Agents that prolong the half-life of GLP-1, i.e. dipeptidyl peptidase-IV (DPP-IV) inhibitors, are also valuable as insulin secretagogues.

Biguanides have been used for decades. The mechanism of action of this class of compounds is still unclear, but it has now been found that the glucose lowering effect of metformin is largely due to its inhibition of hepatic glucose output.

Insulin sensitizers are another class of orally administered agents. The target of the recently introduced antidiabetic agents, insulin sensitizers, appears to be peroxisome proliferator-activated receptors (PSAR-γ). These agents are described to increase insulin-mediated glucose degradation and inhibit glucose production without directly stimulating insulin secretion.

Clinical data for sulfonylureas, biguanide, and insulin sensitizer therapy in NIDDM patients show that even at the highest therapeutic dose, blood glucose and hemoglobin concentrations do not fall below levels associated with long-term diabetic complications.

The last class of orally administered agents is the α-glucosidase class. α-Glucosidases are enzymes responsible for the complex digestion of sugars in the gastrointestinal tract and thus for the absorption of simple sugars. α-Glucosidase inhibitors prevent the rapid digestion of sugars and thus prolong their absorption. These inhibitors attenuate the postprandial glucose excursion typically seen in diabetic patients.

Many experimental approaches aim at overproduction of glucose in the liver. Agents of this class, hepatic glucose performance inhibitors, include: (a) glycogen phosphorylase inhibitors, preventing hepatic glycogen accumulation failure, (b) glucose-6-phosphatase inhibitors that block glucose release due to both gluconeogenesis and glycogenolysis; (c) glucagon antagonists that play a role in reducing the stimulatory effect of glucagon in the production of hepatic glucose; and (d) amylin aconists that regulate glycemic control by partially inhibiting glucagon secretion; and (e) oxidation inhibitors, fatty acids that reduce the stimulatory effect oxidation of fatty acids to gluconeogenesis.

U.K. Diabetes Prospective Study show that patients who receive maximum insulin, sulphonylurea or metformin therapy are unable to maintain normal blood glucose during the six-year study period. U.K. Prospective Diabetes Study 16. Diabetes, 44: 1249-158 (1995). Clinical experience with a co-established class of insulin sensitizers is insufficient to determine whether or not these agents are able to maintain glycemic control over the long term. However, insulin sensitizers require the functioning of the pancreas in order to be active and thus have limited importance in the treatment of advanced diabetes. Thus, there is a continuing interest in alternative therapies in the field of NIDDM treatment.

It is believed that the rate of hepatic glucose production, characteristic of NIDDM patients, is increased primarily due to the over-regulation of gluconeogenesis. Magnusson et al., J. Clin. Invesz. 90: 1323-1327 (1992). Gluconeogenesis is a highly regulated bicsynthetic pathway that requires eleven enzymes whose cursors such as lactate, pyruvate, alarin and glycerin are converted to glucose. Seven enzymes catalyze reversible reactions and are common in both gluconeogenesis and glycolysis. The four enzymes catalyze reactions that are only gluconeogenesis-specific, namely pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase and glucose-6-phosphatase. Total flow through the reaction pathway is regulated by specific activities enzymes catalyze the corresponding steps in the direction of substrate availability. Dietary factors (e.g.

and fats) and hormones (e.g., insulin, glucagon, these enzymes, glycolysis and sugars, proteins glucocorticoids and epinephrine) coordinate the enzymatic activities in the gluconeogenesis and glycolithic reaction pathways through gene expression and post-translational mechanisms.

C-ruber has reported that some nucleosides may decrease blood glucose concentrations throughout the animal body by inhibiting FBPase. These compounds exert their activity by undergoing phosphorylation to the corresponding monophosphate. Gruber et al. (US Patent No. 5,658,889, EP 0 427 799 B1) discloses the use of AMP inhibitors of the FBPase site for the treatment of diabetes. WO 98/39342 (US Patent No. 6,054,587), WO 98/39343 (US Patent No. 6,110,903), WO 98/39344, and WO 00/14095 disclose the use of FBPase inhibitors for the treatment of diabetes.

SUMMARY OF THE INVENTION

Description of the invention

In view of the predominant need for diabetes therapy, other methods of treating diabetes are needed. None of the references herein are considered to be prior art.

The present invention provides a combination therapy and composition for the treatment of diabetes or other diseases and conditions responsive to improved glycemic control and / or altered peripheral insulin sensitivity and / or increased insulin secretion. Therapy involves administration of at least one FBPase inhibitor and at least one antidiabetic agent, either together or at different times, to obtain the desired response. While any suitable antidiabetic agent may be used to combine with an FBPase inhibitor, the antidiabetic agents used in the invention are typically selected from one or more of the following groups: (a) insulin secretagogues (e.g., sulfonylureas, nonsulfonylureas, GLP-1 receptor agonists, DPP-IV inhibitors or other agents known to increase insulin secretion), (b) insulin or insulin analogs, (c) insulin sensitizers (eg rosiglitazone and pioglitazone), (d) biguanides (eg metformin and phenformin) (e) α-glucosidase inhibitors (e.g. acarbose), (f) glycogen phosphorylase inhibitors, (g) glucose-6-phosphatase inhibitors, (h) glucagon antagonists, (i) amylin antagonists or (j) fatty acid oxidation inhibitors .

In some embodiments of the invention, the combination of at least one FBPase inhibitor with at least one of the aforementioned antidiabetic agents results in a reduction in hepatic glucose production as compared to a reduction in glucose when an antidiabetic agent is administered in the absence of an FBPase inhibitor. In addition, combination therapy may result in improved insulin sensitivity and / or insulin secretion compared to the values observed for each agent separately, as well as providing beneficial effects on the metabolism of sugars and / or lipids (e.g. fats) and / or proteins.

In particular embodiments of the present invention, the combination therapy achieves similar advantages as seen with therapy with one or the other agent alone, but at significantly lower therapeutic doses. This phenomenon can be particularly advantageous when potentially harmful side effects are associated with the therapy. For example, in a particular embodiment of the present invention, the combination therapy of the present invention is useful in alleviating some of the potentially harmful effects associated with FBPase inhibitor therapy. Similarly, the combination of the present invention may ameliorate some of the potentially harmful effects associated with anti-diabetic agents such as hypennulinemia, hypoglycemia, weight gain, gastrointestinal disorders, liver abnormalities, and cardiovascular side effects.

Compared to the responses associated with therapies involving anti-diabetic agents without an FBPase inhibitor, the combination of the invention has the ability to increase the primary response rate. In addition, the combination of the invention has the ability to reduce, delay or prevent the occurrence of secondary failure.

The present invention also relates to methods and compositions for treating an animal having diabetes by administering a composition comprising a pharmaceutically effective amount of at least one FBPase inhibitor and a pharmaceutically effective amount of at least one additional antidiabetic agent. In particular embodiments, the compositions of the invention are useful in treating, ameliorating, or preventing one or more diabetic symptoms. In addition to methods of treatment and compositions for treating animals having diabetes, methods and compositions for treating diseases and conditions characterized by insulin resistance, including obesity, hypertension, increased glucose tolerance, pregnancy diabetes, and polycystic ovarian syndrome are also within the scope of the invention. In addition, individuals with syndrome X, kidney disease, or pancreatitis are also effectively treated in a particular embodiment with the combination therapy of the invention. Particularly preferred combinations have these beneficial effects as well as high potency and low toxicity.

definition

In accordance with the present invention, the following terms are used with the following meanings unless otherwise indicated:

The term diabetes includes NIDDM and IDDM.

The term "brittle diabetic" refers to a person with insulin-dependent diabetes mellitus associated with glycemic instability, characterized by frequent and extreme oscillations between hypoglycemia and hyperglycemia.

Nomenclature of X, X ^2, X ³ and X ⁴ groups, used in the formulas II, II-A, III, III-A, IV, IV-A, VI, Vla, V-2, V-2-A, X, XA, VII-1, VII-1A, VII-2 and VII-2-A, starting with a group attached to phosphorus and ending with a group attached to a heteroaromatic or aromatic ring. For example, when X is an alkylamino group of formula (VI), the following structure is meant:

P (0) (YR ¹⁾ 2 -alk-NR- (heteroaromatic ring)

Similarly, A, B, D, E, L, J, A, B, D ”, E”, A ² , L ² , E ² , J ² , J ³ , J ⁴ , J ⁵ , J ⁶ , J ⁷ and Y ³ groups and other heteroaromatic or aromatic ring substituents are described in such a way that the term ends with a group attached to the heteroaromatic or aromatic ring. Generally, substituents are named such that the term ends with a group at the point of attachment.

The term aryl refers to aromatic groups having 5 to 14 ring atoms and at least one ring having a conjugated π-electron system. The term aryl includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted. Suitable aryl groups include, for example, phenyl and furan-2,5-diyl.

Carbocyclic aryl groups are groups wherein the ring atoms of the aromatic system are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and polycyclic or fused compounds such as e.g. an optionally substituted naphthyl group.

Heterocyclic aryl or heteroaryl groups are groups having from 1 to 4 heteroatoms as ring atoms in the aromatic ring, the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include, for example, oxygen, sulfur, nitrogen, and selenium. Suitable heceroaryl groups include, for example, furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl and the like, all of which may be optionally substituted.

The term nullification and nullification denotes the formation of another cyclic group on an existing aryl or heteroaryl group. The newly formed ring may be carbocyclic or heterocyclic, saturated or unsaturated and may contain 2 to 9 new atoms, of which 0 to 3 may be heteroatoms selected from N, O and S. The annulment may include atoms from the X group as part of the newly formed ring . For example, the phrases L ² and E 'together form a null cyclic group with respect to the group XA include:

The term biaryl represents aryl groups containing more than one aromatic ring and includes both fused ring systems and aryl groups substituted with another aryl group. Such groups may be optionally substituted. Suitable biaryl groups include e.g. naphthyl and biphenyl.

The term alicyclic refers to groups that combine the properties of aliphatic and cyclic groups. Such cyclic groups include, but are not limited to, aromatic, cycloalkyl, and bridged cycloalkyl groups. Cyclic groups include heterocycles. Cyclohexenylethyl and cyclohexylzyl are examples of suitable alicyclic groups. Such groups may be optionally substituted.

The term optionally substituted includes groups substituted with no to four substituents independently selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, lower alicyclic, heterocyclic alkyl, hydroxy, lower alkoxy, lower aryloxy, heteroaryloxy, perhaloalkyloxy, perhaloalkyloxy, , heteroaryloxy, heteroarylalkyl, heteroaralkyloxy, azido, amino, guanidino, amidino, halo, lower alkylthio, oxo, acylalkyl, carboxyester, carboxyl, alkyl, amino, amino, carboxyamido, nitro, , alkoxyaryl, arylamino, aralkylamino, phosphono, sulfonyl, carboxamidoalkyleryl, carboxamidoaryl group, hydroxyalkvlovú group, a haloalkyl group, alkylaminoalkylkarboxylovú group, aminokarboxamidoalkylovú group, a cyano group, a lower alkoxyalkvlovú, lower perhaloalkyl, and arylalkyloxyalkyl.

The term substituted includes groups substituted with one to four substituents independently selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, lower alicyclic, heterocyclic alkyl, hydroxy, lower alkoxy, lower aryloxy, perhaloalkyloxy, aralkyloxy, aralkyloxy, heteroaryloxy, heteroarylalkyl, heteroaralkyloxy, azido, amino, guanidino, amidino, halo, lower alkylthio, oxo, acylalkyl, carboxyester, carboxy, alkyl, amino, amino, acyloxy, amino, alkoxyaryl, arylamino, aralkylamino, phosphono, sulfonyl, carboxamidoalkylaryl, carboxamidoaryl , hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy, aminocarboxamidoalkyl, cyano, lower alkoxyalkyl, lower perhaloalkyl and arylalkyloxyalkyl. Substituted aryl and substituted heteroaryl preferably denote an aryl or heteroaryl group substituted with 1 to 3 substituents. Preferably, the substituents are selected from the group consisting of lower alkyl, lower alkoxy, lower perhaloalkyl, halo, hydroxy and amino. Substituted in the description of the R ⁵ or R ⁵³ group does not include cancellation.

The term aralkyl refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl and the like. and may be substituted. The term -aralkyl- denotes a divalent -arylalkylene- group.

The term -alkylaryl- refers to an -alk-aryl- group wherein alk is an alkylene group. Lower-alkylaryl also refers to groups wherein alkylene is lower alkylene.

The term lower refers herein to organic radicals or definitions of compounds of up to 10 carbon atoms, preferably up to 6 carbon atoms, and preferably from 1 to 4 carbon atoms. These groups may have straight or branched and somewhat cyclic chains.

The term arylamino (a) and aralkylamino (b) refer to the group -NRR ', wherein (a) R is aryl and R' is hydrogen, alkyl, aralkyl or aryl and (b) R is aralkyl and R 'is hydrogen, aralkyl, aryl or alkyl.

The term acyl describes a -C (O) R group wherein R is alkyl or aryl.

The term carboxy refers to the group -C (O) OH.

The term carboxyesters refers to the group -C (O) OR, wherein R is alkyl, aryl, aralkyl or alicyclic, all of which may be substituted.

The term oxo denotes = O in an alkyl group.

The term amino denotes -NRR ', wherein R and R' are independently selected from hydrogen, alkyl, aryl, aralkyl and alicyclic, all of which except hydrogen are optionally substituted and R and R 'may form a cyclic ring system.

The terms carbonylamino and -carbonylamino- refer to RCONR- and -CONR-, wherein each R is independently hydrogen or alkyl.

The term halogen or halo refers to -F, -Cl, -Br and -I.

The term alkylaminoalkylcarboxy- refers to an alkyl-NR-alk-C (O) -O- group wherein alk is an alkylene group and R and H are lower alkyl.

The term alkylaminocarbonyl- refers to an alkyl-NR-C (O) - group wherein alk is an alkylene group and R and H are lower alkyl.

The term -oxyalkyl- refers to the group -Ο-alk-, where alk is an alkylene group.

The term -oxyalkylamino- refers to -O-alk-NR-, wherein alk is an alkylene group and R is H or alkyl. Thus, -oxyalkylamino- is synonymous with -oxyalkyleneamino.

The term -alkylcarboxyalkyl- refers to the group -alk-C (O) -Ο-alk-, wherein each alk is independently an alkylene group.

The term alkyl refers to saturated aliphatic groups including straight, branched or cyclic chains. The alkyl groups may be optionally substituted. Suitable alkyl groups include, for example, those containing from 1 to about 20 carbon atoms (e.g., methyl, isopropyl, and cyclopropyl).

The term cyclic alkyl or cycloalkyl refers to alkyl groups which are cyclic groups containing 3 to 10 atoms, more preferably from 3 to 6 atoms. Suitable cyclic groups include norbornyl and cyclopropyl. These groups may be substituted.

The terms heterocyclic and heterocyclic alkyl refer to cyclic groups having from 3 to 10 atoms, more preferably from 3 to 6 atoms, containing at least one heteroatom, preferably 1 to 3 heteroatoms. Suitable heteroatoms include oxygen, sulfur and nitrogen. The heterocyclic groups may be attached via nitrogen or via a ring carbon atom. Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl and pyridyl.

The term phosphono refers to -PO ₃ R ² , wherein R is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl and alicyclic.

The term sulfonyl or sulfonyl refers to -S (O) 2 OR, wherein R is selected from the group consisting of hydrogen, alkyl, aryl; aralkyl and alicyclic groups.

The term alkenyl refers to unsaturated groups that contain at least one carbon-carbon double bond and include straight, branched, and cyclic groups. The alkenyl groups may be optionally substituted. Suitable alkenyl groups include allyl.

1-alkenyl refers to alkenyl groups where the double bond is located between the first and second carbon atoms. When the 1-alkenyl group is attached to another group, e.g. it is a W substituent attached to the cyclic phosphoramidate, attached to the first carbon atom.

The term alkynyl refers to unsaturated groups that contain at least one carbon-carbon triple bond and include straight, branched, and cyclic groups. The alkynyl groups may be optionally substituted. Suitable alkynyl groups include ethynyl.

1-alkynyl refers to alkynyl groups where the double bond is located between the first and second carbon atoms. When a 1-alkynyl group is attached to another group, e.g. it is a W substituent attached to the cyclic phosphoramidate, attached to the first carbon atom.

The term alkylene denotes a divalent saturated aliphatic group having a straight, branched or cyclic chain.

The term -cycloalkylene-COOR ³ denotes a divalent cyclic alkyl group or a heterocyclic group having 4 to 6 ring atoms with a 1 to 1 heteroatom selected from O, N and S. The cyclic alkyl or heterocyclic group is substituted with -C00R ³ .

The term acyloxy refers to an ester -O-C (O) R group wherein R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl or alicyclic.

The term aminoalkyl- denotes an NR ² -alk- group wherein alk is an alkylene group and R is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, aralkyl or alicyclic.

The term -alkyl (hydroxy) refers to an alkyl chain having a pendant OH group. When the term is used to describe a group X, the position of the OH group is at position a to the phosphorus atom.

The term alkylaminoalkyl- denotes an alkyl-NR-alk- group wherein alk is alkylene and R is H or lower alkyl. Lower alkviaminoalkyl- denotes groups wherein the alkyl and alkylene groups are lower alkyl and lower alkylene.

The term arylaminoalkyl- denotes an aryl-NR-alk- group, wherein alk is an alkylene group and R is H, an alkyl, aryl, aralkyl or alicyclic group. For lower arylaminoalkyl, the alkylene group is lower alkylene.

The term alkylaminoaryl- refers to an alkyl-NR-aryl- group wherein aryl is a divalent group and R is H, an alkyl, aralkyl or alrcyclic group. In lower alkylaminoaryl, the alkyl group is lower alkyl.

The term alkoxyaryl refers to an aryl group substituted with an alkyloxy group. In lower alkyloxyaryl, the alkyl group is lower alkyl.

The term aryloxyalkyl- denotes an alkylene group substituted with an aryloxy group.

The term aralkyloxyalkyl- refers to an aryl-alk-O-alk- group wherein alk is an alkylene group. Lower aralkyloxyalkyl refers to groups wherein the alkylene group is lower alkylene.

The term -alkoxy- or -alkyloxy- refers to the group -alk-Ο-, where alk is an alkylene group. The term alkoxy- denotes an alkyl-O- group.

The term -alkoxyalkyl- or -alkyloxyalkyl- refers to the group -alk-O-alk-, wherein each alk is independently selected from an alkylene group. In lower-alkoxyalkyl, each alkylene is lower alkylene.

The term alkylthio- and -alkylthio- refers to alkyl-Sa-alk-S- groups wherein alk is an alkylene group.

The term -alkylthioalkyl - denotes an -alk-S-alk group, wherein each alk is independently an selected alkylene group. In the lower-alkylthioalkyl group, each alkylene group is lower alkylene.

The term alkoxycarbonyloxy- refers to alkyl-O-C (O) -O-.

The term aryloxycarbonyloxy- refers to aryl-O-C (O) -O-.

The term alkylthiocarbonyloxy- refers to alkyl-S-C (O) -O-.

The term -alkoxycarbonylamino- denotes -alk-OC (O) -NR ¹ -, wherein alk is alkylene and R ¹ is selected from the group consisting of hydrogen, alkyl, aryl, alicyclic and aralkyl.

The term -alkylaminocarbonylamino- denotes an alk-NPC-C (O) -NR ¹ - wherein alk is an alkylene containing hydrogen, alkyl, and each R ¹ is selected from an aryl, aralkyl and alicyclic group.

The term amido or carboxamido refers to NR ² -C (O) and RC (O) -NR ¹ -, wherein each R and R ¹ is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl and alicyclic. Terine does not include urea, -NR-C (O) -NR-.

The term -carboxamidoalkylaryl or carboxamidoaryl refers to aryl-alk-NR 1 C (O) - and -ar-NR ¹ -R C (O) - wherein ar is aryl, alk is alkylene and each R ¹ is selected from hydrogen, alkyl , aryl, aralkyl and alicyclic groups.

The term -alkylcarboxamido- or -alkylcarbonylamino- refers to the group -alk-C (O) N (R) - wherein alk is an alkylene group and R is H or lower alkyl.

The term -alkylaminocarbonyl- refers to the group -alk-NR-C (O) wherein alk is an alkylene group and R is H or lower alkyl.

Aminocarboxamidoalkyl- term refers to the group NR ^Z-C (0) -N (R) -alk- wherein R is alkyl or H and alk denotes an alkylene group. Lower aminocarboxamidoalkyl- also denotes groups wherein alk is lower alkylene.

The term thiocarbonate refers to -O-C (S) -O-, either in a chain or in a cyclic group.

The term hydroxyalkyl refers to an alkyl group substituted with one OH group.

The term haloalkyl refers to an alkyl group substituted with one halo group selected from the group consisting of I, Cl, Br and F.

The term cyano denotes -ON.

The term nitro refers to -NO2.

The term acylalkyl refers to alkyl-C (O) -alk, where alk is alkylene.

The term heteroarylalkyl refers to an alkyl group substituted with a heteroaryl group.

When used in conjunction with X, X ² , X ³ or X ⁴ , the term -1,1-dihaloalkyl- denotes a group X, X ² , X ³ or X ⁴ wherein the halogens at the 1-position are and to the phosphorus atom.

The term perhalo refers to groups wherein each CH bond has been replaced by a C-halo bond for an aliphatic or aryl group. Suitable perhaloalkyl groups include, for example, CF ₅ and CFCI 2.

The term guanidino refers to both -NR-C (NR) -NR ² and -N = C (NR ² ) ₂ , wherein each group is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl and alicyclic, wherein: with the exception of hydrogen, they are all optionally substituted.

The term amidino refers to -C (NR) -NR ² wherein each R group is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl and alicyclic, all of which, except hydrogen, are all optionally substituted.

The term 2-thiazolyl or 2-oxazolyl or 2-selénozolyl refers to the corresponding base and its attachment of the X group, X ^2, X ³ or X ⁴ in the 2-position of the heterocycle.

The term pharmaceutically acceptable salt includes salts of compounds of formulas I, II, II, II-A, III, III-A, IV, IV-A, V-1,

VIA, V-2, V-2-A, VI, VI-A, VII-1, VII-1A, VII-2 and VII-2-A, X or XA and their prodrugs derived from a combination of the compounds of the invention and organic or inorganic acids or bases. Suitable acids include, for example, hydrochloric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and maleic acid.

The term prodrug is used herein to refer to any compound that, when administered to a biological system, generates a drug substance (biologically active agent) in one or more steps involving spontaneous chemical reactions, enzymatically catalyzed chemical reactions, or both. Standard prodrugs are formed using groups attached to functional groups such as e.g. H0-, HS-, HOOC-, R ² N-, associated with the FBPase inhibitor, that cleave in vivo. Prodrugs of these groups are well known in the art and are often used to enhance oral bioavailability or other properties favorable to formulation, administration or drug activity. Standard prodrugs include, but are not limited to, carboxylate esters wherein the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of hydroxyls, thiols, and amines wherein the attached groups are acyl, alkoxycarbonyl, aminocarbonyl, phosphate or sulfate. Standard prodrugs of phosphonic acids are also included and may be represented by R ¹ in formulas I, ΙΑ, II, II-A, III, III-A, IV, IV-A, VI, Vla, V-2, V-2 A, VI, VI-A, VII-1, VII-1A, VII-2, and VII-2-A, X or XA. The groups are illustrated by examples, but not exhaustively, and one skilled in the art could prepare other than known prodrug variants. These prodrugs of compounds I, II, II, II-A, III, III-A, IV, IV-A, VI, VIA, V-2, V-2-A, VI, VI-A, VII-1, VII -A, VII-2 and VII-2-A, X or XA are within the scope of this invention. Prodrugs must undergo some form of chemical transformation to produce a compound that is biologically active. In some cases, pro-drugs are biologically active, usually less than the drug alone, and serve to improve efficacy or safety through increased oral bioavailability, pharmacodynamics, half-life, and the like.

The term prodrug ester in the present invention refers to the following groups from a combination of these groups (the calculation is not exhaustive):

[1] Acyloxyalkyl esters which are well described in the literature et al., J.

represented by the general formula A.

wherein R, R 'and R' 'are independently hydrogen, alkyl, aryl, alkylaryl or an acyclic group (see WO 90/08155, WO 90/10636).

[2] Additional acyloxyalkyl esters are possible in which an alicyclic ring is formed, as shown in formula B. provided that these esters generate nucleotides containing

It has demonstrated phosphorus within cells through a designed sequence of reactions beginning with de-esterification followed by a series of elimination reactions (e.g., Freed et al., Biochem. Pharm. 38: 3193-3198

IN

wherein R is hydrogen, alkyl, arylthio, alkylamino, aryl.

aryl, alkylaryl, alkoxy, alkylthio, arylamino, cycloalkyl or alicyc20 [3] Another class of these double esters, known as alkylcarbonyloxymethyl esters, are the compounds shown in formula A, wherein R is alkoxy, aryloxy, alkylthio, alkylthio, arylthio, arylthio, arylthio R 1 and R 2 are independently hydrogen, alkyl, aryl, alkylaryl and alicyclic. This class of compounds has been studied in the field of β-lactam antibiotics (Tatsuo Nishimura et al., J. Antibiotics, 1987, 40 (1), 81-90, for a review, see Ferres, H., Drugs of Today, 1983, 19, 499 ). Recently, Cathy, M.S., et al. (Abstract from AAPS Western Regional Meeting, April, 1997) showed that these alkyloxycarbonyloxymethyl ester prodrugs of (9 - [(R) -2-phosphonomethoxy) propyl] adenine (PMPA) are available in up to 30% of dogs.

[4] Aryl esters have also been used as phosphonate prodrugs (e.g., Erion, DeLambert et al., J. Med. Chem. 37: 498, 1994, Serafinowska et al., J. Med. Chem. 38, 1372, 1995) . Phenyl, as well as mono and polysubstituted phenyl proesters, generate parent phosphonic acid in animal and human studies (Formula C). Another approach has been described wherein Y is a carboxylic ester ortho to phosphate. Khamnei and Torrence, J. Med. Chem., 39, 4109-4115 (1996).

wherein Y is hydrogen, alkyl, aryl, arylalkyl, alkoxy, acyloxy, halogen, amino, alkoxycarbonyl, hydroxy, cyano, or alicyclic.

[5] Benzyl esters that generate parent phosphonic acids are also described. In some cases, using the substituents in the para position may accelerate the hydrolysis. Benzyl analogs with 4-acyloxy or 4-alkyloxy groups (Formula D, X = H,

OR or O (CO) R or O (CO) OR) can generate the 4-hydroxy compound more readily than by the action of enzymes, e.g. oxidases, esterases, and the like. Examples of these prodrugs are described in Mitchell et al., J. Chem. Soc. Perkin Trans I, 2345 (1992), Brook et al., WO 91/19721.

wherein X and Y are independently hydrogen, alkyl, aryl, alkylaryl, alkoxy, acyloxy, hydroxy, cyano, nitro, perhaloalkyl, halogen, or alkyloxycarbonyl, and R 'and R are independently H, alkyl, aryl an alkylaryl group, a halogen, and an alicyclic group.

[6] Also described are thio-group-containing phosphonate proesters that are useful for delivering FBPase inhibitors to hepatocytes. These proesters contain a protected thioethyl group as shown in Formula E. One or more of the phosphonate oxygen may be esterified. Since the mechanism leading to de-esterification requires the generation of free thiolate, a variety of thiol protecting groups are possible. For example, the disulfide is reduced by a reductase mediated process (Puech et al., Antiviral Res. 22, 155-174 (1993)). Thioesters will also generate free thiolates after esterase-mediated hydrolysis. Benzaria et al., J. Med. Chem. 39, 4958 (1996). Cyclic analogs are also possible and have been shown to release phosphonate in isolated rat hepatocytes. The following cyclic disulfides have not been previously described and are novel.

v) formula E wherein Z is an alkylcarbonyl group, an alkoxycarbonyl group, an arylcarbonyl group or an alkylthio group.

Other examples of suitable prodrugs include the proester classes described in Biller and Magnin (US Patent No. 5,157,027), Serafinowska et al., (J. Med. Chem. 38, 1372 (1995)), Starrett et al., (J. Med., 37, 1857 (1994)), Martin et al., J. Pharm. Sci. 76, 180 (1987), Alexander et al., Collect. Czech. Chem. Commun., 59, 1853 (1994)) and EPO patent application 0 632 048 A1. Some of the listed structural classes are optionally substituted, including fused lactones attached at the ω position (formulas E-1 and E-2) and optionally substituted 2-oxo-

-1,3-dioxolenes attached via methylene k phospho- (formula E-3) such as needed: 0 0 0 A Ä A Q? 0 0 H 0 / o-p— | O-P-- I R -O-p— I omega 1 1 1 3-ptalidyl 2-furan · 2-oxo-4,5- • didehydro-1,3- 5-yl -dioxolár.ľľ.eiyl (E-I) (E-2) 1 (E-3)

wherein R is hydrogen, alkyl, cycloalkyl or alicyclic, and

Y is hydrogen, alkyl, aryl, alkylaryl, cyano, alkoxy, acyloxy, halogen, amino, alicyclic, or alkoxycarbonyl.

Prodrugs of Formula E-3 are examples of optionally substituted alicyclic derivatives wherein the cyclic moiety comprises a carbonate or thiocarbonate.

[7] Propyl phosphonate proesters can also be used to deliver FBPase inhibitors to hepatocytes. These proesters may contain a hydroxyl group or derivatives of a hydroxyl group at the 3-propyl position as shown in Formula F. One or more of the phosphonate oxygen may be esterified.

wherein R is alkyl, aryl or heteroaryl,

X is hydrogen, alkylcarbonyloxy or alkyloxycarbonyloxy; and

Y is alkyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, halogen, hydrogen, hydroxy, acyloxy or amino.

[8] Phosphoramidate derivatives have been used as phosphate prodrugs (e.g., McGuigan et al., J. Med. Chem., 1999, 42, 393 and references cited) and phosphonate prodrugs (Bischofberger et al., U.S. Pat.

798,340 and references cited therein) as shown in the formulas

G a H.

0 II NAV alkyl --- P- -N-- R ' | . H \ HN R · b CO alkyl R ^ R '

formula H formula G

Cyclic phosphoramidates have also been studied as phosphonate prodrugs, because of their possible higher stability compared to non-cyclic phosphoramidates (e.g., Starrett et al., J. Med. Chem. 1994, 37, 1857).

Another type of nucleotide prodrugs has been described as a combination

S-acyl-2-thioethyl ester and phosphoramidate (Egron et al., Nucleosides and Nucleotides 1999, 18, 981) as shown in Formula J.

HN

Other prodrugs are possible based on the literature as substituted ethyls, e.g. bis (trichloroethyl) esters as described in McGuigan et al., Bioorg. Med. Chem. Lett. 3: 1207-1210 (1993) and as phenyl and benzyl combined nucleotide esters described in Meier C. et al., Bioorg. Med. Chem. Lett. 7: 99-104 (1997).

structure

has a plane of symmetry through the phosphorus-oxygen double bond when R ° = R ⁶ , V = W, W '= H, and V and W point both up or down. The structure has a center of symmetry or an alternate axis of symmetry with the axis running through the oxygen-phosphorus double bond when R ⁵ = R ⁶ , V = W, W '= H and V and W are substituents on opposite sides of the plane, one pointing down and the other pointing hcreate. The same is true of structures where each -NR ⁶ is replaced with -O-.

Cis-stereochemistry, when used to describe stereochemistry at phosphorus in cyclic phosphoramidates, indicates a configuration wherein V or W are trans to the phosphorus-oxygen double bond.

The terms cyclic T, 3'-propane ester, cyclic 1,3-propane ester, cyclic 1 ', 3'-propanyl ester and cyclic 1,3-propanyl ester refer to the following:

The terms V ² and Z ² are joined together via an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 atoms, optionally containing 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom of three atoms from both groups Y as follows:

attached to phosphorus includes

The above structure (left) has an additional 3 carbon atoms that form a five membered cyclic group. This cyclic group must have the above substitution in order to be oxidized.

The terms V and Z are joined together through an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, which is fused to an aryl group attached at the β and γ position to Y attached to the phosphorus, including the following:

The terms V and W are joined together through an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy and aryloxycarbonyloxy attached to one of the above carbon atoms. which is three atoms from group Y attached to phosphorus includes the following:

More likely said structure having an acyloxy substituent which is three carbon atoms from Y and an optional substituent, -CH ₃ , new 6-membered circle. Must there be at least one hydrogen on each of us leduj úcich positions: carbon connected to Z, both carbons and to carbon marked 3 and carbon connected to the above OC (O) CH ₃ • expression W and W 'are linked together through an additional 2 to

atoms to form a cyclic structure, optionally containing 0 to 2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl include the following:

The above structure has V = aryl and a spiro-fused cyclopropyl group for W and W '.

The term cyclic phosph (oramid )ate refers to

FROM

wherein Y is independently -O- or -NR ⁶ -. The attached carbon atom to V must have a CH bond. The carbon atom attached to Z must also have a CH bond.

The term phosphoramidate refers to phosphonates and phosphoramidates which are compounds of the formula -PO (YR ¹ ) (YR ¹ ), including the cyclic form, wherein Y is independently -O- or -NR ⁶ -.

The term increase refers to the improvement of particular properties.

The term increased oral availability refers to an increase in at least 50% absorption of the dose of the parent drug or prodrug (not according to the invention) from the gastrointestinal tract. More preferably at least 100%. Oral bioavailability measurement typically refers to the measurement of a prodrug, drug or drug metabolite in blood, tissues or urine after oral administration compared to measurement after systemic administration.

The term parent drug refers to any compound that provides the same biologically active agent. The parent dosage form is P (O) (OH) ₂ -XM and standard prodrugs such as esters.

The term drug metabolites refers to a compound produced in vivo or in vitro from a parent drug, which may include a biologically active drug.

The term pharmacodynamic half-life refers to the time after drug or prodrug administration at which one half of the measured pharmacological response is observed to disappear. The pharmacodynamic half-life is increased when the half-life is preferably increased by at least 50%.

The term pharmacokinetic half-life refers to the time after administration of a drug or prodrug at which the plasma or tissue concentration of the drug is reduced by one-half.

The term glycemic control describes reducing postprandial and / or decreasing blood glucose concentration, reducing hemoglobin Ale concentration, ameliorating glycosuria, reducing hepatic glucose performance, or adjusting glucose body stores or any standard parameter useful for determining glucose homeostasis.

The term therapeutic index describes the ratio of dose of a drug or prodrug that produces a therapeutically advantageous response compared to a dose that produces an adverse response such as death, an increase in signs that indicate toxicity and / or pharmacological side effects.

The term biologically active drug or agent refers to a chemical entity that produces a biological effect. Thus, the active drug or agent includes compounds that are active as P (O) (OH) ₂ -XM.

The term "therapeutically effective amount" refers to an amount having any therapeutic effect in the treatment of a disease or condition.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to combination therapy and formulations for the treatment of diabetes or diseases and conditions responsive to altered glycemic control and / or increased peripheral insulin sensitivity and / or increased insulin secretion. Therapy comprises administering at least one FBPase inhibitor and at least one antidiabetic agent, either together or at different times, to obtain the desired response. While any suitable antidiabetic agent may be used to combine with an FBPase inhibitor, the antidiabetic agents used in the invention are typically selected from one or more of the following groups: (a) insulin secretagogues (e.g., sulfonylureas, nonsulfonylureas, GLP-1 receptor agonists, inhibitors DPP-IV or other agents known to increase insulin secretion), (b) insulin or insulin analogs, (c) insulin sensitizers (eg rosiglitazone and pioglitazone), (d) biguanides (eg metformin and phenformin) (e) α-glucosidase inhibitors (e.g. acarbose), (f) glycogen phosphorylase inhibitors, (g) glucose-6-phosphatase inhibitors, (h) glucagon antagonists, (i) amylin antagonists, or (j) fatty acid oxidation inhibitors.

In particular embodiments of the present invention, the combination of at least one FBPase inhibitor with at least one of the aforementioned antidiabetic agents results in a decrease in hepatic glucose production as compared to a reduction in glucose when an antidiabetic agent is administered in the absence of an FBPase inhibitor. In addition, combination therapy may result in improved insulin sensitivity and / or insulin secretion compared to the values observed for each agent separately, as well as providing beneficial effects on the metabolism of sugars and / or lipids (e.g. fat) and / or proteins.

In particular embodiments of the present invention, the combination therapy achieves similar advantages as seen with therapy with one or the other agent alone, but at significantly lower therapeutic doses. This phenomenon can be particularly advantageous when potentially harmful side effects are associated with the therapy. For example, in a particular embodiment of the present invention, the combination therapy of the present invention is useful in alleviating some of the potentially harmful effects associated with FBPase inhibitor therapy. Similarly, the combination of the invention may ameliorate some of the potentially harmful effects associated with anti-diabetic agents such as hyperinsulinemia, hypoglycemia, weight gain, gastrointestinal disorders, liver abnormalities, and cardiovascular side effects.

Compared to the responses associated with therapies involving anti-diabetic agents without an FBPase inhibitor, the combination of the invention has the ability to increase the primary response rate. In addition, the combination of the invention has the ability to reduce, delay or prevent the occurrence of secondary failure.

The present invention also relates to methods and compositions for treating animals having NIDDM or IDDM by administering a composition comprising the same. a pharmaceutically acceptable amount of at least one FBPase inhibitor; and a pharmaceutically effective amount of at least one additional antidiabetic agent. In particular embodiments, the compositions of the invention are useful in treating, ameliorating, or preventing one or more symptoms of NIDDM or IDDM. In addition to methods of treatment and compositions for treating animals having NIDDM or IDDM, methods and compositions for treating diseases and conditions characterized by insulin resistance, including obesity, hypertension, increased glucose tolerance, pregnancy diabetes, and polycystic ovarian syndrome are also within the scope of the invention. . In addition, individuals with syndrome X, kidney disease, or pancreatitis are also effectively treated in a particular embodiment with the combination therapy of the invention. Individuals referred to as brittle diabetics may also be treated in particular embodiments of the invention with the combination therapy of the invention.

Particularly preferred combinations have these preferred uses, as well as high potency and low toxicity. The toxicity of the combination can be determined, for example, by standard pharmaceutical procedures in cell cultures or experimental animal models, e.g. by specifying LD50 and ED50 ·

The combinations of the invention may be administered to patients in any suitable manner, for example, orally, rectally, nasally, topically, vaginally, parenterally (including the subcutaneous, intramuscular, intravenous and intradermal routes) and transdermally. Oral administration is preferred.

Combination therapy entails administering the agents to the host, either separately or simultaneously. In one embodiment, both agents are not administered simultaneously, either in the same capsule or in the form of separate capsules. In one embodiment, both agents are administered during a meal (i.e., the time period begins just before the meal and ends just after the meal). In another embodiment, the antidiabetic agent is administered during a meal and the FBPase inhibitor is administered during a fasting period such as during sleep. In one embodiment, both agents are administered within one hour, 30 minutes, 10 minutes, 5 minutes, or 1 minute apart. In another embodiment, one agent is administered first and the other is administered 1 to 12 hours, typically 3 to 6 hours, 6 to 9 hours, or 9 to 12 hours after the first.

FBPase inhibitors

The combination of the invention comprises at least one FBPase inhibitor. In most embodiments, the combination will include a single FBPase inhibitor. The FBPase inhibitors used in the present invention are compounds that can inhibit human FBPase activity (Examples AB), can inhibit glucose production in hepatocytes (Examples CD), reduce glucose concentration in fasting animals (Examples EG), or reduce blood concentrations of glucose in diabetic animal models (Examples V and W). Preferred FBPase inhibitors are compounds that inhibit enzyme activity as determined by performing in vitro inhibition studies (Examples A and B).

In some cases, in vivo metabolic activation of the compounds may require the generation of FBPase inhibitors. This class of compounds may be inactive in screening for enzyme inhibition (Example A), may or may not be active in hepatocytes (Examples C and D), but is active in vivo as demonstrated by glucose lowering in normal fasted rats (Examples E, F) , G) and / or in animal models of diabetes (Examples K, V to Z, AA to JJ).

Although the present invention is not limited to the following structure, FBPase inhibitors have the following formulas:

O, II

R ¹ YP — M

R ¹⁸ O

R ¹⁴ ---- C (O) - (CR ¹² R ¹³ ) _{n -} N - P - M

NR ¹⁵ R ^ie

LA

A ²

R ¹ ·

R ^m - (O) C - (CR ¹² R ¹³ ) _n - |! | ---

r ¹⁵ r ¹ · ^ mA

R ¹ * O

^Rm - <O) C- ^(CR "R ¹³⁾ '- N-fluoro-Q ^ xi] £ ^ NR ¹⁵ R ^1'

IV-A

V-1-A

Π

R ^m 40) C - (CR 1 - V n - PH - X)

(X-A)

VI

VI-A

VH-1

VII-I-A

V H-2

R ¹⁸ '

I ⁰ r '^ ojc-^ ^ ^' n — — —N — P — x ⁴ nr ¹⁵ r ¹⁸

V H-2-A

especially great are compounds of formula I and IA 0 II R ¹⁸ 0 I II R ¹ YP-M | R ¹⁴ ---- C (O) --- (CR ¹² R ¹³⁾ _n - I II -N-P-M I. YR ¹ 1r ^1s r ¹⁸ I IA

or a pharmaceutically acceptable prodrug thereof, wherein the compounds of Formula I and IA are converted to in vivo or in vitro

M-PO3 ² ', which inhibits FBPase. In these preferred compounds:

Y is independently selected from -O- and -NR ⁰ , with the proviso that;

when Y is -O-, R ¹ attached to -O- is independently selected from the group consisting of hydrogen, alkyl, optionally substituted aryl, optionally substituted alicyclic, wherein the cyclic group comprises carbonate or thiocarbonate, optionally substituted -arylalkyl, -C (R ² ) 20 C (O) NR ² 2, -NR ² -C (O) -R ³ , -C (R ² ) ₂ -00 (O) R ³ , -C (R ² ) 2-O-C (O) OR ³ , -C (R ² ) 2 OC (O) SR ³ , -alkyl-SC (O) R ³ , -alkyl-SS-alkylhydroxy and -alkyl-SSS alkylhydroxy, when Y is -NR ⁵ -, R ¹ attached to NR ⁵ is independently selected from hydrogen, - [C (R ² ) 2] q -COOR ³ , -C (R ⁴ ) 2 COOR ³ , - [ C (R ² ) ₂ ] _q - C (O) SR and a -cycloalkylene COOR ³ group, wherein q is 1 or 2 when only one Y is -O-, wherein -O- is not part of a cyclic group containing the other Y, the other Y is -N (R ¹⁸ ) - (CR ¹² R ¹³ ) C (O) -R ¹⁴ , and when Y is independently selected from -0 - and -NR ⁰ , R ¹ and R ¹ together are alkyl-SS-alkyl- and form a cyclic group, or R ¹ and R * form:

where

a) V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl, or

V and Z are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group being fused to an aryl group at the β and γ position to Y attached to V; or

Z is selected from the group consisting of -CHR ² OH, -CHR ² OC (0) R ^3, -CHR ² 0C (S) R ^3, -CHR ² OC (S) OR ^3, -CHR ^y OC (0) SR ^J , -CHR ² OCO ² R ³ , -OR ² , -SR 1, -CHR ² N 3, -CH ₂ aryl, -CH (aryl) OH, -CH (CH = CR ²⁾ 2) OH, -CH (CSCR ^of) OH, -R ^2, -NR 2 group, a group -OCOR ^3, -OCO2R group ^3, group ³ -score, -SCO2R group ^3, NHCOR ² group, -NHCO ² R ³ , -CH ₂ NHaryl, - (CH ₂ ) _p -OR ^2, and - (CH ₂ ) _p -SR ² , wherein p is an integer of 2 or 3, or

Z and W are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl; or

W and W 'are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or

W and W 'are joined together via an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl;

b) V ² , W ² and W are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl group;

Z ² is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OC (S) OR ³ , -CHR ² OC (0) SR ^I, the group -CH (aryl) OH, -CH (CH = CR '2 R ^s OH, -CH (C = CR ^Z) OH, -SR ^2, -CH ₂ NHaryl, group -CH ₂ aryl;

V ² and Z ² are joined together via an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 ring atoms, optionally containing 1 heteroatom, and substituted with a hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy group attached to a carbon atom of three atoms from group Y attached to phosphorus;

c) Z 'is selected from the group consisting of -OH, -OC (O) R ³ , -OCO ² R ³ , and -OC (O) SR ³ ;

D 'is hydrogen;

D 1 is selected from the group consisting of hydrogen, alkyl, -OR ² , -OH, and -OC (O) R ³ ;

each W ³ is independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

with the proviso that:

a) V, Z, W, W 'are not all hydrogen and V ² , Z ² , W ² , W are not all hydrogen;

R ² is selected from R ³ and hydrogen;

R ³ is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;

each R ⁴ is independently selected from the group consisting of hydrogen, alkylene, alkylenearyl and aryl, or together R ⁴ and R ⁴ are joined via 2 to 6 atoms, optionally containing one heteroatom selected from O, N and S;

R c is selected from the group consisting of hydrogen, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl;

n is an integer from 1 to 3;

R ¹⁸ is independently selected from the group consisting of hydrogen, a lower alkyl group, an aryl group, an aralkyl group, or R ¹² and R ¹⁸ are joined together via 1 to 4 carbon atoms to form a cyclic group;

each R ¹² and each R ¹³ are independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, lower aralkyl, all of which may be optionally substituted or R ¹² and R ¹³ are joined together via 2 to 6 carbon atoms optionally containing 1 heteroatom selected from O, N and S to form a cyclic group;

each R ¹⁴ is independently selected from the group consisting of -OR ¹⁷ , -N (R ¹⁷ ) 2, -NHR ¹⁷ , -SR ^17, and -NR ² R ²⁰ ;

R ¹⁵ is selected from the group consisting of hydrogen, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ¹⁶ are joined together via 2 to 6 atoms to form a cyclic group wherein the cyclic group optionally includes one heteroatom selected from 0 , N and S;

R ¹⁶ j ^E selected from a group - (CR ^d R ¹³⁾ n C (O) R ^14, H, lower alkyl, lower aryl, and lower aralkyl, or R ¹⁵ and R ¹⁶ are connected via the 2 and 6 atoms to form a cyclic group, wherein the cyclic group optionally comprises one heteroatom selected from O, N and S;

each R ¹⁷ is independently selected from the group consisting of lower alkyl, lower aryl and lower aralkyl, or when R ¹⁴ is -N (R ¹ ) ₂ , both R ¹⁷ are joined via 2 to 6 atoms to form a cyclic group wherein the cyclic group optionally comprises one heteroatom selected from O, N and S;

R ²⁰ is selected from the group consisting of hydrogen, lower alkyl R ^3, and -C (O) -lower R ³ .

Preferred FBPase inhibitors are those wherein M-PO3 ² has an IC ₅₀ on an isolated human FBPase enzyme of less than or equal to 5 μΜ. Similarly preferred are FBPase inhibitors having an IC = _{0 of} less than 50 mM for glucose production in isolated rat hepatocytes. Particularly preferred are those compounds that bind to AMP instead of FBPase.

Preferably, the oral bioavailability is at least 5%. More preferably, the oral bioavailability is at least 10%.

Prodrugs of Formula IA may have two isomeric forms on the phosphorus. Preferably, the phosphorus is not chiral. It is also preferred that the chiral center is not at the amino group attached to the phosphorus. It is also preferred that N is 1 and R ¹² is hydrogen, then the carbon attached to R ¹² and R ¹³ has the stereochemistry S.

In one aspect, compounds of general formula are preferred

Or of formula IA wherein M is -XR ^; or a pharmaceutically acceptable prodrug or salt thereof, wherein R ² is selected from:

Each D is independently selected from group C,

N, O, S and Se and wherein only one G is O, S or Se and at most one G is N;

each G 'is independently selected from C and N and wherein no more than two G' groups are N;

A is selected from the group consisting of hydrogen, -NR ⁴ 2, -CONR ⁴ 2, -CO ₂ R ³ , halogen, -S (O) R ',

-SO ² R ³ , alkyl, alkenyl, alkynyl, perhaloalkyl, haloalkyl, aryl, -CH 2 OH, -CH 2 NR ⁴ 2, -CH ₂ CN, -CN, -CN, -C (S) NH ₂ , -OR ^3, -SR ^3, -N _3, -NHC (S) NR ⁴ 2, -NHAc group, a is zero;

each B and D are independently selected from-H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, -C ^(O) R, -C (O) SR ³ , -SO ² R ¹¹ , -S (O) R ³ , -CN, -NR ⁹ 2, -OR ³ , -SR ³ , perhaloalkyl, halogen, -NO 2, and zero, all except hydrogen , -CN groups, perhaloalkyl, -NO _2, and halogen are optionally substituted;

E is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, -C (O) OR ³ , -CONR ⁴ 2, -CN, -NR ⁹ 2 -NO ₂ , -OR ³ , -SR ³ , perhaloalkyl, halogen and zero, all except hydrogen, cyano, perhaloalkyl and halogen are optionally substituted;

J is selected from hydrogen or zero;

X is an optionally substituted linking group that connects R ⁵ to a phosphorous atom through 2 to 4 atoms, injected with 0 to 1 heteroatom selected from N, O and S, provided that when X is urea or carbamate, then there are 2 heteroatoms, measured by the shortest path between R ⁵ and the phosphorus atom and wherein the atom attached to the phosphorus is a carbon atom and wherein X is selected from the group consisting of -alkyl (hydroxy) -, -alkynyl, -heteroaryl, -carbonylalkyl, 1, 1-dihaloalkyl, alkoxyalkyl, alkyloxy, alkylthioalkyl, -alkyl, thio, -alkylaminocarbonyl, alkylcarbonylamino, -alkoxycarbonyl, -carbonyloxyalkyl, optionally substituted with alkyl, -alkoxycarbonylamino, -alkoxycarbonylamino, -alkoxycarbonyl, X is not substituted with -COOR ² , -SO 3 H, or PO ³ R ² 2;

R ² is selected from R ³ and hydrogen;

R ³ is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;

each R ⁴ is independently selected from the group consisting of hydrogen and alkyl or R ⁴ and R ⁴ together form a cyclic alkyl group;

each R ⁹ is independently selected from hydrogen, alkyl, aralkyl and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group;

R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ² ;

with the proviso that:

1) when G 'is N, then A, B, D or E is zero;

2) at least one of A and B or A, B, D and E is not selected from hydrogen or zero;

3) when R ⁵ is a six membered ring, then X is not a bivalent atom, an optionally substituted -alkoxy group or an optionally substituted -alkylthio group;

4) when G is N, then A or B is not a halogen or a group directly bonded to G via a heteroatom;

5) when X is not an aryl group, then R ⁵ is not substituted with two or more aryl groups.

More preferred R ⁵ groups include pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiazolyl, pyrazolyl, isoxazolyl,

1,2,3-oxadiazolyl

1,2,4-oxadiazolyl,

1,2,5-oxadiazolyl

1,3,4-oxadiazolyl,

1,2,4-thiadiazolyl, with a group,

1,3,4-thiadiazolyl, pyridinyl, pyrimidines, pyrazinyl, pyridazinyl,

A 1,3,5-triazinyl group, a 1,2,4-triazinyl group, and a 1,3-seza-azolyl group, all of which contain at least one substituent.

Preferably R ³ is not 2-thiazolyl or 2-oxazolyl. When R ⁵ is 2-thiazolyl, 2-oxazolyl or 2-selenazolyl and X is -alkoxyalkyl, -alkylthioalkyl, -alkyloxy or -alkylthio, then it is preferred that A is not -CONH 2 and B is not hydrogen. Similarly, when R ⁵ is 2-thiazolyl, 2-oxazolyl or 2-selenazolyl, then X is not -alkyloxyalkyl, -alkylthioalkyl, -alkyloxy or -alkylthio.

A is selected from the group consisting of hydrogen, -NR ₂ , -CONR ⁴ 2, -CO ² R ³ , halogen, C 1 -C 6 alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C 1 - C 8 perhaloalkyl, C 1 -C 8 haloalkyl, aryl, -CH 2 OH, -CH ₂ NR ⁴ 2 / -CH 2 CN, -CN, -C (S) NH 1, -OR ⁴ , -SR ⁴ , a group -N 3, -NHC (S) NR ⁴ 2, -NHAc, and a group of zero.

B and D are independently selected from-H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alxoxyalkylovú, -C (O) ^RU, -C (O) SR ^3, -SO 2 R ⁿ , -S (O) R ³ , -CN, -NR ² 2, -OR ³ , -SR ³ , perhaloalkyl, halogen and zero, all except hydrogen, CN, perhaloalkyl and halogen are substituted.

E is selected from hydrogen, C -C alkyl, C ₂ -C ₆ alkenyl, C ₂ -C alkynyl, aryl, C4-C6 alicyclic, alkoxyalkyl, -C (O) OR ^3, -CONR ⁴ 2, -CN, -NR ⁹ 2, -OR ³ , -SR ³ , C 1 -C 6 perhaloalkyl, halogen and zero, all except hydrogen, CN, perhaloalkyl and halogen are optionally substituted.

Each R ⁴ is independently selected from the group consisting of hydrogen and C 1 -C ₂ alkyl.

More preferred are compounds of formula I or ΣΑ, wherein M is -XR ⁵ , wherein R ⁵ is selected from:

where

A is selected from the group consisting of hydrogen, -NR ⁴ 2, -CONR ⁴ 2, -CO ₂ R ³ , halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 perhaloalkyl, C 1 -C 6 haloalkyl, aryl, -CH 2 OH, -CH 2 NR ⁴ 2, -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , a group -N 3, -NHC (S) NR ⁴ 2, and -NHAc group;

B and D "are independently selected from-H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, -C ^(O) R, -C (O) SR ^3, a group -SO 2 R ^n, -S (O) R ^3, -CN, -NR ⁹ 2, -OR ^3, -SR ^3, perhaloalkyl, and halo, all except H, CN, perhaloalkyl the groups and halogen are optionally substituted;

E is selected from the group consisting of hydrogen, C 1 -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₄ -C ₆ alicyclic, alkoxyalkyl, -C (O) OR ³ , -CONR ⁴ 2, -CN, -NR ⁹ 2, -OR ³ , -SR ³ , C 1 -C 6 perhaloalkyl and halogen, all except hydrogen, CN, perhaloalkyl and halogen are optionally substituted ;

each R ³ is selected from the group consisting of C 1 -C ₅ alkyl, C 6 aryl, C ₃ -C 6 heteroaryl, C ₃ -C 8 alicyclic, C 2 -C 7 heteroalicyclic, C 7 -C 10 aralkyl and C ₄ -C 8 heteroaralkyl ;

each R ⁴ and R ⁹ is independently selected from the group consisting of hydrogen and C ₁ -C ₂ alkyl;

X is selected from the group consisting of -heteroaryl, -alkylcarbonylamino, -alkylaminocarbonyl, and

an alkoxycarbonyl group;

each R ¹¹ is selected from the group consisting of -NR ⁴ ₂ , -OH, -OR ³ , C 1 -C 6 alkyl, aryl, and C 3 -C 6 heteroaryl.

More preferred are those compounds wherein X is -heteroaryl or -alkoxycarbonyl.

Particularly preferred are those compounds of formula V-1-A and formula V-2-A wherein

A is selected from the group consisting of -NH ₂ , -CONH ₂ , halogen, -CH 3, CF 3, -CH ₂ -halo, -CN, -OCH 3, -SCH _3, and hydrogen;

B is selected from hydrogen, -CfOlR ^11, -C (O) ^SR3, alkyl, aryl, alicyclic, halo, -CN, -SR ^3, -OCH 3, and -NR ⁹ ₂ .

D 'is selected from H, -C ^(O) R, -C (0) SR ^3, -NR ⁹ _2, alkyl, aryl, alicyclic, halo, -CN, and - SR ³ .

E is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, lower alicyclic, halogen, -CN, -C (O) OR ^3, and -SR ³ .

Also preferred are compounds of formula V-1, V-2, V-1-A and V-2-A, wherein

OR ¹² R ¹⁸ O

R ¹³ NR ¹⁸ R ¹⁸ is selected from the group consisting of:

wherein C * has the stereochemistry S;

R ¹⁸ and R ¹⁵ are selected from the group consisting of hydrogen and methyl;

each R ¹² and R ¹³ is independently selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl and benzyl; or R ¹² and R ¹³ are joined via 2 to 5 carbon atoms to form a cycloalkyl group;

n is 1;

R ¹⁴ is -OR ¹¹ ;

R ¹⁶ is - (CR ¹² R ¹³ ) n C (O) -R ¹⁴ , a

R ¹¹ is selected from the group consisting of methyl, ethyl, propyl, phenyl and benzyl.

Also particularly preferred are compounds wherein R ⁵ is selected from:

Also particularly preferred are compounds wherein R ⁵ is selected from:

Also particularly preferred are compounds wherein R ⁵ is selected from:

D *

In one particularly preferred embodiment, R ⁵ is

A is selected from the group consisting of -NH ₂ , -CONH ₂ , halogen, -CH ₃ , C EJ, with -CH ₂ -halo, -CN, -OCH ₃ , -SCH _3, and hydrogen ;

B is selected from-H, -C (O) ^RU, -C (O) ^SR3, alkyl, aryl, alicyclic, halo, -CN, -SR ^3, -OCH 3, and -NR ⁹ 2.

X is selected from the group consisting of -heteroaryl, -alkoxycarbonyl, and -alkylaminocarbonyl, all of which are optionally substituted.

Even more preferred are compounds wherein X is selected from the group consisting of methyleneoxycarbonyl and furan-2,5-diyl, and pharmaceutically acceptable salts and prodrugs thereof. More preferred are compounds wherein A is -NH ₂ , X is furan-2,5-diyl, and B is -S (CH ₂ ) ₂ CH ₃ ; wherein A is -NH ₂ , X is furan-2,5-diyl and B is -CH ₂ -CH (CH ₃ ) ₂ ; wherein A is -NH ₂ , X is furan-2,5-diyl and B is -COOEt; wherein A 1 is -NH ₂ , X is furan-2,5-diyl and B is -SMe or wherein A is NH ₂ , X is methyleneoxycarbonyl and B is -CH (CH 3) ₂ .

A particularly preferred FBPase inhibitor is a compound of the formula:

Most preferred are those thiazoles wherein A is -NH 2, X is furan-2,5-diyl, B 1 'is -S (CH ₂ ) ₂ CH _3, and wherein or

where C * has the stereochemistry S.

Most preferred are those thiazoles wherein A "is -NH 2, X is furan-2,5-diyl, B" is

-CH ₂ -CH (CH ₃ ) 2 · Particularly preferred compounds are:

is a

where C * has the stereochemistry S.

In another embodiment of the invention, R ³ is

X is selected from the group consisting of furan-2,5-diyl and methyleneoxycarbonyl, A is -NH _2, and pharmaceutically acceptable salts thereof, and prodrugs thereof. More preferred are compounds wherein X is a furan-2,5-diyl group and B is a -SCH 2 CH 2 CH 3 group.

In another preferred aspect, R ⁵ is

A is -NH ₂ , E and D "are hydrogen, B is selected from cyclopropyl and n-propyl, X is selected from methyleneoxycarbonyl and furan-2,5-diyl, and pharmaceutically acceptable salts thereof, and its prodrugs.

In another preferred aspect of the invention, R ⁵ is

D "

A is -NH ₂ , E and D is hydrogen, B "is selected from the group consisting of cyclopropyl and n-propyl, X is selected from the group consisting of furan-2,5-diyl and methyleneoxycarbonyl, and pharmaceutically acceptable salts thereof, and its prodrugs.

Preferred X groups include -heteroaryl, -alkyl-carbonylamino, -alkylaminocarbonyl, and -alk-oxycarbonyl. More preferred are heteroaryl and -alkoxycarbonyl.

Compounds of formula IA are preferred.

Also preferred are compounds of formulas XII, XIII and XIV:

ch ₂ —cc

XIV:

More preferred are compounds of formula

R ¹⁴ -C (O) - (CR ¹² R ¹³ ) _n - N - P

R ^{14 -} C (O) - (CR ¹² R ¹³ ) _{n - N} - P --- CH ₂ -O-R-nr nr ¹⁵ r ¹⁰

Preferred A includes -NH ₂ , -CONH 2, halogen, -CH ₃ , CF 3, -CH 2 -halo, -CN, -OCH 3, -SCH _3, and hydrogen. More preferred A '' groups include -NH ₂ , -Cl, -Br, and -CH ₃ groups.

Preferred B consisting of hydrogen, -C (O) R ^31, -C (O) ^SR3, alkyl, aryl, alicyclic, halo, -CN, -SR ^3, -NR% and - OCH3. More preferred are hydrogen, -C (O) OR ³ , -C (O) SR ³ , -C 1 -C 8 alkyl, alicyclic, halogen, heteroaryl and -SR ³ .

Preferred D "of hydrogen, -C ^(O) R, -C (O) ^SR3, alkyl, aryl, alicyclic, halo, -NR ⁹ _2, and -SR ^third More preferred are hydrogen, -C (O) OR ³ , lower alkyl, alicyclic, and halogen.

A preferred E consisting of hydrogen, _Ci-C6 alkyl, lower alicyclic, halo, -CN, -C (O) OR ^J, -SR ^3, and -CONR ⁴ _second More preferred are hydrogen, -Br and -Cl.

Preferred R ¹⁸ groups include hydrogen, methyl and ethyl. More preferred are hydrogen and methyl. Particularly preferred is hydrogen.

Preferred compounds include those wherein each R ¹² and R ¹³ are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CH ₂ CH ₂ -SCn 3, phenyl, and benzyl, or R ¹² and R ¹³ are linked via a chain of 2 to 5 carbon atoms to form a cycloalkyl group. More preferred is when each R ¹² and R ¹³ are independently selected from H, methyl, isopropyl, isobutyl and benzyl, or ^{R, and} R, and ^Lj are connected via 2-5 carbon atoms to form a cycloalkyl group. Also more preferred are those compounds wherein R ¹² and R ¹³ are independently selected from the group consisting of hydrogen, methyl, isopropyl and benzyl, or R ¹² and R ¹³ are joined together via 4 carbon atoms to form a cyclopentyl group. Particularly preferred are those, wherein R ^u and R ¹³ are both hydrogen, methyl, or R ^{l of} the hydrogen and R ⁿ is selected from methyl, isopropyl and Benzyl. Most preferred are those compounds wherein n is 1 and R ¹ 'is hydrogen, then the carbon attached to R and R ¹³ has the stereochemistry S.

Preferably n is an integer from 1 to 2. More preferably, n is 1.

Preferred compounds include those wherein R ¹⁴ is independently selected from the group consisting of -OR ¹¹ and -SR ^17, and R ¹⁷ is selected from optionally substituted methyl, ethyl, propyl, tert-butyl, and benzyl. More preferred are compounds wherein each R ¹⁴ is independently selected from the group consisting of -OR ¹⁷ and R ¹¹ 'is selected from the group consisting of methyl, ethyl, propyl, and benzyl. Most preferred are compounds wherein R ¹⁷ is selected from the group consisting of ethyl and benzyl.

Preferred compounds are those wherein R ¹⁵ is not hydrogen. More preferred are compounds wherein R ¹⁵ and R ¹⁶ are independently selected from the group consisting of lower alkyl and lower aralkyl, or R ¹⁵ and R ¹⁶ are joined together via a chain of 2 to 6 atoms, optionally containing 1 heteroatom selected from 0, N and S. Also, more preferred are compounds wherein R ¹⁵ and R ¹⁶ are independently selected from C 1 -C 5 alkyl or R ¹⁵ and R ¹⁶ are joined together via 2 to 6 atoms, optionally including 1 heteroatom selected from 0, N and S. In one aspect, they are particularly preferred compounds wherein -NR ¹⁵ R ¹⁶ is a cyclic amine. Particularly preferred are those compounds wherein the -NR ¹⁵ R ¹⁶ is selected from the group consisting of morpholinyl and pyrrolidinyl.

More preferred are compounds wherein R ¹⁶ is - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ . Particularly preferred are those compounds having the general formula:

R ¹⁸ O

R ¹⁴ - C (Oy - (CR ¹² R ¹³ ) _n - N - p - X - R ⁵

Wherein X is selected from the group consisting of furan-2,5-diyl, -alkoxycarbonyl- and -alkylaminocarbonyl-.

More preferred are those compounds wherein n is 1. Particularly preferred are those compounds wherein when R ¹² and R ¹³ are not the same, then NH 2 -CR ¹² R ¹³ -C (O) -R ¹⁴ is an ester or thioester of a naturally occurring amino acid and R ¹⁴ is selected from -OR ¹⁷ and -SR ¹⁷ .

More preferred are compounds wherein n is 1 and wherein

R ¹⁸ is selected from the group consisting of hydrogen, methyl and ethyl;

R ^u and R ¹³ are independently selected from H, methyl, isopropyl, isobutyl and benzyl, or are connected via a chain of 2-5 carbon atoms to form a cycloalkyl group;

R ¹⁴ is -OR ¹⁷ ;

R ¹⁷ j ^E selected from methyl, ethyl, propyl, t-butyl, and benzyl, and

R ¹⁵ and R ¹⁶ are independently selected from the group consisting of lower alkyl and lower aralkyl, or R ¹⁵ and R ¹⁶ are joined together via a chain of 2 to 6 atoms, optionally including 1 heteroatom selected from 0 and N.

In one aspect, compounds of Formula IA wherein M is is preferred

G 1 is selected from -O- and -S-;

A ² , L ² , E ² and J ² are selected from the group consisting of

-NH _2, a group -ΝΟ2, H, -OR ^2, -SR ^2, -C (O) NR ⁴ 2 Z halo, -COR ^11, -SO 2 R ³ group, guanidinyl, amidinyl, aryl, aralkyl, alkyloxyalkyl, -SCN, -NHSO ² R ⁹ , - SO 2 NR ⁴ 2, -CN, -S (O) R ³ , perhaloacyl, perhaloalkyl, perhaloalkoxy, C 1 -C 5 alkyl, C ₂ The -C ₅ alkenyl group, the C 2 -C 5 alkynyl group and the lower alicyclic group or L ² and E ² or and J ² together form an annulled cyclic group.

X ² is selected from the group consisting of -CR ² 2 ", -CF 2 -, -OCR ² 2 -, -SCR ² 2-, -C (O) -O-, -C (O) - S-, -C (S) -O-, and CR ² 2-NR ¹⁹ - and wherein the atom attached to phosphorus is a carbon atom, with the proviso that X ² is not substituted with -COOR ² , -SO 3 H or -PO ³ R ² 2;

R ² is selected from R ³ and hydrogen;

R ^{3 e} j selected from alkyl, aryl, alicyclic, and aralkyl;

each R ⁴ is independently selected from hydrogen and alkyl or together R ⁴ and R ⁴ form a cyclic alkyl group;

each R ⁹ is independently selected from the group consisting of hydrogen, alkyl, aralkyl and alicyclic, or together R ⁹ and R ⁹ together form a cyclic alkyl group;

^The R is selected from c group consisting of alkyl, aryl, -NR ² _2, and -OR ^2;

^{1 S} R is selected from a lower alkyl group, hydrogen, a radical -COR ^2, and pharmaceutically acceptable prodrugs and salts thereof.

More preferred are compounds wherein G is -S-.

Most preferred are compounds wherein A ² , L ² , E ² and J ² are independently selected from hydrogen, -NR ⁴ ₂ , S-C 5 N, halogen, -OR ³ , hydroxy, -alkyl (OH) , aryl, alkyloxycarbonyl, -SR ³ , lower perhaloalkyl and C 1 -C 5 alkyl or L ² * 1 and E 'form a null cyclic group. More preferred are compounds wherein A ² , L ² , E ² and J ² are independently selected from hydrogen, -NR ⁴ ₂ , -SC 4 N, halogen, lower alkoxy, hydroxy, lower alkyl (hydroxy), a lower aryl group and a C 1 -C 5 alkyl group or L ² and E ² form a null cyclic group.

Most preferred A ² groups include -NH ₂ , hydrogen, halogen and C 1 -C 5 alkyl.

Most preferably, the L ² and E ² groups are independently selected from the group consisting of hydrogen, -SC 1 N, lower alkoxy, C 1 -C 5 alkyl, lower alkyl (hydroxy), lower aryl and halogen, or L ² and E * together form an annulled cyclic group containing an additional 4 carbon atoms.

Most preferred J ² groups include hydrogen and C 1 -C 5 alkyl.

Preferred X ² groups include -CF 2 ^_, -CH2-, -C (0) -0-, -CH ₂ -O-, -CH ₂ -S-, -CH ₂ -NH- group and -CH ₂ -N (C (O) CH ₃ ) -. More preferred are -CH 2 -O-, -CH ₂ -S-, and -CH ₂ -N (C (O) CH ₃ ) -. Most preferred is -CH ₂ -O-.

o _r

One preferred aspect includes a compound wherein A is selected from the group consisting of hydrogen, -NH ₂ , -CH ₃ , -CI, and -Br.

1) is hydrogen, lower alkyl, halogen, lower alkyl2 oxy, hydroxy, -alkylene-OH or together with E form a cyclic group selected from the group consisting of aryl, cyclic alkyl, heteroaryl, heterocyclic alkyl;

E ² is selected from the group consisting of hydrogen, lower alkyl, halogen, SCN, lower alkyloxycarbonyl, lower alkyloxy or together with L ² form a cyclic group selected from the group consisting of aryl, cyclic alkyl, heteroaryl or heterocyclic alkyl;

J ² is selected from the group consisting of hydrogen, halogen and lower alkyl;

G is -S-;

X ² is -CH ₂ -O-;

and pharmaceutically acceptable salts and prodrugs thereof.

Particularly preferred are those compounds wherein

R ¹⁸ is selected from the group consisting of hydrogen, methyl and ethyl;

R ¹² and R ¹³ are independently selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl and benzyl or are joined together via 2 to 5 carbon atoms to form a cycloalkyl group;

R ¹⁴ is -OR ¹⁷ ;

R ¹ 'is selected from the group consisting of methyl, ethyl, propyl, tert-butyl and benzyl, and

R ¹⁵ and R ¹⁶ are independently selected from the group consisting of lower alkyl and lower aralkyl or R ¹⁵ and R ¹⁶ are joined together via 2 to 6 atoms, optionally including 1 heteroatom selected from 0 and N.

Also more preferred are those compounds wherein A ² is NH ₂ , L ² is selected from -Et and -Cl, E ² is selected from -SCN, -Et and -Br and J ² is hydrogen. Particularly preferred are those compounds wherein

0 II R ¹² R ¹⁸ 0 1 II 14 »R ¹⁴ --- C— C- I II N --- P ---- R ¹³ NR ¹³ R ¹⁶ is selected from the group consisting of CH ₃ 0 11 r

EtOOC --- C --- HN-P --- CH ₃ ² a

fI dl EtOOC — C * - HN --- P - i where C * has the stereochemistry S.

Preferred R ¹⁸ groups include hydrogen, methyl, and ethyl. More preferred are hydrogen and methyl. Particularly preferred is hydrogen.

Preferred compounds include those wherein each R ¹² and R ¹³ is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CH 2 CH 2 -CH 3, phenyl and benzyl, or R ¹² and R ¹³ are joined together via 2 to 5 carbon atoms to form a cycloalkyl group. More preferred are compounds wherein each R ¹² and R ¹³ is independently selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl and benzyl, or R ¹¹ and R ¹³ are linked via 2 to 5 carbon atoms to form a cycloalkyl group. Also preferred are such compounds wherein each R ¹² and R ¹³ are independently selected from H, methyl, isopropyl and benzyl, or R and ^Δ R are connected via 4 carbon atoms to form a cyclopentyl group. Particularly preferred are those compounds wherein R ¹² and R ¹³ are both hydrogen, both methyl or R ¹² is hydrogen and R ¹³ is selected from the group consisting of methyl, isopropyl and benzyl. Most preferred are those compounds wherein n is 1 and R ¹² is hydrogen, then the carbon attached to R ¹² and R ¹³ has the stereochemistry S.

Preferably n is an integer from 1 to 2. More preferably, n is equal to 1.

Preferred compounds include those wherein each R ¹⁴ is independently selected from the group consisting of -OR ¹⁷ and -SR ¹⁷ ; and R ¹⁷ is selected from the group consisting of optionally substituted methyl, ethyl, propyl, tert-butyl and benzyl. More preferred are those compounds wherein R ¹⁴ is independently selected from -OR 'and R ¹⁷ is selected from the group consisting of methyl, ethyl, propyl, and benzyl. Most preferred are those compounds wherein R ¹⁷ is selected from the group consisting of ethyl and benzyl.

Preferred are compounds wherein R ¹⁵ is not hydrogen. More preferred are compounds wherein R ¹⁵ and R ¹⁶ are independently selected from the group consisting of lower alkyl and lower aralkyl, or R ¹⁵ and R ¹⁶ are joined together via 2 to 6 atoms, optionally containing 1 heteroatom selected from 0, N and S. Also preferred are compounds wherein R ¹⁵ and R ¹⁶ are independently selected from C 1 -C ₆ alkyl or wherein R ¹⁵ and R ¹⁶ are joined together via 2 to 6 atoms, optionally containing 1 heteroatom selected from 0, N and S. in one aspect, particularly preferred are compounds wherein -NR ¹⁵ R ¹⁶ is a cyclic amine. Particularly preferred are such compounds wherein -NR ¹⁵ R ^{1 q} is selected from the group consisting of morpholinyl and pyrrolidinyl.

Preferred are compounds wherein R * ⁵ is - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ .

More preferred are compounds wherein n is 1 and wherein

R ¹⁸ is selected from the group consisting of hydrogen, methyl and ethyl;

R ¹² and R ¹³ are independently selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl and benzyl, or are joined together via 2 to 5 carbon atoms to form a cycloalkyl group;

R ¹⁴ is -OR ¹⁷ ;

R ¹⁷ is selected from the group consisting of methyl, ethyl, propyl, tert-butyl and benzyl, and

R ¹⁵ and R ¹⁶ are independently selected from the group consisting of lower alkyl and lower aralkyl or R ¹⁵ and R ¹⁶ are joined together via 2 to 6 atoms, optionally containing 1 heteroatom selected from O and N. Particularly preferred are those compounds which: have the formula:

R ¹⁸ O

C (O) - (CR ¹² R ¹³ ) h N - P - M

More preferred are compounds wherein n is 1. Particularly preferred are those compounds wherein R ¹² and R ¹³ are not the same, then the NH ₂ - (CR ¹² R ¹³ ) n C (O) -R ^{14 group} is an ester or a thioester naturally occurring. and R ¹⁴ is selected from -OR ¹⁷ and -SR ¹⁷ .

In one aspect, compounds of Formula IA or Formula I wherein M is is preferred

A

A, E and L are selected from the group consisting of -NR ₂ , -NO ₂ , hydrogen, -OR ⁷ , -SR ',

-C (O) NR ^{4 * *} 2, halogen, -COR ¹¹ , -SO ² R ³ , guamidine, amidine, -NHSO 2 R ¹⁵ , -SO ₂ NR ⁴ ₂ , -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C 1 -C 5 alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl and a lower alicyclic group or A and L together form a cyclic group or L and E together form a cyclic group or together E and J form a cyclic group including an aryl, cyclic alkyl and heterocyclic group;

J is selected from the group consisting of -NR ⁸ _2, -NO 2 radical, hydrogen, -OR ^7, -SR ^7, -C (O) NR ⁴ 2, halo, -C (0) R ¹¹ group, -CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or together with Y, and form a, cyclic alkyl and heterocyclic groups;

X ³ is selected from the group consisting of -alkyl (hydroxy) -, -alkyl-, -alkynyl-, -aryl-, -carbonyl-, alkyl-, -1,1-dihaloalkyl-, - alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, - carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted, with the proviso that X ³ is not substituted with -C00R ² , -SO 3 H, or -PO ³ R ² 2;

Y ³ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C (O) R ³ , -S (O) R ³ , -C (0) -R ^n, a group -CONHR ^3, -NR ² _2, and a group of ^J -0R, all except H are optionally substituted;

R ² is selected from R ³ and hydrogen;

R ³ is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;

each R ⁴ is independently selected from the group consisting of hydrogen and alkyl or R ⁴ and R ⁴ together form a cyclic alkyl group;

R ⁵ is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic;

R ⁷ is independently selected from the group consisting of hydrogen, lower alkyl, lower alicyclic, lower aralkyl, lower aryl and -C (O) R ¹⁰ ;

R ⁸ is independently selected from the group consisting of hydrogen, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, and -C (O) R ¹⁰ ; or together form a bidentate alkyl group;

each R ⁹ is independently selected from the group consisting of hydrogen, alkyl, aralkyl and alicyclic, or together R ⁹ and R ⁹ together form a cyclic alkyl group;

R ¹⁰ is selected from the group consisting of hydrogen, lower alkyl, -NH ₂ , lower aryl and lower perhaloalkyl;

R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ² , and pharmaceutically acceptable prodrugs and salts thereof.

In another aspect of the invention, compounds of Formula I or Formula IA are described above, with the proviso that:

a) when X ³ is alkyl or alkylene, then A is -N (R ⁸ ₂ );

(b) X ³ is not an alkylamine and an alkylaminoalkyl substituted with a phosphonic ester and acids; and

c) A, L, E, J and Y ³ may together form 0 to 2 cyclic groups.

More preferred are those compounds wherein X ³ is not an -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl- and -alkylthio- group. Particularly preferred are such compounds with the additional condition that when X ³ is an aryl or alkylaryl group, said aryl or alkylaryl group is not linked by 1,4 through a six membered aromatic ring.

Particularly preferred benzimidazole compounds include those wherein A, L, and E are independently selected from the group consisting of hydrogen, -NR ⁸ 2, -NO 2, hydroxy, halogen, -OR ⁷ , alkylaminocarbonyl, -SR ⁷ , lower perhaloalkyl and C 1 -C 5 alkyl or E and J together form a cyclic group, and wherein J is selected from hydrogen, halogen, lower alkyl, lower hydroxyalkyl, -NR ⁸ 2, lower R ⁸ ₂ N-alkyl , lower haloalkyl, lower perhaloalkyl, lower alkenyl, lower alkynyl, lower aryl, heterocyclic and alicyclic, and wherein Y is selected from the group consisting of alicyclic and lower alkyl, wherein X ³ is selected from the group consisting of -heteroaryl -, -alkylcarbonylamino-, -alkylaminocarbonyl- and -alkoxycarbonyl-. More preferred are those compounds wherein

^{1 S} R is selected from H, methyl and ethyl;

R ¹² and R ¹³ are independently selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl and benzyl or are joined together via 2 to 5 carbon atoms to form a cycloalkyl group;

R ¹⁴ is -OR ¹⁷ ;

R ¹⁷ is selected from the group consisting of methyl, ethyl, propyl, tert-butyl and benzyl, and

R ¹⁵ and R ¹⁶ are independently selected from the group consisting of lower alkyl and lower aralkyl, or R ¹⁵ and R ¹⁶ are linked together via. 2-6 atoms optionally containing 1 heteroatom selected from O and N. Most preferred are those compounds wherein A is selected from the group consisting of hydrogen, -NH ₂ , -F, and -CH ₃ .

L is selected from the group consisting of hydrogen, -F, -OCH 3, Cl, and -CH 3;

E is selected from hydrogen and Cl;

J is selected from H, halo, C 1 -C 5 hydroxyalkyl, C 1 -C 5 haloalkyl, C C5R ^E ₂ N-alkyl, C1-C5 alicyclic, and C1-C5 alkyl group;

X ³ is selected from the group consisting of -CH ₂ OCH ₂ -, -methyleneoxycarbonyl-, and furan-2,5-diyl, and

Y is lower alkyl.

Also more preferred are such benzimidazoles wherein A is -NH ₂ , L is -F, E is hydrogen, J is ethyl, Y is isobutyl, and X ³ is furan-2,5-diyl, wherein A is -NH ₂ L is -F, E is hydrogen, J is N, N-dimethylaminopropyl, Y is isobutyl and X ³ is furan-2,5-diyl.

Particularly preferred are compounds wherein R ¹² or a ¹⁸ 'llll II

R ¹⁴ CC N ---- P --- R ¹³ NR ¹⁵ R ¹⁶ is selected from the group consisting of

where C * has the stereochemistry S.

In one aspect, compounds of general formula are preferred

A, E, and L are selected from a group -NR 2 ^C, -N02 group, hydrogen, -OR ^7, -SR ^7, -C (O) NR ⁴ 2, halo, -COR ^11, a group - SO ² R ³ , guanidine, amidine, -NHSO ² R ²⁵ , -SO 2 NR ⁴ 2, -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C 1 -C 5 alkyl, C ₂ -C- _; alkenyl, C ₂ -C j alkynyl, and lower alicyclic, or together A and L form a cyclic group, or L and E form a cyclic group, or together E and J form a cyclic group selected from the group of aryl, cyclic alkyl, and heterocyclic;

J is selected from the group consisting of -NR ⁸ 2, -NO 2 radical, hydrogen, -OR ^7, -SR ^7, -C (O) NR ⁴ 2, halo, -C (O) R ^The group -CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl or together with Y ³ from the group consisting of aryl, cyclic alkyl and heterocyclic alkyl groups;

X ³ is selected from the group consisting of -alkyl (hydroxy) -, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkythioalkyl-, -alkythio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino-, all optionally substituted, provided that X ³ is not substituted with -COOR ² , -SO 3 H, or -PO ³ R ² 2;

Y ³ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C (O) R ³ , -S (O) R ³ , -C (0) -R ^11, -CONHR ³ group, -NR ² _2, and a group of ^J -0R, all except H are optionally substituted;

Y is independently selected from -O- and -NR ⁵ , with the proviso that:

when Y is -O-, R ¹ attached to -O- is independently selected from the group consisting of hydrogen, alkyl, optionally substituted aryl, optionally substituted alicyclic, wherein the cyclic group comprises carbonate or thiocarbonate, optionally substituted -arylalkyl, -C (R ² ) 20 C (O) NR ² 2, -NR ² -C (O) -R ³ , -C (R ² ) ₂ -OC (O) R ³ , -C (R ² ) ? -O-C (O) OR ³ , -C (R ² )? C (O) SR ³ , -alkyl-SC (O) R ³ , -alkyl-SS-alkylhydroxy and -alkyl-SSS-alkylhydroxy group

when Y is -NR ⁶ -, R ¹ attached to NR ⁶ is independently selected from 2 3 hydrogen-containing group, - [C (R) 2] _q -COOR, -C (R ⁴ ) 2 COOR ³ , - [ C (R ² ) 2] q - C (O) SR and a -cycloalkylene COOR ³ group, wherein q is 1 or 2 when only one Y is -O-, wherein -O- is not part of a cyclic group containing the other Y, the other Y is -N (R ¹⁸ ) - (CR ¹² R ¹³ ) -C (O) -R ¹⁴ , and when Y is independently selected from -O- and -NR ⁶ , R ¹ and R ¹ together are alkyl-SS -alkyl- and form a cyclic group, or R ¹ and R ¹ form:

where

a) V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl, or

V and Z are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group being fused to an aryl group at the β and γ position to Y attached to V; or o

Z is selected from the group consisting of -CHR'OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OC (S) OR ³ , -CHR ² OC (0) SR ³ , -CHR ² OCO ² R ³ , -OR ² , -SR ² , -CHR ² N 3, -CHaaryl, -CH (aryl) OH, -CH (CH = CR ² 2) OH, -CH (CsCR ² ) OH, -R ² , -NR ² 2, -OCOR ³ , -OCO2R ³ , -SCOR ³ , -SCO2R ³ , -NHCOR ² , - NHCO ² R ³ , -CH 2 NHaryl, - (CH 2) p -OR ² and - (CH 2) _p -SR ² , wherein p is an integer of 2 or 3, or

Z and W are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl; or

W and W 'are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or

W and W 'are joined together via an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V must be an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group;

b) V ² , W ² and W "are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl ;

Z ² is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OC (S) OR ³ , -CHR ² OC (O) SR ³ , -CH (aryl) OH, -CH (CH = CR 2) OH, -CH (C = CR ² ) OH, -SR ² , -CH ² NHaryl, -CH ₂ aryl; or

V ² and Z ² are joined together via an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 ring atoms optionally containing 1 heteroatom and substituted with hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom of three group Y atoms attached to phosphorus;

c) Z 'is selected from the group consisting of -OH,

-OC (O) R ³ , -OCO ₂ R ^3, and -OC (O) SR ³ ;

D 'is hydrogen;

D is selected from the group consisting of hydrogen, alkyl, -OR ² , -OH, and -OC (O) R ³ ;

each W ³ is independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

with the proviso that:

a) V, Z, W, W 'are not all hydrogen and V ² , Z ² , W ² , W''are not all hydrogen;

R ² is selected from R ³ and hydrogen;

R ³ is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;

each R ⁴ is independently selected from the group consisting of hydrogen, alkylene, or together R ⁴ and R ⁴ form a cyclic alkyl group;

R ⁶ is selected from the group consisting of hydrogen, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl;

Pi ⁵ is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic;

R 'is independently selected from the group consisting of hydrogen, lower alkyl, lower alicyclic, lower aralkyl, lower aryl and -C (O) R ¹⁰ ;

R ⁸ is independently selected from the group consisting of hydrogen, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, and -C (O) R ¹⁰ ; or together form a bidentate alkyl group;

each R ^a is independently selected from-H, alkyl, aralkyl, and alicyclic;

R ¹⁰ j ^E selected from-H, lower alkyl, -NH _2, lower aryl, and lower perhaloalkyl;

R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ² , and n is an integer from 1 to 3;

R ¹⁸ is independently selected from the group consisting of hydrogen, lower alkyl, aryl, aralkyl or R ¹² and R ¹⁸ are joined together via 1 to 4 carbon atoms to form a cyclic group;

each R ¹² and each R ¹³ is independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R ¹² and R ¹³ are joined together via 2 to 6 carbon atoms, optionally containing 1 heteroatom selected from O, N and S to form a cyclic group;

each R ¹⁴ is independently selected from the group consisting of -OR ¹ ', -N (R ¹⁷ ) ₂ , -NHR ¹⁷ , -SR ^17, and -NR ^: R ²⁰ ;

λ

R ¹⁵ is selected from the group consisting of hydrogen, lower alkyl, lower aryl and lower aralkyl or R ¹⁵ and R ¹⁵ are joined together via 2 to 6 atoms to form a cyclic group wherein the cyclic group optionally comprises one heteroatom selected from O , N and S;

R ¹⁶ is selected from the group consisting of - (CR ¹² R ¹³ ) n C (O) -R ¹⁴ , hydrogen, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ¹⁶ are joined together via 2 to 6 atoms to form a cyclic group, wherein the cyclic group optionally comprises one heteroatom selected from O, N and S;

each R ¹⁷ is independently selected from the group consisting of lower alkyl, lower aryl and lower aralkyl, or when R ¹⁴ is -N (R ¹⁷ ) ₂ , both R ¹⁷ are joined via 2 to 6 atoms to form a cyclic group, wherein the cyclic group optionally comprises one heteroatom selected from O, N and S;

R ²⁰ is selected from the group consisting of hydrogen, lower alkyl R ^3, and -C (O) -lower R ³ ;

and pharmaceutically acceptable prodrugs and salts thereof.

Preferred A, L and E groups of formula III include hydrogen, -NR ⁸ ₂ , -NO ₂ , hydroxy, alkylaminocarbonyl, halogen, -OR ⁷ , -SR ⁷ , lower perhaloalkyl, and C 1 -C 5 alkyl or E and J together form a cyclic group. The cyclic group may be an aromatic group, a cyclic alkyl group or a heterocyclic alkyl group and may be optionally substituted. Suitable aromatic groups include thiazole. Particularly preferred A, L and E groups are -NR ⁸ ; hydrogen, hydroxy, halogen, lower alkoxy, lower perhaloalkyl and lower alkyl.

Preferred A groups for formula III include -NR ⁸ 2, hydrogen, halogen, lower perhaloalkyl and lower alkyl.

Preferred L and E groups for formula III include hydrogen, lower alkoxy, lower alkyl and halogen.

Preferred J groups for formula III include hydrogen, halogen, lower alkyl, lower hydroxyalkyl, -NR ⁸ 2, lower R ^8, 2N-alkyl, lower haloalkyl, lower perhaloalkyl, lower alkenyl, lower alkynyl, lower aryl, heterocyclic, and alicyclic, or together with L ³ forms a cyclic group. This cyclic group may be an aromatic group, a cyclic alkyl group or a heterocyclic group and may be optionally substituted. Particularly preferred J groups include hydrogen, halogen, lower alkyl, lower hydroxyalkyl, -NR ⁸ 2, lower R ^8, 2N-alkyl, lower haloalkyl, lower alkenyl, alicyclic, and aryl. Alicyclic and lower alkyl are particularly preferred.

Preferred X ³ groups for formula III include -alkyl-, -alkynyl-, -aryl-, -alkoxyalkyl-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -1,1-dihaloalkyl-, - carbonylalkyl group -alkyl (OH) -. Particularly preferred are -heterzaryl-, -alkylaminocarbonyl-, -1,2-dihaloalkyl- and -alkoxyalkyl-. Also particularly preferred are -heteroaryl-, -alkylaminocarbonyl- and alkoxyalkyl-. Particularly preferred are -methylaminocarbonyl-, -methoxymethyl- and -furan-2,5-diyl-.

In another preferred aspect, when X ³ is an aryl group or an alkylaryl group, these groups are not 1,4-linked via a six membered aromatic ring.

Preferred Y ³ groups for formula III include hydrogen, alkyl, aralkyl, aryl and alicyclic, all except hydrogen may be optionally substituted. Particularly preferred are a lower alkyl group and an alicyclic group.

Preferred R ⁴ and R ⁷ groups include hydrogen and a lower alkyl group.

In one preferred aspect of the compounds of Formula III, A, L, and E are independently hydrogen, lower alkyl, hydroxy, halogen, lower alkoxy, lower perhaloalkyl, and -NR ⁸ 2; X ³ is -aryl-, -alkoxyalkyl-, -alkyl-, -alkylthio-, -1,1-dihaloalkyl-, -carbonylalkyl-, -alkyl (hydroxy) -, -alkylaminocarbonyl- and the -alkylcarbonylamino- group, and each R ⁴ and R 'is independently hydrogen and a lower alkyl group. Particularly preferred are compounds wherein A, L and E are independently hydrogen, lower alkyl, halogen and -NR ⁸ 2; J is hydrogen, halo, haloalkyl, hydroxyalkyl, R ⁸ 2 N-alkyl, lower alkyl, lower aryl, heterocyclic, and alicyclic or together with ^Y3 forms a cyclic group, and ^X3 is-heteroaryl, alkylaminocarbonyl -1,1-dihaloalkyl- and -alkoxyalkyl-. Particularly preferred are those compounds wherein A is hydrogen, -NH 2, -F and -CH 3, L is hydrogen, -F, -OCH 3, -Cl and -CH ₃ , E is hydrogen and -CH 3, J is hydrogen, halogen, C 1 -C ₅ hydroxyalkyl, C 1 -C 5 haloalkyl, C 1 -C 5 R ⁸ 2N-alkyl, C 1 -C 5 alicyclic and C 1 -C 5 alkyl, X ³ is -CH ₂ OCH ₂ - and furan -2,5-Dilyl Y ³ is a lower alkyl group. Most preferred are the following compounds and salts thereof, and prodrugs and salts thereof:

1) A is -NH ₂ , L is -F, E is hydrogen, J is hydrogen, Y ^J is isobutyl and X ³ is -furan-2,5-diyl-;

2) A, L and J are hydrogen, E is -Cl, Y ³ is isobutyl and X is -furan-2,5-diyl-;

3) A is -NH ₂ , L is -F, E and J are hydrogen, Y ³ is cyclopropylmethyl and X ³ is -furan-2,5-diyl-;

4) A is -NH ₂ , L is -F, E is hydrogen, J is ethyl, Y ³ is isobutyl and X ³ is -furan-2,5-diyl-;

5) A is -CH ₃ , L is -Cl, E and J are hydrogen, Y ³ is isobutyl and X ³ is -furan-2,5-diyl-;

6) A is -NH ₂ , L is -F, E is hydrogen, J is -Cl, Y ³ is isobutyl and X ³ is -furan-2,5-diyl-;

7) A is -NH ₂ , L is -F, E is hydrogen, J is -Br, Y ³ is isobutyl and X ³ is -CH ₂ OCH ₂ -;

8) A, L, E and J are -CH ₃ , Y ³ is cyclopropylmethyl and X ³ is -furan-2,5-diyl-.

Also particularly preferred are compounds wherein A is -NH ₂ , L is -F, E is -H, J is bromopropyl, bromobutyl, chlorobutyl, cyclopropyl, hydroxypropyl or N, N-dimethylaminopropyl and X ³ is furan-2, 5-diyl. Preferred prodrugs are wherein R ¹ is a pivaloyloxymethyl group or an HCl salt thereof.

In another aspect, compounds of formula I are preferred

I or I-A, wherein M is

where

Z ^a is selected from alkyl and halo,

At ⁶ and V 0, they are independently selected from the group consisting of hydrogen, hydroxy, acyloxy or together, form a lower cyclic ring containing at least one oxygen;

W ^e is selected from the group consisting of amino and lower alkylamino;

and pharmaceutically acceptable prodrugs and salts thereof.

In one aspect of this formula VI:

invention

general compounds

where

Z ⁶ is selected from the group consisting of alkyl and halogen,

U ⁶ and V ⁶ are independently selected from the group consisting of hydrogen, hydroxy, acyloxy or together form a lower cyclic ring containing at least one oxygen;

W ⁶ is selected from the group consisting of amino and lower alkylamino;

Y is independently selected from -0- and -NR ^6, with the proviso that:

when Y is -O-,

R ¹ attached to -O- is independently selected from the group consisting of hydrogen, alkyl, optionally substituted aryl, optionally substituted alicyclic, wherein the cyclic group comprises carbonate or thiocarbonate, optionally substituted -arylalkyl, -C (R ² ) 20C (O) NR ² 2, -NR ² -C (O) -R ³ , -C (R ² ) ² -OC (O) R ³ , -C (R ² ) 2 -O-C ( O) OR ³ , -C (R ² ) ₂ OC (O) SR ³ , -alkyl-SC (O) R ³ , -alkyl-SS-alkylhydroxy and -alkyl-SSS-alkylhydroxy when Y is -NR ⁶ -, -C (R ⁴ ) o COOR ³ , -COOR ³ , wherein q is 1 or 2,

R ¹ attached to -NR ⁶ - is independently selected from hydrogen, - [C (R ² ) ₂ 1 q ^- COOR ',

- (C (R ² ) ₂ ) qC (O) SR and -cycloalkylene-6 when only one Y is -O-, wherein -O- is not part of the cyclic group containing the other Y, the other Y is -N (R ¹⁸ ) - (CR ¹² R ¹³ ) -C (O) -R ¹⁴ , and when Y is independently selected from -O- and -NR ⁶ , R ¹ and R ¹ together are alkyl-SS-alkyl- and form a cyclic group, or R ¹ and R ¹ consist of:

where

a) V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl, or

V and Z are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group being fused to an aryl group at the β and γ position to Y attached to V; or

Z is selected from the group consisting of -CHFYOH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OC (S) OR ³ , -CHR ² OC (O) ) SR ³ , -CHR ² OCO ² R ³ , -OR ² , -SR ² , -CHR ² N 3, -CH ₂ aryl, -CH (aryl) OH, -CH (CH = CR ² 2) OH, -CH (C = CR ² ) OH, -R ² , -NR ² 2, -OCOR ³ , -OCO2R ^J , -SCOR, -SCO2R ³ , -NHCOR ² , -NHCO ² R ³ , -CH ₂ NHaryl, - (CH ₂ ) _p -OR ^2, and - (CH ₂ ) _p -SR ² , wherein p is an integer of 2 or 3, or

W is joined together via another 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl; or

W and W 'are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or

W and W 'are joined together via an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl;

b) V ² , W ² and W are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

Z ² is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OCO ² R ³ , -CHR ² OC (0) SR ^3, -CHR ² OC (S) ^OR3, -CH (aryl) OH, -CH (CH = CR ² 2) OH, -CH (C ^ CR ²⁾ OH, -SR ^2, -CH ₂ NHaryl, -CH ₂ aryl; or

V ² and Z ² are joined together via an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 ring atoms optionally containing 1 heteroatom and substituted with hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom of three atoms from a group Y attached to phosphorus;

c) 1 'is selected from the group consisting of -OH, -OC (O) R ³ , -OCO ₂ R ^3, and -OC (O) SR ³ ;

D 'is hydrogen;

D '' is selected from the group consisting of hydrogen, alkyl, -OR ² , -OH, and -OC (O) R ³ ;

each W ³ is independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

with the proviso that:

a) V, Z, W, W 'are not all hydrogen and V ² , Z ² , W ² , W are not all hydrogen;

R ² is selected from R ³ and hydrogen;

R ³ is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;

each R ⁴ is independently selected from the group consisting of hydrogen, alkylene, alkylenearyl and aryl, or together R ⁴ and R ⁴ are joined via 2 to 6 atoms, optionally containing 1 heteroatom selected from O, N and S;

R ⁶ is selected from the group consisting of hydrogen, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl;

n is an integer from 1 to 3;

R ¹⁸ is independently selected from the group consisting of hydrogen, lower alkyl, aryl and aralkyl, or R ¹² and R ¹⁸ are taken together through 1 to 4 carbon atoms to form a cyclic group;

each R ¹² and each R ¹³ are independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, lower aralkyl, all of which may be optionally substituted, or R ¹² and R ¹ are joined together via 2 to 6 carbon atoms, optionally containing 1 a heteroatom selected from O, N and S to form a cyclic group;

each R ¹⁴ is independently selected from the group consisting of -OR ¹⁷ , -N (R ¹⁷ ) ₂ , -NHR ¹⁷ , -SR ^17, and -NR ² R ²⁰ ;

R ¹⁵ j ^E selected from-H, lower alkyl, lower aryl, and lower aralkyl, or R ¹⁵ and R ¹⁶ are connected via 2-6 atoms to form a cyclic group, wherein the cyclic group optionally includes one heteroatom selected from O, N and S;

R ¹⁶ is selected from the group consisting of - (CR ¹² R ¹³ ) n C (O) -R ¹⁴ , hydrogen, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ¹⁶ are connected via 2 to 6 atoms, to form a cyclic group, wherein the cyclic group optionally comprises one heteroatom selected from O, N and S;

each R ¹⁷ is independently selected from the group consisting of lower alkyl, lower aryl and lower aralkyl, or when R ¹⁴ is -N (R ¹⁷ ) ₂ , both R ¹⁷ are joined via 2 to 6 atoms to form a cyclic group, wherein the cyclic group optionally comprises one heteroatom selected from O, N and S;

3

R is selected from the group consisting of hydrogen, lower alkyl R and -C (O) -lower R ³ ;

and pharmaceutically acceptable salts or prodrugs thereof.

In another aspect of the invention, compounds of Formula I and Formula IA are those wherein M is:

where:

A ² is selected from the group consisting of -NR ⁸ 2, -NHSO ² R ³ , -OR ²⁵ , -SR ²⁵ , halogen, lower alkyl, -CON (R ⁴ ) 2, guanidino, amidino, hydrogen and a perhaloalkyl group;

E ² is selected from the group consisting of hydrogen, halogen, lower alkylthio, lower perhaloalkyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, -CN, and -NR ⁷ ₂ ;

X ³ is selected from the group consisting of -alkyl (hydroxy) -, -alkyl-, -alkynyl-, -aryl · -, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkythioalkyl-, -alkythio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, a -alkoxycarbonylamino- group and a -alkylaminocarbonylamino- group, all optionally substituted, provided that X ³ is not substituted with -COOR ² , -SO 3 H, or -po ³ R ² 2;

Y ³ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C (O) R ³ , -S (O) R ^J , -C (O) R ^the group -CONHR ^3, -NR ² _2, and -OR ^3, all except H are optionally substituted;

each R ⁴ is independently selected from the group consisting of hydrogen and alkyl, or together R ⁴ together form a cyclic alkyl group;

R ²⁵ is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic;

each R ⁷ is independently selected from the group consisting of hydrogen, lower alkyl, lower alicyclic, lower aralkyl, lower aryl and -C (O) R ¹⁰ ;

each R ⁸ is independently selected from the group consisting of hydrogen, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, -C (O) R ^10, or together both R ⁸ are bidentate alkyl;

R ¹⁰ is selected from the group consisting of hydrogen, lower alkyl, -NH ₂ , lower aryl and lower perhaloalkyl, and

R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ² .

In another aspect, compounds of Formula II are preferred:

where fi

A is selected from the group consisting of -NR ₂ , -NHSO ₂ R ³ , -OR ²⁵ , -SR ²⁵ , halogen, lower alkyl, -CON (R ⁴ ) ₂ , guanidine, amidino, hydrogen and a perhaloalkyl group;

E ² is selected from the group consisting of hydrogen, halogen, lower alkylthio, lower perhaloalkyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, -CN, and -NR ⁷ ₂ ;

X ^{3 e} j selected from the group consisting of -alkyl (hydroxy) -, -alkyl- group, alkynyl group; -, a group -aryl sku82 pin -carbonylalkyl-, -1,1-dihaloalkyl- group, alkoxyalkyl group, -, -alkyloxy-, -alkythioalkyl-, -alkythio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl -alkoxycarbonylamino- and -alkylaminocarbonylamino-, all optionally substituted, provided that X ³ is not substituted with -COOR ² , -SO 3 H, or -PO ³ R ² 2;

Y ³ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C (O) R ³ , -S (O) 2 R ³ , -C (O) R ^the group -CONHR ^3, -NR ² 2, and -OR ^3, all except H are optionally substituted;

Y is independently selected from -0- and -NR ^6, with the proviso that:

when Y is -O-, R ¹ attached to -O- is independently selected from hydrogen, alkyl, optionally substituted aryl, optionally substituted alicyclic, wherein the cyclic group comprises carbonate or thiocarbonate, optionally substituted -arylalkyl, -C (R ² ) 20 C (O) NR ² 2, -NR ² -C (O) -R ³ , -C (R ² ) ² -OC (O) R ³ , -C (R ² ) 2-O-C (O) OR ³ , -C (R ² ) 20 C (O) SR ³ , -alkyl-SC (O) R ³ , -alkyl-SS-alkylhydroxy and -alkyl-SSS-alkylhydroxy when Y is -NR ⁰ -, R ^r attached to -NR ⁰ - is independently selected from the group consisting of hydrogen, - [C (R ² ) 2] q -COOR °, -C (R ¹ ) 2 COOR ³ , a group - [C (R ² ) ₂ ] _q -C (O) SR and a -cycloalkylene-COOR ^{3 group} , wherein q is 1 or 2 when only one Y is -O-, wherein -O- is not part of a cyclic group comprising the other Y, the other Y is -N (R ¹³⁾ - (CR'R ") C (O) -R ^1z? and when Y is independently selected from -O- and -NR ⁶ , R ¹ and R ¹ together are alkyl-SS-alkyl- and form a cyclic group, or R ¹ and R ¹ form:

where

a) V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl, or

V and Z are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group being fused to an aryl group at the β and γ position to Y attached to V; or

Z is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OC (S) OR ³ , -CHR ² OC (0) SR ³ , -CHR ² OCO ² R ³ , -OR ² , -SR ² , -CHR ² N 3, -CH ₂ aryl, -CH (aryl) OH, -CH (CH = CR) ² ) OH, -CH (CsCR ² ) OH, -R ² , -NR ² 2, -OCOR ³ , -OCO ² R ³ , -SCOR ³ , -SCO2R ³ , -NHCOR ² , -NHCO ² R ³ , -CH ₂ NHaryl, - (CH ₂ ) _p -OR ^2, and - (CH ₂ ) _p -SR ² , wherein p is an integer of 2 or 3, or

Z and W are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl; or

W and W 'are independently selected from hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or

W and W 'are joined together via an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl;

b) V ', W ² and W "are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl ;

Z ² is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OCO ² R ³ , -CHR ² OC (0) SR ^3, -CHR ² OC (S) ^OR3, -CH (aryl) OH, -CH (CH = CR ² 2) OH, -CH (C ^ CR ²⁾ OH, -SR ^2, -CH ₂ NHaryl, -CH ₂ aryl; or

V ² and Z ² are joined together via an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 ring atoms, optionally containing 1 heteroatom, and substituted with a hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy group attached to a carbon atom of three atoms from group Y attached to phosphorus;

c) Z 'is selected from the group consisting of -OH, -OC (O) R ³ , -OCC-R ^3, and -OC (O) SR ³ ;

D 'is hydrogen;

D is selected from the group consisting of hydrogen, alkyl, -OR ² , -OH, and -OC (O) R ³ ;

each W ³ is independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl 85, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

with the proviso that:

a) V, Z, W, W 'are not all hydrogen and V ² , Z ² , W ² , W are not all hydrogen;

R ² is selected from R ³ and hydrogen;

R ³ is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;

each R ⁴ is independently selected from the group consisting of hydrogen and alkyl, or together R ⁴ and R ⁴ form a cyclic alkyl group;

R ⁶ is selected from the group consisting of hydrogen, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;

R ²⁵ is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic;

R ⁷ is independently selected from the group consisting of hydrogen, lower alkyl, lower alicyclic, lower aralkyl, lower aryl and -C (O) R ¹⁰ ;

R ⁸ is independently selected from-H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, -C (O) R ¹⁰ or both R ⁸ together form a bidentate alkyl;

R ⁹ is selected from the group consisting of alkyl, aralkyl and alicyclic;

R ¹⁰ is selected from the group consisting of hydrogen, lower alkyl, -NH ₂ , lower aryl and lower perhaloalkyl, and

R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ² ;

n is an integer from 1 to 3;

R is independently selected from the group consisting of hydrogen, lower alkyl, aryl and aralkyl, or R ^K and R ¹⁸ are taken together through 1 to 4 carbon atoms to form a cyclic group;

each R ¹² and each R ¹³ is independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, lower aralkyl, all of which may be optionally substituted or R ¹² and R ¹³ are joined together via 2 to 6 carbon atoms, optionally containing 1 heteroatom selected from O, N and S to form a cyclic group;

each R ¹⁴ is independently selected from the group consisting of -OR ¹⁷ , -N (R ¹⁷ ) ₂ , -NHR ¹⁷ , -SR ¹ ', and -NR ² R ²⁰ ;

R ¹⁵ is selected from the group consisting of hydrogen, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ¹⁶ are joined together via 2 to 6 atoms to form a cyclic group wherein the cyclic group optionally comprises one heteroatom selected from 0 , N and S;

R ¹⁰ is selected from the group consisting of - (CR ' ² R ¹³ ) _n -C (O) -R ¹⁴ , hydrogen, lower alkyl, lower aryl and lower aralkyl or R ¹⁵ and R ¹⁶ are joined together via 2 to 6 atoms to form a cyclic group, wherein the cyclic group optionally comprises one heteroatom selected from O, N, and S;

each R ¹⁷ is independently selected from the group consisting of lower alkyl, lower aryl and lower aralkyl, or when R ¹⁴ is -N (R ¹⁷ ) 2, both R ¹⁷ are joined together via 2 to 6 atoms to form a cyclic group wherein the cyclic group optionally comprises one heteroatom selected from O, N and S;

R ²⁰ is selected from the group consisting of hydrogen, lower R 'and -C (O) -lower R ³ ;

and pharmaceutically acceptable prodrugs or salts thereof.

Preferred A ² groups for formula II include -NR ⁸ 2, lower alkyl, lower perhaloalkyl, lower alkoxy and halogen. Particularly preferred are -NR ⁸ 2 and halogen. Especially preferred is -NR ⁸ 2. Most preferred is -NH ₂ .

Preferred E ² groups for formula II include hydrogen, halogen, lower perhaloalkyl, -CN, lower alkyl, lower alkoxy and lower alkylthio. Particularly preferred E ² groups include hydrogen, -SCH 3, -Et and -Cl. Particularly preferred are H and -SCH _third

Preferred X ³ groups for formula II include -alkyl-, -alkynyl-, -alkoxyalkyl-, alkylthio-, -aryl-, -1,1-dihaloalkyl-, -carbonylalkyl-, - heteroaryl-, -alkylcarbonylamino-, and -alkylaminocarbonyl-. Particularly preferred is -alkyl- substituted with 1 to 3 substituents selected from halogen and OH. Particularly preferred are -alkylaminocarbonyl-, -alkoxyalkyl- and -heteroaryl-. Preferred -alkoxyalkyl- groups include -methoxymethyl- group. Preferred -heteroaryl groups include a -furan-2,5-diyl group, optionally substituted.

Preferred Y ³ groups for formula II include an aralkyl group, an alicyclic group, an alkyl group and an aryl group, all optionally substituted. Lower alkyl is particularly preferred. Particularly preferred Y ³ groups include (2-naphthyl) methyl, cyclohexylethyl, phenylethyl, nonyl, cyclohexylpropyl, ethyl, cyclopropylmethyl, cyclobutylmethylphenyl, (2-methyl) propyl, neopentyl, cyclopropyl, cyclopentyl, (1-imidazolyl) propyl, 2-ethoxybenzyl , 1-hydroxy-2,2-dimethylpropyl, 1-chloro-2,2-dimethylpropyl,

2,2-dimethylbutyl, 2- (spiro-3,3-dimethylcyclohex-2-enyl) propyl and 1-methylneopentyl. Neopentyl and isobutyl are particularly preferred.

Preferred R ⁴ and R ⁷ groups are hydrogen and lower alkyl. Particularly preferred are hydrogen and methyl.

In another preferred aspect, A ² is -NR ⁸ ₂ or halogen, E ² is hydrogen, halogen, -CN, lower alkyl, lower perhaloalkyl, lower alkoxy or lower alkylthio, X ³ is -alkyl-, -alkoxyalkyl -, -alkynyl-, -1,1-dihaloalkyl-, -carbonylalkyl-, -alkyl (OH) -, -alkylcarbonylamino-, -alkylaminocarbonyl-, -alkylthio-, -aryl- or -heteroaryl- and R ⁴ and R ⁷ is hydrogen or lower alkyl. Particularly preferred are those compounds wherein Y ³ is an aralkyl group, an aryl group, an alicyclic group or an alkyl group.

In another preferred embodiment, A ² is -NR ^those 2, E is hydrogen, chlorine or methylthio, and ^X3 is optionally substituted - furan-2,5-diyl-, or -alkoxyalkyl-. Particularly preferred are those compounds wherein A ² is -NR ⁸ 2, X ³ is furan-2,5-diyl- or -methoxymethyl- and Y ³ is a lower alkyl group. Most preferred are those compounds wherein E ² is hydrogen, X ³ is -furan-2,5-diyl- and Y is neopentyl, such where E ² is -SCH 3, X ³ is -furan-2,5-diyla Y ³ is isobutyl and also where E ² is hydrogen, X ³ is -furan-2,5-diyla; Y ³ is (3-chloro-2,2-dimethyl) -propyl. Particularly preferred are those compounds wherein R ¹ is -CH 2 O-C (O) -C (CH ₃ ) ₃ .

According to one aspect of the invention, compounds of formula I or formula IA wherein M is

where

B ⁵ is selected from -NH-, -N = and -CH =;

_l ₌

D ⁵ is selected from the group consisting of a

Q ^{5 e} j selected from -C = and -N-;

with the proviso that:

when B ⁵ is -NH-, Q ⁵ is -C = and D ⁵ is ^C , _l ₌ when B ⁵ is -CH =, Q ⁵ is -N and D ⁵ is ^C , when B ⁵ is -N =, D ⁵ is and Q ⁵ is -C =,

A, E and L are selected from the group consisting of -NR ³ 2, -NO 2, hydrogen, -OR ⁷ , -SR ⁷ , -C (O) NR ¹ '2, halogen, -COR ¹¹ , -SO ² R ³ , guanidine, amidine, -NHSO ² R ²⁵ , -SO ₂ NR ⁴ ₂ , -CN, sulfoxide, per'naloacyl, perhaloalkyl, perhaloalkoxy, C 1 -C 5 alkyl, C 2 -C 5 alkenyl C ₂ -C ₅ alkynyl and a lower alicyclic group or A and L together form a cyclic group or L and E form a cyclic group or together E and J form a cyclic group selected from the group consisting of aryl, cyclic alkyl and heterocyclic groups;

J is selected from the group of -NR _2, -N0 ₂ group, hydrogen, -OR ^7, -SR ^7, -C (O) NR ⁴ _2, halo, -C ^(O) R group, -CN, sulphonyl, sulphoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or together with Y ³ , or a group selected from Y ³ from the group consisting of aryl, cyclic alkyl and heterocyclic;

X ³ is selected from the group consisting of -alkyl (hydroxy) -, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkythioalkyl-, -alkythio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, a -alkoxycarbonylamino- group and a -alkylaminocarbonylamino- group, all optionally substituted, provided that X ³ is not substituted with -COOR ² , -SO 3 H, or -PO ³ R ² 2;

Y ³ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C (O) R ³ , -S (O) 2 R ³ , -C (O) -R ^n, a group -CONHR ^3, -NR ² 2, and -OR ^3, all except H are optionally substituted;

R ⁴ is independently selected from the group consisting of hydrogen and alkyl or R ⁴ and R ⁴ together form a cyclic alkyl group;

R ²⁵ is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic;

R ⁷ is independently selected from the group consisting of hydrogen, lower alkyl, lower alicyclic, lower aralkyl, lower aryl and -C (O) R ¹⁰ ;

R ⁸ is independently selected from the group consisting of hydrogen, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, and -C (O) R ¹⁰ ; or together form a bidentate alkyl group;

R ¹⁰ is selected from the group consisting of hydrogen, lower alkyl, -NH ₂ , lower aryl and lower perhaloalkyl;

R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ² , or pharmaceutically acceptable prodrugs and salts thereof.

Compounds of general interest are preferred of formula IV: A 0 yr ¹ · — —x ³ -CôíC Λ Ϊ YR ¹ 'l IV where: B ⁵ is selected from the group -NH-, -N = = and -CH =; D ⁵ is selected from the group containing ^c and ^N Q ⁵ is selected from the group -C = and -N · T with the proviso that: when B ⁵ is -NH-, Q ⁵ is -C = and D ⁵ is T when B ³ is -CH =, Q ⁵ is -N- and D ⁵ is and When B ³ is -N =, D ⁵ is ^N and Q ⁵ is -C,

A, E and L are selected from the group consisting of -NR ⁸ ₂ , -NO ₂ , hydrogen, -OR ⁷ , -SR ⁷ , -CfOJNRS, halogen, -COR ¹¹ , -SO ² R ³ , guanidine amido, -NHSO 2 R ²⁵ , -SO 2 NR ⁴ 2, -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C 1 -C 5 alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ an alkynyl group and a lower alicyclic group, or A and L together form a cyclic group or L and E form a cyclic group or together E and J form a cyclic group selected from the group consisting of aryl, cyclic alkyl and heterocyclic groups;

J is selected from the group consisting of -NR ⁸ _2, -N0 ₂ group, hydrogen, -OR ^7, -SR ^7, -C (0) NR ¹ 2, halo, -C (0) R ¹¹ , -CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl, and aralkyl, or together with ³ a group selected from the group consisting of aryl, cyclic alkyl and heterocyclic alkyl;

X ^{3 e} j selected from the group consisting of -alkyl (hydroxy) -, -alkyl- group, a group -alkynyl-, -aryl- group, -carbonylalkyl- group, a group of -1, Ι-dihaloalkyl-, -alkoxyalkyl- group, -alkyloxy-, -alkythioalkyl-, -alkythio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxycarbonyl-, -alkoxycarbonylamino- group and -alkylaminckarbonylamino- radical, all optionally substituted, with the proviso that XX is not substituted with -COOR ^2, -SO 3 H, or -PO ₃ R ^2;

Y ³ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C (O) R ³ , -S (O) 2 R ³ , -C (O) -R ^n, a group -CONHR ^3, -NR ² 2, and -OR ^3, all except H are optionally substituted;

Y is independently selected from -O- and -NR ⁵ , with the proviso that:

when Y is -O-, R ¹ attached to -O- is independently selected from the group consisting of hydrogen, alkyl, optionally substituted aryl, optionally substituted alicyclic, wherein the cyclic group comprises carbonate or thiocarbonate, optionally substituted -arylalkyl, -C (R ² ) 20 C (O) NR ² 2, -NR ² -C (O) -R ³ , -C (R ² ) ₂ -OC (O) R ³ , -C (R ² ) 2-O-C (O) OR ³ , -C (R ² ) 2 OC (O) SR ³ , -alkyl-SC (O) R ³ , -alkyl-SS-alkylhydroxy and -alkyl-SSS-alkylhydroxy when Y is -NR ⁵ -, R ¹ attached to -NR ⁶ - is independently selected from hydrogen, - [C (R ') 2] q -COOR ³ , -C (R ⁴ ) 2 COOR ³ , a - [C (R ² ) 2] _q -C (O) SR group and a -cycloalkylene-COOR ³ group wherein q is 1 or 2;

when only one Y is -O-, wherein -O- is not part of the cyclic group containing the other Y, the other Y is -N (R ¹³ ) - (CR ¹² R ¹³ ) -C (O) -R ¹⁴ ; and when Y is independently selected from -O- and -NR ⁰ , R ¹ and R ¹ together are alkyl-SS-alkyl- and form a cyclic group, or R ¹ and R ¹ together form:

where

a) V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl, or

V and Z are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group being fused to an aryl group at the β and γ position to Y attached to V; or

Z is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OC (S) OR ³ , -CHR ² OC (0) SR ³ , -CHR ² OCO ² R ³ , -OR ² , -SR ² , -CHR ² N 3, -CH ² aryl, -CH (aryl) OH, -CH (CH = CR ² 2) OH, -CH (C 1 -C ² ) OH, -R ² , -NR ² ₂ , -OCOR ³ , -OCO ² R ³ , -SCOR ³ , -SCO2R ³ , -NHCOR ² , -NHCO ² R ³ , -CH ₂ NHaryl, - (CH ₂ ) _p -OR ^2, and - (CH ₂ ) _p -SR ² , wherein p is an integer of 2 or 3, or

Z and W are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl; or

W and W 'are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or

W and W 'are joined together via an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl;

b) V ² , and W are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

Z ² is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR'GC (O) SR ³ , -CHR ² OC (S) ^OR3, -CH (aryl) OH,

-CH (CH = CR ² ) OH, -CH (C 1 -C ² ) OH, -SR ² , -CH ₂ NHaryl, -CH ₂ aryl; or

V ² and Z ² are joined together through an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 ring atoms, optionally containing 1 heteroatom, and substituted with a hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy group attached to a carbon atom of three atoms from group Y attached to phosphorus;

c) Z 'is selected from the group consisting of -OH, -OC (O) R ³ , -OCO ₂ R ^3, and -OC (O) SR ³ ;

D 'is hydrogen;

D is selected from the group consisting of hydrogen, alkyl, -OR ² , -OH, and -OC (O) R ³ ;

each W ³ is independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

with the proviso that:

a) V, Z, W, W 'are not all hydrogen and V ² , Z 1, W ² , W are not all hydrogen;

R ² is selected from R ³ and hydrogen;

R ³ is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;

each R ⁴ is independently selected from the group consisting of hydrogen and alkyl, or together R ⁴ and R ⁴ form a cyclic alkyl group;

R ⁶ is selected from the group consisting of hydrogen, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl;

R ²⁵ is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic;

R ⁷ is independently selected from the group consisting of hydrogen, lower alkyl, lower alicyclic, lower aralkyl, lower aryl and -C (O) R ¹⁰ ;

R ⁸ is independently selected from the group consisting of hydrogen, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, -C (O) R ¹⁰ ; or together form a bidentate alkyl group;

each R ⁹ is independently selected from the group consisting of alkyl, aralkyl, and alicyclic;

R ¹⁰ is selected from the group consisting of hydrogen, lower alkyl, -NH ₂ , lower aryl and lower perhaloalkyl;

R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ² , n is an integer from 1 to 3;

R ¹⁸ is independently selected from the group consisting of hydrogen, lower alkyl, aryl, aralkyl or R ¹² and R ¹⁸ are joined together via 1 to 4 carbon atoms to form a cyclic group;

each R ¹² and each R ¹³ is independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, lower aralkyl, all of which may be optionally substituted, or R ¹² and R ¹³ are joined together via 2 to 6 carbon atoms, optionally containing 1 a heteroatom selected from O, N and S to form a cyclic group;

each R ¹⁴ is independently selected from the group consisting of -OR ¹⁷ , -N (R ¹⁷ ) 2, -NHR ¹⁷ , -SR ^17, and -NR ² R ²⁰ ;

R ¹⁵ is selected from the group consisting of hydrogen, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ¹⁶ are joined together via 2 to 6 atoms to form a cyclic group wherein the cyclic group optionally includes one heteroatom selected from O , N and S;

R ¹⁶ j ^E selected from the group consisting of - (CR ² R ¹³⁾ n C (O) R ^14, H, lower alkyl, lower aryl, and lower aralkyl, or R ¹⁵ and R ¹⁶ are connected via 2-6 atoms to form a cyclic group, wherein the cyclic group optionally comprises one heteroatom selected from O, N and S;

each R ¹⁷ is independently selected from the group consisting of lower alkyl, lower aryl and lower aralkyl, or when R ¹⁴ is -N (R ¹ ') 2, both R ¹ ' are joined via 2 to 6 atoms to form a cyclic ring a group wherein the cyclic group optionally comprises one heteroatom selected from O, N and S;

R ^c is selected from the group consisting of hydrogen, lower R ^3, and -C (O) -lower R ³ ;

and pharmaceutically acceptable prodrugs and salts thereof.

Preferred A, L and E groups of formula IV include hydrogen, -NR ⁸ 2, -NO 2, hydroxy, halogen, -OR ⁷ , alkylaminocarbonyl, -SR ⁷ , lower perhaloalkyl, and C 1 -C 5 alkyl, or E and J together form a cyclic group. This cyclic group may be an aromatic group or a cyclic alkyl group and may be optionally substituted. Suitable aromatic groups include thiazole. Particularly preferred A, L and E groups are -NR ⁸ 2, hydrogen, hydroxy, halogen, lower alkoxy, lower perhaloalkyl and lower alkyl.

Preferred A groups for formula IV include -NR ⁸ ₂ , lower alkyl, hydrogen, halogen and lower perhaloalkyl.

Preferred L and E groups for Formula IV include hydrogen, lower alkoxy, lower alkyl, and halogen.

preferred

J groups in formula IV include hydrogen, halogen, lower alkyl, -NR ⁸ _2, lower R ³ ₂ lower N-alkyl hydroxyalkyl, haloalkyl, lower perhaloalkyl lower alkenyl, lower alkynyl, lower aryl , a heterocyclic group and an alicyclic group, or together with Y ³ form a cyclic group. This cyclic group may be an aromatic group or a cyclic alkyl group and may be optionally substituted. Particularly preferred J groups include hydrogen, halogen, lower alkyl, lower hydroxyalkyl, -NR ⁸ 2, lower R ^8, 2N-alkyl, lower haloalkyl, lower alkenyl, alicyclic, and aryl.

Preferred X ³ groups for formula IV include -alkyl-, -alkynyl-, -alkoxyalkyl-, arylthio-, -aryl-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -1, 1- dihaloalkyl-, -carbonylalkyl-, and -alkyl (OH) -. Especially preferred are the group

-1,1-dihaloalkyl-, -alkylaminocarbonyl-, -alkoxyalkyl- and -heteroaryl-. Compounds which are particularly preferred are -heteroaryl-, -alkylaminocarbonyl- and -alkoxyalkyl-. Most preferred are -methylaminocarbonyl-, -methoxymethyl- and -furan-2,5-diyl-.

In one preferred aspect, X ³ is not - (C 2 -C 3 alkyl) aminocarbonyl-.

Preferred Y ³ groups for formula IV include hydrogen, alkyl, aryl, aralkyl and alicyclic, all of which except hydrogen can be optionally substituted. Particularly preferred Y ³ groups include lower alkyl and alicyclic groups.

Preferred R ⁴ and R ⁷ groups include hydrogen and a lower alkyl group.

In one preferred aspect of Formula IV, B ^{5 is} ₌ NH, D ⁵ is ^C, and Q ³ is -C =. In another preferred aspect, _1 is

B ⁵ is -N =, D ⁵ is ^N and Q ⁵ is -C =.

In one preferred aspect of the compounds of formula IV, A, L, and E are independently -NR ⁸ 2, lower alkyl, lower perhaloalkyl, lower alkoxy, halogen, hydroxy or hydrogen; X ³ is -aryl-, -alkoxyalkyl-, -alkyl-, -alkylthio-, -1,1-dihaloalkyl-, -carbonylalkyl-, -alkyl (hydroxy) -alkylaminocarbonyl- and - alkylcarbonylamino-, and each R ⁴ and R 'is independently hydrogen or a lower alkyl group. Particularly preferred are those compounds wherein A, L and E are independently hydrogen, lower alkyl, halogen and -NR ⁸ ; J is hydrogen, halo, haloalkyl, hydroxyalkyl, R ^B 2 N-alkyl, lower alkyl, lower aryl, heterocyclic, and alicyclic or together with ^Y3

100 is a cyclic group, and X ³ is -heteroaryl-, -alkylaminocarbonyl-, -1,1-dihaloalkyl- and -alkoxyalkyl-. Particularly preferred are those compounds wherein A is hydrogen, -NH 2, -F or -CH 3, L is hydrogen, -F, -OCH 3 or -CH 3, E is hydrogen or -CH 3, J is hydrogen, halogen , C 1 -C 5 hydroxyalkyl, C 1 -C 5 haloalkyl, C 1 -C 5 R ⁸ 2N-alkyl, C 1 -C 5 alicyclic or C 1 -C 5 alkyl, X ³ is -CH ₂ OCH ₂ - or furan-2, 5-diyl; and Y ³ is a lower alkyl group.

Preferred are those compounds wherein B ⁵ is NH, D ⁵ is ^C 1 and Q ⁵ is -C = or wherein B ⁵ is -N =, D ⁵ is and Q ⁵ is -C =.

Most preferred are the following compounds and salts thereof, and prodrugs and salts thereof:

1) A is -NH ₂ , L is -F, E is hydrogen, J is hydrogen, Y ³ is isobutyl and X ³ is -furan-2,5-diyl · -;

2) A is -NH ₂ , L is -F, E is hydrogen, J is -Cl, Y ³ is isobutyl and X ³ is -furan-2,5-diyl-;

3) A is hydrogen, L is hydrogen, E is -Cl, J is H, B ⁵ is a group _l ₌₌

NH, D ⁵ is ^C and Q ⁵ is -C =, and Y ³ is isobutyl; and

4) A is methyl, L is hydrogen, E is hydrogen, J is hydrogen, B ³

-N is -N =, D ⁵ is and Q ⁵ is -C = and Y ³ is isobutyl.

Particularly preferred are those compounds wherein R ¹ is -CH ₂ OC (O) -C (CH ₃ ) 3.

Another particularly preferred aspect includes such compounds wherein A,

101

L and E are hydrogen, lower alkyl, halogen or -NR ⁸ ₂ , J is hydrogen, halogen, lower alkyl, lower aryl, heterocyclic or alicyclic, or together with Y ³ form a cyclic group and X ³ is - heteroaryl-, -alkylaminocarbonyl- or -alkoxyalkyl-.

In another aspect, compounds of formula V-1 or V-2 are preferred:

where:

each G is independently selected from C, N, O, S and Se and wherein only one G is O, S or Se and at most one G is N;

each G 'is independently selected from C and N and wherein no more than two G' groups are N;

A is selected from the group consisting of hydrogen, -NR%, -CONR ⁴ 2, -CO ² R ³ , halogen, -S (O) R ³ , -SO ² R ³ , alkyl, alkenyl, alkynyl, perhaloalkyl haloalkyl, aryl, -CH 2 OH, -CH 2 NR ⁴ 2, -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ^J , -N 3 , -NHC (S) NR ⁴ 2, -NHAc group, a is zero;

each B and D are independently selected from-H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyl alkyl group, a -C (O) R ^l, -C (O) SR ^J , -SO 2 R ⁿ , -S (O) R ^J , -CN, -NR ⁹ 2, -OR ^J , -SR ³ , perhaloalkyl, halogen, -NO _2, and zero, all with the exception of hydrogen, -CN, perhalo

102 alkyl, -NO _2, and halogen are optionally substituted;

E is selected from-H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, -C (O) OR ^J, -CONR ⁴ 2, -CN, -NR ⁹ 2 -NO ₂ , -OR ³ , -SR ³ , perhaloalkyl, halogen and zero, all except hydrogen, cyano, perhaloalkyl and halogen are optionally substituted;

J is selected from hydrogen or zero;

X is an optionally substituted linking group that connects R ⁵ to a phosphorus atom via 2 to 4 atoms, including 0 to 1 heteroatom selected from N, O and S, provided that when X is urea or carbamate, then there are 2 heteroatoms, measured by the shortest path between R ⁵ and the phosphorus atom and wherein the atom attached to the phosphorus is a carbon atom and wherein X is selected from the group consisting of -alkyl (hydroxy) -alkyl, -alkynyl, -heteroaryl, -carbonylalkyl- , -1,1-dihaloalkyl, -alkoxyalkyl, -alkyloxy, -alkythioalkyl, -alkythio, -alkylaminocarbonyl, -alkylcarbonylamino, -alkoxycarbonyl, -carbonyloxyalkyl, -alkoxycarbonylamino - and -alkylaminocarbonylamino, all optionally substituted, with the proviso that X is not substituted with -COOR ² , -SO 3 H, or PO ³ R ² ₂ ;

R ² is selected from R ³ and hydrogen;

R ^J is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;

each R ⁴ is independently selected from the group consisting of hydrogen and alkyl or R ⁴ and R ⁴ together form a cyclic alkyl group;

R ⁶ is selected from the group consisting of hydrogen, lower alkyl

103 an acyloxyalkyl group, an alkoxycarbonyloxyalkyl group, and a lower acyl group;

each R ⁹ is independently selected from hydrogen, alkyl, aralkyl and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group;

R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ² , n is an integer from 1 to 3;

Z O _z

R 12 is independently selected from the group consisting of hydrogen, lower alkyl, aryl and aralkyl, or R ¹² and R ¹⁸ are joined together via 1 to 4 carbon atoms to form a cyclic group;

each R ¹² and each R ¹³ is independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, lower aralkyl, all of which may be optionally substituted, or R ¹² and R ¹³ are joined together via 2 to 6 carbon atoms, optionally containing 1 a heteroatom selected from O, N and S to form a cyclic group;

each R ¹⁴ is independently selected from the group consisting of -OR ¹⁷ , -N (R ¹⁷ ) ₂ , -NHR ¹⁷ , -SR ^17, and -NR ² R ²⁰ ;

R ¹⁵ is selected from the group consisting of hydrogen, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ¹⁰ are joined together via 2 to 6 atoms to form a cyclic group wherein the cyclic group optionally includes one heteroatom selected from About us;

R 'is selected from the group consisting of - (CR'R) n C (O) -R ¹⁴ , hydrogen, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ¹⁶ are joined together via 2 to 6 atoms, to form a cyclic group,

104 wherein the cyclic group optionally comprises one heteroatom selected from O, N and S;

each R ¹⁷ is independently selected from the group consisting of lower alkyl, lower aryl and lower aralkyl, or when R ¹⁴ is -N (R ¹⁷ ) ₂ , both R ¹⁷ are joined via 2 to 6 atoms to form a cyclic group, wherein the cyclic group optionally comprises one heteroatom selected from O, N and S;

Ω 7

R is selected from the group consisting of hydrogen, lower R, and -C (O) -lower R ³ ;

with the proviso that:

1) when G 'is N, then A, B, D or E is zero;

2) at least one of A and B or A, B, D and E is not selected from hydrogen or zero;

3) when R ⁵ is a six membered ring, then X is not a bivalent atom, an optionally substituted -alkoxy group or an optionally substituted -alkylthio group;

4) when G is N, then A or B is not a halogen or a group directly bonded to G via a heteroatom;

5) when X is not an -aryl- group, then R ⁵ is not substituted with two or more aryl groups;

Y is independently selected from -O- and -NR ⁰ , with the proviso that:

when Y is -O-, R ¹ attached to -O- is independently selected from the group consisting of hydrogen, alkyl, optionally substituted aryl, optionally substituted alicyclic, wherein the cyclic group comprises carbonate or thiocarbonate, optionally substituted -arylalkyl-, group

105

-C (R ² ) 2 OC (O) NR ² 2, -NR ² -C (O) -R ³ , -C (R ² ) 2 -OC (O) R ³ , -C (R ² ) 2-OC (O) OR ³ , -C (R ² ) ₂ OC (O) SR ³ , -alkyl-SC (O) R ³ , -alkyl-SS-alkylhydroxy and -alkyl-SSS-alkylhydroxy;

when Y is -NR ⁰ -, R ¹ attached to -NR ⁶ - is independently selected from hydrogen, - [C (R ² ) 2] q -COOR ³ , -C (R ⁴ ) 2 COOR ³ , - [C (R ² ) ₂ ] _q -C (O) SR and a -cycloalkylene-COOR ^{3 group} , wherein q is 1 or 2;

when only one Y is -O-, wherein -O- is not part of the cyclic group containing the other Y, the other Y is -N (R ¹⁶ ) - (CR ¹² R ¹³ ) -C (O) -R ¹⁴ ; and when Y is independently selected from -0- and -NR ^6, R ¹ and R ¹ together are alkyl-SS-alkyl to form a cyclic group, or ^R1 and R together are:

where

a) V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl, or

V and Z are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group being fused to an aryl group at the β and γ position to Y attached to v; or

Z is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OC (S) OR ³ , -CHR ² OC (O) SR ³ , -CHR ² OCO ₂ R ³ , -OR ² , -SR ² ,

106 -CHR ² N 3, -CH 2 aryl group, -CH (aryl) OH, -CH (CH = CR ² 2) OH, -CH (C ^ CR ²⁾ OH, -R ^2, -NR ² ₂ , -OCOR ³ , -OCO ² R ³ , -SCOR ³ , -SCO2R ³ , -NHCOR ² , -NHCO ² R ³ , -CH ₂ NHaryl, - (CH ₂ ) _p -OR ^2, and - (CH ₂ ) _p -SR ² , wherein p is an integer of 2 or 3, or

Z and W are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl; or

W and W 'are independently selected from hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, hetercaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or

W and W 'are joined together via an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl;

b) V ² , W ² and W are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

Z 1 is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OCO ² R ³ , -CHR ² OC (O) SR ^3, -CHR ² OC (S) ^OR3, -CH (aryl) OH, -CH (CH = CR ² 7) OH, -CH (C = ^CR2) OH, -SR ^2, -CH ₂ NHaryl, -CH ₂ aryl; or

V ² and Z are joined together via an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 ring atoms

107 atoms, optionally containing 1 heteroatom, and substituted with hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom which is three atoms from group Y attached to phosphorus;

c) Z 'is selected from the group consisting of -OH, -OC (O) R ³ , -OCO ₂ R ^3, and -OC (O) SR ³ ;

D 'is hydrogen;

D is selected from the group consisting of hydrogen, alkyl, -OR ² , -OH, and -OC (O) R ³ ;

each W ³ is independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

with the proviso that:

a) V, Z, W, W 'are not all hydrogen and V ² , Z ² , W ² , W are not all hydrogen;

In one preferred aspect, compounds of Formula V-1 and Formula V-2 are included, wherein

A is selected from the group consisting of -NH 2, -CONH 2, halogen, -CH ₃ , CF 3, -CH 2 -halo, -CN, -OCH ₃ , -SCH _3, and hydrogen;

B is selected from the group consisting of hydrogen, -C (O) R ¹¹ , -C (O) SR ³ , alkyl, aryl, alicyclic, halogen, -CN, -SR ³ , -OR ³ and -NR ⁹ ₂ ;

D is selected from the group consisting of hydrogen,

108

-C (O) R ¹¹ , -C (O) SR ³ , -NR ⁹ ₂ , alkyl, aryl, alicyclic, halogen, and -SR ³ ;

E is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, lower alicyclic, halogen, -CN, -C (O) OR ^3, and -SR ³ .

X is selected from the group consisting of -alkyl (hydroxy), -alkyl, -alkynyl, -aryl, -carbonylalkyl, -1,1-dihaloalkyl, -alkoxyalkyi, -alkyloxy - a group, -alkythioalkyl, -alkythio-, -alkylaminocarbonyl, -alkylcarbonylamino, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino a group and an -alkylaminocarbonylamino group, all optionally substituted when both Y groups are -O-, then R ¹ is independently selected from an optionally substituted aryl group, an optionally substituted benzyl group, a -C (R) 2 OC (O) R group ', -C (R ²⁾ 20 C (0) ^OR3, and hydrogen; or when one Y is -O-, then R ¹ attached to -O- is optionally substituted aryl; and the other Y is -NR ⁶ -, then R ¹ attached to -NR ⁶ - is selected from the group consisting of -C (R ⁴ ) 2 COOR ³ and -C (R ² ) ² COOR ³ ; or when Y is -0- or -NR ⁶ -, then

R ¹ and R ^{1 taken} together form:

where

109

a) V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl, or

V and Z are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group being fused to an aryl group at the β and γ position to Y attached to V; or

Z is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OC (S) OR ³ , -CHR ² OC (O) SR ³ , -CHR ² OCC> 2R ³ , -OR ² , -SR ² , -CHR ² N ₃ , -CH ₂ aryl, -CH (aryl) OH, -CH ( CH = CR ² 2) OH, -CH (CsCR ² ) OH, -R ² , -NR ² 2, -OCOR ³ , -OCO ² R ³ , -SCOR ³ , -SCO2R ³ , - NHCOR ² , -NHCO ² R ³ , -CH 2 NHaryl, - (CH 2) p -OR ^2, and - (CH 2) _p -SR ² wherein p is an integer of 2 or 3; or

Z and W are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl; or

W and W 'are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or

W and W 'are joined together via an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl;

b) V ² , W ² and W "are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl

110 represents a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, a 1-alkenyl group and a 1-alkynyl group;

Z ² is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OCO ² R ³ , -CHR ² OC (O) SR ^3, -CHR ² OC (S) ^OR3, -CH (aryl) OH, -CH (CH = CR ² 2) OH, -CH (ΟξΟΡ ²⁾ OH, -SR ^2, is - CH ₂ NHaryl, -CH ₂ aryl; or

V ² and Z ² are joined together via an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 ring atoms, optionally containing 1 heteroatom, and substituted with a hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy group attached to a carbon atom of three atoms from group Y attached to phosphorus;

c) Z 'is selected from the group consisting of -OH, -OC (O) R ³ , -OCO ₂ R ^3, and -OC (O) SR ³ ;

D 'is hydrogen;

D is selected from the group consisting of hydrogen, alkyl, -OR ² , -OH, and -OC (O) R ³ ;

each W ³ is independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

with the proviso that:

a) V, Z, W, W 'are not all hydrogen and V ² , Z, W ² , W are not all hydrogen;

b) both Y groups are not -NR ⁶ -;

111

R ² is selected from R ³ and hydrogen;

R ³ is selected from the group consisting of alkyl, aryl, alicyclic and aralkyl;

R ⁶ is selected from the group consisting of hydrogen and lower alkyl.

In one particular preferred aspect are included compounds of Formula I wherein M is

group one and their methyleneoxycarbonyl group is -O-, and prodrugs thereof. More preferably, R ¹ attached to -farmaceous such is non-X is selected from and furan-2,5-diyl, at least a tally acceptable salt of the compound, wherein when Y is -O-, visibly selected from hydrogen, optionally substituted phenyl, - CH ₂ OC (O) -tBu, -CH ₂ C (O) Et

-CH ₂ OC (O) -iPr;

and the group when one Y is -NR ⁶ -, then R ¹ attached to -NR 0 - is selected from the group consisting of -C (R ⁴ ) 2 COR ³ , C (R ² ) ² COOR ³ ;

independently or when Y is then R ¹ and R ¹

at least one group

Υ is -O-, where

V is selected from optionally substituted aryl and optionally substituted heteroaryl,

112 and Z, W 'and W are hydrogen, and

R ⁶ is selected from hydrogen and lower alkyl.

Most preferred are the following compounds and salts thereof:

1) A is a group -nh ₂ , X is a furan-2,5-diyl and B is a group -CH ₂ -CH (CH ₃ ) ₂ ; 2) A is a group -nh ₂ , x is a furan-2,5-diyl and B " is a group COOEt; 3) A '' is -NH 2, X is a Furár i-2,5-diyl and B is a group -SCH ₃ ; 4) A '' is a group -nh ₂ , X is a furan-2,5-diyl and B is a group

-SCH ₂ CH ₂ CH ₃ ;

5) A is -NH ₂ , X is methyleneoxycarbonyl, and B is

CH _{(CH3) 2;}

6) A 1 'is -NH ₂ , X is furan-2,5-diyl, and B is 4-morpholinyl.

In another particularly preferred aspect of the invention, the compounds of formula I wherein M is a group -XR ^5, R ³ is

X is furan-2,5-diyl and methyleneoxycarbonyl and A is -NH ₂ ; at least one Y group is -O-, and pharmaceutically acceptable salts and prodrugs thereof. Particularly preferred are those compounds wherein when Y is -O- then R ¹ is independently selected from hydrogen, optionally substituted phenyl, -CH ₂ OC (O) -tBu, -CH ₂ OC (O) Et and -CH ₂ OC (O) -iPr;

113 or when Y is -NR ⁵ -, then R ¹ is independently selected from the group consisting of -C (R ⁴ ) 2 COOR ³ and C (R ² ) ² COOR ³ ;

or when Y is independently selected from -O- and -NR °, then R ¹ and R ¹ are together

where

V is selected from optionally substituted aryl and optionally substituted heteroaryl; and Z, W 'and W are hydrogen. Also particularly preferred are those compounds wherein B is -SCH-CH ₂ CH ₃ .

In another particularly preferred aspect, the compounds of formula I wherein M is -XR ^5, and R ⁵ is

D

A is -NH ₂ , E "and D are hydrogen, B is n-propyl and cyclopropyl, X is furan-2,5-diyl methyleneoxycarbonyl, at least one Y is -O-, and pharmaceutically acceptable salts thereof, and its prodrugs. Particularly preferred are those compounds wherein R ¹ is selected from the group consisting of hydrogen, optionally substituted phenyl, -CH ₂ OC (O) -tBu, -CH ₂ OC (O) -Et, and -CH ₂ OC (O) 1-Pr, or when Y is -NR ⁶ -, then each R ¹ is independently selected from the group consisting of -C (R ⁴ ) 2 COOR ³ and C (R ² ) ² COOR ³ ;

or when Y is independently selected from -O- and -NR ⁶ - and at least one

114

Y is -O-, then R ¹ and R ¹ together are where

V is selected from optionally substituted aryl and optionally substituted heteroaryl; and Z, W 'and W are hydrogen.

In another particularly preferred aspect, the compounds of formula I wherein M is -XR ^5, and R ⁵ is

N

B ¹

D

A is -NH ₂ , D is hydrogen, B is n-propyl and cyclopropyl, X is furan-2,5-diyl methylcarbonyl, at least one Y is -O-, and pharmaceutically acceptable salts and prodrugs thereof . Particularly preferred are those compounds wherein when Y is -O-, then R ¹ is selected from the group consisting of hydrogen, optionally substituted phenyl, -CH ₂ OC (O) -tBu, -CH ₂ OC (O) -Et and -CH ₂ OC (O) -iPr, or when one Y is -O- and its corresponding R ¹ is phenyl, while the other Y is -NH- and its corresponding R ¹ is -CH (Me) C (O ) OEt; or when at least one Y group is -O-, then R ¹ and R ¹ are together

115

where

V is selected from the group consisting of substituted aryl and optionally substituted heteroaryl; and Z, W 'and W are hydrogen.

Preferred are compounds of formula X:

where:

G is selected from -O- and -S-;

A ² , L ² , E ² and J ² are selected from the group consisting of

-NR ⁴ 2, -NO 2, hydrogen, -OR ² , -SR ² , -C (O) NR ⁴ 2 <halogen, -COR ¹¹ , -SO ² R ³ , guanidinyl, amidinyl, aryl a group, aralkyl, alkyloxyalkyl, -SCN, -NHSO 2 R, -SO 2 NR ⁴ 2, -CN, -S (O) R ³ , perhaloacyl, perhaloalkyl, perhaloalkoxy, C 1 -C 5 alkyl, C2 A -C5 alkenyl group, a C2-C5 alkynyl group and a lower alicyclic group, or L- and ^Er or E and J together form an annulled cyclic group;

X ² is selected from the group consisting of -CR ² 2-, -CF 2 -, -CR ² 2 -O-, -CRS-S-, -O (O) -O-, -C (O) ) -S-, -C (S) -O-, CR ² ₂ NR ¹⁹ -, and wherein a

116 attached to phosphorus is a carbon atom, with the proviso that X ² is not substituted with -COOR ² , -SO 3 H, or -PO ³ R ² 2;

R ¹⁹ is selected from the group consisting of alkyl, hydrogen and -COR ² ; and

Y is independently selected from -0- and -NR ^6, with the proviso that:

when Y is -O-, R ¹ attached to -O- is independently selected from the group consisting of hydrogen, alkyl, optionally substituted aryl, optionally substituted alicyclic, wherein the cyclic group comprises carbonate or thiocarbonate, optionally substituted -arylalkyl, -C (R ² ) 20 C (O) NR ² 2, -NR ² -C (O) -R ³ , -C (R ² ) ² -OC (O) R ³ , -C (R ² ) 2-0-C (0) 0R ^J, -C ^(R2) 20C (0) SR ^3, -alkyl-SC (0) R ^3, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkyl hydroxy group, ;

when Y is -NR ⁶ -, R ¹ attached to -NR ⁶ - is independently selected from the group consisting of hydrogen, - [C (R ² ) 2] q -COOR ³ , -C (R ⁴ ) 2 COOR ³ , - [C (R ² ) ₂ ] q C (O) SR and a -cycloalkylene-COOR ³ group wherein q is 1 or 2;

when only one Y is -O-, wherein -O- is not part of the cyclic group containing the other Y, the other Y is -N (R ¹⁸ ) - (CR ¹² R ¹³ ) -C (O) -R ¹⁴ ; and when Y is independently selected from -0- and -NR ^6, R ¹ and R ¹ together are alkyl-SS-alkyl to form a cyclic group, or R ¹ and R ¹ together form:

where

117

a) V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl, or

V and Z are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group being fused to an aryl group at the β and γ position to Y attached to V; or

Z is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OC (S) OR ³ , -CHR ² OC (O) SR ³ , -CHR ² OCO ² R ³ , -OR ² , -SR ² , -CHR ² N 3, -CH ₂ aryl, -CH (aryl) OH, -CH (CH = CR) ² 2) OH, -CH (C = CR ² ) OH, -R ² , -NR ² 2, -OCOR ³ , -OCO ² R ³ , -SCOR ³ , -SCO2R ³ , -NHCOR ² , -NHCO ² R ³ , -CH ₂ NHaryl, - (CH ₂ ) _p -OR ^2, and - (CH ₂ ) _p -SR ² , wherein p is an integer of 2 or 3, or

Z and W are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl; or

W and W 'are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or

W and W 'are joined together via an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl;

b) V ² , W ² and W are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic,

118 aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

Z ² is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OCO ² R ³ , -CHR ² OC (0) SR ^3, -CHR ² OC (S) ^OR3, -CH (aryl) OH, -CH (CH = CR ² 2) OH, -CH (C = ^CR2) OH, -SR ^2, -CH ₂ NHaryl, -CH ₂ aryl; or

V ² and Z ² are joined together via an additional 3 to 5 atoms to form a cyclic group containing 5 to 1 ring atoms, optionally containing 1 heteroatom, and substituted with a hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy group attached to a carbon atom of three atoms from group Y attached to phosphorus;

c) Z 'is selected from the group consisting of -OH, -OC (O) R ³ , -OCO ₂ R ^3, and -OC (O) SR ³ ;

D 'is hydrogen;

D is selected from the group consisting of hydrogen, alkyl, -OR ² , -OH, and -OC (O) R ³ ;

each W ³ is independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

with the proviso that:

a) V, Z, W, W 'are not all hydrogen and V ² , Z ² , W' are not all hydrogen;

R ² is selected from R ³ and hydrogen;

119

R ³ is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;

each R ⁴ is independently selected from the group consisting of hydrogen and alkyl, or together R ⁴ and R ⁴ form a cyclic alkyl group;

R ⁶ is selected from the group consisting of hydrogen, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl;

each R ⁹ is independently selected from the group consisting of hydrogen, alkyl, aralkyl and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group;

R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ² , n is an integer from 1 to 3;

R ¹⁸ is independently selected from the group consisting of hydrogen, lower alkyl, aryl, aralkyl or R ¹² and R ¹⁸ are joined together via 1 to 4 carbon atoms to form a cyclic group;

each R ¹² and each R ¹³ is independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, lower aralkyl, all of which may be optionally substituted, or R ¹² and R ¹³ are joined together via 2 to 6 carbon atoms, optionally containing 1 a heteroatom selected from O, N and S to form a cyclic group;

each R ¹⁴ is independently selected from the group consisting of -OR ¹⁷ , -N (R ¹⁷ ) ₂ , -NHR ¹⁷ , -SR ^17, and -NR ² R ²⁰ ;

R ¹⁵ is selected from the group consisting of hydrogen, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ¹⁶ are joined together via 2 to 6 atoms,

120 thereby forming a cyclic group, wherein the cyclic group optionally comprises one heteroatom selected from O, N and S;

R ¹⁶ is selected from the group consisting of - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ , hydrogen, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ¹⁶ are joined together via 2 to 2 6 atoms to form a cyclic group, wherein the cyclic group optionally comprises one heteroatom selected from O, N and S;

each R ¹⁷ is independently selected from the group consisting of lower alkyl, lower aryl and lower aralkyl, or when R ¹⁴ is -N (R ¹⁷ ) ₂ , both R ¹⁷ are joined via 2 to 6 atoms to form a cyclic group, wherein the cyclic group optionally comprises one heteroatom selected from O, N and S;

R ²⁰ is selected from the group consisting of hydrogen, lower R ^3, and -C (O) -lower R ³ ;

and pharmaceutically acceptable prodrugs and salts thereof.

In one aspect, preferred are compounds of formula X wherein A ² is selected from the group consisting of hydrogen, -NH ₂ , -CH ₃ , -CI, and -Br;

L ² is hydrogen, lower alkyl, halogen, lower alkyl ² oxy, hydroxy, -alkylene-OH or together with E form a cyclic group selected from the group consisting of aryl, cyclic alkyl, heteroaryl, non-heterocyclic alkyl;

E ² is selected from the group consisting of hydrogen, lower alkyl, halogen, SCN, lower alkyloxycarbonyl, lower alkyloxy or together with L ² form a cyclic group selected from the group consisting of aryl, cyclic alkyl, heteroaryl or heterocyclic

121 alkyl;

S ² S ^e is selected from hydrogen, halogen and lower alkyl;

G is -S-;

X ² is -CH 2 -O-; and at least one Y group is -O- and pharmaceutically acceptable salts and prodrugs thereof. Also preferred are those compounds wherein A ² is NH ₂ , G is -S-, L ² is Et, E ² is SCN and J ² is hydrogen. More preferred are those compounds wherein Y is -O- and its corresponding R ¹ is optionally substituted phenyl, while the other Y is -N- and its corresponding R ¹ is -C (R ² ) 2 -COOR ³ . When R ¹ is -CHR ³ COOR ³ , then the corresponding -NR ⁶ - * CHR ³ COOR ³ preferably has stereochemistry L.

Also more preferred are those compounds wherein one Y is -O- and its corresponding R ¹ is phenyl, while the other Y is -NH- and its corresponding R ¹ is -CH (Me) CO ₂ Et.

In compounds of formula I, II, III, IV, VI, V-2, VI, VII-1, VII-2 or X, preferably Y is -O- or one Y is -O- and one Y is -NR ⁶ -. When only one Y is -NR ⁰ -, it is preferably Y closest to W and W 'is -O-. Most preferred are prodrugs wherein both Y groups are -O-;

In another particularly preferred embodiment, the two Y-O- group, and R ¹ and R ¹ together are and V is phenyl substituted with 1 to 3 halogens. Particularly preferred are 3-bromo-4-fluorophenyl. 3-chlorophenyl, 3-bromophenyl and 3,5-dichlorophenyl.

In another particularly preferred aspect, it comprises compounds wherein one

122

Y is -O- and its corresponding R ¹ is phenyl or phenyl substituted with 1 to 2 substituents selected from the group consisting of -NHC (O) CH 3, -F, -Cl, -Br, -C (O) OCH 2 CH 3, and -CH 3 while the other Y is -NR ⁵ - and its corresponding R ¹ is -C (R ² ) COOR ³ , each R ² is independently selected from the group consisting of hydrogen, methyl and -CH 2 CH ₃ . More preferably, R ⁶ is hydrogen and R ¹ attached to N- is -CH (Me) CO ₂ Et.

In another aspect of the invention, the following compounds of Formula VII are:

ABOUT

R ¹ Y — P --- X ^{4 —} R ⁵⁵ VII

YR ¹ wherein R ⁵⁵ is selected from:

where:

G ² is selected from C, O and S;

G ³ and G ⁴ are independently selected from C, N, O and S;

wherein a) no more than one of G ² , G ³ and G ⁴ is O or S; b) when G ² is O or S, no more than one of G ³ and G ⁴ is N; c) at least one of G ² , G ³ and G ⁴ is C; and d) G ² , G ³ and G ⁴ are not all C;

G ⁵ , G 0 and G ⁷ are independently selected from C and N, wherein no more than two of G 1, G and G are N;

J ³ , J ⁴ , J ⁵ , J ⁵ and J ⁷ are independently selected from hydrogen, -NR ⁴ 2, -CONR ⁴ 2, -CO ₂ R,

123 halogen, -S (O) ₂ NR ⁴ 2, -SO 2 R ³ radical, an alkyl, alkenyl, alkynyl, alkylaryl group, a perhaloalkyl, haloalkyl, aryl, heteroaryl, alkylene-OH, - C (O) R ^11, -OR ^11, a group -alkylene-NR ⁴ 2, the group alkylene-CN, -CN, -C (S) NR ⁴ 2, -OR ^2, -SR ^2, -N 3 radical, radical -N02, -NHC (S) NR ⁴ _2, and -NR ²¹ COR ^2;

X ⁴ is selected from the group consisting of:

(i) a linker group containing 2 to 4 atoms measured by the least number of atoms connecting the aromatic ring carbon and the phosphorus atom and is selected from the group consisting of -furanyl-, -thienyl-, -pyridyl-, -oxazolyl-, -imidazolyl-, -phenyl- , -pyrimidinyl-, -pyrazinyl- and -alkynyl, all of which may be optionally substituted; and ii) a linker group containing 3 to 4 atoms, as measured by the least number of atoms connecting the aromatic ring carbon and the phosphorus atom, and is selected from the group consisting of -alkylcarbonylamino-, -alkylaminocarbonyl-, -alkoxycarbonyl-, -alkoxy-, -alkylthio-, -alkylcarbonyloxy -, -alkyl-S (O) -, -alkyl-S (O) ₂ - and -alkoxyalkyl-, all of which may be optionally substituted;

Y is independently selected from -0- and -NR ^6;

when Y is -O-, R ¹ attached to -O- is independently selected from the group consisting of hydrogen, alkyl, optionally substituted aryl, optionally substituted alicyclic, wherein the cyclic group comprises carbonate or thiocarbonate, optionally substituted -arylalkylene, -C (R ² ) 20 C (O) NR ² 2, -NR ² -C (O) -R ³ , -C (R ² ) ² -OC (O) R ³ , -C (R ² ) 2-O-C (O) OR ³ , -C (R ² ) 20 C (O) SR ³ , -alkyl-SC (O) R ³ , -alkyl-SS-alkylhydroxy and -alkyl-SSS-alkylhydroxy ;

when Y is -NR ⁶ -, R ¹ attached to -NR ⁶ - is independently selected from

124 hydrogen-containing group, - [C (R ² ) 2] q -COOR ³ , -C (R ⁴ ) 2 COOR ³ , - [C (R ² ) ₂ ] _q -C (O) SR, and - cycloalkylene-COOR ³ wherein q is 1 or 2;

when only one Y is -O-, wherein -O- is not part of the cyclic group containing the other Y, the other Y is -N (R ¹⁸ ) - (CR ¹² R ¹³ ) -C (O) -R ¹⁴ ; and when Y is independently selected from -O- and -NR ^6, then R ¹ and R ¹ together are alkyl-SS-alkyl to form a cyclic group, or R ¹ and R ¹ together form:

a) V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl, or

V and Z are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group being fused to an aryl group in the β and y position to Y attached to V; or

Z is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OC (S) OR ³ , -CHR ² OC (0) SR ³ , -CHR ² OCO ² R ³ , -OR ² , -SR ² , -CHR ² N 3, -CH ² aryl, -CH (aryl) OH, -CH (CH = CR ² 2) OH, -CH (CsCR ² ) OH, -R ² , -NR ² ', -OCOR ³ , -OCO2R ³ , -SCOR ³ , -SCO2R ³ , -NHCOR ² , - NHCO ² R ³ , -CH ₂ NHaryl, - (CH ₂ ) _p -OR ^2, and - (CH ₂ ) _p -SR ² , wherein p is an integer of 2 or 3; or

125

Z and W are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl; or

W and W 'are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or

W and W 'are joined together via an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V must be aryl, substituted aryl, niceroaryl or substituted heteroaryl; or

b) V ² , W ² and W are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

Z ² is selected from the group of -CHR ² OH, -CHR ² OC (0) R ^3, -CHR ² OC (S) R ^3, -CHR ² OCO2R ^'>, -CHR ² OC (0 ) SR ^3, -CHR ² OC (S) ^OR3, -CH (aryl) OH, -CH (CH = CR ² 2) OH, -CH (C = ^CR2) OH, -SR ² -CH ₂ NHaryl, -CH ₂ aryl; or

V ² and Z ² are joined together via an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 ring atoms, optionally containing 1 heteroatom, and substituted with a hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy group attached to a carbon atom of three atoms from group Y attached to phosphorus;

c) Z 'is selected from the group consisting of -OH,

126

-OC (O) R ³ , -OCO ₂ R ^3, and -OC (O) SR ³ ;

D 'is hydrogen;

D is selected from the group consisting of hydrogen, alkyl, -OR ² , -OH, and -OC (O) R ³ ;

each W ³ is independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

with the proviso that:

a) V, Z, W, W 'are not all hydrogen and V ² , Z ² , W ² , W are not all hydrogen;

R ² is selected from R ³ and hydrogen;

R ³ is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;

each R ⁴ is independently selected from the group consisting of hydrogen and alkyl, -alkylenaryl, and aryl, or together R ⁴ and R ⁴ are joined via 2 to 6 atoms, optionally including one heteroatom selected from O, N and S;

R c is selected from the group consisting of hydrogen, lower alkyl, acyloxyalkyl, alkoxycarbonylcycloalkyl and lower acyl;

R ⁷ is lower R ³ ;

each R ⁹ is independently selected from the group consisting of hydrogen, alkyl, aralkyl and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group;

127

R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ² ; and each R ¹² and R ¹³ is independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, lower aralkyl, all of which may be optionally substituted, or R ¹² and R ¹³ are joined together via 2 to 6 atoms optionally containing 1 heteroatom selected from O, N and S to form a cyclic group;

each R ¹⁴ is independently selected from the group consisting of -OR ¹⁷ , -N (R ¹⁷ ) ₂ , -NHR ¹⁷ , -SR ^17, and -NR ² OR ²⁰ ;

R ¹⁵ is selected from the group consisting of hydrogen, lower alkyl, lower aryl, lower aralkyl, or together with R ¹⁵ are connected via 2 to 6 atoms, optionally including one heteroatom selected from O, N, and S;

R ¹⁶ is selected from the group consisting of - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ , hydrogen, lower alkyl, lower aryl, lower aralkyl or, together with R ¹⁵ , linked via 2 to 6 atoms optionally comprising one heteroatom selected from O, N and S;

each R ¹⁷ is independently selected from the group consisting of lower alkyl, lower aryl and lower aralkyl, or R ¹⁷ and R ¹⁷ are connected to N via 2 to 6 atoms, optionally including one heteroatom selected from O, N, and S;

R ¹⁸ is independently selected from the group consisting of hydrogen, lower alkyl, aryl, aralkyl or R ¹² and R ¹⁸ are joined together via 1 to 4 carbon atoms to form a cyclic group;

R ¹⁹ is selected from the group consisting of hydrogen and lower acyl;

128

R ²⁰ is selected from the group consisting of hydrogen, lower R ^3, and -C (O) - (lower R ³ );

R ²¹ is selected from groups containing hydrogen; and lower R ³ ; n is an integer from 1 to 3; with that provided that: D when G ⁵ , G ⁶ or G ⁷ is a N, then matching J ⁴ , J ³ or J ⁶ is a null; 2) when G ² , G ³ or G ⁴ is a N, then matching J, J and or J ³ is a null; 3) when G ³ or G ⁴ is N, then the corresponding J ⁴ or J ³ not is a

halogen or a group directly bonded to G ³ or G ⁴ via a heteroatom;

4) when both Y groups are -NR ⁶ - and R ¹ and R ¹ are not joined to form a cyclic phosphoramidate, then at least one R ¹ is - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ ;

5) R ¹ may be selected from the group consisting of lower alkyl only when the second YR ¹ is -NR ¹⁸ - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ ;

and pharmaceutically acceptable prodrugs and salts thereof.

Suitable X ⁴ groups include

(i) a linker group having 2 to 4 atoms measured by the smallest number of atoms connecting the aromatic ring carbon and the phosphorus atom and selected from the group consisting of -furanyl-, -thienyl-, -pyridyl-, -oxazolyl-, -imidazolyl-; -pyrimidines1-, -pyrazinyla-alkynyl-, all of which may be optionally substituted; and ii) a linker group having 3 to 4 atoms measured at least

Is selected from the group consisting of -alkylcarbonylamino-, -alkylaminocarbonyl-, -alkoxycarbonyl-, -alkoxy-, -alkylthio-, -alkylcarbonyloxy-, -alkyl-S (O) - , -alkyl-S (O) ₂ - and -alkoxyalkyl-, all of which may be optionally substituted;

In another aspect of the invention, the following compounds of Formula VII are included:

wherein R ⁵⁵ is selected from the group consisting of:

G ² is selected from C, O and S;

G ³ and G ⁴ are independently selected from C, N, O and S;

where: (a) no more than one from G ² , G ³ a G ⁴ is O or S; b) when G ² is 0 or S, not more than One of G ³ and G ⁴ is N; c) at least is a- day of G ² , G ³ and G ⁴ is C and d) G ² , G ³ and G ⁴ not are all C; G ⁵ , G ⁶ and G 'are independently selected from group C and N, where not

more than two of G ⁵ , G ⁶ and G 'are N;

J ³ , J ⁴ , J ⁵ , J 0 and J 1 are independently selected from the group consisting of hydrogen, -NR ⁴ 2, -CONR ⁴ 2, -CO ₂ R ³ , halo, -S (O) ) ₂ NR ⁴ 2, -S (O) R ^3, -SO 2 R ³ radical, an alkyl

130 is a group, a group, an alkenyl group, an alkynyl group, an alkylenaryl haloalkyl group,

-C (O) R ^11, perhaloalkyl ^of -0R heteroaryl,, aryl, -alkylene-OH, -alkylene-NR ⁴ 2, common -CN, -C (S) NR ⁴ 2, -OR ² p a group, a fief-CN group,

-SR ² , -N ₃ , -NO ₂ , -NR ²¹ COR ² ;

group

-alkyl group

X ⁴ is selected from the group consisting of:

(i) a linker group containing 2 to 4 atoms, as measured by the least number of atoms connecting the aromatic ring carbon and the phosphorus atom, and is selected from the group consisting of -furanyl-, -thienyl-, -pyridyl-, -oxazolyl-, -imidazolyl-, -phenyl-, -pyrimidinyl-, -pyrazinyl- and -alkynyl, all of which may be optionally substituted; and (ii) a linking group containing 3 to 4 atoms, as measured by the least number of atoms connecting the aromatic ring carbon and the phosphorus atom, and is selected from the group consisting of -alkylcarbonylamino-, -alkylaminocarbonyl-, -alkoxycarbonyl-, -alkoxy- and -alkoxyalkyl-, all of which may be optionally substituted;

Y is independently selected from -O- and -NR ^6;

when Y is -O-, R ¹ attached to -O- is independently selected from the group consisting of hydrogen, alkyl, optionally substituted aryl, optionally substituted alicyclic, wherein the cyclic group comprises carbonate or riocarbonate, optionally substituted -arylalkylene, -C (R ² ) 2 OC (O) NR ² 2, -NR ² -C (O) -R ³ , -C (R ² ) ² -OC (O) R ³ , -C (R ² ) 2-OC (O) OR ³ , -C (R ') 20 C (O) SR ³ , -alkyl-SC (O) R ³ , -alkyl-SS-alkylhydroxy and -alkyl-SSS-alkylhydroxy;

when Y is -NR ⁰ - and R ¹ attached thereto is - (CR ¹² R ¹³ ) -C (O) -R ¹⁴ , then the second YR ¹ is selected from the group consisting of -NR ¹⁵ R ¹⁶ , -OR ⁷ and -NR ¹⁸ - (CR ¹² R ¹³ ) -C (O) -R ¹⁴ ;

when only one Y is -O-, wherein -O- is not part of the cyclic group containing the other Y, the other Y is -N (R ¹⁸ ) - (CR ¹² R ¹³ ) -C (O) -R ¹⁴ ; and when any of Y is independently selected from -O- and -NR ⁶ , then R ¹ and R ¹ together are alkyl-SS-alkyl- and form a cyclic group, or R ¹ and R ¹ are together:

where

a) V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl; or

Z is selected from the group consisting of -CHR OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OC (S) OR ³ , -CHR ² OC ( O) SR ³ , -CHR ² OCO ² R ³ , -OR ² , -SR ² , -CHR ² N 3, -CH ₂ aryl, -CH (aryl) OH, -CH (CH = CR ²⁾ 2) OH, -CH (C = CR ² ) OH, -R ² , -NR ² 2, -OCOR ³ , -OCO ² R ³ , -SCOR ³ , -SCO2R ³ , -NHCOR ² -NHCO ² R ³ , -CH ₂ NHaryl, - (CH ₂ ) _p -OR ^2, and - (CH ₂ ) _p -SR ² , wherein p is an integer of 2 or 3; or

V and Z are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group being fused to an aryl group at the β and γ position to Y attached to V; or

Z and W are joined together through an additional 3 to 5 atoms of 132 movs to form a cyclic group, optionally containing 1 heteroatom, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl; or

W and W 'are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or

W and W 'are joined together via an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl;

b) V ² , W ² and W are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

Z ² is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OCO ² R ³ , -CHR ² OC (0) SR ^3, -CHR ² OC (S) ^OR3, -CH (aryl) 0H, -CH (CH = CR ² 2) OH, -CH (CSCR ²⁾ OH, -SR ^2, is - CH ₂ NHaryl, -CH ₂ aryl; or

V ² and Z ² are joined together via an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 ring atoms, optionally containing 1 heteroatom, and substituted with a hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy group attached to a three-carbon carbon atom from group Y attached to phosphorus;

c) 1 'is selected from the group consisting of -OH, -OC (O) R ³ , -OCO ₂ R ^3, and -OC (O) SR ³ ;

133

D 'is hydrogen;

D is selected from the group consisting of hydrogen, alkyl, -OR ² , -OH, and -OC (O) R ³ ;

each W ³ is independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

with the proviso that:

a) V, Z, W, W 'are not all hydrogen and V ² , Z ² , W ² , W are not all hydrogen; and

R ² is selected from R ³ and hydrogen;

R ³ is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;

each R ⁴ is independently selected from the group consisting of hydrogen and alkyl, -alkylenaryl, and aryl, or together R ⁴ and R ⁴ are joined via 2 to 6 atoms, optionally including one heteroatom selected from O, N and S;

R ⁶ is selected from the group consisting of hydrogen, lower alkyl, acyloxyalkyl, aryl, aralkyl, alkoxycarbonyloxyalkyl and lower acyl, or together with R ^X1 is linked via 1 to 4 carbon atoms to form a cyclic group;

R ⁷ is lower R ³ ;

each R ⁹ is independently selected from the group consisting of hydrogen, alkyl, aralkyl and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group;

134

R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ² ; and each R ¹² and R ¹³ is independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, lower aralkyl, all of which may be optionally substituted, or R ¹² and R ¹³ are joined together via a chain of 2 to 6 atoms, optionally containing 1 a heteroatom selected from O, N and S to form a cyclic group;

each R ¹⁴ is independently selected from the group consisting of -OR ¹⁷ , -N (R ¹⁷ ) ₂ , -NHR ¹⁷ , -SR ¹ ', and -NR ² OR ²⁰ ;

R ¹⁵ is selected from the group consisting of hydrogen, lower alkyl, lower aryl, lower aralkyl, or together with R ¹⁶ are connected via 2 to 6 atoms, optionally including one heteroatom selected from O, N, and S;

R ¹⁶ is selected from the group consisting of - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ , hydrogen, lower alkyl, lower aryl, lower aralkyl, or together with R ¹⁵ is connected via 2 to 6 atoms optionally comprising one heteroatom selected from O, N and S;

each R ¹⁷ is independently selected from the group consisting of lower alkyl, lower aryl and lower aralkyl, or R ¹⁷ and R ¹⁷ are connected to N via 2 to 6 atoms, optionally including one heteroatom selected from O, N and S;

R ¹⁸ is independently selected from the group consisting of hydrogen, lower alkyl, aryl and aralkyl, or R ¹² and R ¹⁸ are joined together via 1 to 4 carbon atoms to form a cyclic group;

R ¹⁹ is selected from the group consisting of hydrogen and lower acyl;

135

R ²⁰ is selected from the group consisting of hydrogen, lower R ^3, and -C (O) - (lower R ³ );

R ²¹ is selected from the group consisting of hydrogen and lower R ³ ;

n is an integer from 1 to 3;

with the proviso that:

1) when G ⁵ , G 0 or G ⁷ is N, then the corresponding J ⁴ , J ⁵ or J 0 is zero;

2) when X ⁴ is substituted furanyl, then at least one of J ³ , J ⁴ , J ⁵ and J ⁶ is not hydrogen or zero;

3) when X ⁴ is not substituted furanyl, then at least two of J ³ , J ⁴ ,

J ⁵ and J ⁶ in formula VII-5 or J ³ , J ⁴ , J ³ , J ⁶ , J ⁷ in formula VII-β are not hydrogen or zero;

4) when G ² , G ³ or G ⁴ is 0 or S, then the corresponding J ³ , J ⁴ or J ⁵ is zero;

5) when G ³ or G ⁴ is N, then the corresponding J ⁴ or J ³ is not halogen or a group directly bonded to G ³ or G ⁴ via a heteroatom;

6) when both Y groups are -NR ⁰ - and R ¹ and R ¹ are not joined to form a cyclic phosphoramidate, then at least one of R ¹ is - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ ;

7) when X ⁴ is -alkylcarbonylamino- or -alkylaminocarbonyl-, then G ³ , G 0 and G ⁷ are not all C;

8) when X ⁴ is -alkoxyalkyl- and G ⁵ , G ⁶ and G ⁷ are all C, then neither J ⁴ nor J ⁶ can be substituted with an acylated amine;

9) when R ⁵⁵ is substituted phenyl, then J ⁴ , J ⁵ and J ⁶ are not puri

136 nyl, purinylalkylene, deazapurinyl or deazapurine alkylene;

10) R ¹ can be lower alkyl only when another YR ¹ is -NR ¹⁸ - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ ;

11) where R ⁵⁵ is substituted phenyl and ^X4 is 1,2-ethynyl, then J ^4, or J is ^a heterocyclic group;

12) when X ⁴ is 1,2-ethynyl, then G ⁵ or G ⁷ cannot be N; and pharmaceutically acceptable prodrugs and salts thereof.

In one aspect of the invention, compounds of Formula VII-1 are included.

J ³

In another aspect of the invention, compounds of Formula VII-2 are included.

In another aspect of the invention, compounds of formula VII-1-A are included.

137

In another aspect of the invention are included compounds of formula VII-2-A.

R ¹⁸ r, J i ⁰ I

II *

R ¹⁴ - (O) C - (CR ¹² R ¹³ ) f - N - P - NR ^{1 S} R ^W ILJ ^ ^C % 7- ^G \ _{j5 15}

J Vn-2-A

In one aspect of the invention, compounds of formula VII-1 or VII-2 are included, provided that when X ⁴ is -alkoxyalkyl and R ⁵⁵ is substituted thienyl, substituted furanyl or substituted phenyl, then J ⁴ , J ⁵ or J ⁵ is not halogen or alkenyl.

In another aspect of the invention, compounds of formula VII-1 or VII-2 are included, provided that when X ⁴ is -alkoxyalkyl, then R ⁵⁵ is not substituted thienyl, substituted furanyl, or substituted phenyl.

In another aspect of the invention, compounds of formula VII-1 or VII-2 are included, with the further proviso that when X ⁴ is -alkoxyalkyl and G ⁵ , G ⁶ and G ⁷ are all C, then neither J ³ nor J ⁷ is not attached via a nitrogen atom.

In another aspect of the invention, compounds of formula VII-1 or VII-2 are included, with the further proviso that when X ⁴ is -alkoxyalkyl or -alkoxycarbonyl, then R ⁵⁵ is not substituted phenyl.

In another aspect of the invention are included compounds of formula VII-1 or VII-2 wherein when Y is -O-, then R ¹ attached to -O- is independently selected from hydrogen, optionally substituted aryl, optionally substituted alicyclic a group wherein the cyclic group comprises a carbonate or thiocarbonate, optionally substituted with arylalkylene

138, -C (R ²⁾ 2-0C (O) ^R3, -C ^(R2) 2-OC (O) OR ^3, -C (R ²⁾ ₂ OC (0) ^SR3, -alkyl-SC (O) R ³ and -alkyl-SS-alkylhydroxy;

when Y is -NR ⁵ -, then R ¹ attached to -NR ⁵ - is independently selected from hydrogen and - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ ;

or when any of Y is independently selected from -O- and -NR ⁵ , then R ¹ and R ¹ are together

where

a) V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl, or

V and Z are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group being fused to an aryl group at the β and γ position to Y attached to V; or

Z is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OC (S) OR ³ , -CHR ² OC (O) SR ³ , -CHR ² OCO ² R ³ , -OR ² , -SR ² , -CHR ² N 3, -CH ₂ aryl, -CH (aryl) OH, -CH (CH-CR) ² 2 OH, -CH (C = ^CR2) OH, -R ^2, -NR ^2?, a group -OCOR ^3, -OCO2R group ^3, group ³ -score, -SC02R group ", a group -NHCOR ² , -NHCO ² R ³ , -CH ₂ NHaryl, - (CH ₂ ) _p -OR ^2, and - (CH ₂ ) _p -SR ² , wherein p is an integer of 2 or 3, or

Z and W are joined together via an additional 3 to 5 atom atoms to form a cyclic group, optionally containing 1 heteroatom, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl; or

W and W 'are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or

W and W 'are joined together via an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl;

b) V ² , W ² and W are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

Z ² is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OCO ² R ³ , -CHR ² OC (0) SR ³ , -CHR ² OC (S) OR ³ , -CH (aryl) OH, -CH (CH = CR ² 21 OH), -CH (C = CR ² ) OH, -SR ² , -CH ₂ NHaryl, -CH ₂ aryl;

V ² and Z ² are joined together via an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 ring atoms, optionally containing 1 heteroatom, and substituted with a hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy group attached to a carbon atom of three atoms from group Y attached to phosphorus;

c) Z 'is selected from the group consisting of -OH, -OC (O) R ³ , -OCO ₂ R ^3, and -OC (O) SR ³ ;

140

D je is hydrogen;

D is selected from the group consisting of hydrogen, alkyl, -OR ² , -OH, and -OC (O) R ³ ;

each W ³ is independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

with the proviso that:

a) V, Z, W, W 'are not all hydrogen and V ² , Z ² , W ² , W are not all hydrogen; and

b) both Y groups are not -NR ⁶ -;

R ² is selected from the group consisting of R ³ and hydrogen;

R ³ is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;

R ⁶ is selected from the group consisting of hydrogen and lower alkyl.

In another aspect of the invention are included compounds wherein when Y groups are -O-, then R ¹ is independently selected from the group consisting of optionally substituted aryl, optionally substituted benzyl, -C (R ² ) 2 OC (O) R ³ , -C (R ² ) 20 C (O) OR ³ and hydrogen, or when Y is -NR ⁰ -, then R ¹ attached to said -NR ⁶ - is selected from the group consisting of -C (R ⁴ ) 2 - C (0) 0R, and ^J-C (R ²⁾ 2 C (0) ^OR3, and the other Y is -0-, then R ¹ attached to said -0- is selected from the group consisting of optionally substituted aryl, the group - C (R ² ) 20 C (O) R ³ and -C (R ² ) 20 C (O) OR ³ . Within this group are compounds wherein both Y are -O- and R ¹ is

141 hydrogen.

In another aspect of the invention are included compounds wherein at least one Y is -O- and R ¹ and R ¹ are together

where

a) V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl, or

V and Z are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group being fused to an aryl group at the β and γ position to Y attached to V; or

Z is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OC (S) OR ³ , -CHR ²⁰ OC (0) SR ³ , -CHR ² OCO ² R ³ , -OR ² , -SR ² , -CHR ² N 3, -CH ² aryl, -CH (aryl) OH, -CH (CH = CR ² 2) OH, -CH (C 1 -C ² ) OH, -R ² , -NR ² ₂ , -OCOR ³ , -OCO ² R ³ , -SCOR ³ , -SCO2R ³ , -NHCOR ² , -NHCO ² R ³ , -CH ₂ NHaryl, - (CH ₂ ) _p -OR ^d, and - (CH ₂ ) _p -SR ² wherein p is an integer of 2 or 3; or

Z and W are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl; or

W and W 'are independently selected from the group consisting of hydrogen,

142 alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or

W and W 'are joined together via an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl;

b) V ² , W ² and W are independently selected from hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

Z ² is selected from the group consisting of -CHR ² CH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OCO ² R ^J , -CHR ² OC (0) SR ^3, -CHR ² OC (S) ^OR3, -CH (aryl) OH, -CH (CH = CR ² 2) OH, -CH (CSCR ²⁾ -OH, -SR, CH ₂ NHaryl, -CH ₂ aryl; or

V ² and Z ² are joined together via an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 ring atoms, optionally containing 1 heteroatom, and substituted with a hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy group attached to a three-carbon carbon aroma atoms from group Y attached to phosphorus;

c) Z 'is selected from the group consisting of -OH, -OC (O) R ³ , -OCO ₂ R ^3, and -OC (O) SR ³ ;

D 'is hydrogen;

D is selected from the group consisting of hydrogen, alkyl, -OR ² , -OH, and -OC (O) R ³ ;

143 each W ³ is independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

with the proviso that:

a) V, Z, W, W 'are not all hydrogen and V ² , Z ² , W ² , W "are not all hydrogen; and

b) both Y groups are not -NR ⁶ -;

R ² is selected from the group consisting of R ³ and hydrogen;

R ³ is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;

R c is selected from the group consisting of hydrogen and lower alkyl.

In another aspect of the invention are included compounds wherein Y is -O- and R ¹ is optionally substituted aryl, and the other Y is -NR ⁶ -, wherein R ¹ attached to said -NR ⁶ - is selected from the group consisting of -C (R ⁴ ) 2 -C (O) OR ³ and -C (R ² ) 2 C (O) OR ³ . In another embodiment, such compounds are those wherein R ¹ attached to -O- is selected from the group consisting of phenyl and phenyl substituted with 1 to 2 substituents selected from the group consisting of -NHC (O) CH 3, -F, -Cl, -Br, C (O) OCH2CH3, and -CH3, and wherein ^R? attached to -NR ⁶ - is -C (R ²⁾ 20 C (0) ^OR3; each R ² is independently selected from the group consisting of -CH ₃ , -CH ₂ CH _3, and hydrogen. Within this group are compounds wherein the substituents of said phenyl are selected from the group consisting of 4-NHC (O) CH ₃ , -Cl, -Br, 2-C (O) OCH ₂ CH _3, and -CH ₃ .

In another aspect of the invention are included compounds of formula VII wherein J ³ , J ⁴ , J ⁵ , J 0 and J ⁷ are independently selected

144 from the group consisting of -CO ₂ R ³ , halogen, hydrogen, -NR ⁴ 2, -CONR ⁴ 2, -SO ₂ NR ⁴ ₂ , lower alkyl, lower alkenyl, lower alkylaryl, lower alkynyl a lower perhaloalkyl group, a lower haloalkyl group, a lower aryl group, a lower alkylene-OH group, a -OH group, -OR ¹¹ , a -CR ² 2-NR ⁴ 2 group, a -CN group, a -C (S) group NR ⁴ 2, -OR ² , -SR ² , -N 3, -NO ₂ , -NHC (S) NR ⁴ 2, -NR ²¹ COR ² ; -CR ² 2 CN;

X ⁴ is selected from the group

(i) 2,5-furanyl, 2,5-thienyl, 1,3-phenyl, 2,6-pyridyl, 2,5-oxazolyl, 5,2-oxazolyl, 2,4-oxazolyl, 4,2-oxazolyl; 2,4-imidazolyl, 2,6-pyrimidinyl, 2,6-pyrazinyl;

ii) 1,2-ethynyl; and iii) a linker group containing 3 to 4 atoms measured by the least number of atoms connecting the aromatic ring carbon and the phosphorus atom and is selected from the group consisting of -alkylcarbonylamino-, -alkylaminocarbonyl-, -alkoxycarbonyl- and -alkoxyalkyl -;

when both Y groups are -O-, then R ¹ is independently selected from the group consisting of optionally substituted aryl, optionally substituted benzyl, -C (R ² ) 20 C (O) R ³ , -C (R ² ) 20 C (O) OR ³ and hydrogen, or when Y is -O-, then R ¹ attached to -O- is optionally substituted aryl, and when the other Y is -NR ⁶ -, then R ¹ is selected from the group consisting of - C (R ⁴ ) 2 C (O) OR ³ and -C (R ² ) 2 C (O) OR ³ ; or when Y is -O- or -NR ⁰ -, then R ¹ and R ¹ are together

145

where

a) V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl, or

V and Z are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group being fused to an aryl group at the β and γ position to Y attached to V; or

Z is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OC (S) OR ³ , -CHR ² OC (0) SR ³ , -CHR ² OCO ² R ³ , -OR ² , -SR 1, -CHR ² N ₃ , -CH ₂ aryl, -CH (aryl) OH, -CH (CH = CR) ² 2) OH, -CH (C = CR ² ) OH, -R ² , -NR ² 2, -OCOR ³ , -OCO ² R ³ , -SCOR ³ , -SCO2R ³ , -NHCOR ² , -NHCO ² R ³ , -CH ₂ NHaryl, - (CH ₂ ) _p -OR ^2, and - (CH ₂ ) p -SR ⁴ wherein p is an integer of 2 or 3; or

Z and W are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl; or

W and W 'are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or

146

W and W 'are joined together via an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl;

b) V ² , W ² and W are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

Z ² is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OCC> 2R ³ , -CHR ² OC ( 0) SR ^3, -CHR ² OC (S) ^OR3, -CH (aryl) OH, -CH (CH = CR ² 2) OH, -CH (C ^ CR ²⁾ OH, -SR ² , -C 1-4 NHaryl, -C 1-4 aryl; or

V 1 and Z ² are joined together via an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 ring atoms, optionally containing 1 heteroatom, and substituted with a hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy group attached to a carbon atom of three atoms from group Y attached to phosphorus;

c) Z 'is selected from the group consisting of -OH, -OC (O) R ³ , -OCO ² R ³ , and -OC (O) SR ³ ;

D 'is hydrogen;

D 1 is selected from the group consisting of hydrogen, alkyl, -OR ² , -OH, and -OC (O) R ³ ;

each W ^J is independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

147 with the proviso that:

a) V, Z, W, W 'are not all hydrogen and V ² , Z ² , W ² , W are not all hydrogen; and

b) both Y groups are not -NR ⁶ -;

R ² is selected from the group consisting of R ³ and hydrogen;

R ³ is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;

R ⁶ U ^e is selected from hydrogen and lower alkyl.

In another aspect R ⁵⁵ is substituted phenyl, X ⁴ is furan-2,5-diyl, J ³ , J ⁴ , J ⁵ , J ⁶ and J ⁷ are independently selected from the group consisting of -OR ³ , -SO ² NHHR ⁷ , -CN, hydrogen, halogen, -NR ⁴ 2, - (CH ₂ ) aryl, - (CH ₂ ) NHaryl, and -NO ₂ , at least one Y group is -O-, and pharmaceutically acceptable salts thereof and prodrugs.

In another aspect of the invention there are compounds wherein when Y is -O-, then R ¹ attached to -O- is independently selected from hydrogen, optionally substituted phenyl, -CH ₂ OC (O) -tBu, -CH ₂ OC (O) OEt and -CH ₂ OC (O) OiPr when Y is -NR ⁶ -, then R ¹ attached to -NR ⁶ - is independently selected from the group consisting of -C (R ² ) 2 C (O) OR ³ and -C (R ⁴ ) 2 C (O) OR ³ ; or when Y is -O- or -NR ⁶ - and at least one Y is -O-, then R ¹ and R ¹ together are ·

148 where

V is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl and Z, W 'and W are hydrogen, and

R ⁶ is selected from the group consisting of hydrogen and lower alkyl.

In one embodiment of the invention are included compounds wherein both Y groups are -O- and R ¹ is hydrogen. In another aspect of the invention there are compounds wherein both Y groups are -O- and R ¹ is -CH ₂ OC (O) OEt. In another embodiment of the invention there are compounds wherein both Y groups are -O- and R ¹ and R ¹ are together and V is phenyl substituted with 1 to 3 halogens. Within this group are compounds wherein V is selected from the group consisting of

3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 3-chlorophenyl and 3-bromophenyl.

In one embodiment of the invention, there are those compounds wherein n is 1 and the carbon attached to R ¹² and R ¹³ has the stereochemistry S.

In another embodiment of the invention are included compounds wherein R ¹⁵ is not hydrogen.

In another embodiment of the invention, compounds of formula VII-1 or VII-2 are those wherein -NR ¹⁵ R ¹⁶ is a cyclic amine. Within this group are compounds wherein -NR ¹⁵ R ¹⁶ is selected from the group consisting of morpholinyl and pyrrolidinyl. In another aspect of the invention, R ¹⁶ groups include - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ . In another embodiment of the invention, the compounds are of the formula

R ¹⁴ —C (O) --- (CR ¹² R ¹³ ) n --- N-

149

Within this group are compounds wherein n is 1. In one aspect of the invention are included compounds wherein when R ¹² and R ¹³ are not the same, then R ¹⁴ -C (O) -CR ¹² R ¹³ -NH ₂ is an ester or a thioester of a naturally occurring amino acid and R ¹⁴ is selected from the group consisting of -OR ¹⁷ and -SR ¹⁷ .

In one aspect of the invention there are compounds wherein one Y is -O- and its corresponding R ¹ is optionally substituted phenyl, while the other Y is -NH- and its corresponding R ¹ is -C (R ² ) 2 -COOR ³ . When R ¹ is -C (R ² ) ₂ -COOR ³ , then the corresponding -NR ^{6 '} - * CHR ³ COOR ³ generally has stereochemistry L.

In view of the above, the inventors envisage any combination of the Markush groups mentioned above and the sub-Markush groups for any of the variables listed in the following Tables A-Q.

150

Table A. Table of sub-Markush groups for variable R ¹

Sub-Markush group R ¹ 1 optionally substituted aryl, optionally substituted benzyl, -C (R ² ) 2 OC (O) R ³ , -C (R ² ) ² O-C (O) OR ^3, and hydrogen 2 optionally substituted aryl, -C (R ² ) 2 OC (O) R ³ , -C (R ² ) ² O-C (O) OR ³ 3 aryl and -C (R ² ) ₂ -aryl 4 -alkylene-SS-alkylenehydroxyl, -alkylene-AC (O) R ³ and -alkylene-SSS-alkylenehydroxy or together R ¹ and R ¹ alkylene-SS-alkylene form a cyclic group 5 hydrogen 6 -C (R ² ) ₂ C (O) OR ³ 7 -C (R ⁴ ) 2 C (O) OR ³ , -C (R ² ) 2 C (O) OR ^j 8 -C (R ² ) 20 C (O) R ³ , -C (R ² ) 20 C (O) OR ³ 9 optionally substituted aryl 10 together ^R1 and ^R1 are -alkyl-SS-alkyl to form a cyclic group 11 optionally substituted phenyl, -CH ₂ OC (O) 0-tBu, -CH ₂ OC (O) OEt, -CH ₂ OC (O) O-iPr, 12 hydrogen, optionally substituted aryl, optionally substituted alicyclic, wherein the cyclic group comprises a carbonate or thiocarbonate, optionally substituted -alkylenaryl, -C (R ² ) 20 C (O) R ³ , -C (R ² ) 2 OC (O) OR ³ , -C (R ² ) ₂ OC (O) SR ³ , -alkylene-SC (O) r ^3, and -alkylene-SS-alkylenehydroxy 13 hydrogen and - (CR ¹² R ¹³ ) _n - C (O) R ¹⁴

151

Sub-Markush group R ¹ in \ V ² W ^{3 h} A_ hA \ 14 x of ² - / a? —c td-Z — d · ^h V- H \ \ \ W ' W ^2X T W ww ^{3 h} A 15 w ^ l w * v ² H and 16 of ² —-J H \ W ^2X T w * w ³ ha 17 “7 · / n» · 77 · 7x- \ L ^m Λ W w ³ 18 - (CR ¹² R ^lj) _n -C (O) R ¹⁴

152

Sub-Markush group R ¹ 19 R ¹ is selected from the group consisting of phenyl and phenyl substituted with 1 to 2 substituents selected from the group consisting of -NHC (O) CH ₃ , -F, -Cl, -Br, -C (O) OCH ₂ CH _3, and -CH ₃ 20 R ¹ attached to -NR ⁶ - is -C (R ² ) 2 C (O) OR ^J , and each R ² is independently selected from -CH 3, -CH ₂ CH _3, and hydrogen 21 phenyl substituted with 1 to 2 substituents selected from the group consisting of 4-NHC (O) CH ₃ , -Cl, -Br, 2-C (O) OCH ₂ CH _3, and -CH ₃ 22 substituted phenyl 23 -CH ₂ OC (O) OEt 24 in wherein V is phenyl substituted with 1 to 3 halogens

153

Table B. Table of sub-Markush groups for variable R ⁴

Sub-Markush group R ⁴ 1 hydrogen, lower alkyl and lower aryl 2 hydrogen, C ₁ -C ₄ alkyl 3 hydrogen 4 substituted phenyl 5 4-hydroxyphenyl 6 R ⁴ and R ⁴ are joined together via 2 to 5 atoms, optionally containing one heteroatom from the group O, N and S 7 R ⁴ and R ⁴ are joined together by 2 to 5 atoms, optionally containing one O

Table C. Table of sub-Markush groups for variable R ^1z

Sub-Markush group R ¹² 1 hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CH2CH2-SCH3, phenyl and benzyl 2 hydrogen, methyl, isopropyl, isobutyl and benzyl 3 hydrogen, methyl, isopropyl and benzyl 4 methyl 5 hydrogen 6 R ¹² and R ^1J are connected via 2-5 atoms to form a cycloalkyl group 7 R ¹² and R ^1J are connected via 2-5 atoms to form a cycloalkyl group 8 is equal to R ^iJ and R ¹⁴ -C (0) -CR ^{l of} R ⁴ -NH 2 is an ester or thioester of a naturally occurring amino acid and R ¹⁴ is selected from -OR ¹ ', and SR ¹⁷

154

Table D. Table of sub-Markush groups for variable R ¹³

Sub-Marku- R ¹³ Shov pina and with ku- 1 hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CH2CH2-SCH3, phenyl and benzyl 2 hydrogen, methyl, isopropyl, isobutyl and benzyl 3 hydrogen, methyl, isopropyl and benzyl 4 methyl, isopropyl and benzyl 5 methyl 6 hydrogen Ί R ¹² and R ^1J are connected via 2-5 carbon atoms to form a cycloalkyl group 8 R ¹² and R ¹³ are joined together via 4 carbon atoms to form a cyclopentyl group 9 not the same as R ^13, R ^14, and -C (0) -CR ¹² R ^iJ -NH 2 is an ester or thioester of a naturally occurring amino acid and R ¹⁴ is selected from OR ¹⁷ and SR ¹⁷

Table E. Table of sub-Markush groups for variable R ¹³

Sub-Markush group R ¹⁵ 1 lower alkyl and lower aralkyl 2 C 1 -C 6 alkyl 3 methyl, ethyl, propyl 4 R ¹⁵ and R ¹⁶ are joined together via 2 to 6 atoms, optionally containing one heteroatom selected from O, N and S 5 R ^Ib and R ¹⁰ are joined together via 2 to 6 atoms, optionally containing 1 heteroatom selected from O and N

155

Table F. Table of sub-Markush groups for variable R ^1S

Sub-Markush group R ¹⁶ 1 lower alkyl and lower aralkyl 2 C 1 -C 6 alkyl 3 C 1 -C 3 alkyl 4 R ^ib and R ^ib are joined together via 2 to 6 atoms, optionally containing one heteroatom selected from O, N, and S 5 R ^1b and R ^1b are joined together via 2 to 6 atoms, optionally containing one heteroatom selected from O, N and S 6 lower alkyl

Table G. Table of sub-Markush groups for variable X ⁴

Sub-Markush group X ⁴ 1 2,5-furanyl, 2,5-thienyl, 2,6-pyridyl, 2,5-oxazolyl, 5,2-oxazolyl, 2,4-oxazolyl, 4,2-oxazolyl, 2,4-imidazolyl, 2, 6-pyrimidinyl, 2,6-pyrazinyl and 1,3-phenyl, 2 2,5-furanyl, 2,6-pyridyl, 2,5-oxazolyl, 2,4-imidazolyl and 1,3-phenyl, 3 2,5-furanyl, methyleneoxycarbonyl, methyleneoxymezylene and methyleneaminocarbonyl 4 2,5-furanyl 5 1,2-ethynyl 6 -alkylenecarbonylamino-, -alkyleneamininocarbonyl-, -alkyleneoxycarbonyl- and -alkyleneoxyalkylene 7 -methylenecarbonylamino-, -methyleneamininocarbonyl-, -methyleneoxycarbonyl- and -methyleneoxymethylene 8 alkylenoxyalkylene 9 alkyleneoxycarbonyl 10 alkyleneoxyalkylene and alkyleneoxycarbonyl

156

Table H. Table of sub-Markush groups for variable V

Sub-Markush group IN 1 hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl 2 aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl 3 aryl, substituted aryl, heteroaryl and substituted heteroaryl, 4 aryl and substituted aryl 5 heteroaryl and substituted heteroaryl 6 optionally substituted monocyclic heteroaryl containing at least one nitrogen atom 7 phenyl and substituted phenyl 8 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 3-chlorophenyl, 2-bromophenyl, 3,5-difluorophenyl and 3-bromophenyl and this group is trans to the phosphorus-oxygen double bond 9 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 3-chlorophenyl, 2-bromophenyl, 3,5-difluorophenyl, phenyl and 3-bromophenyl 10 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 3-chlorophenyl- nyl, 2-bromophenyl, 3,5-difluorophenyl and 3-bromophenyl 11 4-pyridyl 12 hydrogen

157

Sub-Marku- shova sku- pina IN 13 V and W are joined together through an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy and aryloxycarbonyloxy attached to one of said carbon atoms, that is three atoms from Y attached to phosphorus 14 V and W are joined together via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and monosubstituted with a substituent selected from the group consisting of hydroxyl, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy and aryloxycarbonyloxy attached to one of said carbon atoms by is three atoms from Y attached to phosphorus 15 Together V and W form a cyclic group selected from the group of -CH ₂ -CH (OH) -CH ₂ -, -CH ₂ CH (OCOR ³⁾ -CH 2 and -CH 2 CH (OCO2R ³⁾ -CH 2 16 V and Z are joined together via an additional 3 to 5 atoms, optionally containing 1 heteroatom, to form a cyclic group that is fused to the aryl group at the β and γ position to the Y group 17 V and Z are joined together via an additional 3 to 5 atoms, optionally containing 1 heteroatom, to form a cyclic group that is fused to the aryl group at the β and γ position to the Y group and the aryl group is optionally substituted monocyclic aryl and the link between T and the aryl group is selected from -O-, -CH ₂ CH ₂ , -OCH _2, and -CH ₂ O 18 the same aryl, substituted aryl, heteroaryl or substituted heteroaryl as W and V is cis to W 19 optionally substituted aryl and optionally substituted heteroaryl

158

Table I. Table of sub-Markush groups for variable V ²

Sub-Markush group V ² 1 hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl 2 hydrogen, alkyl, alicyclic, aralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, 3 aryl, substituted aryl, heteroaryl and substituted heteroaryl, 4 aryl and substituted aryl 5 heteroaryl and substituted heteroaryl 6 optionally substituted monocyclic heteroaryl containing at least one nitrogen atom 7 phenyl and substituted phenyl 8 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 2-bromophenyl and 3,5-difluorophenyl 9 4-pyridyl 10 V ² and W ² are joined together via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxyl, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy and aryloxycarbonyloxy attached to one of said carbon atoms such that it is three atoms from Y attached to phosphorus 11 V ² and W ² are joined together via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and monosubstituted with a substituent selected from the group consisting of hydroxyl, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy and aryloxycarbonyloxy attached to one of said carbon atoms. that is, three atoms from Y attached to phosphorus 12 V ² and W ² together form a cyclic group selected from the group consisting of -CH 2 -CH (OH) -CH 2 -, -CH ₂ CH- (OCOR ^J ) -CH _2, and -CH ₂ CH- (OCO ₂ R ³ ) -CH ₂ - 13 V ² and Z ² are joined together via an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 ring atoms optionally containing 1 heteroatom and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to one carbon atoms such that it is three atoms from Y attached to phosphorus 14 hydrogen

159

Table J. Table of sub-Markush groups for variable W

Sub-Markush group W 1 hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl 2 hydrogen, alkyl, alicyclic, aralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; 3 hydrogen, -R ³ , aryl, substituted aryl, heteroaryl and substituted heteroaryl, 4 aryl, substituted aryl, heteroaryl and substituted heteroaryl 5 same as W ' 6 hydrogen 7 V and W are joined together via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy attached to one of said carbon atoms so that is, three atoms from Y attached to phosphorus 8 V and W are joined together through an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and monosubstituted with a substituent selected from the group consisting of hydroxyl, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy attached to one of said carbon atoms, that is, three atoms from Y attached to phosphorus 9 V and W are taken together to form a cyclic group selected from the group consisting of -CH ₂ -CH (OH) -CH ₂ -, -CH ₂ CH- (OCOR ³ ) -CH ₂ - and -CH ₂ CH- (OCO ₂ R ³ ) -CH - 10 V and W are connected to form a cyclic group selected from the group of -CH ₂ -CH (OH) -CH ₂ -, -CH ₂ CH (OCOR ³⁾ -CH 2 and -CH 2 CH (OCO2R ³⁾ -chloroform - 11 V and W 'are joined together via an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V is aryl, substituted aryl, heteroaryl or substituted heteroaryl 12 the same aryl, substituted aryl, heteroaryl or substituted heteroaryl as V and W is cis to V

160

Table K. Table of sub-Markush groups for variable W '

Sub-Markush group W ' 1 hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl 2 hydrogen, alkyl, alicyclic, aralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, 3 hydrogen, -R ^J , aryl, substituted aryl, heteroaryl and substituted heteroaryl, 4 same as W 5 hydrogen 6 V and W 'are joined together via an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V is aryl, substituted aryl, heteroaryl or substituted heteroaryl

161

Table L. Table of sub-Markush groups for variable W ²

Sub-Markush group W ² 1 hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl 2 hydrogen, alkyl, alicyclic, aralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, 3 hydrogen, -R ³ , aryl, substituted aryl, heteroaryl and substituted heteroaryl, 4 aryl, substituted aryl, heteroaryl and substituted heteroaryl 5 same as W 6 hydrogen 7 V ² and W ² are joined together via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy and arvloxycarbonyloxy attached to one of said carbon atoms such that it is three atoms from Y attached to phosphorus 8 V and W are joined together via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and monosubstituted with a substituent selected from the group consisting of hydroxyl, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy and arylcarbonyloxy, attached to one of said carbon atoms by is three atoms from Y attached to phosphorus 9 V and W are taken together to form a cyclic group selected from the group consisting of -CH ₂ -CH (OH) -CH ₂ -, -CH ₂ CH- (OCOR ³ ) -CH ₂ - and -CH ₂ CH- (OCChR ³ ) -CH - 10 V ² and W ² are joined together to form a cyclic group selected from the group consisting of -CH 2 -CH'OH) -CH 2 -, -CH ₂ CH- (OCOR ³ ) -CH 2 - and -CH ₂ CH- (OCO ₂ R ³ ) -CH _: -

162

Table M. Table of sub-Markush groups for variable Y

Sub-Markush group Y 1 both Y groups are -0- 2 both Y groups are -NR ⁶ - 3 Y is -O- located next to the groups W ', W, W and W 4 Y is -O- located next to V or V ² 5 one Y is -NR ⁶ - and the other Y is -O- 6 one Y is -NR ¹⁵ R ¹⁶ and the other YR ¹ is selected from the group consisting of -NR ¹⁵ R ¹⁵ , -OR ¹⁷ or NR ¹⁸ - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ 7 one Y is -NR ⁶ - and the other YR ¹ is -NR ¹⁵ R ^1c and R ¹³ is not hydrogen 8 one Y is -NR ⁶ - and the other YR ¹ is -NR 6 ^; R ¹⁶ and R ¹⁴ are - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ 9 both Y groups are -NR ⁶ - so that the phosphonate prodrug group has a plane of symmetry through the phosphorus-oxygen double bond 10 one Y is -NR ⁶ - and the other YR ¹ is -MR ¹⁵ R ¹ ', where -NR * ^: R 10 is a cyclic amine 11 one Y is -NR ⁶ - and the other YR ¹ is -NR 1 R ¹ ', wherein -NR ¹⁵ R ¹⁶ is selected from the group consisting of morpholinyl and pyrrolidinyl 12 one Y is -NR ⁰ -, and the other YR ¹ is -NR ¹⁵ R ^{i0, i5} wherein -NR ° rV is - (CR ¹² R ¹³⁾ _n -C (0) -R ¹⁴

163

Table N. Table of sub-Markush groups for variable Z

Sub-Markush group from 1 -OR ² , -SR ² , -R ² , -NR ² 2, -OC (O) R ³ , -OCO ² R ³ , -SC (O) R ³ , -SCO ₂ R ³ , -NHC (O) R ² , -NHCO ² R ³ , - (CH 2) _p -OR ² and - (CH ₂ ) _p -SR ² , 2 -OR ² , -R ² , -OC (O) R ³ , -OCO ² R ³ , -NHC (O) R ² , -NHCO ² R ³ , - (CH ₂ ) _p -OR ² and - (CH ₂ ) _p -SR ² , 3 -OR ² , hydrogen, -OC (O) R ³ , -OCO ₂ R ³ , -NHC (O) R ² , 4 -CHR ² OH, -CHR ² OC (O) R ^3, and -CHR ² O-CO ₂ R ³ 5 -CHR ² OH, -CHR ² OC (0) R ³ , -CHR ² OC (S) R ³ , -CHR ² OC (S) or ³ , -CHR ² OC (0) SR ³ , -CHR ² OCO ² R ³ , -OR ^2, -SR ^2, -CHR ² N3z _-CH2 aryl, -CH (aryl) OH, -CH (CH = CR ² 2) OH, -CH (C = ^CR2) OH, -R ^2, -nr ² 2, -ocor ³ , -oco2r ³ , -scor ³ , -sco2r ³ , -NHCOR ² , -NHCO ² R ³ , -CH ₂ NHaryl, - (CH ₂ ) _p -OR ² and - (CH ₂ ) _p -SR ² , 6 -OR ² , -SR ² , -CH ² N 3, -R ² , -OC (O) R ² , -OCO ² R ³ , -SC (O) R ³ , -SCO ² R ³ , -NHC (O) R ² , - NHCO ² R ³ , -CH 2 NHaryl, - (CH 2) ² -OR ² and - (CH 2) _p -SR ² , 7 -OR ² , -R ² , -OC (O) R ³ , -OCO ² R ³ , -CH ³ -NHC (O) R ² , -NHCO ₂ R ³ , - (CH 2) p -OR ² and - (CH 2) _p -SR ² , 8 hydrogen, OR ² and -NHC (O) R ² 9 hydrogen 10 V and Z are joined together via an additional 3 to 5 atoms, optionally containing 1 heteroatom, to form a cyclic group that is fused to the aryl group at the β and γ position to the Y group . 11 V and Z are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, and V is aryl, substituted aryl, heteroaryl or substituted heteroaryl

164

Table O. Table of sub-Markush groups for variable Z '

Sub-Markush group FROM' 1 -OR ² , -SR ² , -R ² , -NR ² 2, -OC (O) R ³ , -OCO ² R ³ , -SC (O) R ³ , -SCO ₂ R ³ , -NHC (O) R ² ,. -NHCO ² R ³ - (CH 2) _p -OR ¹⁹ and - (CH ₂ ) _p -SR ¹⁹ , 2 -OR ² , -R ² , -OC (O) R ³ , -CO ² R ³ , -NHC (O) R ² , -NHCO ² R ³ , - (CH ₂ ) _p -OR ¹⁹ and - (CH ₂ ) _p -SR ¹⁹ , 3 -OR ² , hydrogen, -OC (O) R ³ , -OCO ₂ R ^3, and -NHC (O) R ² , 4 -CHR ² OH, -CHR ² OC (O) R ^3, and -CHR ² O-CO ₂ R ³ 5 -OH, -OC (O) R ³ , -OCO ₂ R ^3, and -OC (O) R ³ 6 -OH, -OC (O) R ³ , -OCO ₂ R ³ 7 -OR ² , -SR ² , -CH ² N 3, -R ² , -OC (O) R ³ , -OCO ² R ³ , -SC (O) R ³ , -SCO ² R ³ , -NHC (O) R ² , - NHCO ² R ³ , -CH 2 NHaryl, - (CH 2) 2 -OR ¹⁹ and - (CH 2) _p -SR ¹⁹ , 8 -OR ² , -R ² , -OC (O) R ³ , -OCO ² R ³ , -CH 3, -NHC (O) R ² , -NHCO ₂ R ³ , - (CH 2) p -OR ¹⁹ and - (CH 2) _P -SR ¹⁹ 9 hydrogen, -OR ² and -NHC (O) R ² 10 hydrogen

165

Table P. Table of sub-Markush groups for variable Z ²

Sub-Markush group of ² 1 -OR ² , -SR ² , -R ² , -NR ² 2, -OC (O) R ³ , -OCO ² R ³ , -SC (O) R ³ , -SCO ₂ R ³ , -NHC (O) R ² , -NHCO ² R ³ , -CH ₂ NHaryl, - (CH ₂ ) _p -OR ¹⁹ and - (CH ₂ ) _p -SR ¹⁹ , 2 -OR ² , -R ² , -OC (O) R ³ , -OCO ² R ³ , -NHC (O) R ² , -NHCO ² R ³ , - (CH ₂ ) p -OR ¹⁹ and - (CH ₂ ) _p -SR ¹⁹ , 3 -OR ² , hydrogen, -OC (O) R ³ , -OCO ₂ R ^3, and -NHC (O) R ² , 4 -CHR ² OH, -CHR ² OC (O) R ^3, and -CHR ² O-CO ₂ R ³ 5 -CHR ² OH, -CHR ² OC (0) R ³ , -CHR ² OC (S) R ³ , -CHR ² OCO ² R ³ , -CHR ² OC (0) SR ³ , -CHR ² OC (S) OR ³ , -CH (aryl) OH, -CH (CH = CR ² ) OH, -CH (C = CR ² ) OH, -SR ² , -CH ₂ NHaryl, -CH ₂ aryl, 6 -CHR ² OH, -CHR ² OC (0) R ³ , -CHR ² OC (S) r ³ , -chr ² oco ₂ r ³ , -CHR ² OC (O) SR ³ , -CHR ² OC (S) or ³ , -CH ₂ aryl, 7 -OR ^2, -SR ^2, -CHR ² N 3, -R ^2, -OC (O) ^R3, -0C02R ^3, -SC (O) ^R3, -SCO2R ^3, -NHCO2R ^3, -CH2NHaryl, - ( CH 2) p -OR ¹⁹ and - (CH 2) _p . -SR ¹⁹ , 8 -OR ² , -R ² , -OC (O) R ² , -OCO ₂ R ³ , -CH 3, -NHCO ₂ R ³ , - (CH 2) p -OR ¹⁹ and - (CH 2) _p -SR ¹⁹ , 9 hydrogen, OR ² and -NHC (O) R ² 10 hydrogen 11 V ² and Z ² are joined together via an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 ring atoms, optionally containing 1 heteroatom, and substituted with a hydroxy, acyloxy, alkoxy, carbonyloxy or aryloxycarbonyloxy group attached to a carbon atom which is three atoms from Y attached to phosphorus

166

Table Q. Table of Markush groups by variables

Markush Group A Markush Group B Markush Group C Markush Group D Markush Group E n 1 and 2 1 2 1 and the carbon attached to R ¹² and R ¹³ has the stereochemistry S p 2 3 R ² hydrogen, lower alkyl, lower aryl, lower alicyclic and lower aralkyl ethyl, methyl and hydrogen hydrogen and aryl hydrogen R ³ lower alkyl, lower aryl, lower alicyclic, lower aralkyl lower alkyl, lower aryl ethyl and methyl R ⁵⁵ substituted phenyl, substi bolded pyrrolyl, substituted oxazolyl, substituted thiazolyl, substituted isothiazolyl, substituted pyrazolyl, substituted isoxazolyl, substituted pyridyl, subs- substituted thienyl, substituted furanyl, substituted pyrimidinyl, substituted pyridazinyl substituted pyrrolyl, substituted oxazolyl, substituted thiazolyl, substituted iso- thiazolyl, substituted pyrazolyl, substituted isoxazolyl, substituted pyridyl, substituted thienyl, substituted furanyl, substituted pyrimidinyl, substituted pyridazinyl substituted pyrrolyl, substituted oxazolyl, substituted thiazolyl, substituted isothiazolyl, substituted pyrazolyl, substituted isoxazolyl, substituted pyridyl, substituted pyrimidinyl, substituted pyridazinyl substituted thienyl, substituted furanyl, substituted phenyl substituted phenyl R hydrogen, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl hydrogen and lower alkyl, acyloxyalkyl hydrogen and C, -C ₆ alkyl, hydrogen, methyl and ethyl hydrogen and methyl R ⁷ lower alkyl, lower aryl and lower alicyclic lower alkyl and lower arvl lower aryl substituted phenyl phenyl, phenyl substituted with 4-NHCO) -CH ₃ , -C 1, -Br, 2-C (O) O-CH ₃ CH], or -C 1-6 alkyl; _? R ^{; i} alkyl and aryl lower alkyl C 1 -C 10 alkyl methyl r ^'11 OR ¹ ', SR ¹ ' and NR ¹ R 1 ⁰ OR ¹ ', SR ¹⁷ OR ¹⁷ ,

167

Markush Group A Markush Group B Markush Group C Markush Group D Markush Group E R ¹ ' lower alkyl, lower aryl, lower aralkyl, alicyclic, or together R ¹ 'and R ¹⁷ are linked via 2 to 6 atoms, optionally including 1 heteroatom selected from N, O and S methyl, ethyl, isopropyl, propyl, tert-butyl and benzyl methyl, ethyl, isopropyl, propyl and benzyl ethyl and isopropyl · R ¹⁸ hydrogen, lower alkyl, aryl and aralkyl hydrogen and lower alkyl hydrogen, methyl and ethyl together R ¹² and R ¹⁸ are joined by 1 to 4 carbon atoms to form a cyclic group R ¹⁵ hydrogen and acetyl hydrogen R ²⁰ hydrogen, C ₁ -C ₆ alkyl, C ₄ -C ₆ aryl, C ₂ -C 6, alicyclic and C 5 -C 7 aralkyl hydrogen and C4 alkyl D hydrogen, alkyl, OH and -OC (O) R ³ hydrogen G ² C and 0 C 0 G ³ Time C WITH G ⁴ C and N C N

168

Markush Group A Markush Group B Markush Group C Markush Group D Markush Group E J ³ H, -NR ⁴ -, --C (O) NR ⁴ 2, -CO 2 R ^3, halo, -S (O) 2 NHR ⁴ _2, lower alkyl, lower alicyclic, lower alkenyl, lower alkynyl, lower perhaloalkyl, lower haloalkyl, lower aryl, lower alkylaryl, lower alkylene-OH, -OR ¹¹ , -CR ² 2NR ⁴ 2, -CN, -C (S) NR ⁴ , -OR ² , -SR ² , -N3, -NO 2, -NHC (S) NR ⁴ 2, -NR ²¹ C (O) R ^2, and -CR ² ₂ CN hydrogen, -NO ₂ , lower alkyl, lower aralkyl, lower alkoxy, lower perhaloalkyl, halogen, -CH _: NHR ⁴ , -C (O) NR ⁴ 2, -S (O), NHR ⁴ , -OH, - NH 2 and -NHC (O) R ² -OCH ₃ , -CN, hydrogen, halogen, -NH, and -NO; -OCH ₃ H, -OR ^3, -N0 _2, halo gene, - _(CH) -aryl, - (CH _{I '),} - -NHaryl, -S (0) 2 NHR ^7, -CN, -NR ^4, J ⁴ hydrogen, -NR ⁴ -, -C (O) NR ⁴ ₂ , -CO ₂ R ³ , halogen, -S (O) ₂ NHR ⁴ ₂ , lower alkyl, lower alicyclic, lower alkenyl, lower alk phenyl, lower perhaloalkyl, lower haloalkyl, lower aryl, lower alkylaryl, lower alkvlén -OH, -OR ^11, -CR _² nR ⁴ ,, -CN, -C (S) nR ⁴ 2, -OR ^2, -SR ² , -N 3, -NO ,, -NHC (S) NR ⁴ ,, -NR ²¹ C (O) R ^2, and -CR ² ₂ CN hydrogen, -NO ₂ , lower alkyl, lower aralkyl, lower alkoxy, lower perhaloalkyl, halogen, -CH ₂ NHR ⁴ , -C (O) NR ⁴ , -S (O) ₂ NHR ⁴ , -OH, - NH, and -NHC (O) R ² -OCH 3 -CN, hydrogen, halogen, -nh ₂ and -NO, is not halogen or alkenyl hydrogen, -OR ', -NO ₂ , halogen, - (CH ₂ ), - aryl, - (CH ₂ ) ₂ -NHaryl, -S (O), -NHR ⁷ , -CN, -NR ⁴ ,

169

Markush Group A Markush Group B Markush Group C Markush Group D Markush Group E J ³ hydrogen, -NR ⁴ -, -C (O) NR ⁴ ₂ , -CO ₂ R ³ , halogen, -S (O), NHR ⁴ , lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, lower haloalkyl, lower aryl, lower alkylaryl, lower alkylene-OH, -OR ¹¹ , -CR ² 2NR ⁴ 2, -CN, -C (S) NR ⁴ , -OR ² , -SR ² , -n 3, -NO 2, -NHC (S) NR% -NR ²¹ C (O) R ² and -CR ² 2 CN hydrogen, -NO ₂ , lower alkyl, lower alkylaryl, lower alkoxy, lower perhaloalkyl, halogen, -ch ₂ nhr ⁴ ₂ , -c (δ) nrS, -S (O), NHR ⁴ , -OH, -NH ₂ and -NHC (0) R ² -OCH _3, -CN, hydrogen, halogen, -NH _2, and -NO _Z is not halogen or alkenyl H, -0R ^J, -NO ,, halo gene, - (CH _{2) 2} -aryl, - (CH) ₂ - -NHaryl, -S (0) NHR ^7, -CN, -NR ^4;

Markush Group A Markush Group B Markush Group C Markush Group D Markush Group E y hydrogen, -nr ⁴ , -, -C (O) NR ⁴ ₂ , -CO ₂ R ³ , halogen, -S (O); NHR ⁴ 2, lower alkyl, lower alenyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, lower haloalkyl, lower aryl, lower alkylaryl, lower alkylene-en-OH, -OR ^{11, -CR:, NR4,,} -CN, -C (S) NR ⁴ ,, -OR ^2, -SR ^2, -N 3 , -no ,, -NHC (S) NR ^4;, -NR ²¹ C (0) R ² and -CR _^2? CN hydrogen, -NO 2, lower alkyl, lower alkylaryl, lower alkoxy, lower perhaloalkyl, halogen, -CH ₂ NHR ⁴ , -C (O) NR ⁴ ₂ , -S (O) ₂ NHR ⁴ , -OH, -NH, and -NHC (O) R ² -OCH ₃ , -CN, hydrogen, halogen, -NO ₂ and -CH, NHR ⁴ , is not halogen or alkenyl H, -OR ^- ', -NO ,, halo, - (CH,), - aryl, - (CH,), - NHaryl, -S (0) - NHR \ -CN, -NR \

170

Markush Group A Markush Group B Markush Group C Markush Group D Markush Group E hydrogen, -NR ⁴ -, -C (O) NR ⁴ 2, -co 2 R ³ , halogen, -S (O); NHR ⁴ 2, lower alkyl, lower alkenyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, lower haloalkyl, lower aryl, lower alkylaryl, lower alkylene-OH, -OR ¹¹ , -CR ² 2NR ⁴ 2, -CN, -C (S) NR ⁴ 2, -OR ² , -SR ² , -n 3, _-NO2, -NHC (S) NR ²¹ NR ⁴ ,, C (0) R ² and -CR ² ₂ CN H, -N0 _2, lower alkyl, lower aryl, lower alkylaryl, lower alkoxy, lower perhaloalkyl, halo, CH, NHR ^4, -C (0) ^NR4 ,, S (0) 2 NHR ^4, -OH, - NH 2 and -NHC (O) R ² -OCH 3, -CN, hydrogen, halogen, and lower alkyl w ³ hydrogen, alkyl hydrogen W hydrogen, alkyl, aralkyl, alicyclic, aryl, heteroaryl, 1-alkenyl a 1-alkynyl, hydrogen, -R ³ , aryl, substituted aryl, heteroaryl and substituted heteroaryl hydrogen, alkyl, aralkyl, alicyclic, aryl, heteroaryl, substituted heteroaryl same as W ² hydrogen G ⁵ C N G ° C N G ' C N

171

In general, preferred substituents V, Z, W, W ', V ² , Z ² , W ² , W, Z', D ', D and W ³ in formulas I, II, III, IV, VI, V-2 , VI, VII-1, VII-2 or X are selected to exhibit one of the following characteristics:

(1) increase oxidation reaction, since this reaction is likely to be a rate determining step and must therefore compete with the drug elimination process, (2) increase stability in aqueous solution and in the presence of non-p450 enzymes, (3) increase cellular penetration, e.g. . the substituents are not charged or do not have a high molecular weight since both of these properties may limit oral bioavailability as well as cellular penetration, (4) promote the β-elimination reaction following the initial oxidation by producing open ring products having one or more more of the following features:

(a) do not recycle;

(b) are subject to limited covalent hydration;

(c) promote β-elimination by assisting in proton peeling;

d) prevent addition reactions which form stable products, e.g. thiols to the originally hydroxylated product or nucleophilic addition to the carbonyl generated after ring opening, and

(e) limit the metabolism of reaction intermediates (eg, open ring ketones).

(5) lead to non-toxic and non-mutagenic by-products with one or more of the following characteristics. Both properties can be minimized by the use of substituents which

172 limit Michael addition, e.g.

a) electron-donor Z moieties that reduce the polarization of the double bond,

b) W groups which sterically block nucleophilic addition to β-carbon,

c) From the group that eliminates the double bond after the elimination reaction either through rheutomerization (enol-ketc) or hydrolysis (e.g. enamine),

(d) In groups containing groups which add to α, β-unsaturated ketones to form a ring,

e) From the group that forms a stable ring by Michael addition to the double bond,

(f) groups enhancing the detoxification of by-products using one or more of the following characteristics:

(i) confined to the liver, and (ii) susceptible to detoxification reactions (e.g., ketone reduction), and (6) ability to generate a pharmacologically active product.

In another embodiment of the invention, when Y is independently selected from -O- and -NR ⁵ - with the proviso that:

when Y is -O-, R ¹ attached to -O- is independently selected from the group consisting of hydrogen, alkyl, optionally substituted aryl, optionally substituted alicyclic, wherein the cyclic group comprises carbonate or thiocarbonate, optionally substituted -arylalkyl, -C (R ² ) ² C (O) NR ² 2, -NR ² -C (O) -R ³ , -C (R ² ) ² -OC (O) R ³ , -C (R ² ) 2-O-C (O) OR ³ , -C (R ² ) ₂ OC (O) SR ³ , -alkyl-SC (O) R ³ , -alkyl-SS-alkylhydroxy and -alkyl-SSS-alkylhydroxy when Y is -NR ⁵ -, R ¹ attached to -NR ⁶ - is independently selected from

173 hydrogen-containing groups, - [C (R ² ) 2] q -COOR ³ , -C (R ⁴ ) 2 COOR ³ , - [C (R ² ) ₂ ] _q -C (O) SR, and - cycloalkylene-COOR ³ wherein q is 1 or 2; and when only one Y is -O-, wherein -O- is not part of the cyclic group containing the other Y, the other Y is -N (R ¹⁸ ) - (CR ¹² R ¹³ ) -C (O) -R ¹⁴ ; and when Y is independently selected from -O- and -NR ⁵ , R ¹ and R ¹ together form:

where

a) V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl, or

Z is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OC (S) OR ³ , -CHR ² OC (O) SR ^3, -CHR ² OCO2R ^3, -OR ^2, -SR ^2, -CHR ² N 3, -CH 2 aryl group, -CH (aryl) OH, -CH (CH = CR 2 ^Z ) OH, -CH (C ^ CR ²⁾ OH, -R ^2, -NR ² 2, -OCOR ³ group, -OCO2R group ^3, group ³ -score, -SCO2R ³ group, a group -NHCOR ^Z, -NHCO2R group ^3, group -CH2NHaryl, - (CH _{2) p} -OR ^Z, and - (CH _{2) p} -SR ^2, wherein p is an integer of 2 or 3, or

V and Z are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group being fused to an aryl group at the β and γ position to Y attached to V; or

174

Z and W are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl; or

W and W 'are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or

W and W 'are joined together via an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl;

b) V ² , W ² and W are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic; aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

Z ² is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OC (O) SR ³ , -CHR ² OC (S) OR ³ , -CH (aryl) OH, -CH (CH = CR ² ) OH, -CH (C = CR ² ) OH, -SR ² , -CH ² NHaryl, -CH ₂ aryl; or

V ² and Z ² are joined together via an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 ring atoms, optionally containing 1 heteroatom, substituted with a hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy group attached to a carbon atom of three atoms from group Y attached to phosphorus;

c) Z 'is selected from the group consisting of -OH,

175

-OC (O) R ³ , -OCO ₂ R ^3, and -OC (O) SR ³ ;

D 'is hydrogen;

D is selected from the group consisting of hydrogen, alkyl, -OR ² , -OH, and -OC (O) R ³ ;

each W ³ is independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

with the proviso that:

a) V, Z, W, W 'are not all hydrogen and V ² , Z ² , W ² , W are not all hydrogen;

b) both Y groups are not -NR ⁶ -;

R ² is selected from R ³ and hydrogen;

R ³ is selected from the group consisting of alkyl, aryl, alicyclic and aralkyl;

R ⁶ is selected from the group consisting of hydrogen and lower alkyl.

More preferred are compounds wherein both Y groups are -O- then R ¹ is independently selected from optionally substituted aryl, optionally substituted benzyl, -C (R ² ) 20 C (O) R ³ , -C (R 3) ² ) 20C (O) OR ³ , and hydrogen, and when Y is -NR ⁶ -, then R ¹ attached to said -NR ⁶ - group is selected from the group consisting of -C (R X = COOR ³ , -C (R)); ² ) ² COOR ³ , and the second Y group is -O- and then R ¹ attached to said -O- is selected from the group consisting of optionally substituted aryl, -C (R ² ) 200 (O) R ^3, and -C ( R ² ) ₂₀ C (0) OR ³ .

176

In another aspect, when one Y is -O-, then its corresponding R ¹ is phenyl and the other Y is -NH- and its corresponding R ¹ is -CH ₂ CO ₂ Et.

In yet another aspect, when one Y is -O-, then its corresponding R ¹ is phenyl and the other Y is -NH- and its corresponding R ¹ is -C (Me) ₂ CO ₂ Et.

In another aspect, when one Y is -O-, then its corresponding R ¹ is 4-NHC (O) CH 3 -phenyl and the other Y is -NH- and its corresponding R ¹ is -CH ₂ CO ₂ Et.

In another aspect, when one Y is -O-, its corresponding R ¹ is 2-CO 2 Et-phenyl and the other Y is -NH- and its corresponding R ¹ is -CH ₂ CO ₂ Et.

In another aspect, when one Y is -O-, then its corresponding R ¹ is 2-CH 3 -phenyl and the other Y is -NH- and its corresponding R ¹ is -CH ₂ CO ₂ Et.

In another aspect of the invention there are compounds wherein both Y groups are -O- and R ¹ is aryl or -C (R ² ) ₂ -aryl.

Also preferred are compounds wherein both Y groups are -O- and at least one R ¹ is selected from the group consisting of -C (R ² ) 20 C (O) R ³ and -C (R ² ) 20 C (O) OR ³ .

In another aspect, compounds are preferred wherein both Y groups are -O- and at least one R ¹ is -alkyl-SS-alkylhydroxyl, -alkyl-SC (O) R ³ and -alkyl-SSS-alkylhydroxy, or R ¹ and R 2 ¹ are together-alkyl-SS-alkyl to form a cyclic group.

In one preferred embodiment, the compounds are those wherein both Y groups are -O- and R ¹ is hydrogen.

In one aspect, particularly preferred are compounds wherein both Y groups are -O- and R ¹ is -CH ₂ OC (O) OEt.

More preferred are compounds wherein at least one Y group is -O

177, and R ¹ and R ¹ together form:

where

a) V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl, or

Z is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OC (S) OR ³ , -CHR ² OC (0) SR ³ , -CHR ² OCO ² R ³ , -OR ² , -SR ² , -CHR ² N 3, -CH ² aryl, -CH (aryl) OH, -CH (CH = CR ² 2) OH, -CH (C = CR ² ) OH, -R ² , -NR ² 2, -OCOR ³ , -OCO ² R ³ , -SCOR ³ , -SCO2R ³ , -NHCOR ² , -NHCO ² R ³ , -CH ₂ NHaryl, - (CH ₂ ) _p -OR ^2, and - (CH ₂ ) _p -SR ² , wherein p is an integer of 2 or 3, or

V and Z are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group being fused to an aryl group at the β and γ position to Y attached to V; or

Z and W are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl; or

W and W 'are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl

178 and 1-alkynyl; or

W and W 'are joined together via an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl;

b) V ² , W ² and W are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

Z ² is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OC (O) SR ³ , -CHR ² OC (S) OR ³ , -CH (aryl) OH, -CH (CH = CR ² ) OH, -CH (C 1 -C ² ) OH, -SR ² , -CH ₂ NHaryl, -CH ₂ aryl; or

V ² and Z ² are joined together via an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 ring atoms, optionally containing 1 heteroatom, and substituted with a hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy group attached to a carbon atom of three atoms from group Y attached to phosphorus;

c) Z 'is selected from the group consisting of -OH, -OC (C) R ³ , -OCO ₂ R ^3, and -OC (O) SR ³ ;

D 'is hydrogen;

D is selected from the group consisting of hydrogen, alkyl, -OR ² , -OH, and -OC (O) R ³ ;

each W ³ is independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl

179-pin, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

with the proviso that:

a) V, Z, W, W 'are not all hydrogen and V ² , Z ² , W ² , W are not all hydrogen;

(b) both Y groups do not represent -NR ⁶ -

R ² is selected from R ³ and hydrogen;

R ³ is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;

R ⁶ is selected from the group consisting of hydrogen and lower alkyl.

In another aspect, more preferred are compounds wherein one Y group is -O- and R ¹ is optionally substituted aryl, and the other Y is -NR ⁵ -, wherein R ¹ on said -NR ⁶ - is selected from the group consisting of C (R 1) ⁴ ) 2 COOR ³ and -C (R ² ) 2 C (O) OR ³ . Particularly preferred are those compounds wherein R ¹ attached to -O- is phenyl and R ¹ attached to -NH is -CH (Me) CO ₂ Et and the -NH * CH (Me) CO ₂ Et group has the L configuration.

Particularly preferred compounds are those wherein R ¹ attached to -O is selected from the group consisting of phenyl and phenyl substituted with 1 to 2 substituents selected from the group consisting of -NHAc, -F, -Cl, -Br, -COOEt and -CH 3, and R ¹ attached to -NR ⁶ is -C (R ² ) ² COOR ³ wherein R ² and R ³ are independently from each other hydrogen, -CH 3 and -Et. For these compounds, when R ¹ attached to -O- is phenyl substituted with -NHAc or -COOEt, then preferably any -NHAc is attached at the 4-position and any -COOEt group is attached at the 2-position. More preferred are compounds wherein substituents on the substituted phenyl are 4-NHC (O) CH 3, -Cl, -Br, 2-C (O) OCH ₃ CH ₃ or -CH ₃ .

In one aspect of the invention, prodrugs are preferred

180 of Formula 6-i:

IN

wherein V is selected from the group consisting of aryl, heteroaryl and substituted heteroaryl, 1-alkenyl and 1-alkynyl. More preferred are compounds wherein V groups of formula 6-i are aryl and substituted aryl groups, including phenyl and substituted phenyl. Particularly preferred are heteroaryl groups including monocyclic substituted and unsubstituted heteroaryl groups. Particularly preferred are 4-pyridyl and 3-bromopyridyl.

More preferably, V groups of formula 6-i are aryl, substituted aryl, heteroaryl, and substituted heteroaryl. Preferably Y is -O-. Particularly preferred are aryl and substituted aryl groups including phenyl and phenyl substituted with 1 to 3 halogens. Particularly preferred are 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl,

3-chlorophenyl and 3-bromophenyl.

It is also particularly preferred that V is selected from the group consisting of monocyclic heteroaryl and monocyclic substituted heteroaryl containing at least one nitrogen atom. Most preferred are compounds wherein heteroaryl and substituted heteroaryl are

4-pyridyl and 3-bromopyridyl.

It is also preferred that V and Z are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing one heteroatom, which is fused to an aryl group at the β and γ position to Y attached to the phosphorus. In such compounds, preferred aryl groups are optionally substituted monocyclic aryl groups and the link between the Z and γ position of the aryl group is selected from the group consisting of O, CH ₂ , CH ₂ CH ₂ , OCH ₂ or CH ₂ O.

In another aspect, compounds are preferred wherein V and W are taken together

181 linked through an additional 3 carbon atoms to form an optionally substituted cyclic group of 6 carbon atoms and monosubstituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy and aryloxycarbonyloxy attached to one carbon atom that is three atoms of Y attached to phosphorus. In such compounds, it is more preferred that V and W form a cyclic group selected from -CH ₂ -CH (OH) -CH ₂ -, -CH ₂ CH (OCOR ³ ) -CH ₂ - and -CH ₂ CH (OCO ₂ ) R ³ ) - CH2.

In another preferred embodiment, the V group is 1-alkene. It is known that oxidation by p450 enzymes takes place on benzylic and allyl carbons.

In another aspect, preferred V groups are hydrogen when Z is selected from the group consisting of -CHR ² OH, -CHR ²⁰ CO ³ and -CHR ²⁰ CO ₂ R ³ .

In another aspect, when V is aryl, substituted aryl, heteroaryl or substituted heteroaryl, preferably Z is -OR ² , -SR ² , -CHR ² N 3, -R ", -NR ² 2, - OCOR ² , -OCO2R ³ , -SCOR ', -SCO2R ³ , -NHCOR ² , -NHCO2R ³ , -CH 2 NHaryl, - (CH 2) p -OR ² and - (CH 2) _p -SR ² . More preferably, Z is -OR ² , -R ² , -OCOR ', -OCO ² R ³ , -CH 3, -NHCOR ² , -NHCO ² R, - (CH 2) p -OR ^2, and - ( CH 2) _p -SR ^second Most preferred are Z groups including -OR ² , hydrogen, -OCOR ² , -OCO ₂ R ^3, and -NHCOR ² .

Preferred W and W 'groups include hydrogen, R ³ , aryl, substituted aryl, heteroaryl and substituted aryl. Preferably W and W 'are the same groups. More preferably, W and W 'are hydrogen.

In one aspect, compounds of Formula I and IA preferably have a group

Z is hydrogen, alkyl, alicyclic hydroxy, alkoxy, NHCOR. Preferred are those compounds wherein

182

Z reduces the ability of byproducts, or, in the case of vinylarylketone, the ability to undergo Michael addition. Preferred Z moieties are those which provide electrons to the vinyl moiety, a known strategy for reducing the ability of α, β-unsaturated carbonyl compounds to undergo Michael addition. For example, a methyl group at a similar position on acrylamide results in the compound having no mutagenic activity, while the unsubstituted vinyl analog is highly mutagenic. Other groups may serve in a similar manner, e.g. Z = OR, NHAc and the like. Other groups may also prevent Michael addition, especially groups that lead to the removal of the double bond itself, such as Z = OH, -OC (O) R, -OCO ₂ R and NH ₂ , which will be subject to rapid rheutomerization after the elimination reaction. Some of the W and W 'groups are also preferred in this role because they prevent the β-carbon addition reactions or destabilize the product. Another preferred Z group is one which comprises a nucleophilic group capable of addition to the α, β-unsaturated double bond after the elimination reaction, i.e. (CH ₂ ) _P SH or (CH ₂ ) _P OH, where p is 2 or 3. Further preferred groups are those groups attached to V which are capable of addition to the α, β-unsaturated double bond after the elimination reaction:

In another aspect, prodrugs of the formula are preferred

I-7:

where

7-i

183

Z is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OCO ₂ R 3, -CHR ² OC (O) SR ³ and -CHR ²⁰ O (S) OR ³ . Preferably Y is -O-. More preferred groups include -CHR ²⁰ OH, -CHR ²⁰ OCl ³ R ^3, and -CHR ²⁰ OCC> 2 R ³ .

In another preferred aspect, preferred prodrugs of Formula 8-i are:

where

Z 'is selected from the group consisting of -OH, -OC (O) R ³ , -COO ² R ³ , and -OC (O) SR ³ ,

D ⁴ and D ³ are independently selected from the group consisting of hydrogen, alkyl, OR ² , -OH and -OC (O) R ³ , with the proviso that at least one of D ⁴ and D ³ is hydrogen. Preferably Y is -O-.

In one preferred embodiment, W 'and Z are hydrogen, W and V are both the same aryl, substituted aryl, heteroaryl or substituted heteroaryl, such that the phosphonate group prodrugs:

has a plane of symmetry. Preferably Y is -O-.

In another embodiment, W and W 'are hydrogen, V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, and Z is selected from the group consisting of hydrogen, OR ² and -NHCOR ² . More preferred are those compounds wherein Z is hydrogen.

184 p-450 oxidation may be sensitive to stereochemistry, which may be either on a phosphorus atom or on a carbon bearing an aromatic group. The prodrugs of the invention have two isomeric forms on the phosphorus. Preferred stereochemistry is one that allows both oxidation and elimination reactions. Cis-stereochemistry at the phosphorus atom is preferred.

Preferred compounds of formula 8-i use a Z 'moiety which is capable of undergoing an oxidation reaction to form unstable intermediates which decompose via an elimination reaction to form R ⁵ -X-PO ^{3 2} ', R ⁵ -XP (O) ( NHR ^S ) 2 or R ⁵ -XP (O) (O *) (NHR ⁶ ). A particularly preferred Z 'group is OH. The groups D ⁴ and D ³ are preferably hydrogen, alkyl and -OR ² , -OC (O) R ³ , but at least one of D ⁴ or D ³ must be hydrogen.

The following prodrugs of formula I, II, III, IV, V-1, V-2, VI, VII-1, VII-2 and X are preferred:

acyloxyalkyl;

alkoxycarbonyloxyalkyl;

aryl esters;

Benzyl and substituted benzyl esters;

Ester-containing disulfide;

Substituted (1,3-dioxolen-2-one) methyl esters;

Substituted 3-phthalidyl esters;

Cyclic [5-hydroxycyclohexane-1,3-diyl] diesters and hydroxy protected forms;

Cyclic [2-hydroxymethylpropane-1,3-diyl] diesters and hydroxy protected forms;

Cyclic (1-arylpropane-1,3-diyl);

Bis ω substituted lactone esters; and all mixed esters formed by combining all the above esters;

More preferred are:

185

Bis-pivaloyloxymethyl esters;

Bis-isobutyryloxymethyl esters;

Cyclic [2-hydroxymethylpropane-1,3-diyl] diester;

Cyclic [2-acetoxymethylpropane-1,3-diyl] diester;

Cyclic [2-methyloxycarbonyloxymethylpropane-1,3-diyl] diester;

Cyclic [1-phenylpropane-1,3-diyl] diesters;

Cyclic [1- (2-pyridyl) propane-1,3-diyl] diesters;

Cyclic [1- (3-pyridyl) propane-1,3-diyl] diesters;

Cyclic [1- (4-pyridyl) propane-1,3-diyl] diesters;

Cyclic [5-hydroxycyclohexane-1,3-diyl] diesters and hydroxy protected forms;

Bis-benzoylthiomethyl esters;

Bis-benzoylthioethyl esters;

Bis-benzoyloxymethyl esters;

Bis-p-fluorobenzoyloxymethyl esters;

Bis-6-chloronicotinoyloxymethyl esters;

Bis-5-bromonicotinoyloxymethyl esters;

Bis-thiophenecarbonyloxymethyl esters;

Bis-2-furoyloxymethyl esters;

Bis-3-furoyloxymethyl esters;

diphenyl;

Bis (4-methoxyphenyl) esters;

Bis (2-methoxyphenyl) esters;

Bis (2-ethoxyphenyl) esters;

The mono (2-ethoxyphenyl) esters;

Bis (4-acetamidophenyl) esters;

Bis (4-acetoxyphenyl) esters;

Bis (4-hydroxyphenyl) esters;

Bis (2-acetoxyphenyl) esters;

Bis (3-acetoxyphenyl) esters;

Bis (4-morpholinophenyl) esters;

Bis [4- (1-triazolophenyl) esters;

Bis (3-N, N-dimethylaminophenyl) esters;

Bis (1,2,3,4-tetrahydronaphthalen-2-yl) ester;

186

Bis (3-chloro-4-methoxy) benzyl esters;

Bis (3-bromo-4-methoxy) benzyl esters;

Bis (3-cyano-4-methoxy) benzyl esters;

Bis (3-chloro-4-acetoxy) benzyl esters;

Bis (3-bromo-4-acetoxy) benzyl esters;

Bis (3-cyano-4-acetoxy) benzyl esters;

Bis- (4-chloro) benzyl esters;

Bis (4-acetoxy) benzyl esters;

Bis- (3,5-dimethoxy-4-acetoxy) benzyl esters;

Bis (3-methyl-4-acetoxy) benzyl esters;

Bis (benzyl) esters;

Bis- (3-methoxy-4-acetoxy) benzyl esters;

Bis (6'-hydroxy-3 ', 4'-dithia) hexyl esters;

Bis (6'-acetoxy-3 ', 4'-dithia) hexyl esters;

(3,4-dithiahexan-l, 6-diyl) esters;

Of bis (5-methyl-l, 3-dioxolen-2-on-4-yl) methyl esters;

Of bis (5-ethyl-l, 3-dioxolen-2-on-4-yl) methyl esters;

Bis (5-tert-butyl-1,3-dioxolen-2-one-4-yl) methyl esters;

Bis (5,6,7-trimethoxy) phthalidyl esters;

Bis- (cyclohexyloxycarbonyloxymethyl) esters;

Bis- (isopropyloxycarbonyloxymethyl) esters;

Bis- (ethyloxycarbonyloxymethyl) esters;

Bis- (methyloxycarbonyloxymethyl) esters;

Bis- (isopropylthiocarbonyloxymethyl) esters;

Bis- (phenyloxycarbonyloxymethyl) esters;

Bis- (benzyloxycarbonyloxymethyl) esters;

Bis- (phenylthiocarbonyloxymethyl) esters;

Bis- (p -methoxyphenoxycarbonyloxymethyl) esters;

Bis- (m -methoxyphenoxycarbonyloxymethyl ·) esters;

Bis- (o -methoxyphenoxycarbonyloxymethyl) esters;

Bis- (o -methylphenoxycarbonyloxymethyl) esters;

Bis- (p -chlorophenoxycarbonyloxymethyl) esters;

Bis (1,4-biphenoxycarbonyloxymethyl) esters;

Bis [(2-phthalimidoethyl) oxycarbonyloxymethyl] esters;

Bis (N-phenyl-N-metylkarbamoyloxymetyl) esters;

187

Bis (2,2,2-trichloroethyl) esters;

Bis (2-bromoethyl) esters;

Bis (2-iodoethyl) esters;

Bis (2-azidoethyl) esters;

Bis (2-acetoxyethyl) esters;

Bis (2-aminoethyl (esters;

Bis (2-N, N-dimethylaminoethyl) esters;

Bis (2-aminoethyl) esters;

Bis- (methoxycarbonylmethyl) esters;

Bis (2-aminoethyl) esters;

Bis [N, N-di- (2-hydroxyethyl)] karbamoylmetylestery;

Bis (2-aminoethyl) esters;

Bis (2-methyl-5-tiazolmetyl) esters;

Bis (bis-2-hydroxyetylkarbamoylmetyl) esters;

O-phenyl- [N- (1-ethoxycarbonyl (ethyl) phosphoramidates) (—P (O) (OPh) (N (H) -CH (Me) CO ₂ Et)

O-phenyl- [N- (1-methoxycarbonyl) ethyl] phosphoramidates] -P (O) (OPh) - (N (H) CH (Me) CO ₂ Me)

O- (3-chlorophenyl) - [N- (1-ethoxycarbonyl) ethyl] phosphoramidates (-P (O) (O-Ph-3-Cl) (NHCH (Me) CO ₂ Et)

O- (2-chlorophenyl) - [N- (1-ethoxycarbonyl) ethyl] phosphoramidates (-P (O) (OPh-2-Cl) (NHCH (Me) CO ₂ Et)

O- (4-chlorophenyl) - [N- (1-ethoxycarbonyl) ethyl] phosphoramidates (-P (O) (OPh-4-Cl) (NHCH (Me) CO ₂ Et)

O- (4-acetamidophenyl) - [N- (1-ethoxycarbonyl) ethyl] phosphoramidates (-P (O) (OPh-4NHAc) (NH-CH (Me) CO ₂ Et)

O- (2-ethoxycarbonylphenyl) - [N- (1-ethoxycarbonyl) ethyl] phosphoramidates (-P (O) (OPh-2-CO ₂ Et) (NH-CH (Me) CO ₂ Et)

O-phenyl- [N- (1-ethoxycarbonyl-1-methyl) ethyl] phosphoramidates (-P (O) (OPh) (NH-C (Me) ₂ CO ₂ Et)

O-Phenyl- [N- (1-methoxycarbonyl-1-methyl) ethyl] phosphoramidates (-P (O) (OPh) (NH-C (Me) ₂ CO ₂ Me)

O- (3-chlorophenyl) - [N- (1-ethoxycarbonyl-1-methyl) ethyl] phosphoramidates (-P (O) (OPh-3-Cl) (NH-C (Me) ₂ CO ₂ Et)

0- (2-chlorophenyl) - [N- (1-ethoxycarbonyl-1-methyl) ethyl] phosphoramidates

188 (-Ρ (Ο) (OPh-2-Cl) (NH-C (Me) ₂ CO ₂ Et)

O- (4-chlorophenyl) - [N- (1-ethoxycarbonyl-1-methyl) ethyl] phosphoramidates (-P (O) (OPh-4-Cl) (NH-C (Me) ₂ CO ₂ Et)

O- (4-acetamidophenyl) - [N- (1-ethoxycarbonyl-1-methyl) ethyl] phosphoramidates (-P (O) (OPh-4-NHAc) (NH-C (Me) ₂ CO ₂ Et)

O- (2-ethoxycarbonylphenyl) - [N- (1-ethoxycarbonyl-1-methyl) ethyl] phosphoramidates (-P (O) (OPh-2-CO ₂ Et) (NH-C (Me) ₂ CO ₂ Et)

O-phenyl- [N- (ethoxycarbonyl) methyl] phosphoramidates (-P (O) (OPh) (NH-CH ₂ CO ₂ Et)

O-phenyl- [N- (methoxycarbonyl) methyl] phosphoramidates (-P (O) (OPh) (NH-CH ₂ CO ₂ Me)

O- (3-chlorophenyl) - [N- (ethoxycarbonyl) methyl] phosphoramidates (-P (O) (OPh-3-Cl) (NH-CH ₂ CO ₂ Et)

O- (2-chlorophenyl) - [N- (ethoxycarbonyl) methyl] phosphoramidates (-P (O) (OPh-2-Cl) (NH-CH ₂ CO ₂ Et)

O- (4-chlorophenyl) - [N- (ethoxycarbonyl) methyl] phosphoramidates (-P (O) (OPh-4-Cl) (NH-CH ₂ CO ₂ Et)

O- (4-acetamidophenyl) - [N- (ethoxycarbonyl) methyl] phosphoramidates (-P (O) (OPh-4NHAc) (NH-CH ₂ CO ₂ Et)

O- (2-ethoxycarbonylphenyl) - [N- (ethoxycarbonyl) methyl] phosphoramidates (-P (O) (OPh-2-CO ₂ Et) (NH-CH ₂ CO ₂ Et)

The following compounds are most preferred:

Bis-pivaloyloxymethyl esters;

Bis-isobutyryloxymethyl esters;

cyclic (2-hydroxymethylpropane-l, 3-diyl) ester; cyclic (2-acetoxymethylpropan-l, 3-diyl) ester; cyclic (2-methyloxycarbonyloxymethylpropan-l, 3-diyl) ester; cyclic (2-cyclohexylcarbonyloxymethylpropan-l, 3-diyl) ester; cyclic [Phenylpropan-1,3-diyl] diesters; cyclic [1- (2-pyridyl) propane-1,3-diyl] diesters; cyclic [1- (3-pyridyl) propan-1,3-diyl] diesters; cyclic [L- (4-pyridyl) propan-1,3-diyl] diesters; cyclic [5-hydroxycyclohexane-1,3-diyl] diesters and hydroxy protecting

189 unformed forms;

Bis-benzoylthiomethyl esters;

Bis-benzoylthioethyl esters;

Bis-benzoyloxymethyl esters;

Bis-p-fluorobenzoyloxymethyl esters;

Bis-6-chloronicotinoyloxymethyl esters;

Bis-5-bromonicotinoyloxymethyl esters;

Bis-thiophenecarbonyloxymethyl esters;

Bis-2-furoyloxymethyl esters;

Bis-3-furoyloxymethyl esters;

Diphenyl esters;

Bis (2-methylphenyl) esters;

Bis (2-methoxyphenyl) esters;

Bis (2-ethoxyphenyl) esters;

Bis (4-methoxyphenyl) esters;

Bis (3-bromo-4-methoxy-benzyl) ester;

Bis (4-acetoxybenzyl) esters;

Bis (3,5-dimethoxy-4-acetoxybenzyl) esters;

Bis (3-methyl-4-acetoxybenzyl) esters;

Bis- (3-methoxy-4-acetoxybenzyl) esters;

Bis (3-chloro-4-acetoxybenzyl) esters;

Bis (cyclohexyloxycarbonyloxymethyl) esters;

Bis- (isopropyloxycarbonyloxymethyl) esters;

Bis- (ethyloxycarbonyloxymethyl) esters;

Bis- (methyloxycarbonyloxymethyl) esters;

Bis- (isopropylthiocarbonyloxymethyl) esters;

Bis (fenvloxykarbonyloxymetyl) esters;

Bis- (benzyloxycarbonyloxymethyl) esters;

Bis (phenylcarbonyloxymethyl) esters;

Bis- (p -methoxyphenoxycarbonyloxymethyl) esters;

Bis- (m -methoxyphenoxycarbonyloxymethyl) esters;

Bis- (o -methoxyphenoxycarbonyloxymethyl) esters;

Bis (o-methylphenoxycarbonyloxymethyl) esters;

Bis- (p -chlorophenoxycarbonyloxymethyl) esters;

Bis- (1,4-biphenoxycarbonyloxymethyl) esters;

190

Bis [(2-phthalimidoethyl) oxycarbonyloxymethyl] esters;

Bis (6-hydroxy-3,4-dithia) hexyl esters;

Cyclic (3,4-dithiahexane-1,1β-diyl) esters;

Bis (2-bromoethyl) esters;

Bis (2-aminoethyl) esters;

Bis (2-N, N-diethylaminoethyl) ester;

O-Phenyl- [N- (1-ethoxycarbonyl) ethyl] phosphoramidates (-P (O) (OPh) (NH- * CH (Me) CO ₂ Et)

O-Phenyl- [N- (1-methoxycarbonyl) ethyl] phosphoramidates (-P (O) (OPh) (NH-CH (Me) CO ₂ Me)

O- (3-chlorophenyl) - [N- (1-ethoxycarbonyl) ethyl] phosphoramidates (-P (O) (OPh-3-Cl) (NH- * CH (Me) CO ₂ Et)

O- (2-chlorophenyl) - [N- (1-ethoxycarbonyl) ethyl] phosphoramidates (-P (O) (OPh-2-Cl) (NH-CH (Me) CO ₂ Et)

O- (4-chlorophenyl) - [N- (1-ethoxycarbonyl) ethyl] phosphoramidates (-P (O) (OPh-4-Cl) (NH- * CH (Me) CO ₂ Et)

O- (4-acetamidophenyl) - [N- (1-ethoxycarbonyl) ethyl] phosphoramidates (-P (O) (OPh-4NHAc) (NH-CH (Me) CO ₂ Et)

O- (2-ethoxycarbonylphenyl) - [N- (1-ethoxycarbonyl) ethyl] phosphoramidates (-P (O) (OPh-2-CO ₂ Et) (NH- * CH (Me) CO ₂ Et)

O-phenyl- [N- (1-ethoxycarbonyl-1-methyl) ethyl] phosphoramidates (-P (O) (OPh) (NH-C (Me) ₂ CO ₂ Et)

O-Phenyl- [N- (1-methoxycarbonyl-1-methyl) ethyl] phosphoramidates (-P (O) (OPh) (NH-C (Me) ₂ CO ₂ Me)

O- (3-chlorophenyl) - [N- (1-ethoxycarbonyl-1-methyl) ethyl] phosphoramidates (-P (O) (OPh-3-Cl) (NH-C (Me) ₂ CO ₂ Et)

O- (2-chlorophenyl) - [N- (1-ethoxycarbonyl-1-methyl) ethyl] phosphoramidates (-P (O) (OPh-2-Cl) (NH-C (Me) ₂ CO ₂ Et)

O- (4-chlorophenyl) - [N - (1-ethoxycarbonyl-1-methyl) ethyl] phosphoramidates (-P (O) (OPh-4-Cl) (NH-C (Me) ₂ CO ₂ Et)

O- (4-acetamidophenyl) - [N- (1-ethoxycarbonyl-1-methyl ·) ethyl] phosphoramidate (-P (O) (OPh-4-NHAc) (NH-C (Me) ₂ CO ₂ Et)

O- (2-ethoxycarbonylphenyl) - [N- (1-ethoxycarbonyl-1-methyl) ethyl] phosphoramidates (-P (O) (O-2-CO ₂ Et) (NH-C (Me) ₂ CO ₂ Et)

191

In the above compounds, an asterisk (*) on carbon indicates the L-configuration.

O-phenyl- [N- (ethoxycarbonyl) methyl] phosphoramidates (= P (O) (OPh) (NH-CH ₂ CO ₂ Et)

O-phenyl- [N- (methoxycarbonyl) methyl] phosphoramidates (-P (O) (OPh) (NH-CH ₂ CO ₂ Me)

O- (3-chlorophenyl) - [N- (ethoxycarbonyl) methyl] phosphoramidates (-P (O) (OPh-3-Cl) (NH-CH ₂ CO ₂ Et)

O- (2-chlorophenyl) - [N- (ethoxycarbonyl) methyl] phosphoramidates (-P (O) (OPh-2-Cl) (NH-CH ₂ CO ₂ Et)

O- (4-chlorophenyl) - [N- (ethoxycarbonyl) methyl] phosphoramidates (-P (O) (OPh-4-Cl) (NH-CH ₂ CO ₂ Et)

O- (4-acetamidophenyl) - [N- (ethoxycarbonyl) methyl] phosphoramidates (-P (O) (OPh-4NHAc) (NH-CH ₂ CO ₂ Et)

O- (2-ethoxycarbonylphenyl) - [N- (ethoxycarbonyl) methyl] phosphoramidates (-P (O) (OPh-2-CO ₂ Et) (NH-CH ₂ CO ₂ Et).

The compounds listed in Table 1 correspond to preferred compounds of formula IA wherein M is R ⁵ -X as defined in the following formulas: formula i, formula ii and formula iii, wherein Q ¹ and Q ² correspond to NR ¹⁵ R ¹⁵ and N ( R ¹⁸ ) - (CR ¹² R ^{± 3} ) mC (O) -R ¹⁴ in formula IA.

formula i

ABOUT

II ¹¹ 1 _R 5_L — o-CH — p — Q ¹ ' ₂

Q ²

formula iii formula ii

In the above formulas i, ii and iii, R 1 may be substituted by A and B. Preferred compounds of formulas i, ii and iii are listed in Table 1 by numbers assigned to R ³ , A, B, Q ¹ and Q ² in the above formulas i, ii and iii according to the following convention: Q ¹ . Q ² . R ⁵ . (B) A. For each group, the structure is assigned the number given in the following Tables for R ⁵ , A, B, Q ¹ and Q ² .

192

The variables R ⁵ are divided into two groups, each containing four different structures.

Compounds listed in Table 1 of formulas i, ii and iii, wherein the R ⁵ groups are assigned the following numbers:

Group 1:

1 2 3 4 mX S ^> B '0- ^ 8 MT h ₃ c Etγ Et ^B

Group 2:

The following numbers have been assigned to the A group variable:

it contains eight different substituents.

Q ¹ and Q 'groups are assigned the following numbers:

Group 1:

Q ¹ and Q ²

-NH-CH ₂ -C (O) R ¹⁴

193

-NH-CH (CH ₃ ) -C (O) R ¹⁴

3. -NH-C (CH ₃ ) ₂ -C (O) R ¹⁴

4. -NH-C (CH ₂ ) ₂ CH ₂ -C (O) R ¹⁴

-NH-CH (CH (CH ₃ ) ₂ ) -C (O) R ¹⁴

-NH-CH (CH ₂ (CH (CH ₃ ) ₂ )) -C (O) R ¹⁴

-NH-CH (CH ₂ CH ₂ SCH ₃ ) -C (O) R ¹⁴

8. -NH-CH (CH ₂ SCH ₂ Ph) -C (O) R ¹⁴

Group 2:

Q ¹ and Q ²

-NH-CH ₂ CH ₂ -C (O) R ¹⁴

-NH-CH (CH ₂ CH ₂ COR ¹⁴ ) -C (O) R ¹⁴

3. -NH-CH (CH ₂ COR ¹⁴ ) -C (O) R ¹⁴

-NH-CH (CH ₂ CONH ₂ ) -C (O) R ¹⁴

-NH-CH (COR ¹⁴ ) CH ₂ -C (O) R ¹⁴

-NH-CH (CH ₂ OR ¹⁷ ) -C (O) R ¹⁴

-NH-CH (CH ₂ CH ₂ COR ¹⁴ ) -C (O) R ¹⁴

8. -NH-CH (CH ₂ OH) -C (O) R ¹⁴

Group 3:

Q ¹ and Q ² First -NH-CH (CH ₂ -C ₆ H ₅ OH) -C (O) R ¹⁴ Second -NH-C (c-propyl) -C (O) R ¹⁴ Third -NH-C (c-pentyl) -C (O) R ¹⁴ 4. -NH-C (c-hexyl) -C (O) R ¹⁴ 5th -NH-CH (CH ₂ Ph) -C (O) R ¹⁴ 6th -N (CH ₃ ) -CH ₂ -C (O) R ¹⁴ 7. Λ hH-COR 14 8th nr ¹⁸ y ¹⁹ where R ¹⁴ is selected from obs moving OMe, OEz, OBn, O-tBu O-nPr, OPh, -N (Me) ₂ , morpholine, SMe, Set; R ¹⁷ is methyl, ethyl, ben- benzyl and propyl; R ¹⁸ is hydrogen, Me, Et, Bn, Pr and Ph and ^R19 is Me, Et, Bn. Pr and Ph; R ¹⁸ and R ¹⁹ are morpholinyl and pyrrolidinyl.

194

Thus, when R ⁵ is selected from group 1 R ⁵ , and Q ¹ and Q ² are selected from group 1 Q ¹ and group 1 Q ² , compound 3.3.1.2.1 shown in Table 1 corresponds to the following structure of general formula i:

and when R ¹⁴ is ethoxy, the structure would be:

Alternatively, when Q ¹ and Q ² are selected from group 3Q ¹ and group

2R ⁵ , then the corresponding merger 3Q ² , and R ⁵ is selected from the group of 3.3.1.2.1 shown in the Table corresponding to the structure of Formula I below.

The numbers in the Table also correspond to the preferred benzothiazole and benzoxazole compounds of formula X.

These preferred compounds are shown as general formulas iv

195

formula v

Preferred compounds of formula (iv) are shown in Table 1 using the numbers assigned to A, B, D, Q ¹ and Q ² in the above formulas (iv) and according to the following convention: Q ¹ . Q ² .ABD For each group, the structures are assigned the numbers given in the following tables for A, B, D, Q ¹ and Q ² .

The variables Q ¹ and Q ² are divided into two groups, each containing eight different substituents. Q ¹ and Q ² groups are identified by the following numbers:

Group 1:

Q ¹ and Q ²

-NH-CH ₂ -C (O) R ¹⁴

-NH-CH (CH ₃ ) -C (O) R ¹⁴

3. -NH-C (CH ₃ ) 2 -C (O) R ¹⁴

4. -NH-C (CH ₂ ) ₂ CH ₂ -C (O) R ¹⁴

-NH-CH (CH (CH ₃ ) ₂ ) -C (O) R ¹⁴

-NH-CH (CH ₂ (CH (CH ₃ ) ₂ )) -C (O) R ¹⁴

-NH-CH (CH ₂ CH ₂ SCH ₃ ) -C (O) R ¹⁴

8. -NH-CH (CH ₂ SCH ₂ Ph) -C (O) R ¹⁴

Group 2:

Q ¹ and Q ²

-NH-CH ₂ CH ₂ -C (O) R ¹⁴

-NH-CH (CH ₂ CH ₂ COR ¹⁴ ) -C (O) R ¹⁴

3. -NH-CH (CH ₂ COR ¹⁴ ) -C (O) R ¹⁴

-NH-CH (CH ₂ CONH ₂ ) -C (O) R ¹⁴

196

-NH-CH (COR ¹⁴ ) CH ₂ -C (O) R ¹⁴

-NH-CH (CH ₂ OR ¹⁷ ) -C (O) R ¹⁴

-NH-CH (CH ₂ CH ₂ COR ¹⁴ ) -C (O) R ¹⁴

8. -NH-CH (CH ₂ OH) -C (O) R ¹⁴

Group 3:

Q ¹ and Q ²

-NH-CH (CH ₂ -C ₅ H ₅ OH) -C (O) R ¹⁴

-NH-C (c-propyl) -C (O) R ¹⁴

3. -NH-C (c-pentyl) -C (O) R ¹⁴

4. -NH-C (c-hexyl) -C (O) R ¹⁴

-NH-CH (CH ₂ Ph) -C (O) R ¹⁴

6. -N (CH ₃ ) -CH ₂ -C (O) R ¹⁴

Λ ₇ —N- ³ —C0R14

8. NR ¹⁸ R ¹⁹

Variable B is divided into three groups, each containing eight different substituents. The B groups are marked with the following numbers:

Group 1:

1 2 3 4 ~ 1 7 8 B = H Me et nPr br Pr Cl cPr

Group 2:

1 2 3 4 5 6 7 8 B = CN F OMe OEt SMe Set 2 -furanyl C (0) OEt

Group 3:

1 2 3 4 5 6 7 8 B = B and D B and D B and D B and D B and D B and D B and D B and D they are they are are connections- are connections- they are they are they are are spc- j ené, Jene, no, at né, pri- Jene, Jene, j ené, Jene, while while what did- what did- while while while while arises arises ká fúra- ká fúra- vzni ká arises vzni ká arises

197

cyclo the phenyl alkenylcarbonyl alkenylcarbonyl cyclo the phenyl furanyl furanyl hexyl circle circle (0 circle (0 hexylo- circle circle hunting circle connected connected circle (0 conn. circle (0 na B) na D) jený na Remind B) jený na D)

Group 3 for variable B can only be combined with group 3 for variable D.

Variable D is divided into three groups, each containing four different substituents.

Group 1:

1 2 3 4 D = H Me et SCN

Group 2:

Variable D is replaced with the group marked with the following number:

1 2 3 Δ D = SMe Set CH ₂ 0Me OMe

Group 3:

1 2 3 4 D = zero zero zero zero

Compounds listed in Table 1 of formulas iv and v, where the groups A are assigned the following numbers:

1 2 3 4 A = nh ₂ H Me Cl

wherein R ¹⁴ is selected from the group consisting of OMe, OEt, OBn, O-tBu, O-nPr, OPh, -N (Me) ₂ , morpholine, SMe, SEt; R ¹⁷ is methyl, ethyl, benzyl and propyl; R ¹⁸ is hydrogen, Me, Et, Bn, Pr, and Ph, and R ¹⁹ is Me, Et, Bn, Pr, and Ph; R ¹⁸ and R ¹⁹ are morpholinyl and pyrrolidinyl.

198

Thus, compound 2.2.1.7.4 of Group 1 for B, D, Q ¹ and Q ² corresponds to the following structure of formula (iv):

and when R ¹⁴ is ethoxy, the structure would be:

OEt

Similarly, in Group 3 for the variables B, compound 2.2.1.7.4 corresponds to the following structure iv

and when R ¹⁴ is ethoxy, the compound will have the following structure:

199

200

Table 1

1.1.1.1.1 1.1.1.1.2 1.1.1.1.3 1.1.1.1.4 1.1.1.2.1 1.1.1.2.2 1.1.1.2.3 1.1.1.2.4 1.1.1.3.1 1.1.1.3.2 1.1.1.3.3 1.1.1.3.4 1.1.1.4.1 1.1.1.4.2 1.1.1.4.3 1.1.1.4:4 1.1.1.5.1 1.1.1.5.2 1.1.1.5.3 1.1.1.5.4 1.1.1.6.1 1.1.1.6.2 1.1.1.6.3 1.1.1.6.4 1.1.1.7.1 1.1.1.7.2 1.1.1.73 1.1.1.7.4 1.1.1.8.1 1.1.1.8.2 1.1.1.8.3 1.1.1.8.4 1.1.2.1.1 1.1.2.1.2 1.1.2.1.3 1.1.2.1.4 1.1.2.2.1 1.1.2.2.2 1.1.2.2.3 1.1.2.2.4 1.1.2.3.1 1.1.2.3.2 1.1.2.3.3 1.1.2.3.4 1.1.2.4.1 1.1.2.4.2 1.1.2.4.3 1.1.2.4.4 1.1.2.5.1 1.1.2.5.2 1.1.2.5.3 1.1.2.5.4 1.1.2.6.1 1.1.2.6.2 1.1.2.6.3 1.1.2.6.4 1.1.2.7.1 1.1.2.7.2 1.1.2.73 1.1.2.7.4 1.1.2.8.I 1.1.2.8.2 1.1.2.8.3 1.1.2.8.4 1.1.3.1.1 1.1.3.1.2 1.1.3.1.3 1.1.3.1.4 1.1.3.2.1 1.1.3.2.2 1.1.3.2.3 1.1.3.2.4 1.1.3.3.1 1.1.3.3.2 1.1.3.3.3 1.1.3: 3.4 1.1.3.4.1 1.1.3.4.2 1.1.3.4.3 1.1.3.4.4 1.1.3.5.1 1.1.3.5.2 í.1.3.5.3 1.1.3.5.4 1.1.3.6.1 1.1.3.6.2 1.1.3.6.3 1.1.3.6.4 1.1.3.7.1 1.1.3.7.2 1.1.3.7.3 1.1.3.7.4 1.1.3.8.1 1.1.3.8.2 1.1.3.8.3 1.1.3.8.4 1.1.4.1.1 1.1.4.1.2 1.1.4.1.3 1.1.4.1.4 1.1.4.2.1 1.1.4.2.2 l.1.4.2.3 1.1.4.2.4 1.1.4.3.1 1.1.4.3.2 1.1.4.3.3 1.1.4.3.4 1.1.4.4.1 1.1.4.4.2 l.1.4.4.3 1.1.4.4.4 1.1.4.5.1 1.1.4.5.2 1.1.4.5.3 1.1.4.5.4 1.1.4.6.1 1.1.4.6.2 1.1.4.6.3 1.1.4.6.4 1.1.4.7.1 1.1.4.7.2 1.1.4.7.3 1.1.4.7.4 l.1.4.8.1 1.1.4,8.2 1.1.4.8.3 1.1.4.8.4 1.2.1.1.1 1.2.1.1.2 1.2.1.1.3 1.2.1.1.4 1.2.1.2.1 1.2.1.2.2 1.2.1.2.3 1.2.1.2.4 1.2.1.3.1 1.2.1.3.2 1.2.1.3.3 1.2.1.3.4 1.2.1.4.1 1.2.1.4.2 1.2.1.4.3 1.2.1.4.4 1.2.1.5.1 1.2.1.5.2 1.2.1.5.3 1.2.1.5.4 1.2.1.6.1 1.2.1.6.2 1.2.1.6.3 1.2.1.6.4 1.2.1.7.1 1.2.1.7.2 1.2.1.7.3 1.2.1.7.4 1.2.1.8.1 1.2.1.8.2 1.2.1.8.3 1.2.1.8.4 1.2.2.1.1 1.2.2.1.2 1.2.2.1.3 1.2.2.1.4 1.2.2.2.1 1.2.2.2.2 1.2.2.2.3 1.2.2.2.4 1.2.2.3.1 1.2.2.3.2 1.2.2.3.3 1.2.2.3.4 1.2.2.4.1 1.2.2.4.2 1.2.2.4.3 1.2.2.4.4 1.2.2.5.1 1.2.2.5.2 1.2.2.5.3 1.2.2.5.4 1.2.2.6.1 1.2.2.6.2 1.2.2.6.3 1.2.2.6.4 1.2.2.7.1 1.2.2.7.2 1.2.2.7.3 1.2.2.7.4 1.2.2.8.1 1.2.2.8.2 1.2.2.8.3 1.2.2.8.4 1.2.3.1 1.2,3.1.2 1.2.3.1.3 1.2.3.1.4 1.2.3.2.1 1.2.3.2.2 1.2.3.2.3 1.2.3.2.4 ) .2.3.3.1 1.2.3.3.2 1.2.3.3.3 1.2.3.3.4 I.2.3.4.1 1.2.3.4.2 1.2.3.4.3 1.2.3.4.4 1.2.3.5.1 1.2.3.5.2 1.2.3.5.3 1.2.3.5.4 1.2.3.6.1 1.2.3.6.2 1.2.3.6.3 1.2.3.6.4 1.2.3.7.1 1.2.3.7.2 1.2.3.7.3 1.2.3.7.4 1.2.3.8.1. 1.2.3.8.2 1.2.3.8.3 1.2.3.8.4 1.2.4.1.1 1.2.4.1.2 1.2.4.1.3 1.2.4.1.4 1.2.4.2.1 1.2.4,2.2 1.2.4.2.3 1.2.4.2.4 1.2.4.3.1 1.2.4.3.2 1.2.4.3.3 1.2.4.3.4 1.2.4.4.1 1.2.4.4.2 1.2.4.4.3 1.2.4.4.4 1.2.4.5.1 1.2.4.5.2 1.2.4.5.3 1.2.4.5.4 1.2.4.6.1 1.2.4.6.2 1.2.4.6.3 l.2.4.6.4 1.2.47.1 1.2.4.7.2 1.2.4.7.3 1.2.4.7.4 I.2.4.8.1 l.2.4.8.2 1.2.4.8.3 1.2.4.8.4 1.3.1.1.1 1.3.1.1.2 1.3.1.1.3 1.3.1.1.4 1.3.1.2.1 1.3.1.2.2 1.3.1.2.3 1.3.1.2.4

201

Table 1- continued

1.3.1.3.1 1.3.1.3.2 1.3.1.3.3 1.3.1.3.4 1.3.1.4.1 1.3.1.4.2 1.3.1.4.3 1.3.1.4.4 1.3.1.5.1 1.3.1.5.2 1.3.1.5.3 1.3.1.5.4 1.3.1.6.1 1.3.1.6.2 1.3.1.6.3 1.3.1.6.4 1.3.1.7.1 1.3.1.7.2 1.3.1.7.3 1.3.1.7.4 1.3.1.8.1 1.3,1.8.2 1.3.1.8.3 1.3.1.8.4 1.3.2.1.1 1.3.2.1.2 1.3.2.1.3 1.3.2.1.4 1.3.2.2.1 ) .3.2.2.2 1.3.2.2.3 1.3.2.2.4 1.3.2.3.1 1.3.2.3.2 1.3.2.3.3 1.3.2.3.4 1.3.2.4.1 1.3.2.4.2 1.3.2.4.3 1.3.2.4.4 1.3.2.5.I 1.3.2.5.2 1.3.2.5.3 1.3.2.5.4 1.3.2.6.1 1.3.2.6.2 1.3.2.6.3 1.3.2.6.4 1.3.2.7.1 1.3.2.7.2 1.3.2.7.3 1.3.2.7.4 1.3.2.8.1 1.3.2.8.2 1.3.2.8.3 1.3.2.8.4 1.3.3.1.1 1.3.3.1.2 1.3.3.1.3 1.3.3.1.4 1.3.3.2.1 1.3.3.2.2 1.3.3.2.3 1.3.3.2.4 1.3.3.3.1 1.3.3.3.2 1.3.3.3.3 1.3.3.3.4 I.3.3.4.1 I.3.3.4.2 1.3.3.4.3 1.3.3.4.4 1.3.3.5.1 1.3.3.5.2 1.3.3.5.3 1.3.3.5.4 I.3.3.6.1 1.3.3.6.2 I.3.3.6.3 1.3.3.6.4 1.3.3.7.1 1.3.3.7.2 1.3.3.7.3 1.3.3.7.4 1.3.3.8.1 1.3.3.8.2 1.3.3.8.3 1.3.3.8.4 1.3.4.1.1 1.3.4.1.2 1.3.4.1.3 1.3.4.1.4 1.3.4.2.1 1.3.4.2.2 1.3.4.2.3 1.3.4.2.4 1.3.4.3.1 1.3.4.3.2 1.3.4.3.3 1.3.4.3.4 1.3.4.4.1 1.3.4.4.2 1.3.4.4.3 1.3.4.4.4 1.3.4.5.1 1.3.4.5.2 1.3.4.5.3 1.3.4.5.4 1.3.4.6.1 1.3.4.6.2 1.3.4.6.3 1.3.4.6.4 1: 3.4.7.1 l.3.4.7.2 1.3.4.7.3 1.3.4.7.4 1.3.4.8.1 1.3.4.8.2 1.3.4.8.3 1.3.4.8.4 1.4.1.1.1 1.4.1.1.2 1.4.1.1.3 1.4.1.1.4 1.4.1.2.1 1.4.1.2.2 1.4.1.2.3 1.4.1.2.4 1.4.1.3.1 1.4.1.3.2 1.4.1.3.3 1.4.1.3.4 1.4.1.4.1 1.4.1.4.2 1.4.1.4.3 1.4.1.4.4 1.4.1.5.1 1.4.1.5.2 1.4.1.5.3 1.4.1.5.4 1.4.1.6.1 1.4.1.6.2 1.4.1.6.3 1.4.1.6.4 1.4.1.7.1 1.4.1.7.2 1.4.1.7.3 1.4.1.7.4 1.4.1.8.1 1.4.1.8.2 1.4.1.8.3 1.4.1.8.4 1.4.2.1.1 1.4.2.1.2 1.4.2.1.3 1.4.2.1.4 1.4.2.2.1 1.4.2.2.2 1.4.2.2.3 1.4.2.2.4 1.4.2.3.1 1.4.2.3.2 1.4.2.3.3 1.4.2.3.4 1.4.2.4.1 1.4.2.4.2 1.4.2.4.3 1.4.2.4.4 1.4.2.5.1 1.4.2.5.2 1.4.2.5.3 1.4.2.5.4 1.4.2.6.1 1.4.2.6.2 1.4.2.6.3 1.4.2.6.4 1.4.2.7.1 1.4.2.7.2 1.4.2.7.3 1.4.2.7.4 1.4.2.8.1 1.4.2.8.2 1.4.2.8.3 1.4.2.8.4 1.4.3.1.1 1.4.3.1.2 1.4.3.1.3 1.4.3.1.4 1.4.3.2.1 1.4.3.2.2 1.4.3.2.3 1.4.3.2.4 1.4.3.3.1 1.4.3.3.2 1.4.3.3.3 1.4.3.3.4 1.4.3.4.1 1.4.3.4.2 1.4.3.4.3 1.4.3.4.4 1.4.3.5.1 1.4.3.5.2 1.4.3.5.3 1.4.3.5.4 1.4.3.6.1 l.4.3.6.2 1.4.3.6.3 1.4.3.6.4 1.4.3.7.1 1.4.3.7.2 1.4.3.7.3 1.4.3.7.4 1.4.3.8.1 1.4.3.8.2 1.4.3.8.3 1.4.3.8.4 1.4.4.1.1 1.4.4.1.2 1.4.4.1.3 1.4.4.1.4 1.4.4.2.1 1.4.4.2.2 1.4.4.2.3 1.4.4.2.4 1.4.4.3.1 1.4.4.3.2 1.4.4.3.3 1.4.4.3.4 1.4.4.4.1 1.4.4.4.2 1.4.4.4.3 1.4.4.4.4 1.4.4.5.1 1.4.4.5.2 1.4.4.5.3 1.4.4.5.4 1.4.4.6.1 1.4.4.6.2 1.4.4.6.3 1.4.4.6.4 1.4.4.7.1 1.4.4.7.2 1.4.4.7.3 1.4.4.7.4 1.4.4.8.1 1.4.4.8.2 1.4.4.8.3 1.4.4.8.4 1.5.1.1.1 1.5.1.1.2 1.5.1.1.3 1.5.1.1.4 1.5.1.2.1 1.5.1.2.2 1.5.1.2.3 1.5.1.2.4

202

Table 1 - continued

1.5.1.3.1 1.5.1 1.3.2 1.5.1.33 1.5.1.3.4 1.5.1.4.1 1.5.1.4.2 1.5.1.4.3 1.5.1.4.4 1.5.1.5.1 1.5.1.5.2 1.5.1.5.3 1.5.1.5.4. 1.5.1.6.1 1.5.1.6.2 1.5.1.6.3 1.5.16.4 1.5.1.7.1 1.5.1.7.2 1.5.1.7.3 1.5.1.7.4 1.5.1.8.1 1.5.1.8.2 1.5.1.8.3 1.5.1.8.4 1.5.2.1.1 1.5.2.1.2 1.5.2.1.3 1.5.2.1.4 1.5.2.2.1 1.5.2.2.2 1.5.2.2.3 1.5.2.2.4 1.5.2.3.1 1.5.2.3.2 1.5.2.3.3 1.5.2.3.4 1.5.2.4.1 1.5.2.4.2 1.5.2.4.3 1.5.2.4.4 1.5.2.5.1 1.5.25.2 1.5.2.5.3 1.52.5.4 1.5.2.6.1 1.5.2.6.2 1.5.2.6.3 1.5.2.6.4 1.5.2.7.1 1.5.2.7.2 1.5.2.7.3 1.5.2.7.4 1.5.2.8.1 1.5.2.8.2 1.5.2.8.3 1.5.2.8.4 1.5.3.1.1 1.5.3.1.2 1.5.3.1.3 1.5.3.1.4 1.5.3.2.1 1.5.3.2.2 1.5.3.2.3 1.5.3.2.4 1.5.3.3.1 1.5.3.3.2 1.5.3.3.3 1.5.3.3.4 1.5.3.4.1 1.5.3.4.2 1.5.3.4.3 1.5.3.4,4 1.5.3.5.1 1.5.3.5.2 1.5.3.5.3 1.5.3.5.4 1.5.3.6.1 1.5.3.6.2 1.5.3.6.3 1.5.3.6.4 1.5.3.7.1 1.5.3.7.2 1.5.3.7.3 1.5.3.7.4 1.5.3.8.1 1.5.3.8.2 1.5.3.8.3 1.5.3.8.4 1.5.4.1.1 1.5.4.1.2 1.5.4.1.3 1.5.4.1.4 1.5.4.2.7 1.5.4.2.2 1.5.4.2.3 ) .5.4.2.4 1.5.4.3.1 1.5.4.3.2 1.5.4.3.3 1.5.4.3.4 1.5.4.4.1 1.5.4.4.2 1.5.4.4.3 1.5.4.4.4 1.5.4.5.1 1.5.4.5.2 1.5.4.5.3 1.5.4.5.4 1.5.4.6.1 1.5.4.6.2 1.5.4.6.3 1.5.4.6.4 1.5.4.7.1 1.5.4.7.2 1.5.4.7.3 1.5.4.7.4 1.5: 4.8.1 1.5.4.8.2 1.5.4.8.3 1.5.4.8.4 1.6.1.1.1 1.6.1 1.1.2 1.6.1.1.3 1.6.1.1.4 1.6.1.2.1 1.6.1.2.2 1.6.1.2.3 1.6.1.2.4 1.6.1.3.1 1.6.1.3.2 1.6.1.3.3 1.6.1.3.4 1.6.1.4.1 1.6.1.4.2 1.6.1.4.3 1.6.1.4.4 1.6.1.5.1 1.6.1.5.2 1.6.1.5.3 1.6.1.5.4 1.6.1.6.1 1.6.1.6.2 1.6.1.6.3 1.6.1.6.4 1.6.1.7.1 1.6.1.7.2 1.6.1.7.3 1.6.1.7.4 1.6.1.8.1 1.6.1.82 1.6.1.8.3 1.6.1.8.4 1.6.2.1.1 1.6.2.1.2 1.6.2.1.3 1.6.2.1.4 1.6.2.2.1 1.6.2.2.2 1.6.2.2.3 1.6.2.2.4 1.6.2.3.1 1.6.2.3.2 1.6.2.3.3 1.6.2.3.4 1.6.2.4.1 1.6.2.4.2 1.6.2.4.3 1.6.2.4.4 1.6.2.5.1 1.6.2.5.2 1.6.2.5.3 1.6.2.5.4 1.6.2.6.1 1.6.2.6.2 1.6.2.6.3 1.6.2.6.4 1.6.2.7.1 1.6.2.7.2 1.6.2.7.3 1.6.2.7.4 1.6.2.8.1 1.62.8.2 1.6.2.8.3 1.6.2.8.4 1.6.3.1.1 1.6.3.1.2 1.6.3.1.3 1.6.3.1.4 1.6.3.2.1 1.6.3.2.2 1.6.3.2.3 1.6.3.24 1.6.3.3.1 1.6.3.3.2 ' 1.6.3.3.3 1.6.3.3.4 1.6.3.4.1 1.6.3.4.2 1.6.3.4.3 1.6.3.4.4 1.6.3.5.1 1.6.3.5.2 1.6.3.5.3 1.6.3.5.4 1.6.3.6.1 1.6.3.6.2 1.6.3.6.3 1.6.3.6.4 1.6.3.7.1 1.6.3.7.2 1.6.3.7.3 1.6.3.7.4 1.6.3.8.1 1.6.3.8.2 1.6.3.8.3 1.6.3.8.4 1.6.4.1.1 1.6.4.1.2 1.6.4.1.3 1.6.4.1.4 1.6.4.2.1 1.6.4.2.2 1.6.4.2.3 1.6.4.2.4 1.6.4.3.1 1.6.4.3.2 1.6.4.3.3 1.6.4.3.4 1.6.4.4.1 1.6.4.4.2 1.6.4.4.3 1.6.4.4.4 1.6.4.5.1 1.6.4.5.2 1.6.4.5.3 1.6.4.5.4 1.6.4.6.1 1.6.4.6.2 1.6.4.6.3 1.6.4.6.4 7.6.4.7.1 1.6.4.7.2 1.6.4.7.3 1.6.4.7.4 1.6.4.8.1 1.6.4.8.2 16.4.8.3 1.6.4.8.4 1.7.1.1.1 1.7.1.1.2 1.7.1.1.3 1.7.1.1.4 1.7.1.2.1 1.7.1.2.2 1.7.1.2.3 1.7.1.2.4

203

Table 1 - continued

1.7.1.3.1 1.7.1.3.2 1.7.1.3.3 1.7.1.3.4 1.7.1.4.1 1.7.1.42 1.7.1.4.3 1.7.1.4.4 1.7.1.5.1 1.7.1.5.2 1.7.1.5.3 1.7.1.5.4 1.7.1.6.1 1.7.1.6.2 1.7.1.6.3 1.7.1.6.4 1.7.1.7.1 1.7.1.7.2 1.7.1.7.3 1.7.1.7.4 1.7.1.8.1 1.7.1.82 1.7.1.8.3 1,7.1.8.4 1.7.2.1.1 1.7.2.1.2 1.7.2.1.3 1.7.2.1.4 1.7.2.2.1 1.7.22.2 1.72.2.3 1.72.2.4 1.7.2.3.1 1.7.2.3.2 1.7.2.3.3 1.7.2.3.4 1.7.2.4.1 1.72.4.2 1.72.4.3 1.72.4.4 1.7.2.5.1 1.7.2.5.2 1.7.2.5.3 1.7.2.5.4 1.7.2.6.1 1.72.6.2 1.7 2.6.3 1.72.6.4 1.7.2.7.1 1.7.2.7.2 1.7.2.7.3 1.7.2.7.4 1.7.2.8.1 1.7.2.82 1.72.8.3 1.72.8.4 1.7.3.1.1 1.7.3.1.2 1.7.3.1.3 1.7.3.1.4 1.7.3,2.1 1,7.32.2 1.7.32.3 1.7.32.4 1.7.3.3.1 1.7.3.3.2 1.7.3.3.3 1.7.3.3.4 1.7.3.4.1 1.7.3.42 1.7.3.4.3 1.7.3.4.4 1.7.3.5.1 1.7.3.5.2 1.7.3.5.3 1.7.3.5.4 1.7.3.6.1 1.7.3.62 1.7.3.6.3 1.7.3.6.4 1.7.3.7.1 1.7.3.7.2 1.7.3.7.3 1.7.3.7.4 1.7.3.8.1 1,7.3.82 1.7.3.8.3 1.7.3.8.4 1.7.4.1.1 1.7.4.1.2 1.7.4.1.3 1.7.4.1.4 1.1.4.2.1 1.7.42.2 1.7.42.3 1.7.42.4 1.7.4.3.1 1.7.4.3.2 1.7.4.3.3 1.7.4.3.4 1,7.4.4.1 1.7.4.42 1.7.4.4.3 1.7.4.4.4 1.7.4.5.1 1,7.4.5.2 1.7.4.5.3 1.7.4.5.4 1.7.4.6.1 1.7.4.62 1.7.4.6.3 1.7.4.6.4 1.7.4.7.1 1.7.4.7.2 1.7.4.7.3 1.7.4.7.4 1.7.4.8.1 1.7.4.82 1.7.4.8.3 1.7.4.8.4 1.8.1.1.1 1.8.1.1.2 1.8.1.1.3 1.8.1.1.4 1.8.1.2.1 1.8.12.2 1.8.12.3 1.8.12.4 1.8.1.3.1 1.8.1.3.2 1.8.7.3.3 1.8.1.3.4 1.8.1.4.1 1.8.1.42 1.8.1.4.3 1.8.1.4.4 1.8.1.5.1 1.8.1.5.2 1.8.1.5.3 1.8.1.5.4 1.8.1.6.1 1.8.1.62 1.8.1.6.3 1.8.1.6.4 1.8.1.7.1 1.8.1.7.2 1.8.1.7.3 1.8.1.7.4 1.8.1.8.1 1.8.1.82 1.8.1.8.3 1.8.1.8.4 1.8.2.1.7 1.8.2.1.2 1.8.2.1.3 1.8.2.1.4 1.8.2.2.1 1.8.2.22 1.8.22.3 1.822.4 1.8.2.3.1 1.8.2.3.2 1.8.2.3.3 1.8.2.3.4 1.8.2.4.1 1.8.2.42 1.82.4.3 1.82.4.4 1.8.2.5.1 1.8.2.5.2 1.8.2.5.3 1.8.2.5.4 1.8.2.6.1 1.82.6.2 1.82.6.3 1.82.6.4 1.8.2.7.1 1.8.2.7.2 1.8.2.7.3 1.8.2.7.4 1.8.2.8.1 1.8.2.82 1.82.83 1.82.8.4 1.8.3.1.1 1.8.3.1.2 1.8.3.1.3 1.8.3.1.4 1.8.3.2.1 1.8.3.22 1.8.32.3 1.8.32.4 1.8.3.3.1 1.8.3.3.2 1.8.3.3.3 1.8.3.3.4 1.8.3.4.1 1.8.3.42 1.8.3.4.3 1.5.3.44 1.8.3.5.1 1.8.3.5.2 1.8.3.5.3 1.8.3.5.4 1.8.3.6.1 1.5.3.62 1.8.3.6.3 1.8.3.6.4 1.8.3.7.1 1.8.3.7.2 1.8.3.7.3 1.8.3.7.4 1.8.3.8.1 1.8.3.82 1.8.3.8.3 1.8.3.8.4 1.8.4.1.1 1.8.4.1.2 1.8.4.1.3 1.5.4.1.4 1.8.4.2.1 1.8.4.22 1.8.42.3 1.8.42.4 1.8.4.3.1 1.8.4.3.2 1.8.4.3.3 1.8.4.3.4 1.8.4.4.1 1.8.4.42 1.8.4.4.3 1.8.4.4.4 1.8.4.5.1 1.8.4.5.2 1.8.4.5.3 1.8.4.5.4 1.8.4.6.1 1.8.4.62 1.8.4.6.3 1.8.4.6.4 1.8.4.7.1 1.8.4.7.2 1.8.4.7.3 1.8.4.7.4 1.8.4.8.1 1.8.4.82 1.8.4.8.3 1.8.4.8.4 2.1.1.1.1 2.1.1.1.2 2.1.1.1.3 2.1.1.1.4 2.1.12.1 2.1.1.22 2.1.12.3 2.1.12.4

204

Table 1 - continued

2.1.1.3.1 2.1.7.3.2 2.1.1.3.3 2.1.1.3.4 2.1.1.4.1 2.1.1.4.2 2.1.1.4.3 2.1.1.44 2.1.1.5.1 2.1.1.5.2 2.7.1.5.3 2.1.1.5.4 2.1.1.6.1 2.1.1.6.2 2.1.1.G.3 2.1.1.6.4 2.1.1.7.1 2.1.1.7.2 2.1.1.7.3 2.1.1.7.4 2.1.1.8.1 2.1.1.8.2 2.1.1.8.3 2.1.1.8.4 2.1.2.1.1 2.1.2.1.2 2.1.2.1.3 2.1.2.1.4 2.1.2.2.1 2.1.2.22 2.1.2.2.3 2.1.2.2.4 2.1.2.3.1 2.7.2.3.2 2.1.2.3.3 2.1.2.3.4 2.1.2.4.1 2.1.2.4.2 2.1.2.4.3 2.1.2.4.4 2.1.2.5.1 2.1.2.5.2 2.1.2.5.3 2.1.2.5.4 2.1.2.6.1 2.1.2.6.2 2.1,2.6.3 2.1.2.6.4 2.1.2.7.7 2.1.2.7.2 2.1.2.7.3 2.1.2.7.4 2.1.2.8.1 2.1.2.8.2 2.1.2.8.3 2.1.2.8.4 2.1.3.1.1 2.1.3.1.2 2.1.3.1.3 2.1.3.1.4 2.1.3.2.1 2.1.3.2.2 2.1.3.2.3 2.1.3.2.4 2.1.3.3.1 2.1.3.3.2 2.1.3.3.3 2.1.3.3.4 2.1.3.4.1 2.1.3.4.2 2.1.3.4.3 2.1.3.4.4 2.1.3.5.1 2.1.3.5.2 2.1.3.5.3 2.1.3.5.4 2.1.3.6.1 2.1.3.6.2 2.1.3.6.3 2.1.3.6.4 2.1.3.7.) 2.1.3.7.2 2.1.3.7.3 2.1.3.7.4 2.1.3.8.1 2.1.3.8.2 2.1.3.8.3 2.1.3.8.4 2.1.4.1.1 2.1.4.1.2 2.1.4.1.3 2.1.4.1.4 2.1.4.2.1 2.1.4.2.2 2.1.4.2.3 2.1.4.2.4 2.1.4.3.1 2.1.4.3.2 2.1.4.3.3 2.1.4.3.4 2.1.4.4.1 2.1.4.4.2 2.1.4.4.3 2.1.4.4.4 2.1.4.5.1 2.1.4.5.2 2.1.4.5.3 2.1.4.5.4 2.1.4.6.1 2.1.4.6.2 2.1.4.6.3 2.1.4.6.4 2.1.4.7.1 2.1.4.7.2 2.1.4.7.3 2.1.4.7.4 2.1.4.8.1 2.1.4.8.2 2.1.4.8.3 2.1.4.8.4 2.2.1.1.1 2,2.1.1.2 2.2.1.1.3 2.2.1.1.4 2.2.1.2.1 2.2.1.2.2 2.2.1.2.3 2.2.1.2.4 2.2.1.3.1 2.2.1.3.2 2.2.1.3.3 2.2.1.3.4 2.2.1.4.1 2.2.1.4.2 2.2.1.4.3 2.2.1.4.4 2.2.1.5.1 2.2.1.5.2 2.2.1.5.3 2.2.1.5.4 2.2.1.6.1 2.2.1.6.2 2.2.1.6.3 2.2.1.6.4 2.2.1.7.1 2.2.1.7.2 2.2.1.7.3 2.2.1.7.4 2.2.1.8.1 2.2.1.8.2 2.2.1.8.3 2.2.1.8.4 2.2.2.1.1 2.2.2.1.2 2.2.2.1.3 2.2.2.1.4 2.2.2.2.1 2.2.2.2.2 2.2.2.1.3 2.2.2.2.4 2.2.2.3.1 2.2.2.3.2 2.2.2.3.3 2.2.2.3.4 2.2.2.4.1 2.2.2.4.2 2.2.2.4.3 2.2.2.4.4 2.2.2.5.1 2.2.2.5.2 2.2.2.5.3 2.2.2.5.4 2.2.2.6.1 2.2.2.6.2 2.2.2.6.3 2.2.2.6.4 3.2.2.7.1 2.2.2.7.2 2.2.2.7.3 2.2.2.7.4 2.2.2.8.1 2.2.2.8.2 2.2.2.8.3 2.2.2.8.4 2.2.3.1.1 2.2.3.1.2 2.2.3.1.3 2.2.3.1.4 2.2.3.2.1 2.2.3.2.2 2.2.3.2.3 2.2.3.2.4 2.2.3.3.1 2.2.3.3.2 2.2.3.3.3 2.2.3.3.4 2.2.3.4.1 2.2.3.4.2 2.2.3.4.3 2.2.3.4.4 2.2.3.5.1 2.2.3.5.2 2.2.3.5.3 2.2.3.5.4 2.2.3.6.1 2.2.3.6.2 2.2.3.6.3 2.2.3.6.4 2.2.3.7.1 2.2.3.7.2 2.2.3.7.3 2.2.3.7.4 2.2.3.8.1 2.2.3.8.2 2.2.3.8.3 2.2.3.8.4 2.2.4.1.1 2.2.4.1.2 2.2.4.1.3 2.2.4.1.4 2.2.4.2.1 2.2.4.2.2 2.2.4.2.3 2.2.4.2.4 2.2.4.3.1 2.2.4.3.2 2.2.4.3.3 2.2.4.3.4 2.2.4.4.1 2.2.4.4.2 2.2.4.4.3 2.2.4.4.4 2.2.4.5.1 2.2.4.5.2 2.2.4.5.3 2.2.4.5.4 2.1.4.6.1 2.2.4.6.2 2.2.4.6.3 2.2.4.6.4 2.2.4.7.1 2.2.4.7.2 2.2.4.7.3 2.2.4.7.4 2.2.4.8 J 2.2.4.8.2 2.2.4.8.3 2.2.4.8.4 2.3.1.1.1 2.3.1.1.7 2.3.1.1.3 2.3.7.1.4 2.3.1.2.1 2.3.1.2.2 2.3.1.2.3 2.3.1.2.4

205

Table 1 - continued

2.3.1.3.1 2.3.1.3.2 2.3.1.3.3 2.3.7.3.4 2.3.1.4.1 2.3.1.4.2 2.3.1.4.3 2.3.1.4.4 2.3.1.5.1 2.3.1.5.2 2.3.1.5.3 2.3.1.5.4 2.3.1.6.1 2.3.1.6.2 2.3.1.6.3 2.3.1.6.4 2.3.1.7.1 2.3.1.7.2 2.3.1.7.3 2.3.1.7.4 2.3.1.8.1 2.3.1.8.2 2.3.1.8.3 2.3.1.8.4 2.3.2.1.1 2.3.2.1.2 2.3.2.1.3 2.3.2.1.4 2.3.2.2.1 2.3.2.2,2 2.3.2.2.3 2.3.2.2.4 2.3.2.3.1 2.3,2.3.2 2.3.2.3.3 2.3.2.3.4 2.3.2.4.1 2.3.2.4.2 2.3.2.4.3 2.3.2.4.4 2.3.2.5.1 2.3.2.5.2 2.3.2.5.3 2.3.2.5.4 2.3.2.6.1 2.3.2.6.2 2.3.2.6.3 2.3.3.6.4 2.3.2.7.1 2.3.2.7.2 2.3.2.7.3 2.3.2.7.4 2.3.2.8.1 2.3.2.8.2 2.3.2.8.3 2.3.3.8.4 2.3.3.1.1 2.3.3.1.2 2.3.3.1.3 2.3.3.1.4 2.3.3.2.1 2.3.3.2.2 2.3.3.2.3 2.3.3.1.4 2.3.3.3.1 2.3.3.3.2 2.3.3.3.3 2.3.3.3.4 2.3.3.4.1 2.3.3.4.2 2.3.3.4.3 2.3.3.4.4 2.3.3.5.1 2.3.3.5.2 2.3.3.5.3 3.3.5.4 2.3.3.6.1 2.3.3.6.2 2.3.3.6.3 2.3.3.6 4 2.3.3.7.1 2.3.3.7.2 2.3.3.7.3 7.3.7.4 2.3.3.8.1 2.3.3.8.2 2.3.3.8.3 2.3.3.8.4 2.3.4.1.1 2.3.4.1.2 2.3.4.1.3 2.3.4.1.4 2.3.4.2.1 2.3.4.2.2 2.3.4.2.3 2.3.4.2.4 2.3.4.3.1 2.3 4.3.2 2.3.4.3.3 2.3.4.3.4 2.3.4.4.1 2.3.4.4.2 2.3.4.4.3 2.3.4.4.4 2.3.4.5.1 2.3.4.5.2 2.3.4.5.3 2.3.4.5.4 2.3.4.6.1 2.3.4.6.2 2.3.4.6.3 2.3.4.6.4 2.3.4.7.1 2.3.4.7.2 2.3.4.7.3 2.3.4.7.4 2.3.4.8.1 2.3.4.8,2 2.3.4.8.3 2.3.4.8 4 2.4.1.1.1 2.4.1.1.2 2.4.1.1.3 2.4.1.1.4 2.4.1.2.1 2.4.1.2.2 2.4.1.2.3 2.4.1.2.4 2.4.1.3.1 2.4.1.3.2 2.4.1.3.3 2.4.1.3.4 2.4.1.4.1 2.4.1.4.2 2.4.1.4.3 2.4.1.4.4 2.4.1.5.1 2.4.1.5.2 2.4.1.5.3 2.4.1.5.4 2.4.1.6.1 2.4.1.6.2 2.4.1.6.3 2.4.1.6.4 2.4.1.7.1 2.4.1.7.2 2.4.1.7.3 2.4.1.7.4 2.4.1.8.1 2.4.1.8.2 2.4.1.8.3 2.4.1.8.4 2.4.2.1.1 2.4.2.1.2 2.4.2.1.3 2.4.2.1.4 2.4.2.2.1 2.4.2.2.2 2.4.2.2.3 2.4.2.2.4 2.4.2.3.1 2.4.2.3.2 2.4.2.3.3 2.4.2.3.4 2.4.2.4.1 2.4.2.4.2 2.4.2.4.3 2.4.2.4.4 2.4.2.5.1 2.4.2.5.2 2.4.2.5.3 4.2.5.4 2.4.2.6.1 2.4.2.6.2 2.4.2.6.3 2.4.2.6.4 2.4.2.7.1 2.4.2.7.2 2.4.2.7.3 2.4.2.7.4 2.4.2.8.1 2.4.2.8.2 2.4.2.8.3 2.4.2.8.4 2.4.3.1.1 2.4.3.1.2 2.4.3.1.3 2.4.3.i.4 2.4.3.2.1 2.4.3.2.2 2.4.3.2.3 2.4.3.2.4 2.4.3.3.1 2.4.3.3.2 2.4.3.3.3 2.4.3.3.4 2.4.3.4.1 2.4.3.4.2 2.4.3.4.3 2.4.3.4.4 2.4.3.5.1 2.4.3.5.2 2.4.3.5.3 2.4.3.5.4 2,4.3.6.1 2.4.3.6.2 2.4.3.6.3 2.4.3.6.4 2.4.3.7.1 2.4.3.7.2 2.4.3.7.3 2.4.3.7.4 2.4.3.8.1 2.4.3.8.2 2.4.3.8.3 2.4.3.8.4 2.4.4.1.1 2.4.4.1.2 2.4.4.1.3 2.4.4.1.4 2.4.4.2.1 2.4.4.2.2 2.4.4.2.3 2.4.4.2.4 2.4.4.3.1 2.4.4.3.2 2.4.4.3.3 2.4.4.3.4 2.4.4.4.1 2.4.4.4.2 2.4.4.4.3 2.4.4.4.4 2.4.4.5.1 2.4.4.5.2 2.4.4.5.3 2.4.4.5.4 2.4.4.6.1 2.4.4.6.2 2.4.4.6.3 2.4.4.6.4 2.4.4.7.1 2.4.4.7.2 2.4.4.7.3 2.4.4.7.4 2.4.4.8.1 2.4.4.8.2 2.4.4.8.3 2.4.4.8.4 2.5.1.1.1 2.5.1.1.2 2.5.1.1.3 2.5.1.1.4 2.5.1.2.1 2.5.1.2.2 2.5.1.2.3 2.5.1.2.4

206

Table 1 - continued

2.5.1.3.1 2.5.1.3.2 2.5.1.3.3 2.5.1.3.4 2.5.1.4.1 2.5.1.4.2 2.5.1.4.3 2.5.1.4.4 2.5.1.5.1 2.5.1.5.2 2.5.1.5.3 2.5.1.5.4 2.5.1.6.1 2.5.1.6.2 2.5.1.6.3 2.5.1.6.4 2.5.1.7.1 2.5.1.7.2 2.5.1.7.3 2.5.1.7.4 2.5.1.8.7 2.5.1.8.2 2.5.1.8.3 2.5.1.8.4 2.5.2.1.1 2.5.2.1.2 2.5.2.1.3 2.5.2.1.4 2.5.2.2.1 2.5.2.2.2 2.5.2.2.3 2.5.2.2.4 2.5.2.3.1 2.5.2.3.2 2.5.2.3.3 2.5.2.3.4 2.5.2.4.1 2.5.2.4.2 2.5.2.4.3 2.5.2.4.4 2.5.2.5.1 2.5.2.5.2 2.5.2.5.3 2.5.2.5.4 2.5.2.6.1 2.5.2.6.2 2.5.2.6.3 2.5.2.6.4 2.5.2.7.1 2.5.2,7.2 2.5.2.7.3 2.5.2.7.4 2.5.2.8.1 2.5.2.8.2 2.5.2.8.3 2.5.2.8.4 2.5.3.1.1 2.5.3.1.2 2.5.3.1.3 2.5.3.1.4 2.5.3.2.1 2.5.3.2.2 2.5.3.2.3 2.5.3.2.4 2.5.3.3.1 2.5.3.3.2 Z. J.J.J.J 2.5.3.3.4 2.5.3.4.1 2.5.3.4.2 2.5.3.4.3 2.5.3.4.4 2.5.3.5.1 2.5.3.5.2 2.5.3.5.3 2.5.3.5.4 2.5.3.6.1 2.5.3.6.2 2.5.3.6.3 2.5.3.6.4 2.5.3.7.1 2.5.3.7.2 2.5.3.7.3 2.5.3.7.4 2.5.3.8.7 2.5.3.8.2 2.5.3.8.3 2.5.3.8.4 2.5.4.1.7 2.5.4.1.2 2.5.4.1.3 2.5.4.1.4 2.5.4.2.1 2.5.4.2.2 2.5.4.2.3 2.5.2.2.4 2.5.4.3.1 2.5.4.3.2 2.5.4.3.3 2.5.4.3.4 2.5.4.4.1 2.5.4.4.2 2.5.4.4.3 2.5.4.4.4 2.54.5.1 2.5.4.5.2 2.5.4.5.3 2.5.4.5.4 2.5.4.6.1 2.5.4.6.2 2.5.4.6.3 2.5.4.6.4 2.5.4.7.1 2.5.4.7.2 2.5.4.7.3 2.5.4.7.4 2.5.4.8.1 2.5.4.8.2 2.5.4.8.3 2.5.4.8.4 2.6.1.1.1 2.6.1,1.2 2.6.1.1.3 2.6.1.1.4 2.6.1.2.1 2.6.1.2.2 2.6.1.2.3 2.6.1.2.4 2.6.1.3.1 2.6.1.3.2 2.6.1.3.3 2.6.7.3.4 2.6.1.4.1 2.6.1.4.2 2.6.1.4.3 2.6.1.4.4 2.6.1.5.1 2.6.1.5.2 2.6.1.5.3 2.6.1.5.4 2.6.1.6.1 2.6.1.6.2 2.6.1.6.3 2.6.1.6.4 2.6.7.7.1 2.6.1.7.2 2.6.1.7.3 3.6.1.7.4 2.6.1.8.1 2.6.1.8.2 2.6.1.8.3 2.6.1.8.4 2.6.2.1.1 2.6.2.1.2 2.6.2.1.3 2.6.2.1.4 2.6.2.2.1 2.6.2.2.2 2.6.2.2.3 2.6.2.2.4 2.6.2.3.1 2.6.2.3.2 2.6.2.3.3 2.6.2.3.4 2.6.2.4.1 2.6.2.4.2 2.6.2.4.3 2.6.2.4.4 2.6.2.5.1 2.6.2.5.2 2.6.2.5.3 2.6.2.5.4 2.6.2.6.1 2.6.2.6.2 2.6.2.6.3 2.62.6.4 2.6.2.7.1 2.6.2.7.2 2.6.2.7.3 2.6.2.7.4 2.6.2.8.1 2.6.2.8.2 2.6.2.8.3 2.6.2.8.4 2.6.3.1.1 2.6.3.1.2 2.6.3.1.3 2.6.3.1.4 2.6.3.2.1 2.6.3.2.2 2.6.3.2.3 2.6.3.2.4 2.6.3.3.1 2.6.3.3.2 2.6.3.3.3 3.6.3.3.4 2.6.3.4.1 2.6.3.4.2 2.6.3.4.3 2.6.3.4.4 2.6.3.5.1 2.6.3.5.2 2.6.3.5.3 2.6.3.5.4 2.6.3.6.1 2.6.3.6.2 2.6.3.6.3 2.6.3.6.4 2,6.3.7.1 2.6.3.7.2 2.6.3.7.3 2.6.3.7.4 2.6.3.8.1 2.6.3.82 2.6.3.8.3 2.63.8.4 2.6.4.1.1 2.6.4.1.2 2.6.4.1.3 2.6.4.1.4 2.6.4.2.1 2.6.4.2.2 2.6.4.2.3 2.6.4.2.4 2.6.4.3.1 2.6.4.3.2 2.6.4.3.3 2.6.4.3.4 2.6.4.4.1 2.6.4.4.2 2.6.4.4.3 2.6.4.4.4 2.6.4.5.1 2.6.4.5.2 2.6.4.5.3 2.6.4.5.4 2.6.4.6.1 2.6.4.6.2 2.6.4.6.3 2.6.46.4 2.6.4.7.1 2.6.4.7.2 2.6.4.7.3 2.6.4.7.4 2.6.4.8.1 2.6.4.8.2 2.6.4.8.3 2.6.4.8.4 2.7.1.7.1 2.7.1.1.2 2.7.1.1.3 2.7.1.1.4 2.7.1.2.1 2.7.1.2.2 2.7.1.2.3 2.7.1.2.4

207

Table 1 - continued

2.7.I.3.1 2.7.1.3.2 2.7.1.3.3 2.7.1.3.4 2.7.1.4.1 2.7.1 4.2 2.7.1.4.3 2.7.1.4.4 2.7.1.5.1 2.7.1.5.2 2.7.1.5,3 2.7.1.5.4 2.7.1.6.1 2.7.1.6.2 2.7.1.6.3 2.7.1.6.4 2.7.1.7.1 2.7.1.7.2 2.7.1.7.3 2.7.1.7.4 2.7.1.8.1 2.7.1.8.2 2.7.1.8.3 2.7.1.8.4 2.7.2.1.1 2.7.2.1.2 2.7.2.1.3 2.7 2.1.4 2.7.2.2.1 2.7.2.2.2 2.7.2.2.3 2.7.2.2.4 2.7.2.3.1 2.7.2.3.2 2.7.2.3.3 2.7.2.3.4 2.7.2.4.1 2.7.2.4.2 2.7.2.4.3 2.7.2.4.4 2.7.2.5.1 2.7.2.5.2 2.7.2.5.3 2.7.2.5.4 2.7.2.6.1 2.7.2.6.2 2.7.2.6.3 2.7.2.6.4 2.7: 2.7.1 2.7.2.7.2 2.7.2.7.3 2.7.2.7.4 2.7.2.8.1 2.7.2.8.2 2.7.2.8.3 2.7.2.8.4 2.7.3.1.1 2.7.3.1.2 2.7.3.1.3 2.7.3.1.4 2.7.3.2.1 2.7.3.2.2 2.7.3.2.3 2.7.3.2.4 2.7.3.3.1 2.7.3.3.2 2.7.3.3.3 2.7.3.3.4 2.7.3.4.1 2.7.3.4.2 2.7.3.4.3 2.7.3.4.4 2.7.3.5.1 2.2.7.3.5 2.7.3.5.3 2.7.3.5.4 2.7.3.6.1 2.7.3.6.2 2.7.3.G.3 2.7.3.6.4 2.7.3.7.1 2.7.3.7.2 2.7.3.7.3 2.7.3.7.4 2.7.3.8.1 2.7.3.8.2 2.7.3.8.3 2.7.3.8.4 2.7.4.1.1 2.7.4.1.2 2.7.4.1.3 2.7.4.1.4 2.7.4.2.1 2.7.4.2.2 2.7.4.2.3 2.7.4.2.4 2.7.4.3.1 2.7.4.3.2 2.7.4.3.3 2.7.4.3.4 2.7.4.4.1 2.7.4.4.2 2.7.4.4.3 2.7.4.4.4 2.7.4.5.1 2.7.4.5.2 2.7.4.5.3 2.7.4.5.4 2.7.4.6.1 2.7.4.6.2 2.7.4.6.3 2.7.4.6.4 2.7.4.7.1 2.7.4.7.2 2.7.4.7.3 2.7.4.7.4 2.7.4.8.1 2.7.4.8.2 2.7.4.8.3 2.7.4.8.4 2.8.1.1.1 2.8.1.1.2 2.8.1.1.3 2.8.1.1.4 2.8.1.2.1 2.8.1.2.2 2.8.1.2.3 2.8.1.2.4 2.8.1.3.1 2.8.1: 3.2 2.8.1.3.3 2.8.1.3.4 2.8.1.4.1 2.8.1.4.2 2.8.1.4.3 2.8.1.4.4 2.8.1.5.1 2.8.1.5.2 2.8.1.5.3 2.8.1.5.4 2.8.1.6.1 2.8.1.6.2 2.8.1.6.3 2.8.1.6.4 2.8.1.7.1 2.8.1.7.2 2.8.1.7.3 2.8.1.7.4 2.8.1.8.1 2.8.1.8.2 2.8.1.8.3 2.8.1.8.4 2.8.2.1.1 2.8.2.1.2 2.8.2.1.3 2.8.2.1.4 2.8.2.2.1 2.8.2.2.2 2.8.2.2.3 2.8.2.2.4 2.8.2.3.1 2.8.2.3.2 2.8.2.3.3 2.8.2.3.4 2.8.2.4.1 2.8.2.4.2 2.8.2.4.3 2.8.2.4.4 2.8.2.5.1 2.8.2.5.2 2.8.2.5.3 2.8.2.5.4 2.8.2.6.1 2.8.2.6.2 2.8.2.6.3 2.8.2.6.4 2.8.2.7.1 2.8.2.7.2 2.8.2.7.3 2.8.2.7.4 2.8.2.8.1 2.8.2.8.2 2.8.2.8.3 2.8.2.8.4 2.8.3.1.1 2.8.3.1.2 2.8.3.1.3 2.8.3.1.4 2.8.3.2.1 2.8.3.2.2 2.8.3.2.3 2.8.3.2.4 2.8.3.3.1 2.8.3.3.2 2.8.3.3.3 2.8.3.3.4 2.8.3.4.1 2.8.3.4.2 2.8.3.4.3 2.8.3.4.4 2.8.3.5.1 2.8.3.5.2 2.8.3.5.3 2.8.3.5.4 2.8.3.6.1 2.8.3.6.2 2.8.3.6.3 2.8.3.6.4 2.8.3.7.1 2.8.3.7.2 2.8.3.7.3 2.8.3.7.4 2.8.3.8.1 2.8.3.8.2 2.8.3.8.3 2.8.3.8.4 2.8.4.1.1 2.8.4.1.2 2.8.4.1.3 2.8.4.1.4 2.8.4.2.1 2.8.4.2.2 2.8.4.2.3 2.8.4.2.4 2.8.4.3.1 2.8.4.3.2 2.8.4.3.3 2.8.4.3.4 2.8.4.4.1 2.8.4.4.2 2.8.4.4.3 2.8.44.4 2.8.4.5.1 2.8.4.5.2 2.8.4.5.3 8.4.5.4 2.8.4.6.1 2.8.4.6.2 2.8.4.6.3 2.8.4.64 2.8.4.7.1 2.8.4.7.2 2.8.4.7.3 2.8.4.7.4 2.8.4.8.1 2.8.4.8.2 2.8.4.8.3 2.8.4.8.4 3.1.1.1.1 3.1.1.1.2 3.1.1.1.3 3.1.5.1 4 3.1.1.2.1 3.1.1.2.2 3.1.1.2.3 3.1.1.2.4

208

Table 1 - continued

3.1.1.3.1 3.1.1.3.2 3.1.1.3.3 3.1.1.3.4 3.1.1.4.1 3.1.1.4.2 3.1.1.4.3 3.1.1.4.4 3.1.1.5.1 3.1.1.5.2 3.1.1.5.3 3.1.1.5.4 3.1.1.6.1 3.1.1.6.2 3.1.1.6.3 3.1.1.6.4 3.1.1.7.1 3.1.1.7.2 3.1.1.7.3 3.1.1.7.4 3.1.1.8.1 3.1.1.8.2 3.1.1.8.3 3.1.1.8.4 3.1.2.1.1 3.1.2.1.2 3.1.2.1.3 3.1.2.1.4 3.1.2.2.1 3.1.2.2.2 3.1.2.2.3 3.1.2.2.4 3.1.2.3.1 3.1.2.3.2 3.1.2.3.3 3.1.2.3.4 3.1.2.4.7 3.1.2.4.2 3.1.2.4.3 3.1.2.4.4 3.1.2.5.1 3.1.2.5.2 3.1.2.5.3 3.1.2.5.4 3.1.2.6.1 3.1.2.6.2 3.1.2.6.3 3.1.2.6.4 3.1.2.7.1 3.1.2.7.2 3.1.2.7.3 3.1.2.7.4 3.1.2.8.1 3.1.2.8.2 3.1.2.8.3 3.1 2.8.4 3.1.3.1.1 3.1.3.1.2 3.1.3.1.3 3.1.3.1.4 3.1.3.2.1 3.1.3.2.2 3rd). 3.2.3 3.1.3.2.4 3.1.3.3.1 3.1.3.3.2 j.1j.j 3.1.3.3.4 3.1.3.4.1 3.1.3.4.2 3.1.3.4.3 3.1.3.4.4 3.1.3.5.1 3.1.3.5.2 3.1.35.3 3.1.3.5.4 3.1.3.6.1 3.1.3.6.2 3.1.3.6.3 3.1.3.6.4 3.1.3.7.1 3.1.3.7.2 3.1.3.7.3 3.1.3.7.4 3.1.3.8.1 3.1.3.8.2 3.1.3.8.3 3.1.3.8.4 3.1.4.1.1 3.1.4.1.2 3.1.4.1.3 3.1.4.1.4 3.1.4.2.1 3.1.4.2.2 3.1.4.2.3 3.1.4 2.4 3.1.4.3.1 3.1.4.3.2 3.1.4.3.3 3.I.4.3.4 3.1.4.4.1 3.1.4.4.2 3.1.4.4.3 3.1.4.4.4 3.1.4.5.1 3.1.4.5.2 3.1.4.5.3 3.1.4.5.4 3.1.4.6.1 3.1.4.6.2 3.1.4.6.3 3.1.4.6.4 3.1.4.7.1 3.1.4.7.2 3.1.4.7.3 3.1.4.7.4 3.1.4.8.1 3.1.4.8.2 3.7.4.8.3 3.1.4.8.4 3.2.1.1.1 3.2.1.1.2 3.2.1.1.3 3.2.1.1.4 3.2.1.2.1 3.2.1.2.2 3.2.1.2.3 3.2.1.2.4 3.2.1.3.1 3.2.1.3.2 3.2.1.3.3 3.2.1.3.4 3.2.1.4.1 3.2.1.4.2 3.2.1.4.3 3.2.1.4.4 3.2.1.5.1 3.2.1.5.1 3.2.1.5.3 3.2.1.5.4 3.2.1.6.1 3.2.1.6.2 3.2.1.6.3 3.2.1.6.4 3.2.1.7.1 3.2.1.7.2 3.2.1.7.3 3.2.1.7.4 3.2.1.8.1 3.2.1.8.2 3.2.1.8.3 3.2.1.8.4 3.2.2.1.1 3.2.2.1.2 3.2.2.1.3 3.2.2.1.4 3.2.2.2.1 3.2.2.2.2 3.2.2.2.3 3.2.2.2.4 3.2.2.3.1 3.2.2.3.2 3.2.2.3.3 3.2.2.3.4 3.2.2.4.1 3.2.2.4.2 3.2.2.4.3 3.2.2.4.4 3.2.2.5.1 3.2.2.5.2 3.2.2.5.3 3.2.2.5.4 3.2.2.6.1 3.2.2.6.2 3.2.2.6.3 3.2.2.6.4 3.2.2.7.1 3.2.2.7.2 3.2.2.7.3 3.2.2.7.4 3.2.2.8.1 3.2.2.8.2 3.2.2.8.3 3.2.2.8.4 3.2.3.1.1 3.2.3.1.2 3.2.3.1.3 3.2.3.1.4 3.2.3.2.1 3.2.3.2.2 3.2.3.2.3 3.2.3.2.4 3.2.3.3.1 3.2.3.3.2 3.2.3.3.3 3.2.3.3.4 3.2.3.4.7 3.2.3.4.2 3.2.3.4.3 3.2.3.4.4 3.2.3.5.1 3.2.3.5.2 3.2.3.5.3 3.2.3.5.4 3.2.3.6.1 3.2.3.6.2 3.2.3.6.3 3.2.3.6.4 3.2.3.7.1 3.2.3.7.2 3.2.3.7.3 3.2.3.7.4 3.2.3.8.1 3.2.3.8.2 3.2.3.8.3 3.2.3.5.4. 3.2.4.1.1 3.2.4.1.2 3.2.4.1.3 3.2.4.1.4 3.2.4.2.1 3.3.4.2.2 3.2.4.2.3 3.2.4.2.4 3.2.4.3.1 3.2.4.3.2 3.2.4.3.3 3.2.4.3.4 3.2.4.4.) 3.2.4.4.2 3.2.4.4.3 3.2.4.4.4 3.2.4.5.1 3.2.4.5.2 3.2.4.5.3 3.2.4.5.4 3.2.4.6.1 3.2.4.6.2 3.2.4.6.3 3.2.4.6.4 3.2.4.7.1 3.2.4.7.2 3.2.4.7.3 3.2.4.7.4 3.2.4.5.1 3.2.4.8.2 3.2.4.8.3 3.2.4.5.4 3.3.1.1.1 3.3.1.1.2 3.3.1.1.3 3.3.7.1.4 3.3.1.2.1 3.3.1.2.2 3.3.1.2.3 3.3.1.2.4

209

Table 1 - continued

3.3.1.3.1 3.3.1.3.2 3.3.1.3.3 3.3.1.3.4 3.3.1.4.1 3.3.1.4.2 3.3.1.4.3 3.3.1.4.4 3.1.5.1 3.3.1.5.2 3.3.1.5.3 3.3.1.5.4 3.3.1.6.1 3.3.1.6.2 3.3.1.6.3 3.3.1.6.4 3.3.1.7.1 3.3.1.7.2 3.3.1.7.3 3.3.1.7.4 3.3.1.8.1 3.3.1.8.2 3.3.1.8.3 3.3.1.8.4 3.3.2.1.1 3.3.2.1.2 3.3.2.1.3 3.3.2.1.4 3.3.2.3.1 3.3.2.2.2 3.3.2.2.3 3.3.2.2.4 3.3.2.3.1 3.3.2.3.2 3.3.2.3.3 3.3.2.3.4 3.3.2.4.1 3.3.2.4.2 3.3.2.4.3 3.3.2.4.4 3.3.2.5.1 3.3.2.5.2 3.3.2.5.3 3.3.2.5.4 3.3.2.6.1 3.3.2.6.2 3.3.2.6.3 3.3.2.6.4 3.3.2.7.1 3.3.2.7.2 3.3.2: 7.3 3.3.2.7.4 3.3.2.8.1 3.3.2.8.2 3.3.2.8.3 3.3.2.5.4 3.3.3.1.1 3.3.3.1.2 3.3.3.1.3 3.3.3.1.4 3.3.3.2.1 3.3.3.2.2 3.3.3.2.3 3.3.3.2.4 3.3.3.3.1 n λ n 3.3.3.3.4 3.3.3.4.1 3.3.3.4.2 3.3.3.4.3 3.3.3.4.4 3.3.3.5.1 3.3.3.5.2 Λ -i O e j.3.j.5.j 3.3.3.5.4 3.3.3.6.1 3.3.3.6.2 3.3.3.6.3 3.3.3.6.4 3.3.3.7.1 3.3.3.7.2 3.3.3.7.3 3.3.3.7,4 3.3.38.1 3.3.3.8.2 3.3.3.5.3 3.3.3.8.4 3.3.4.1.1 3.3.4.1.2 3.3.4.1.3 3.3.4.1.4 3.3.4.2.1 3.3.4.2.2 3.3.4.2.3 3.3.4.2.4 3.3.4.3.1 3.3.4.3.2 3.3.4.3.3 3.3.4.3.4 3.3.4.4.1 3.3.4.4.2 3.3.4.4.3 3.3.4.4.4 3.3.4.5.1 3.3.4.5.2 3.3.4.5.3 3.3.4.5.4 3.3.4.6.1 3.3.4.6.2 3.3.4.6.3 3.3.4.6.4 3.3.4.7.1 3.3.4.7.2 3.3.4.7.3 3.3.4.7.4 3.3.4.8.1 3.3.4.8.2 3.3.4.5.3 3.3.4.8.4 3.4.1.1.1 3.4.1.1.2 3.4.1.1.3 3.4.1.1.4 3.4.1.2.1 3.4.1.2.2 3.4.1.2.3 3.4.1.2.4 3.4.1.3.1 3.4.1.3.2 3.4.1.3.3 3.4.1.3.4 3.4.1.4.1 3.4.1.4.2 3.4.1.4.3 3.4.1.4.4 3.4.1.5.1 3.4.1.5.2 3.4.1.5.3 3.4.1.5.4 3.4.1.6.1 3.4.1.6.2 3.4.1.6.3 3.4.1.6.4 3.4.1.7.1 3.4.1.7.2 3.4.1.7.3 3.4.1.7.4 3.4.1.8.1 3.4.1.8.2 3.4.1.8.3 3.4.1.8.4 3.4.2.1.1 3.4.2.1.2 3.4.2.1.3 3.4.2.1.4 3.4.2.2.1 3.4.2.2.2 3.4.2.2.3 3.4.2.2.4 3.4.2.3.1 3.4.2,3.2 3.4.2.3.3 3.4.2.3.4 3.4.2.4.1 3.4.2.4.2 3.4.2.4.3 3.4.2.4.4 3.4.2.5.1 3.4.2.5.2 3.4.2.5.3 3.4.2.5.4 3.4.2.6.1 3.4.2.6.2 3.4.2.6.3 3.4.2.6.4 3.4.2.7.1 3.4.2.7.2 3.4.2.7.3 3.4.2.7.4 3.4.2.8.1 3.4.2.8.2 3.4.2.8.3 3.4.2.8.4 3.4.3.1.1 3.4.3.1.2 3.4.3.1.3 3.4.3.1.4 3.4.3.2.1 3.4.3.2.2 3.4.3.2.3 3.4.3.2.4 3.4.3.3.1 3.4.3.3.2 3.4.3.3.3 3.4.3.3.4 3.4.3.4.1 3.4.3.4.2 3.4.3.4.3 3.4.34.4 3.4.3.5.1 3.4.3.5.2 3.4.3.5.3 3.4.3.5.4 3.4.3.6.1 3.4.3.6.2 3.4.3.6.3 3.4.3.6.4 3.4.3.7.1 3.4.3.7.2 3.4.3.7.3 3.4.3.7.4 3.4.3.8.1 3.4.3.8.2 3.4.3.8.3 3.4.3.8.4 3.4.4.1.1 3.4.4.1.2 3.4.4.1.3 3.4.4.1.4 3.4.4.2.1 3.4.4.2.2 3.4.4.2.3 3.4.4.24 3.4.4.3.1 3.4.4.3.2 3.4.4.3.3 3.4.4.3.4 3.4.4.4.1 3.4.4.4.2 3.4.4.4.3 3.4.4.4.4 3.4.4.5.1 3.4.4.5.2 3.4.4.5.3 3.4.4.5.4 3.4.4.6.1 3.4.46.2 3,4.4.6.3 3.4.4.6.4 3.4.4.7.1 3.4.4.7.2 3.4.4.7.3 3.4.4.7.4 3.4.4.8.1 3.4.4.8.2 3.4.4.8.3 3.4.4.8.4 3.5.1.1.1 3.5.1.1.2 3.5.1.1.3 3.5.1.1.4 3.5.1.2.1 3.5.1.2.2 3.5.1.2.3 3.5.1.2.4

210

Table 1 - continued

3.5.1.3.1 3.5.1.3.2 3.5.1.3.3 3.5.1.3.4 3.5.1.4.1 3.5.1.4.2 3.5.1.4.3 3.5.1.4,4 3.5.1.5.1 3.5.1.5.2 3.5.1.5.3 3.5.I.5.4 3.5.1.6.1 3.5.1.6.2 3.5.1.6.3 3.5.1.6.4 3.5.1.7.1 3.5.1.7.2 3.5.1.7.3 3.5.1.7.4 3.5.1.8.1 3.5.1.8.2 3.5.1.8.3 3.5.1.8.4 3.5.2.1.1 3.52.1.2 3.5.2.1.3 3.5.2.1.4 3.5.2.2.1 3.5.2.2.2 3.5.2.2.3 3.5.2.2.4 3.5.2.3.1 3.5.2.3.2 3.5.2.33 3.5.2.3.4. 3.5.2.4.1 3.5.2.4.2 3.5.2.4.3 3.5.2.4.4 3.5.2.5.1 3.5.1.5.2 3.5.2.5.3 3.5.2.5.4 3.5.2.6.1 3.5.2.6.2 3.5.2.6.3 3.5.2.6.4 3.5.2.7.1 3.5.2.7.2 3.5.2.7.3 3.5.2.7.4 3.5.2.8.1 3.5.2.8.2 3.5.2.8.3 3.5.2.84 3.5.3.1.1 3.5.3.1.2 3.5.3.1.3 3.5.3.1.4 3.5.3.2.1 3.5.3.2.2 3.5.3.2.3 3.5.3.2.4 3.5.3.3.1 3.5.3.3.2 3.5.3.3.3 3.5.3.3.4 3.5.3.4.1 3.5.3.4.2 3.5.3.4.3 3.5.3.4.4 3.5.3.5.1 3.5.3.5.2 3.5.3.5.3 3.5.3.5.4 3.5.3.6.1 3.5.3.6.2 3.5.3.6.3 3.5.3.6.4 3.5.3.7.1 3.5.3.7.2 3.5.3.7.3 3.5.3.7.4 3.5.3.8.1 3.5.3.8.2 3.5.3.8.3 3.5.3.8.4 3.5.4.1.1 3.5.4.1.2 3.5.4.1.3 3.5.4.1.4 3.5.4.2.1 3.5.4.2.2 3.5.4.2.3 3.5.4.2.4 3.5.4.3.1 3.5.4.3.2 3.5.4.3.3 3.5.4.3.4 3.5.4.4.1 3.5.4.4.2 3.5.4.4.3 3.5.4.4.4 3.5.4.5.1 3.5.4.5.2 3.5.4.5.3 3.5.4.5.4 3.5.4.6.1 3.5.4.6.2 3.5.4.6.3 3.5.4.6.4 3.5.4.7.1 3.5.4.7.2 3.5.4.7.3 3.5.4.7.4 3.5.4.8.1 3.5.4.8.2 3.5.4.8.3 3.5.4.8.4 3.6.1.1.1 3.6.1.1.2 3.6.1.1.3 3.6.1.1.4 3.6.1.2.1 3.6.1.2.2 3.6.1.2.3 3.6.1.2.4 3.6.1.3.1 3.6.1.3.2 3.6.1.3.3 3.6.1.3.4 3.6.1.4.1 3.6.1.4.2 3.6.1.4.3 3.6.1.4.4 3.6.1.5.1 3.6.1.5.2 3.6.1.5.3 3.6.1.5.4 3.6.1.6.1 3.6.1.6.2 3.6.1.6.3 3.6.1.6.4 3.6.1.7.1 3.6.1.7.2 3.6.1.7.3 3.6.1.7.4 3.6.1.8.1 3.6.1.8.2 3.6.1.8.3 3.6.1.8.4 3.6.2.1.1 3.6.2.1.2 3.6.2.1.3 3.6.2.1.4 3.6.2.2.1 3.6.2.2.2 3.6.2.2.3 3.6.2.2.4 3.6.2.3.1 3.6.2.3.2 3.6.2.3.3 3.6.2.3.4 3.6.2.4.1 3.6.2.4.2 3.6.2.4.3 3.6.2.4.4 3.6.2.5.1 3.6.2.5.2 3.6.2.5.3 3.6.2.5.4 3.6.2.6.1 3.6.2.6.2 3.6.2.6.3 3.6.2.6.4 3.6.2.7.1 3.6.2.7.2 3.6.2.7.3 3.6.2.7.4 3.6.2.8.1 3.6.2.8.2 3.6.2.8.3 3.6.2.8.4 3.6.3.1.1 3.6.3.1.2 3.6.3.1.3 3.6.3.1.4 3.6.3.2.1 3.6.3.2.2 3.6.3.2.3 3.6.3.2.4 3.6.3.3.1 3.6.3.3.2 3.6.3.3.3 3.6.3.3.4 3.6.3.4.1 3.6.3.4.2 3.6.3.4.3 3.6.3.4.4 3.6.3.5.1 3.6.3.5.2 3.6.3.5.3 3.6.3.5.4 3.6.3.6.1 3.6.3.6.2 3.6.3.6.3 3.6.3.6.4 3.6.3.7.1 3.6.3.7.2 3.6.3.7.3 36.3.7.4 3.6.3.8.1 3.6.3.8.2 3.6.3.8.3 3.6.3.8.4 3.6.4.1.1 3.6.4.1.2 3.6.4.1.3 3.6.4.1.4 3.6.4.2.1 3.6.4.2.2 3.6.4.2.3 3.6.4.2.4 3.6.4.3.1 3.6.4.3.2 3.6.4.3.3 3.6.4.3.4 3.6.4.4.1 3.6.4.4.2 3.6.4.4.3 3.6.4.4.4 3.6.4.5.1 3.6.4.5.2 3.6.4.5.3 3.6.4.5.4 3.6.4.6.1 3.6.4.6.2 3.6.4.6.3 3.6.4.6.4 3.6.4.7.1 3.6.4.7.2 3.6.4.7.3 3.6.4.7.4 3.6.4.8.1 3.6.4.8.2 3.6.4.8.3 3.6 4.8.4 3.7.2.1.1 3.7.1.1.2 3.7.1.1.3 3.7.1.1.4 3.7.1.2.1 3.7.1.2.2 3.7.1.2.3 3.7 1.2.4

211

Table 1 - continued

3.7.1.3.1 3.7.1.3.2 3.7.1.3.3 3.7.1.3.4 3.7.1.4.1 3.7.1 4.2 3.7.1.4.3 3.7.1.4.4 3.7.1.5.7 3.7.1.5.2 3.7.1.5.3 3.7.1.5.4 3.7.1.6.1 3.7.1.6.2 3.7.1.6.3 3.7.1.6.4 3.7.1.7.1 3.7.1.7.2 3.7.1.7.3 3.7.1.7.4 3.7.1.8.1 3.7.1.8.2 3.7.1.8.3 3.7.1.8.4 3.7 2.7.1 3.72.1.2 3.7.2.1.3 3.7.2.1.4 3.7.2.2.1 3.7.2.2.2 3.7.2 2.3 3.7.2.2.4 3.7.2.3.1 3.7.2.3.2 3.7.2.3.3 3.7.2.3.4 3.7.2.4.1 3.7.2.4 2 3.7.2.4.3 3.7.2.4.4 3.7.2.5.1 3.7.2.5.2 3.7.2.5.3 3.7.2.5.4 3.7.2.6.1 3.7.2.6.2 3.7.2.6.3 3.7.2.6.4 3.7.2.7.1 3.7.2.7.2 3.7.2.7.3 3.7.2.7.4 3.7 2.8.1 3.7.2.8.2 3.7.2.8.3 3.7 2.8.4 3.7.3.7.1 3.7.3.1.2 3.7.3.1.3 3.7.3.1.4 3.7.3.2.1 3.7.3.2.2 3.7.3 2.3 3.7.3.2.4 3.7.3.3.1 3.7 3.3.2 J. /.D.D.D 3.7.3.3.4 3.7.3.4.1 3.7.3.4.2 3.7.3.4.3 3.7.3.4.4 3.7.3.5.1 3.7.3.5.2 3.7.3.5.3 3.7.3.5.4 3.7.3.6.1 3.7.3.6.2 3.7.3.6.3 3.7.3.6.4 3.7.3.7.1 3.7.3.7.2 3.7.3.7.3 3.7.3.7.4 3.7.3.8.1 3.7.3.8.2 3.7.3.8.3 3.7.3.8.4 3.7.4.1.1 3.7.4.1.2 3.7.4,1.3 3.7.4.1.4 3.7.4.2.1 3.7.4.2.2 3.7.4.2.3 3.7.4.2.4 3.7.4.3.1 3.7.4.3.2 3.7.4.3.3 3.7.4.3.4 3.7.4.4.1 3.7.4.4.2 3.7.4.4.3 3.7.4.4.4 3.7.4.5.1 3.7.4.5 2 3.7.4.5.3 3.7.4.5.4 3.7.4,6.1 3.7.4.6.2 3.7.4.6.3 3.7.4.6.4 3.7.4.7.1 3.7.4.7.2 3.7.4.7.3 3.7.4.7.4 3.7.4.8.1 3.7.4.8.2 3.7.4.8.3 3.7.4.8.4 3.8.1.1.1 3.8.1.1.2 3.8.1.1.3 3.8.1.1.4 3.8.1.2.1 3.8.1.2.2 3.8.1 2.3 3.8.1.2.4 3.8.1.3.1 3.8.1.3.2 3.8.1.3.3 3.8.1.3.4 3.8.1.4.1 3.8.1.4.2 3.8.1.4.3 3.8.1.4.4 3.8.1.5.1 3.8.1.5.2 3.8.1.5.3 3.8.1.5.4 3.8.1.6.1 3.8.1.6.2 3.8.1.6.3 3.8.1.6.4 3.8.1.7.1 3.8.1.7.2 3.8.1.7.3 3.8.1.7.4 3.8.1.8.1 3.8.1.8.2 3.8.1.8.3 3.8.1.8.4 3.8.2.1.1 3.8.2.1.2 3.8.2.1.3 3.B.2.1.4 3.8.2 2.1 3.8.2.2.2 3.8.2.2.3 3.8 2.2.4 3.8.2.3.1 3.8.2.3.2 3.8.2.3.3 3.8.2.3.4 3.8.2.4.1 3.8.2.4.2 3.8.2.4.3 3.8 2.4.4 3.8.2.5.1 3.8.2.5.2 3.8.2.5.3 3.8.2.5.4 3.8.2.6.1 3.8.2.6.2 3.8.2.6.3 3.8.2.6.4 3.8.2.7.1 3.8.2.7.2 3.8.2.7.3 3.8.2.7.4 3.8.2.8.1 3.8 2.8.2 3.8.2.8.3 3.8.2.8.4 3.8.3.1.1 3.8.3.1.2 3.8.3.1.3 3.8.3.1.4 3.8.3.2.1 3.8.3 2.2 3.8.3 2.3 3.8.3.2.4 3.8.3.3.1 3.8.3,3 2 3.8.3.3.3 3.8.3.3.4 3.8.3.4.1 3.8 3.4.2 3.8.3.4.3 3.8.3.4.4 3.8.3.5.1 3.8.3.5.2 3.8.3.5.3 3.8.3.5.4 3.8.3.6.1 3.8.3.6.2 3.8.3.6.3 3.8.3.6.4 3.8.3.7.7 3.8.3.7.2 3.8.3.7.3 3.8.3.7.4 3.8.3.8.1 3.8.3.8.2 3.8.3.8.3 3.8.3.8.4 3.8.4.1.1 3.8.4.1.2 3.8.4.1.3 3.8.4.1.4 3.8.4.2.1 3.8.4.2.2 3.8.4.2.3 3.8.4.2.4 3.8.4.3.1 3.8.4.3.2 3.8.4.3.3 3.8.4.3.4 3.8.4.4.1 3.8.4.4.2 3.8.4.4.3 3.8.4.4.4 3.8.4.5.1 3.8.4.5.2 3.8.4.5.3 3.8.4.5.4 3.8.4.6.1 3.8.4.6.2 3.8.4.63 3.8.4.6.4 3.8.4.7.1 3.8.47.2 3.8.4.7.3 3.8.4.7.4 3.8.4.8.1 3.8.4.8.2 3.8.4.8.3 3.8.4.8.4 4.1.1.1.1 4.1.1.1.2 4.1.1.1.3 4.1.1.1.4 4.1.1.2.1 4.1.1.2.2 4.1.1.2.3 4.1.1.2.4

212

Table 1 - continued

4.1.1.3.1 4.1.1.3.2 4.1.1.3.3 4.1.1.3.4 4.1.1.4.1 4.1.1.4.2 4.1.1.4.3 4.1.1.4.4 4.1.1.5.1 4.1.1.5.2 4.1.1.5.3 4.1.1.5.4 4.1.1.6.1 4.1.1.6.2 4.1.1.6.3 4.1.1.6.4 4.1.1.7.1 4.1.1.7.2 4.1.1.7.3 4.1.1.7.4 4.1.1.8.1 4.1.1.8.2 4.1.1.8.3 4.1.1.8.4 4.1.2.1.1 4.1.2.1.2 4.1.2.1.3 4.1.2.1.4 4.1.2.2.1 4.1.2.2.2 4.1.2.2.3 4.7.2.2.4 4.1.2.3.1 4.1.2.3.2 4.1.2.3.3 4.1.2.3.4 4.1.2.4.1 4.1.2.4.2 4.1.2.4.3 4.1.2.4.4 4.1.2.5.1 4.1.2.5.2 4.1.2.5.3 4.1.2.5.4 4.1.2.6.1 4.1.2.6.2 4.1.2.6.3 4.1.2.6.4 4.1.2.7.1 4.1.2.7.2 4.1.2.7.3 4.1.2.7.4 4.1.2.8.1 4.1.2.8.2 4.1.2.8.3 4.1.2.8 4 4.1.3.1.1 4.1.3.7.2 4.1.3.1.3 4.1.3.1.4 4.1.3.2.1 4.1.3.2.2 4.1.3.2.3 4.1.3.2.4 4.1.3.3.1 4.1.3.3.2 4.1.3.3.3 4.1.3.3.4 4.1.3.4.1 4.1.3.4.2 4.1.3.4.3 4.1.3.4.4 4.1.3.5.1 4.1.3.5.2 4.1.3.5.3 4.1.3.5.4 4.1.3.6.1 4.1.3.6.2 4.1.3.6.3 4.1.3.6.4 4.1.3.7.1 4.1.3.7.2 4.1.3.7.3 4.1.3.7.4 4.1.3.8.1 4.1.3.8.2 4.1.3.8.3 4.1.3.8 4 4.1.4.1.1 4.1.4.1.2 4.1.4.1.3 4.1.4.1.4 4.1.4.2.1 4.1.4.2.2 4.1.4.2.3 4.1.4.2.4 4.1.4.3.1 4.1.4.3.2 4.1.4.3.3 4.1.4.3.4 4.1.4.4.1 4.1.4.4.2 4.1.4.4.3 4.1.4.4.4 4.1.4.5.1 4.1.4.5.2 4.1.4.5.3 4.1.4.5.4 4.1.4.6.1 4.1.4.6.2 4.1.4.6.3 4.1.4.6.4 4.1.4.7.1 4.1.4.7:2 4.1.4.7.3 4.7.4.7.4 4.1.4.8.1 4.1.4.8.2 4.1.4.8.3 4.1.4.8.4 4.2.1.1.1 4.2.1.1.2 4.2.1.1.3 4.2.1.1.4 4.2.7.2.1 4.2.1.2.2 4.2.1.2.3 4.2.1.2.4 4.2.1.3.1 4.2.1.3.2 4.2.1.3.3 4.2.1.3.4 4.2.1.4.1 4.2.1.4.2 4.2.1.4.3 4.2.1.4.4 4.2.7.5.1 4.2.1.5.2 4.2.1.5.3 4.2.1.5.4 4.2.1.6.1 4.2.7.6.2 4.2.1.6.3 4.2.1.6.4 4.2.1.7.1 4.2.1.7.2 4.2.1.7.3 4.2.1.7.4 4.2.1.8.1 4.2.1.8.3 4.2.1.8.3 4.2.1.8.4 4.2.2.1.1 4.2.2.1.2 4.2.2.1.3 4.2.2.1.4 4.2.2.2.1 4.2.2.2.2 4.2.2.2.3 4.2.2.2.4 4.2.2.3.1 4.2,2.3.2 4.2.2.3.3 4,2.2.3.4 4.2.2.4.1 4.2.2.4.2 4.2.2.4.3 4.2.2.4.4 4.2.2.5.1 4.2.2.5.2 4.2.2.5.3 4.2.2.5.4 4.2.2.6.1 4.2.2.6.2 4.2.2.6.3 4.2.2.6.4 4.2.2.7.1 4.2.2.7.2 4.2.2.7.3 4.2.2.7.4 4.2.2.8.1 4.2.2.8.2 4.2.2.8.3 4.2.2.8.4 4.2.3.1.1 4.2.3.1.2 4.2.3.1.3 4.2.3.1.4 4.2.3.2.1 4.2.3.2.2 4.2.3.2.3 4.2.3.2.4 4.2.3.3.1 4.2.3.3.2 4.2.3.3.3 4.2.3.3.4 4.2.3.4.1 4.2.3.4.2 4.2.3.4.3 4.2.3.4.4 4.2.3.5.1 4.2.3.5.2 4.2.3.5.3 4.2.3.5.4 4.2.3.6.1 4.2.3.6.2 4.2.3.6.3 4.2.3.6.4 4.2.3.7.1 4.2.3.7.2 4.2.3.7.3 4.2.3.7.4 4.2.3.8.1 4.2.3.8.2 4.2.3.8.3 4.2.3.8.4 4.2.4.1.1 4.2.4.1.2 4.2.4.1.3 4.2.4.1.4 4.2.4.2.1 4.2.4.2.2 4.2.4.2.3 4.2.4.2.4 4.2.4.3.1 4.2.4.3.2 4.2.4.3.3 4.2.4.3.4 4.2.4.4.1 4.2.4.4.2 4.2.4.4.3 4.2.4.4.4 4,2.4.5.1 4.2.4.5.2 4.2.4.5.3 4.2.4.5.4 4.2.4.6.7 4.2.4.6.2 4.2.4.6.3 4.2.4.6.4 4.2.4.7.1 4.2.4.7.2 4.2.4.7.3 4.2.4.7.4 4.2.4.8.1 4.2.4.8.2 4.2.4.8.3 4.2.4.8.4 4.3.1.1.1 4.3.1.1.2 4.3.1.1.3 4.3.1.1.4 4.3.1.2.1 4.3.1.2.2 4.3.1.2.3 4.3.1.2.4

213

Table 1 - continued

4.3.1.3.1 4.3.1.3.2 4.3.1.3.3 4.3.1.3.4 4.3.1.4.1 4.3.1.4.2 4.3.1.4.3 4.3.1.4.4 4.3.1.5.1 4.3.1.5.2 4.3.1.5.3 4.3.1.5.4 4.3.1.6.1 4.3.1.6.2 4.3.1.6.3 4.3.1.6.4 4.3.1.7.1 4.3.1.7.2 4.3.1.7.3 4.3.1.7.4 4.3.1.8.1 4.3.1.8.2 4.3.1.8.3 4.3.1.8.4 4.3.2.1.1 4,3.2.1.2 4.3.2.1.3 4.3.2.1.4 4.3.2.2.I 4.3.2.2.2 4.32.2.3 4.3.2.1.4 4.3.2.3.1 4.3.2.3.2 4.3.2.3.3 4.3.2.3.4 4.3.2.4.1 4.3.2.4.2 4.3.2.4.3 4.3.2.4.4 4.3.2.5.1 4.3.2.5.2 4.3.2.5.3 4.3.2.5.4 4.3.2.6.1 4.3.2.6.2 4.3.2.6.3 4.3.2.6.4 4.3.2.7.1 4.3.2.7.2 4.3.2.7.3 4.3,2.7.4 4.3.2.8.1 4.3.2.8.2 4.3.3.8.3 4.3.2.8.4 4.3.3.1.1 4.3.3.7.2 4.3.3.1.3 4.3.3.1.4 4.3.3.2.1 4.3.3.2.2 4.3.3.2.3 4.3.3.2.4 4.3.3.3.1 4.3.3.3.2 4.3.3.3.3 4.3.3.3.4 4.3.3.4.1 4.3.3.4.2 4.3.3.4.3 4.3.3.4,4 4.3.3.5.1 4.3.3.5.2 4.3.3.5.3 4.3.3.5.4 4.3.3.6.1 4.3.3,6.2 4.3.3.6.3 4.3.3.6.4 4.3.3.7.1 4.3.3.7.2 4.3.3.7.3 4.3.3.7.4 4.3.3.8.1 4.3.3,8.2 4.3.3.8.3 4.3.3.8.4 4.3.4.7.1 4.3.4.1.2 4.3.4.1.3 4.3.4.1.4 4.3.4.2.1 4.3.4.2.2 4.3.4.2.3 4.3.4.2.4 4.3.4.3.1 4.3.4.3.2 4.3.4.3.3 4.3.4.3.4 4.3.4.4.1 4.3.4.4.2 4.3.4.4.3 4.3.4.4.4 4.3.4.5.1 4.3.4.5.2 4.3.4.5.3 4.3.4.5.4 4.3.4.6.7 4.3.4.6.2 4.3.4.6.3 4.3.4.6.4 4.3.4.7.1 4.3.4.7.2 4.3.4.7.3 4.3.4.7.4 4.3.4.8.1 4.3.4.8.2 4.3.4.8.3 4.3.4.8.4 4.4.1.1.1 4.4.1.1.2 4.4.1.1.3 4.4.1.1.4 4.4.1.2.1 4.4.1 2.2 4.4.1.2.3 4.4.1.2.4 4.4.1.3.1 4.4.1.3.2 4.4.1.3.3 4.4.1.3.4 4.4.1.4.1 4.4.1.4.2 4.4.1.4.3 4.4.1.4.4 4.4.1.5.1 4.4.1.5.2 4.4.1.5.3 4.4.1.5,4 4.4.1.6.1 4.4.1.6.2 4.4.1.6.3 4.4.1.6.4 4.4.1.7.1 4.4.1.7.2 4.4.1.7.3 4.4.1.7.4 4.4.1.8.1 4.4.1.8.2 4.4.1.8.3 4.4.1.8.4 4.4.2.1.1 4.4.2.1.2 4.4.2.1,3 4.4.2.1.4 4.4.2.2.1 4.4.2.2.2 4.4.2.2.3 4.4.2.2.4 4.4.2.3.1 4.4.2.3.2 4.4.2.3.3 4.4.2.3.4 4.4.2.4.1 4.4.2.4.2 4.4.2.4.3 4.4.2.4.4 4.4.2.5.1 4.4.2.5.2 4.4.2.5.3 4.4.2.5.4 4.4.2.6.1 4.4.2.6.2 4.4.2.6.3 4.4.2.6.4 4.4.2.7.1 4.4.2.7.2 4.4.2.7.3 4.4.2.7.4 4.4.2.8.1 4.4.2.5.2 4.4.2.8.3 4.4.2.8.4 4.4.3.1.1 4.4.3.1.2 4.4.3.1.3 4.4.3.1.4 4.4.3.2.1 4,4.3.2.2 4.4.3.2.3 4.4.3.2.4 4.4.3.3.1 4.4.3.3.2 4.4.3.3.3 4.4.3.3.4 4.4.3.4.1 4.4.3.4.2 4.4.3.4.3 4.4.3.4.4 4.4.3.5.1 4.4.3.5.2 4.4.3.5.3 4.4.3.5.4 4.4.3.6.1 4.4.3.6.2 4.4.3.6.3 4.4.3.6.4 4.4.3.7.1 4.4.3.7.2 4.4.3.7.3 4.4.3.7.4 4.4.3.8.1 4.4.3.5.2 4.4.3.8.3 4.4.3.8.4 4.4.4.1.1 4.4.4.1.2 4.4.4.1.3 4.4.4.1.4 4.4.4.2.1 4.4.4.2.2 4.4,4.2.3 4.4.4.2.4 4.4.4.3.1 4.4.4.3.2 4.4.4.3.3 4.4.4.3.4 4.4.4.4.1 4.4.4.4.2 4.4.4.4.3 4.4.4.4.4 4.4.4.5.1 4.4.4.5.2 4.4.4.5.3 4.4.4.5.4 4.4.4.6.1 4.4.4.6.2 4.4.4.6.3 4.4.4.6.4 4.4.4.7.1 4.4.4.7.2 4.4.4.7.3 4.4.4.7.4 4.4.4.8.1 4.4.4.8.2 4.4.4.8.3 4.4.4.8.4 4.5.7.1.1 4.5.1.1.2 4.5.1.1.3 4.5.1.1.4 4.5.1.2.1 4.5.1.2.2 4.5.1.2.3 4.5.1.2.4

214

Table 1 - continued

4.5.1.3.1 4.5.1.3.2 4.5.1.3.3 4.5.1.3.4 4.5.1.4.1 4.5.1.4.2 4.5.1.4.3 4.5.1.4.4 4.5.1.5.1 4.5.1.5.2 4.5.1.5.3 4.5.1.5.4 4.5.1.6.1 4.5.1.6.2 4.5.1.6.3 4.5.1.6.4 4.5.1.7.1 4.5.1.7.2 4.5.1.7.3 4.5.1.7.4 4.5.1.8.1 4.5.1.8.2 4.5.1.8.3 4.5.1.8.4 4.5.2.1.1 4.5.2.1.2 4.5.2.1.3 4.5.2.1.4 4.5.2.2.1 4.5.2.2.2 4.5.2.2.3 4.5.2.24 4.5.2.3.1 4.5.2.3.2 4.5.2.3.3 4.5.2.3.4. 4.5.2.4.1 4.5.2.4.2 4.5.2.4.3 4.5.2.4.4 4.5.2.5.1 4.5.2.5.2 4.5.2.5.3 4.5.2.5.4 4.5.2.6.1 4.5.2.6.2 4.5.2.6.3 4.5.2.6.4 4.5.2.7.1 4.5.2.7.2 4.5.2.7.3 4.5.2.7.4 4.5.2.8.1 4.5.2.8.2 4.5.2.8.3 4.5.2.8.4 4.5.3.1.1 4.5.3.1.2 4.5.3.1.3 4.5.3.1.4 4.5.3.2.1 4.5.3.2.2 4.5.3.2.3 4.5.3.2.4 4.5.3.3.1 4.5.3.3.2 4.5.3.3.3 4.5.3.3.4 4.5.3.4.1 4.5.3.4.2 4.5.3.4.3 4.5.3.4.4 4.5.3.5.1 4.5.3.5.2 4.5.3.5.3 4.5.3.5.4 4.5.3.6.1 4.5.3.6.2 4.5.3.6.3 4.5.3.6.4 4.5.3.7.1 4.5.3.7.2 4.5.3.7.3 4.5.3.7.4 4.5.3.8.1 4.5.3.8.2 4.5.3.8.3 4.5.3.8.4 4.5.4.1.1 4.5.4.1.2 4.5.4.1.3 4.5.4.1.4 4.5.4.2.1 4.5.4.2.2 4.5.4.2.3 4.5.4.2.4 4.5.4.3.1 4.5.4.3.2 4.5.4.3.3 4.5.4.3.4 4.5.4.4.1 4.5.4.4.2 4.5.4.4.3 4.5.4.4.4 4.5.4.5.1 4.5.4.5.2 4.5.4.5.3 4.5.4.5.4 4.5.4.6.1 4.5.4.6.2 4,5.4.6.3 4.5.4.6.4 4.5.4.7.1 4.5.4.7.2 4.5.4.7.3 4.5.4.7.4 4.5.4.8.1 4.5.4.8.2 4.5.4.8.3 4.5.4.8.4 4.6.1.7.1 4.6.1.1.2 4.6.1.1.3 4.6.1.1.4 4.6.1.2.1 4.6.1.2.2 4.6.1.2.3 4.6.1.2.4 4.6.1.3.1 4.6.1.3.2 4.6.1.3.3 4.6.1.3.4 4.6.1.4.1 4.6.1.4.2 4.6.1.4.3 4.6.1.4.4 4.6.1.5.1 4.6.1.5.2 4.6.1.5.3 4.6.1.5.4 4.6.1.6.1 4.6.1.6.2 4.6.1.6.3 4.6.1.6.4 4.6.1.7.1 4.6.1.7.2 4.6.1.7.3 4.6.1.7.4 4.6.1.8.1 4.6.1.8.2 4.6.1.8.3 4.6.1.8.4 4.6.2.1.1 4.6.2.1.2 4.6.2.1.3 4.6.2.1.4 4.6.2.2.1 4.6.2.2.2 4.6.2.2.3 4.6.2.2.4 4.6.2.3.1 4.6.2.3.2 4.6.2.3.3 4.6.2.3.4 4.6.2.4.1 4.6.2.4.2 4.6.2.4.3 4.6.2.4.4 4.6.2.5.1 4.6.2.5.2 4.6.2.5.3 4.6.2.5.4 4.62.6.1 4.6.2.6.2 4.6.2.6.3 4.6.2.6.4 4.6.2.7.1 4.6.2.7.2 4.6.2.7.3 4.6.2.7.4 4.6.2.8.1 4.6.2.8.2 4.6.2.8.3 4.6.2.8.4 4.6.3.1.1 4.6.3.1.2 4.6.3.1.3 4.6.3.1.4 4.6.3.2.1 4.6.3.2.2 4.6.3.2.3 4.6.3.2.4 4.6.3.3.1 4.6.3.3.2 4.6.3.3.3 4.6.3.3.4 4.6.3.4.1 4.6.3.4.2 4.6.3.4.3 4.6.3.4.4 4.6.3.5.1 4.6.3.5.2 4.6.3.5.3 4.6.3.5.4 4.6.3.6.1 4.6.3.6.2 4.6.3.6.3 4.6.3.6.4 4.6.3.7.1 4.6.3.7.2 4.6.3.7.3 4.6.3.7.4 4.6.3.8.1 4.6.3.8.2 4.6.3.8.3 4.6.3.S.4 4.6.4.1.1 4.6.4.1.2 4.6.4.1.3 4.6.4.1.4 4.6.4.2.1 4.6.4.2.2 4.6.4.2.3 4.6.4.2.4 4.6.4.3.1 4.6.4.3.2 4.6.4.3.3 4.6.4.3.4 4.6.4.4.7 4.6.4.4.2 4.6.4.4.3 4.6.4.4.4 4.6.4.5.1 4.6.4.5.2 4.6.4.5.3 4.6.4.5.4 4.6.4.6.1 4.6.4.6.2 4.6.4.6.3 4.6.4.6.4 4.6.4.7.1 4.6.4.7.2 4.6.4.73 4.6.4.7.4 4.6.4.8.1 4.6.4.8.2 4.6.4.8.3 4.6.4.8.4 4.7.1.1.1 4.7.1.1.2 4.7.1.1.3 4.7.1.1.4 4.7.7.2.1 4.7.1.2.2 4.7.1.2.3 4.7.1.2.4

215

Table 1 - continued

4.7.1.3.1 4.7.1.3.2 4.7.1.3.3 4.7.1.3.4 4.7.1.4.1 4.7.1.4.2 4.7.1.4.3 4.7.1.4.4 4.7.1.5.1 4.7.1.5.2 4.7.1.5.3 4.7.1.5.4 4.7.1.6.1 4.7.1.6.2 4.7.1.6.3 4.7.1.6.4 4.7.1.7.1 4.7.1.7.2 4.7.1.7.3 4.7.1.7.4 4.7.1.8.1 4.7.1.8.2 4.7.1.8.3 4.7.1.8.4 4.7.2.1.1 4.7.2.1.2 4.7.2.1.3 4.7.2.1.4 4.7.2.2.1 4.7.2.2.2 4.7.2.2.3 4.7.2.2.4 4.7.2.3.1 4.7.2.3.2 4.7.2.3.3 4.7.2.3.4 4.7.2.4.1 4.7.2.4.2 4.7.2.4.3 4.7.2.4.4 4.7.2.5.1 4.7.2.5.2 4.7.2.5.3 4.7.2.5.4 4.7.2.6.1 4.7.2.6.2 4.7.2.6.3 4.7.2.6.4 4.7.2.7.1 4.7.2.7.2 4.7.2.7.3 4.7.2.7.4 4.7.2.8.1 4.7.2.8.2 4.7.2.8.3 4.7.2.8.4 4.7.3.1.1 4.7.3.1.2 4.7.3.1.3 4.7.3.1.4 4.7.3.2.1 4.7.3.2.2 4.7.3.2.3 4.7.3.2.4 4.7.3.3.1 4.7.3.3.2 4.7.3.3.3 4.7.3.3.4 4.7.3.4.1 4.7.3.4.2 4.7.3.4.3 4.7.3.4.4 4.7.3.5.1 4.7.3.5.2 4.7.3.5.3 4.7.3.5.4 4.7.3.6.1 4.7.3.6.2 4.7.3.6.3 4.7.3.6.4 4.7.3.7.1 4.7.3.7.2 4.7.3.7.3 4.7.3.7.4 4.7.3.8.1 4.7.3.8.2 4.7.3.8.3 4.7.3.8.4 4.7.4.1.1 4.7.4.1.2 4.7.4.1.3 4.7.4.1.4 4.7.4.2.1 4.7.4.2.2 4.7.4.2.3 4.7.4.2.4 4.7.4.3.1 4.7.4.3.2 4.7.4.3.3 4.7.4.3.4 4.7.4.4.1 4.7.4.4.2 4.7.4.4.3 4.7.4.4.4 4.7.4.5.1 4.7.4.5.2 4.7.4.5.3 4.7.4.5.4 4.7.4.6.1 4.7.4.6.2 4.7.4.6.3 4.7.4.6.4 4.7.4.7.1 4.7.4.7.2 4.7.4.7.3 4.7.4.7.4 4.7.4.8.1 4.7.4.8.2 4.7.4.8.3 4.7.4.8.4 4.8.1.1.1 4.8.1.1.2 4.8.1,1.3 4.8.1.1.4 4.8.1.2.1 4.8.1.2.2 4.8.1.2.3 4.8.1.2.4 4.8.1.3.1 4.8.1.3.2 4.8.1.3.3 4.8.1.3.4 4.8.1.4.1 4.8.1.4.2 4.8.1.4.3 4.8.1.4.4 4.8.1.5.1 4.8.1.5.2 4.8.1.5.3 4.8.1.5.4 4.8.1.6.1 4.8.1.6.2 4.8.1.6.3 4.8.7.6.4 4.8.1.7.1 4.8.1.7.2 4.8.1.7.3 4.8.1.7.4 4.8.1.8.1 4.8.1.8.2 4.8.1.8.3 4.8.1.8.4 4.8.2.1.1 4.8.2.1.2 4.8.2.1.3 4.8.2.1.4 4.8.2.2.1 4.8.2.2.2 4.8.2.2.3 4.8.2.2.4 4.8.2.3.7 4.8.2.3.2 4.8.2.3.3 4.8.2.3.4 4.8.2.4.1 4.8.2.4.2 4.8.2.4.3 4.8.2.4.4 4.8.2.5.1 4.5.2.5.2 4.8.2.5.3 4.8.2.5.4 4.8.2.6.1 4.8.2.6.2 4.8.2.6.3 4.8.2.6.4 4.8.2.7.1 4.8.2.7.2 4.8.2.7.3 4.8.2.7.4 4.8.2.8.1 4.8.2.8.2 4.8.2.8.3 4.8.2.8.4 4.8.3.l.l 4.8.3.1.2 4.8.3.1.3 4.8.3.1.4 4.8.3.2.1 4.8.3.2.2 4.8.3.2.3 4.8.3.2.4 4.8.3.3.1 4.8.3.3.2 4.8.3.3.3 4.8.3.3.4 4.8.3.4.1 4.8.3.4.2 4.8.3.4.3 4.8.3.4.4 4.8.3.5.7 4.8.3.5.2 4.8.3.5.3 4.8.3.5.4 4.8.3.6.1 4.8.3.6.2 4.8.3.6.3 4.8.3.6.4 4.8.3.7.1 4.8.3.7.2 4.8.3.7.3 4.8.3.7.4 4.8.3.8.1 4.8.3.8.2 4.8.3.8.3 4.8.3.8.4 4.8.4.1.1 4.8.4.1.2 4.8.4.1.3 4.8.4.1.4 4.8.4.2.1 4.8.4.2.2 4.8.4.2.3 4.8.4.2.4 4.8.4.3.1 4.8.4.3.2 4.8.4.3.3 4.8.4.3.4 4.8.4.4.1 4.8.4.4.2 4.8.4.4.3 4.8.4.4.4 4.8.4.5.1 4.8.4.5.2 4.8.4.5.3 4.8.4.5.4 4.8.4.6.1 4.8.4.6.2 4.8.4.6.3 4.8.4.6.4 4.8.4.7.1 4.8.4.7.2 4.8.4.7.3 4.8.4.7.4 4.8.4.8.1 4.8.4.8.2 4.8.4.8.3 4.8.4.8.4 5.1.1.1.1 5.1.1.1.2 5.1.1.1.3 5.1.1.1.4 5.1.1.2.1 5.1.1.2.2 5.1.1.2.3 5.1.1.2.4

216

Table 1 - continued

5.1.1.3.1 5.1.1.3.3 5.1.1.3.3 5.1.1.3.4 5.1.1.4.1 5.1.1.4.2 5.1.1.4.3 5.1.1.4.4 5.1.1.5.1 5.1.1.5.2 5.1.1.5.3 5.1.1.5.4 5.1.1.6.1 5.1.1.6.2 5.1.1.6.3 5.1.1.6.4 5.1.1.7.1 5.1.1.7.2 5.1.1.7.3 5.1.1.7.4 5.1.1.8.1 5.1.1.8.2 5.1.1.8.3 5.1.7.8.4 5.1.2.1.1 5.1.2.1.2 5.1.2.1.3 5.1.2.1.4 5.7.2.2.1 5.1.2.2.2 5.1.2.2.3 5.1.2.2.4 5.1.2.3.1 5.1.2.3.2 5.1.2.3.3 5.12.3.4 5.1.2.4.1 5.1.2.4.2 5.1.2.4.3 S.1.2.4.4 5.1.2.5.1 5.1.2.5.2 5.1.2.5.3 5.1.2.5.4 5.1.2.6.1 5.1.2.6.2 5.1.2.6.3 5.1.2.6.4 5.1.2.7.1 5.1.2.7.2 5.1.2.7.3 5.1.2.7.4 5.1.2.8.7 5.1.2.8.2 5.1.2.8.3 5.1.2.8.4 5.1.3.1.1 5.1.3.1.2 5.1.3.1.3 S.1.3.1.4 5.1.3.2.1 5.1.3.2.2 5.1.3.2.3 5.1.3.2.4 5.1.3.3.1 5.1.3.3.2 5.1.3.3.3 S.l.3.3.4 5.1.3.4.1 5.7.3.4.2 5.1.3.4.3 5.1.3.4.4 5.1.3.5.1 5.1.3.5.2 5.1.3.5.3 5.1.3.5.4 5.1.3.6.1 5.1.3.6.2 5.1.3.6.3 5.1.3.6.4 5.1.3.7.1 5.1.3.7.2 5.1.3.7.3 5.I.3.7.4 5.1.3.8.1 5.1.3.8.2 5.1.3.8.3 5.1.3.8.4 5.1.4.1.1 5.1.4.1.2 5.1.4.1.3 5.1.4.1.4 5.1.4.2.1 5.1.4.2.2 5.1.4.2.3 5.1.4.2.4 5.1.4.3.1 5.1.4.3.2 5.1.4.3.3 5.1.4.3.4 5.1.4.4.1 5.1.4.4.2 5.1.4.4.3 5.1.4.4.4 5.1.4.5.I 5.I.4.5.2 5.1.4.5.3 5.1.4.5.4 5.I.4.6.1 5.1.4.6.2 5.1.4.6.3 5.1.4.6.4 5.1.4.7.1 5.1.4.7.2 5.1.4.7.3 5.1.4.7.4 5.1.4.8.1 5.1.4.8.2 5.1.4.8.3 5.1.4.8.4 5.2.1.1.1 5.2.1.1.2 5.2.1.1.3 5.2.1.1.4 5.2.1.2.1 5.2.7.2.2 5.2.1.2.3 5.2.1.2.4 5.2.1.3.1 5.2.1.3.2 5.2.1.3.3 5.2.1.3.4 5.2.1.4.1 5.2.1.4.2 5.2.1.4.3 5.2.1.4.4 5.2.1.5.1 5.2.1.5.2 5.2.1.5.3 5.2.1.5.4 5.2.1.6.1 5.2.1.6.2 5.2.1.6.3 5.2.1.6.4 5.2.1.7.1 5.2.1.7.2 5.2.1.7.3 5.2.1.7.4 5.2: 1.8.1 5.2.1.8.2 5.2.1.8.3 5.2.1.8.4 5.2.2.1.1 5.2.2.1.2 5.2.2.1.3 5.2.2.1.4 5.2.2.2.1 5.2.2.2.2 5.2.2.2.3 5.2.2.2.4 5.2.2.3.1 5.2.2.3.2 5.2.2.3.3 5.2.2.3.4 5.2.2.4.1 5.2.2.4.2 5.2.2.4.3 5.2.2.4.4 5.2.2.5.I 5.2.2.5.2 5.2.2.5.3 5.2.2.5.4 5.2.2.6.1 5.2.2.6.2 5.2.2.6.3 5.2.2.6.4 5.2.2.7.1 5.2.2.7.2 5.2.2.7.3 5.2.2.7.4 5.2.2.8.1 5.2.2.8.2 5.2.2.8.3 5.2.2.8.4 5.2.3.7.1 5.2.3.1.2 5.2.3.1.3 5.2.3.1.4 5.2.3.2.I 5.2.3.2.2 5.2.3.2.3 5.2.3.2.4 5.2.33.1 5.2.3.3.2 5.2.3.3.3 5.2.3.3.4 5.2.3.4.1 5.2.3.4.2 5.2.3.4.3 5.2.3.4.4 5.2.3.5.1 5.2.3.5.2 5.2.3.5.3 5.2.3.5 5.2.3.6.1 5.2.3.6.2 5.2.3.6.3 5.2.3.6.4 5.2.3.7.1 5.2.3.7.2 5.2.3.7.3 5.2.3.7.4 5.2.3.8.1 5.2.3.8.2 5.2.3.8.3 5.2.3.84 5.2.4.1.1 5.2.4.1.2 5.2.4.1.3 5.2.4.1.4 5.2.4.2.1 5.2.4.2.2 5.2.4.2.3 5.2.4.2.4 5.2.4.3.1 5.2.4.3.2 5.2.43.3 5.2.4.3.4 5.2.4.4.1 5.2.4.4.2 5.2.4.4.3 5.2.4.4.4 5.2.4.5.1 PANS.- 5.2.4.5.2 PANS.- 5.2.4.5.3 5.2.4.54 5.1.4.6.1 5.2.4.6.2 5.2.4.6.3 5.2.4.6.4 5.2.4.7.1 5.2.4.7.2 5.2.4.7.3 5.2.4.7.4 5.2.4.8.1 5.2.4.8.2. 5.2.4.8.3 5.2.4.8.4 5.3.1.1.1 5.3.1.1.2 5.3.1.1.3 5.3.1.1.4 5.3.1.2.1 5.3.1.2.2 5.3.1.2.3 5.3.1.2.4

217

Table 1 - continued

5.3.1.3.1 5.3.1.3.2 5.3.1.3.3 5.3.1.3.4 5.3.1.4.1 5.3.1.4.2 5.3.1.4.3 5.3.1.4.4 5.3.1.5.1 5.3.1.5.2 5.3.1.5.3 5.3.1.5.4 5.3.1.6.1 5.3.1.6.2 5.3.1.6.3 5.3.1.6.4 5.3.1.7.1 5.3.1,7.2 5.3.1.7.3 5.3.1.7.4 5.3.1.8.1 5.3.1.8.2 5.3.1.8.3 5.3.1.8,4 5.3.2.1.1 5.3.2.1.2 5.3.2.1.3 5.3.2.1.4 5.3.2.2.1 5.3.2.2.2 5.3.2.2.3 5.3.2.2.4 5.3.2.3.1 5.3.2.3.2 5.3.2.3.3 5.3.2.3.4 5.3,2.4.1 5.3.2.4.2 5.3.2.4.3 5.3.2.4.4 5.3.2.5.1 5.3.2.5.2 5.3.2.5.3 5.3.2.5.4 5.3.2.6.1 5.3.2.6.2 5.3.2.6.3 5.3.2.6.4 5.3.2.7.1 5.3.2.7.2 5.3.2.7.3 5.3.2.7.4 5.3.2.8.1 5.3.2.8.2 5.3.2.8.3 5.3.2.8.4 5.3.3.1.1 5.3.3.1.2 5.3.3.1.3 5.3.3.1.4 5.3.3.2.1 5.3.3.2.2 5.3.3.2.3 5.3.3.2.4 5.3.3.3.1 5.3.3.3.2 5.3.3.3.3 5.3.3.3.4 5.3.3.4.1 5.3.3.4.2 5.3.3.4.3 5.3.3.4.4 5.3.3.5.1 5.3.3.5.2 5.3.3.5.3 5.3.3.5.4 5.3.3.6.1 5.3.3.6.2 5.3.3.6.3 5.3.3.6.4 5.3.3.7.1 5.3.3.7.2 5.3.3.7.3 5.3.3.7.4 5.3.3.8.1 5.3.3.8.2 5.3.3.8.3 5.3.3.8.4 5.3.4.1.1 5.3.4.1.2 5.3.4.1.3 5.3.4.1.4 5.3.4.2.1 5.3.4.2.2 5.3.4.2.3 5.3.4.2.4 5.3.4.3.1 5.3.4.3.2 5.3.4.3.3 5.3.4.3.4 5.3 4.4.1 5.3.4.4.2 5.3.4.4.3 5.3.4.4.4 5.3.4.5.1 5.3.4.5.2 5.3.4.5.3 5.3.4.5.4 5.3 4.6.1 5.3.4.6.2 5.3.4.6.3 5.3.4.6.4 5.3.4.7.1 5.3.4.7. s 5.3.4.7.3 5.3.4.7.4 5.3.4.8.i 5.3.4.8.2 5.3.4.8.3 5.3.4.8.4 5.4.1.1.1 5.4.1.1.2 5.4.1.1.3 5.4.1.1.4 5.4.1.1.1 5.4.1.2.2 5.4.1.2.3 5.4.1.2.4 5.4.1.3.1 5.4.1.3.2 5.4.1.3.3 5.4.1.3.4 5.4.1.4.1 5.4.1.4.2 5.4.1 4.3 5.4.1.4.4 5.4.1.5.1 5.4.1.5.2 5.4.1.5.3 5.4.1.5.4 5.4.1.6.1 5.4.1.6.2 5.4.1.6.3 5.4.1.6.4 5.4.1.7.1 5.4.1.7.2 5.4.1.7.3 5.4.1.7.4 5.4.1.8.1 5.4.1.8.2 5.4.1.8.3 5.4.1.8.4 5.4.2.1.1 5.4.2.1.2 5.4.2.1.3 5.4.2.1.4 5.4.2.2.1 5.4.2.2.2 5.4.2.2.3 5.4.2.2.4 5.4.2.3.1 5.4.2.3.2 5.4.2.3.3 5.4.2.3.4 5.4.2.4.1 5.4.2.4.2 5.4.2.4.3 5.4.2.4.4 5.4.2.5.1 5.4.2.5.2 5.4.2.5.3 5.4.2.5.4 5.4.2.6.1 5.4.2.6.2 5.4.2.6.3 5.4.2.6.4 5.4.2.7.1 5.4.2.7.2 5.4.2.7.3 5.4.2.7.4 5.4.2.8.1 5.4.2.8.2 5.4.2.8.3 5.4.2.8.4 5.4.3.1.1 5.4.3.1.2 5.4.3.1.3 5.4.3.1.4 5.4.3.2.1 5.4.3.2.2 5.4.3.2.3 5.4.3.2.4 5.4.3.3.1 5.4.3.3.2 5.4.3.3.3 5.4.3.3.4 5.4.3.4.1 5.4.3.4.2 5.4.3.4.3 5.4.3.4.4 5.4.3.5.1 5.4.3.5.2 5.4.3.5.3 5.4.3.5.4 5.4.3.6.1 5.4.3.6.2 5.4.3.6.3 5.4.3.6.4 5.4.3.7.1 5.4.3.7.2 5.4.3.7.3 5.4.3.7.4 5.4.3.3.1 5.4.3.8.2 5.4.3.8.3 5.4.3.8.4 5.4.4.1.1 5.4.4.1.2 5.4.4.1.3 5.4.4.1.4 5.4.4.2.1 5.4.4.2.2 5.4.4.2.3 5.4.4.2.4 5.4.4.3.1 5.4.4.3.2 5.4.4.3.3 5.4.4.3.4 S.4.4.4.7 5.4.4.4.2 5.4.4.4.3 5.4.4.4.4 5.4.4.5.1 5.4.4.5.2 5.4.4.5.3 5.4.4.5.4 5.4.4.6.1 5.4.4.6.2 5.4.4.6.3 5.4.4.6.4 5.4.4.7.1 5.4.4.7.2 5.4.4.7.3 5.4.4.7.4 S.4.4.8.1 5.4.4.8.2 5.4.4.8.3 5.4.4.8.4 5.5.1.1.1 5.5.1.1.2 5.5.1.1.3 5.5.1.1.4 5.5.1.2.1 5.5.1.2.2 5.5.1.2.3 5.5.1.2.4

218

Table 1 - continued

5.5.1.3.1 5.5.1.3.2 5.5.1.3.3 5.5.1.3.4 5.5.1.4.1 5.5.1.4.2 5.5.1.4.3 5.5.1.4.4 5.5.1.5.1 5.5.1.5.2 5.5.1.5.3 5.5.1.5.4 5.5.1.6.1 5.5.1.6.2 5.5.1.6.3 5.5.1.6.4 5.5.1.7.1 5.5.1.7.2 5.5.1.7.3 5.5.1.7.4 5.5.1.8.1 5.5.1.8.2 5.5.1.8.3 5.5.1.8.4 5.5.2.1.1 5.5.2.1.2 5.5.2.1.3 5.5.2.1.4 5.5.2.2.1 5.5.2.2.2 5.5.2.2.3 5.5.2.2.4 5.5.2.3.1 5.5.2.3.2 5.5.2.3.3 5.5.2.3.4 5.5.2.4.1 5.5.2.4.2 5.5.2.4.3 5.5.2.4.4 5.5.2.5.1 5.5.2.5.2 5.5.2.5.3 5.5.2.5.4 5.5.2.6.1 5.5.2.6.2 5.5.2.6.3 5.5.2.6.4 5.5.2.7.1 5.5.2.7.2 5.5.2.7.3 5.5.2.7.4 5.5.2.8.1 5.5.2.8.2 5.5.2.8.3 5.5.2.8.4 5.5.3.1.1 5.5.3.1.2 5.5.3.1.3 5.5.3.1.4 5.5.3.2.1 5.5.3.2.2 5.5.3.2.3 5.5.3.2.4 5.5.3.3.1 5.5.3.3.2 5.5.3.3.3 5.5.3.3.4 5.5.3.4.1 5.5.3.4.2 5.5.3.4.3 5.5.3.4.4 5.5.3.5.1 5.5.3.5.2 5.5.3.5.3 5.5.3.5.4 5.5.3.6.1 5.5.3.6.2 5.5.3.6.3 5.5.3.6.4 5.5.3.7.1 5.5.3.7.2 5.5.3.7.3 5.5.3.7.4 5.5.3.8.1 5.5.3.8.2 5.5.3.8.3 5.5.3.8.4 5.5.4.1.1 5.5.4.1.2 5.5.4.1.3 5.5.4.1.4 5.5.4.2.1 5.5.4.2.2 5.5.4.2.3 5.5.4.2.4 5.5.4.3.1 5.5.4.3.2 5.5.4.3.3 5.5.4.3.4 5.5.4.4.1 5.5.4.4.2 5.5.4.4.3 5.5.4.4.4 5.5.4.5.1 5.5.4.5.2 5.5.4.5.3 5.5.4.5.4 5.5.4.6.1 5.5.4.6.2 5.5.4.6.3 5.5.4.6.4 5.5.4.7.1 5.5.4.7.2 5.5.4.7.3 5.5.4.7.4 5.5.4.8.1 5.5.4.8.2 5.5.4.8.3 5.5.4.8.4 5.6.1.1.1 5.6.1.1.2 5.6.1.1.3 5.6.1.1.4 5.6.1.2.1 5.6.1.2.2 5.6.1.2.3 5.6.1.2.4 5.6.1.3.1 5.6.1.3.2 5.6.1.3.3 5.6.1.3.4 5.6.1.4.1 5.6.1.4.2 5.6.1.4.3 5.6.1.4.4 5.6.1.5.1 5.6.1.5.2 5.6.1.5.3 5.6.1.5.4 5.6.1.6.1 5.6.1.6.2 5.6.1.6.3 5.6.1.6.4 5.6.1.7.1 5.6.1.7.2 5.6.1.7.3 5.6.1.7.4 5.6.1.8.1 5.6.1.8.2 5.6.1.8.3 5.6.1.8.4 5.6.2.1.1. 5.6.2.1.2 5.6.2.1.3 5.6.2.1.4 5.6.2.2.1 5 6 ~> 5.6.2.2.3 5.6.3.2.4 5.6.2.3.1 5.6.2.3.2 5.6.2.3.3 5.6.2.3.4 5.6.2.4.1 5.6.2.4.2 5.6.2.4.3 5.6.2.4.4 5.6.2.5.1 5.6.2.5.2 5.6.2.5.3 5.6.2.5.4 5.6.2.6.1 5.6.2.6.2 5.6.2.6.3 5.6.2.6.4 5.6.2.7.1 5.6.2.7.2 5.6.2.7.3 5.6.2.7.4 5.6.2.8.1 5.6.2.8.2 5.6.2.8.3 5.6.2.8.4 5.6.3.1.1 5.6.3.1.2 5.6.3.1.3 5.6.3.1.4 5.6.3.2.1 5.6.3.2.2 5.6.3.2.3 5.6.3.2.4 5.6.33.1 5.6.3.3.2 5.6.3.3.3 5.6.3.3.4 5.6.3.4.1 5.6.3.4.2 5.6.3.4.3 5.63.4.4 5.6.3.5.1 5.6.3.5.2 5.6.3.5.3 5.6.3.5.4 5.6.3.6.1 5.6.3.6.2 5.6.3.6.3 5.6.3.6.4 5.6.3.7.1 5.6.3.7.2 5.6.3.7.3 5.6.3.7.4 5.6.3.8.1 5.6.3.8.2 5.6.3.8.3 5.6.3.8.4 5.6.4.1.1 5.6.4.1.2 5.6.4.1.3 5.6.4.1.4 5.6.4.2.1 5.6.4.2.2 5.6.4.2.3 5.6.4.2.4 5.6.4.3.1 5.6.4.3.2 5.6.4.3.3 5.6.4.3.4 5.6.4.4.1 5.6.4.4.2 5.6.4.4.3 5.6.4.4.4 5.6.4.5.1 5.6.4.5.2 5.6.4.5.3 5.6.4.5.4 5.6.4.6.1 5.6.4.6.2 5.6.4.6.3 5.6.4.6.4 5.6.4.7.1 5.6.4.7.2 5.6.4.7.3 5.6.4.7.4 5.6.4.8.1 5.6.4.8.2 5.6.4.8.3 5.6.4.8.4 5.7.1.1.1 5.7.1.1.2 5.7.1.1.3 5.7.1.1.4 5.7.1.2.1 5.7.1.2.2 5.7.1.2.3 5.7.1.2.4

219

Table 1 - continued

5.7.1.3.1 5.7.1.3.2 5.7.1.3.3 5.7.1.3.4 5.7.1.4.1 5.7.1.4.2 S.7.1.4.3 5.7.1.4.4 5.7.I.5.1 5.7.1.5.2 5.7.1.5.3 5.7.1.5.4 5.7.7.6.1 5.7.1.6.2 5.7.1.6.3 5.7.1.6.4 5.7.1.7.1 5.7.1.7.2 5.7.1.7.3 5.7.1.7.4 5.7.1.8.1 5.7.1.8.2 5.7.1.8.3 5.7.1.8.4 5.7.2.1.1 5.7.2.1.2 5.7.2.1.3 5.7.2.1.4 5.7.2.2.1 5.7.2.2.2 5.7.2.2.3 5.7.2Λ4 5.7.2.3.1 5.7.2.3.2 5.7.2.3.3 5.7.2.3.4 5.7.2.4.1 5.7.2.4.2 5.7.2.4.3 5.7.2.4.4 5.7.2.5.1 5.7.2.5.2 5.7.2.5.3 5.7.2.5.4 5.7.2.6.1 5.7.2.6.2 5.7.2.6.3 5.7.2.6.4 5.7.2.7.1 5.7.2.7.2 5.7.2.7.3 5.7.2.7.4 5.7.2.8.1 5.7.2.8.2 5.7.2.8.3 5.7.2.8.4 5.7.3.1.1 5.7.3.1.2 5.7.3.1.3 5.7.3.1.4 5.7.3.2.1 5.7.3.2.2 5.7.3.2.3 5.7.3.2.4 5.7.3.3.1 5.7.3.3.2 5.7.3.3.3 5.7.3.3.4 5.7.3.4.1 5.7.3.4.2 7.3.4.3 5.7.3.4.4 5.7.3.5.1 5.7.3.5.2 5.7.3.5.3 5.7.3.5.4 5.7.3.6.1 5.7.3.6.2 5.7.3.6.3 5.7.3.6.4 5.7.3.7.1 5.7.3.7.2 5.7.3.7.3 5.7.3.7.4 5.7.3.8.1 5.7.3.8.2 5.7.3.8.3 5.7.3.8.4 5.7.4.1.1 5.7.4.1.2 5.7.4.1.3 5.7.4.1.4 5.7.4.2.1 7.4.2.2 5.7.4.2.3 5.7.4.2.4 5.7.4.3.1 5.7.4.3.2 5.7.4.3.3 5.7.4.3.4 5.7.4.4.1 5.7.4.4.2 5.7.4.4.3 5.7.4.4.4 5.7.4.5.7 5.7.4.5.2 5.7.4.5.3 5.7.4.5.4 5.7.4.6.1 5.7.4.6.2 5.7.4.6.3 5.7.4.6.4 5.7.4.7.1 5.7.4.7.2 5.7.4.7.3 5.7.4.7.4 5.7.4.8.1 5.7.4.8.2 5.7.4.8.3 5.7.4.8.4 5.8.1.1.1 5.8.1.1.2 5.8.1.1.3 5.8.1.1.4 5.8.1.2.1 5.8.1.2.2 5.8.1.2.3 5.8.1.2.4 5.8.1.3.1 5.8.1.3.2 5.8.1.3.3 5.8.1.3.4 5.8.1.4.1 5.8.1.4.2 5.8.1.4.3 5.8.1.4.4 5.8.1.5.1 5.8.1.5.2 5.8.1.5.3 5.8.1.5.4 5.8.1.6.1 5.8.1.6.2 5.8.1.6.3 5.8.1.6.4 5.8.1.7.1 5.8.1.7.2 5.8.1.7.3 5.8.1.7.4 5.8.1.8.1 5.8.1.8.2 5.8.1.8.3 5.8.1.8.4 5.8.2.1.1 5.8.2.1.2 5.8.2.1.3 5.8.2.1.4 5.8.2.2.1 5.8.2.2.2 5.8.2.2.3 5.8.2.2.4 5.8.2.3.1 5.8.2.3.2 5.8.2.3.3 5.8.2.3.4 5.8.2.4.1 5.8.2.4.2 5.8.2.4.3 5.8.2.4.4 5.8.2.5.1 5.8.2.5.2 5.8.2.5.3 5.8.2.5.4 5.82.6.1 5.8.2.6.2 5.8.2.6.3 5.8.2.6.4 5.8.2.7.1 5.8.2.7.2 5.8.2.7.3 5.8.2.7.4 5.8.2.8.I 5.8.2.8.2 5.8.2.8.3 5.8.2.8.4 5.8.3.1.1 5.8.3.1.2 5.8.3.1.3 5.8.3.1.4 5.8.32.1 5.8.3.2.2 5.8.32.3 5.8.3.2.4 5.8.3.3.1 5.8.3.3.2 5.8.3.3.3 5.8.3.3.4 5.8.3.4.1 5.8.3.4.2 5.8.3.4.3 5.8.3.4.4 5.8.3.5.1 5.8.3.5.2 5.8.3.5.3 5.8.3.5.4 5.8.3.6.1 5.8.3.6.2 5.8.3.6.3 5.8.3.6.4 5.8.3.7.1 5.8.3.7.2 5.8.3.7.3 5.8.3.7.4 5.8.3.8.1 5.8.3.8.2 S.B.3.8.3 5.8.3.8.4 5.8.4.1.1 5.8.4.I.2 5.8.4.1.3 5.8.4.1.4 5.8.4.2.1 5.8.4.2.2 5.8.4.2.3 5.8.4.2.4 5.8.4.3.1 5.8.4.3.2 5.8.4.3.3 5.8.4.3.4 5.8.4.4.1 5.8.4.4.2 5.8.4.4.3 5.8.4.4.4 5.8.4.5.1 5.8.4.5.2 5.8.4.5.3 5.8.4.5.4 5.8.4.6.1 5.8.4.6.2 5.8.4.6.3 5.8.4.6.4 5.8.4.7.1 5.8.4.7.2 5.8.4.7.3 5.8.4.7.4 5.8.4.8.1 5.8.4.8.2 5.8.4.8.3 5.8.4.8.4 6.1.1.1.1 6.1.1.1.2 6.1.1.1.3 6.1.1.1.4 6.1.1.2.1 6.1.1.2.2 6.1.1.2.3 6.1.1.2.4

220

Table 1 - continued

6.1.1.3.1 6.1.1.3.2 6.1.1.3.3 6.1.1.3.4 6.1.1.4.1 6.1.1.4.2 6.1.1.4.3 6.1.1.4.4 6.1.1.5.1 6.1.1.5.2 6.1.1.5.3 6.1.7.5.4 6.7.1.6.1 6.1.7.6.2 6.1.1.6.3 6.1.1.6.4 6.1.1.7.1 6.1.1.7.2 6.1.1.7.3 6.1.1.7.4 6.1.1.8.1 6.1.1.8.2 6.1.1.8.3 6.1.1.8.4 6.1.2.1.1 6.1.2.1.2 6.1.2.1.3 6.1.2.1.4 6.1.2.2.1 6.1.2.2.2 6.1.2.2.3 6.1.2.2.4 6.1.2.3.1 6.1.2.3.2 6.1.2.3.3 6.1.2.3.4 6.1.2.4.1 6.1.2.4.2 6.1.2.4.3 6.1.2.4.4 6.1.2.5.1 6.1.2.5.2 6.1.2.5.3 6.1.2.5.4 6.1.2.6.1 6.1.2.6.2 6.1.2.6.3 6.1.2.6.4 6.1.2.7.1 6.1.2.7.2 6.1.2.7.3 6.1.2.7.4 6.1.2.8.1 6.1.2.8.2 6.1.2.8.3 6.1.2.8.4 6.1.3.1.1 6.1.3.1.2 6.1.3.1.3 6.1.3.1.4 6.1.3.2.1 6.1.3.2.2 6.1.3.2:3 6.1.3.2.4 6.1.3.3.1 6.1.3.3.2 6.1.3.3.3 6.1.3.3.4 6.1.3.4.1 6.1.3.4.2 6.1.3.4.3 6.1.3.4.4 6.1.3.5.1 6.1.3.5.2 6.1.3.5.3 6.1.3.5.4 6.1.3.6.1 6.1.3.6.2 6.1.3.6.3 6.1.3.6.4 6.1.3.7.1 6.1.3.7.2 6.1.3.7.3 6.1.3.7.4 6.1.3.8.1 6.1.3.8.2 6.1.3.8.3 6.1.3.8.4 6.1.4.1.1 6.1.4.1.2 6.1.4.1.3 6.1.4.1.4 6.1.4.2.1 6.1.4.2.2 6.1 4.2.3 6.1.4.2.4 6.1.4.3.1 6.1.4.3.2 6.1.4.33 6.1.4.3.4 6.1.4.4.1 6.1.4.4.2 6.1.4.4.3 6.1.4.4.4 6.1.4.5.7 6.1.4.5.2 6.1.4.5.3 6.1.4.5.4 6.1.4.6.1 6.1.4.6.2 6.1 4.6.3 6.1.4.6.4 6.1.4.7.1 6.1.4.7.2 6.1.4.7.3 6.1.4.7.4 6.1.4.8.1 6.1.4.8.2 6.1.4.8.3 6.1.4.8.4 6.2.1.1.I 6.2.1.1.2 6.2.1.1.3 6.2.1.1.4 6.2.1.2.1 6.2.1.2.2 6.2.1.2.3 6.2.1.2.4 6.2.1.3.1 6.2.1.3.2 6.2.1.3.3 6.2.1.3.4 6.2.1.4.1 6.2.1.4.2 6.2.1.4.3 6.2.1.4.4 6.2.1.5.1 6.2.1.5.2 6.2.1.5.3 6.2.1.5.4 6.2.1.6.1 6.2.1.6.2 6.2.1.6.3 6.2.1.6.4 6.2.1.7.1 6.2.1.7.2 6.2.1.7.3 6.2.1.7.4 6.2.1.8.1 6.2.1.8.2 6.2.1.8.3 6.2.1.8.4 6.2.2.1.1 6.2.2.1.2 6.2.2.1.3 6.2.2.1.4 6.2.2.2.1 6.2.2.2.2 6.2.2.2.3 6.2.2.2.4 6.2.2.3.1 6.2.2.3.2 6.3.2.3.3 6.2.2.3.4 6.2.2.4.1 6.2.2.4.2 6.2.2.4.3 6.2.2.4.4 6.2.2.5.1 6.2.2.5.2 6.2.2.5.3 6.2.2.5.4 6.2.2.6.1 6.2.2.6.2 6.2.3.6.3 6.2.2.6.4 6.2.2.7.I 6.2.2.7.2 6.2.2.7.3 6.2.2.7.4 6.2.2.8.1 6.2.2.8,2 62.2.8.3 6.2.2.8.4 6.2.3.1.1 6.2.3.1.2 6.2.3.1.3 6.2.3.1.4 6.2.3.2.1 6.2.3.2.2 6.2.3.2.3 6.2.3.2.4 6.2.3.3.1 6.2.3.3.2 6.2.3.3.3 6.2.3.3.4 6.2.3.4.1 6.2.3.4.2 6.2.3.4.3 6.2.3.4.4 6.2.3.5.1 6.2.3.5.2 6.2.3.5.3 6.2.3.5.4 6.2.3.6.1 6.2.3.6.2 6.2.3.6.3 6.2.3.6.4 6.2.3.7.1 6.2.3.7.2 6.2.3.7.3 6.2.3.7.4 6.2.3.8.1 6.2.3.8.2 62.3.8.3 6.2.3.8.4 6.2.4.1.1 6.2.4.1.2 6.2.4.1.3 6.2.4.1.4 6.2.42.1 6.2.4.2.2 6.2.4.2.3 6.2.4.2.4 6.2.4.3.1 6.2.4.3.2 6.2.4.3.3 6.2.4.3.4 6.2.44.1 6.2.4.4.2 6.2.4.4.3 6.2.4.4.4 6.2.4.5.1 6.2.4.5.2 6.2.4.5.3 6.2.4.5.4 6.2 4.6.1 6.2.4.6.2 6.2.4.6.3 6.2.4.6.4 6.2 4.7.1 6.2.4.7.2 6.2.4.7.3 6.2.4.7.4 6.2.4.8.1 6.2.4.8.2 6.2.4.83 6.2.4.8.4 6.3.1.1.1 6.3.1.1.2 6.3.1.1.3 6.3.1.1.4 6.3.1.2.1 6.3.1.2.2 6.3.1.2.3 6.3.1.2.4

221

Table 1 - continued

6.3.1.3.1 6.3.1.3.2 6.3.1.3.3 6.3.1.3.4 6.3.1.4.1 6.3.1.4.2 6.3.1.4.3 6.3.1.4.4 6.3.1.5.1 6.3.1.5.2 6.3.1.5.3 6.3.1.5.4 6.3.1.6.1 6.3.1.6.2 6.3.1.6.3 6.3.1.6.4 6.3.1.7.1 6.3.1.7.2 6.3.1.7.3 6.3.1.7.4 6.3.1.8.1 6.3.1.8.2 6.3.1.8.3 6.3.1.8.4 6.3.2.1.1 6.3.2.1.2 6.3.2.1.3 6.3.2.1.4 6.3.2.2.1 6.3.2.2.2 6.3.2.2.3 6.3.2.1.4 6.3.2.3.1 6.3.2.3.2 6.3.2.3.3 6.3.2.3.4 6.3.2.4.1 6.3.2.4.2 6.3.2.4.3 6.3.2.4.4 6.3.2.5.1 6.3.2.5.2 6.3.2.5.3 6.3.2.5.4 6.3.2.6.1 6.3.2.6.2 6.3.26.3 6.3 2.6.4 6.3 2.7.1 6.3.2.7.2 6.3.2.7.3 6.3.2.7.4 6.3.2.8.1 6.3.2.8.2 6.3.2.8.3 6.3.2.8.4 6.3.3.1.1 6.3.3.1.2 6.3.3.1.3 6.3.3.1.4 6.3.3.2.1 6.3.3.2.2 6.3.3.2.3 6.3.3.2.4 6.3.3.3.1 6.3.3.3.2 6.3.3.3.3 6.3.3.3.4 6.3.3.4.1 6.3.3.4.2 6.3.3.4.3 6.3.3.4.4 6.3.3.5.1 6.3.3.5.2 6.3.3.5.3 6.3.3.5.4 6.3.3.6.1 6.3.3.6.2 6.3.3.6.3 6.3.3.6.4 6.3.3.2.1 6.3.3.7.2 6.3.3.7.3 6.3.3.7.4 6.3.3.8.1 6.3.3.8.2 6.3.3.8.3 6.3.3.8.4 6.3.4.1.1 6.3.4.1.2 6.3.4.1.3 6.3.4.1.4 6.3.4.2.1 6.3.4.2.2 6.3.4.2.3 6.3.4 2.4 6.3.4.3.1 6.3.4.3.2 6.3.4.3.3 6.3.4.3.4 6.3.4.4.1 6.3.4.4.2 6.3.4.4.3 6.3.4.4.4 6.3 4.5.1 6.3.4.5.2 6.3.4.5.3 6.3.4.5.4 6.3.4.6.1 6.3.4.6.2 6.3.4.6.3 6.3.4.6.4 6.3.4.7.1 6,3.4.7.2 6.3.4.7.3 6.3.4.7.4 6.3.4.8.1 6.3.4.8.2 6.3.4.8.3 6.3.4.8.4 6.4.1.1.1 6.4.1.1.2 6.4.1.1.3 6.4.1.1.4 6.4.1.2.1 6.4.1.2.3 6.4.1.2.3 6.4.1.2.4 6.4.1.3.1 6.4.1.3.2 6.4.1.3.3 6.4.1.3.4 6.4.1.4 l 6.4.1.4.2 6.4.1.4.3 6.4.1.4.4 6.4.1.5.1 6.4.1.5.2 6.4.1.5.3 6.4.1.5.4 6.4.1.6.1 6.4.1.6.2 6.4.1.6.3 6.4.1.6.4 6.4.1.7.1 6.4.1.7.2 6.4.1.7.3 6.4.1.7.4 6.4.1.8.1 6.4.1.8.2 6.4.1.8 3 6.4.1.8.4 6.4.2.1.1 6.4.2.1.2 6.4.2.1.3 6.4.2.1.4 6 (4.2.2.1 6.4.2.2.2 6.4.2.2.3 6.4.2.2.4 6.4.2.3.1 6.4.2.3.2 6.4.2.3.3 6.4.2.3.4 6.4.2.4.1 6.4.2.4.2 6.4.2.4.3 6.4.2.4.4 6.4.3.5.1 6.4.2.5 2 6.4.2.5.3 6.4.2.5.4 6.4.2.6.1 6.42.6.2 6.4.2.6.3 6.4.2.6.4 6.4.2.7.1 6.4.2.7.2 6.4.2.7.3 6.4.2.7.4 6.4.2.8.1 6.4.2.8.2 6.4.2.8.3 6.4.2.8.4 6.43.1.1 6.4.3.1.2 6.4.3.1.3 6.4.3.1.4 6.4.3.2.1 6.4.3.2.2 6.4.3.2.3 6.4.3.2.4 6.4.3.3.1 6.4.3.3.2 6.4.3.3.3 6.4.3.3.4 6.4.3.4.1 6.4.3.4.2 6.4.3.4.3 6.4.3.4.4 6.4.3.5.1 6.4.3.5.2 6.4.3.5.3 6.4.3.5.4 6.4.3.6.1 6.4.3.6.2 6.4.3.6.3 6.4.3.6.4 6.4.3.7.1 6.4.3.7.2 6.4.3.7.3 6.4.3.7.4 6.4.3.8.1 6.4.3.8.2 6.4.3.8.3 6.4.3.8.4 6.4.4.1.1 Training 6.4.4.1.2 6.4.4.1.3 6.4.4.1.4 6.4.4.2.1 Training 6.4.4.2.2 6.4.4.2.3 G.4.4.2.4 6.4.4.3.1 Training 6.4.4.3.2 6.4.4.3.3 6.4.4.3.4 6.4.4.4.1 6.4.4.4.2 6.4.4.4.3 6.4.4.4.4 6.4.4.5.1 6.4.4.5.2 6.4.4.5.3 6.4.4.5.4 6.4.4.6.1 6.4.4.6.2 6.4.4.6.3 6.4.4.6.4 6.4.4.7.1 6.4.4.7.2 6.4.4.7.3 6.4.4.7.4 6.4.4.8.1 6.4.4.8.2 6.4.4.8.3 6.4.4.8.4 6.5.1.1.1 6.5.1.1.2 6.5.1.1.3 6.5.1.1.4 6.5.1.2.1 6.5.1.2.2 6.5.1.2.3 6.5.1 2.4

222

Table 1 - continued

6.5.1.3.1 6.5.1.3.2 6.5.1.3.3 6.5.1.3.4 6.5.1.4.1 6.5.1.4.2 6.5.1.4.3 6.5.1.4.4 6.5.1.5.1 6.5.1.5.2 6.5.1.5.3 6.5.1.5.4 6.5.1.6.1 6.5.1.6.2 6.5.1.6.3 6.5.1.6.4 6.5.1.7.1 6.5.1.7.2 6.5.1.7.3 6.5.1.7.4 6.5.1.8.1 6.5.1.8.2 6.5.1.8.3 6.5.1.8.4 6.5.2.1.1 6.5.2.1.2 6.5.2.1.3 6.5.2.1.4 6.5.2.2.1 6.5.2.2.2 6.5.2.2.3 6.5.2.2.4 6.5.2.3.1 6.5.2.3.2 6.5.2.3.3 6.5.2.3.4 6.5.2.4.1 6.5.2.4.2 6.5.2.4.3 6.5.2.4.4 6.5.2.5.1 6.5.2.5.2 6.5.2.5.3 6.5.2.5.4 6.5.2.6.1 6.5.2.6.2 6.5.2.6.3 6.5.2.6.4 6.5.2.7.1 6.5.2.7.2 6.5.2.7.3 6.5.2.7.4 6.5.2.8.1 6.5.2.8.2 6.5.2.8.3 6.5.2.8.4 6.5.3.1.1 6.53.1.2 6.5.3.1.3 6.5.3.1.4 6.5.3.2.1 6.5.3.2.2 6.5.3.2.3 6.5.3.2.4 6.5.3.3.1 6.5.3.3.2 6.5.3.3.3 6.5.3.3.4 6.53.4.1 6.53.4.2 6.5.3.4.3 6.5.3.4.4 6.5.3.5.1 6.5.3.5.2 6.5.3.5.3 6.5.3.5.4 6.5.3.6.1 6.5.3.6.2 6.5.3.6.3 6.5.3.6.4 6.5.3.7.1 6.5.3.7.2 6.5.3.7.3 6.5.3.7.4 6.5.3.8.1 6.53.8.2 6.5.3.8.3 6.5.3.8.4 6.5.4.1.1 6.5.4.1.2 6.5.4.1.3 6.5.4.1.4 6.5.4.2.1 6.5.4.2.2 6.5.4.2.3 6.5.4.2.4 6.5.4.3.1 6.5.4.3.2 6.5.4.3.3 6.5.4.3.4 6.5.4.4.1 6.5.4.4.2 6.5.4.4.3 6.5.4.4.4 6.S.4.S.1 6.S.4.S.2 6.5.4.5.3 6.5.4.5.4 6.5.4.6.1 6.5.4.6.2 6.5.4.6.3 6.5.4.6.4 6.5.4.7.1 6.5.4.7.2 6.5.4.7.3 6.5.4.7.4 6.5.4.8.1 6.5.4.8.2 6.5.4.8.3 6.5.4.8.4 6.6.1.1.1 6.6.1.1.2 6.6.1.1.3 6.6.1.1.4 6.6.1.2.1 6.6.1.2.2 6.6.1.2.3 6.6.1.2.4 6.6.1.3.1 6.6.1.3.2 6.6.1.3.3 6.6.1.3.4 6.6.1.4.1 6.6.1.4.2 6.6.1.4.3 6.6.1.4.4 6.6.1.S.l 6.6.1.5.2 6.6.1.5.3 6.6.1.5.4 6.6.1.6.1 6.6.1.6.2 6.6.7.6.3 6.6.1.6.4 6.6.1.7.1 6.6.1.7.2 6.6.1.7.3 6.6.1.7.4 6.6.1.8.1 6.6.1.8.2 6.6.1.8.3 6.6.1.8.4 6.6.2.1.1 6.6.2.1.2 6.6.2.1.3 6.6.2.1.4 6.62.2.1 6.6.2.2.2 6.6.2.2.3 6.6.2.2.4 6.6.2.3.1 6.6.2.3.2 6.6.2.3.3 6.6.23.4 6.6.24.1 6.6.2.4.2 6.6.2.4.3 6.6.2.4.4 6.6.2.5.1 6.6.2.5.2 6.6.2.5.3 6.6.2.5.4 6.6.2.6.1 6.6.2.6.2 6.6.2.6.3 6.6.2.6.4 6.6.2.7.1 6.6.2.7.2 6.6.2.7.3 6.6.2.7.4 6.6.2.8.1 6.6.2.8.2 6.6.2.8.3 6.6.2.8.4 6.6.3.1.1 6.6.3.1.2 6.6.3.1.3 6.6.3.1.4 6.6.3.2.1 6.6.3.2.2 6.6.3.2.3 6.6.3.2.4 6.6.3.3.1 6.6.3.3.2 6.6.3.3.3 6.63.3.4 6.6.3.4.1 6.6.3.4.2 6.6.3.4.3 6.63.4.4 6.6.3.5.1 6.6.3.5.2 6.6.3.5.3 6.63.5.4 6.63.6.1 6.63.6.2 6.6.3.6.3 6.6.3.6.4 6.6.3.7.I 6.6.3.7.2 6.6.3.73 6.63.7.4 6.6.3.8.1 6.63.8.2 6.6.3.8.3 6.63.8.4 6.6.4.1.1 6.6.4.1.2 6.6.4.1.3 6.6.4.1.4 6.6.4.2.1 6.6.4.2.2 6.6.4.2.3 6.6.4.2.4 6.6.4.3.1 6.6.4.32 6.6.4.3.3 6.6.4.3.4 6.6.4.4.1 6.6.4.4.2 6.6.4.4.3 6.6.4.4.4 6.6.4.5.1 6.6.4.5.1 6.6.4.5.3 6.6.4.5.4 6.6.4.6.1 6.6.4.6.2 6.6.4.6.3 6.6.4.6.4 6.6.4.7.1 6.6.4.7.2 6.6.4.7.3 6.6.4.7.4 6.6.4.8.1 6.6.4.8.2 6.6.4.8.3 6.6.4.8.4

223

Table 1 - continued

6.7.1.1.1 6.7.1.1.2 6.7.1.1.3 6.7.1.1.4 6.7.I.2.1 6.7.1.2.2 6.7.1.2.3 6.7.1.2.4 6.7.1.3.1 6.7.1.3.2 6.7.1.3.3 6.7.1.3.4 6.7.1.4.1 6.7.1.4.2 6.7.1.4.3 6.7.1.4.4 6.7.1.5.1 6.7.1.5.2 6.7.1.5.3 6.7.1.5.4 6.7.1.6.1 6.7.1.6.2 6.7.1.6.3 6.7) 6.4. 6.7.1.7.1 6.7.1.7.2 6.7.1.7.3 6.7.1.7.4 6.7.1.8.1 6.7.1.8.2 6.7.1.8.3 6.7.1.8.4 6.7.2.1.1 6.7.2.1.2 6.7.2.1.3 6.7.2.1.4 6.7.2.2.1 6.7.2.2.2 6.7.2.2.3 6.7.2.2.4 6.7.2.3.1 6.7.2.3.2 6.7.2.3.3 6.7.2.3.4 6.7.2.4.1 6.7.2.4.2 6.7.2.4.3 6.7.2.4.4 6.7.2.5.1 6.7.2.5.2 6.7.2.5.3 6.7.2.5.4 6.7.2.6.1 6.7.2.6.2 6.7.2.6.3 6.7.2.6.4 6.7.2.7.1 6.7.2.7.2 6.7.2.7.3 6.7.2.7.4 6.7.2.8.1 6.7.2.8.2 6.7.2.8.3 6.7.2.8.4 6.7.3.1.1 6.7.3.1.2 6.7.3.1.3 6.7.3.1.4 6.7.3.2.1 6.7.3.2.2 6.7.3.2.3 6.7.3.2.4 6.7.3.3.1 6.7.3.3.2 6.7.3.3.3 6.7.3.3.4 6.7.3.4.1 6.7.3.4.2 6.7.3.4.3 6.7.3.4.4 6.7.3.5.1 6.7.3.5.2 6.7.3.5.3 6.7.3.5.4 6.7.3.6.1 6.7.3.6.2 6.7.3.6.3 6.7.3.6.4 6.7.3.7.1 6.7.3.7.2 6.7.3.7.3 6.7.3.7.4 6.7.3.8.1 6.7.3.8.2 6.7.3.8.3 6.7.3.8.4 6.7.4.1.1 6.7.4.1.2 6,7.4.1.3 6.7.4.1.4 6.7.4.2.1 6.7.4.2.2 6.7.4.2.3 6.7.4.2.4 6.7.4.3.1 6.7.4.3.2 6.7.4.3.3 6.7.4.3.4 6.7.4.4.1 6.7.4.4.2 6.7.4 4.3 6.7.4.4.4 6.7.4.5.1 6.7.4.5.2 6.7.4.5.3 6.7.4.5.4 6.7.4.6.1 6.7.4.6.2 6.7.4.6.3 6.7.4.6.4 6.7.4.7.1 6.7.4.7.2 6.7.4.7.3 6.7.4.7.4 6.7.4.8.1 6.7.4.8.2 6.7.4.8.3 6.7.4.8.4 6.8.1.1.1 6.8.1.1.2 6.8.1.1.3 6.8.1.1.4 6.8.1.3.1 6.8.1.2.2 6.8.1.2.3 6.8.1.2.4 6.8.1.3.1 6.8.1.3.2 6.8.1.3.3 6.8.1.3.4 6.8.1.4.1 6.8.1.4.2 6.8.1.4.3 6.8.1.4.4 6.8.1.5.1 6.8.1.5.2 6.8.1.5.3 6.8.1.5.4 6.8.1.6.1 6.8.1.6.2 6.8.1.6.3 6.8.1.6.4 6.8.1.7.1 6.8.1.9.2 6.8.1.7.3 6.8.1.7.4 6.8.1.8.1 6.8.1.8.2 6.8.1.8.3 6.8.1.8.4 6.8.2.1.1 6.8.2.1.2 6.8.2.1.3 6.8.2.1.4 6.8.2.2.1 6.8.2.2.2 6.8.2.2.3 6.8.2.2.4 6.8.2.3.1 6.8.2.3.2 6.8.2.3.3 6.8.2.3.4 6.8.2.4.1 6.8.2.4.2 6.8.2.4.3 6.8.2.4.4 6.8.2.5.1 6.8.2.5.2 6.8.2.5.3 6.8.2.5.4 6.8.2.6.1 6.8.2.6.2 6.8.26.3 6.8.2.6.4 6.8.2.7.1 6.8.2.7.2 6.8.2.7.3 6.8.2.7.4 6.8.2.8.1 6.8.2.8.2 6.B.2.8.3 6.8.2.8.4 6.8.3.1.1 6.8.3.1.2 6.8.3.1.3 6.8.3.1.4 6.8-3.2.1 6.8.3.2.2 6.8.3.2.3 6.8.3.2.4 6.8.3.3.1 6.8.3.3.2 6.8.3.3.3 6.8.3.3.4 6.8.3.4.1 6.8.3.4.2 6.8.3.4.3 6.8.3.4.4 6.8.3.5.1 6.8.3.5.2 6.8.3.5.3 6.8.3.5.4 6.8.3.6.1 68.3.6.2 6.8.3.6.3 6.8.3.6.4 6.8.3.7.1 6.8.3.7.2 6.8.3.7.3 6.8.3.7.4 6.8.3.8.1 6.8.3.8.2 6.8.3.8.3 6.8.3.8.4 6.8.4.1.1 6.8.4.1.2 6.8.4.1.3 6.8.4.1.4 6.8.4.2.1 6.8.4.2.2 6.8.4.2.3 6.8.4.2.4 6.8.4.3.1 6.8.4.3.2 6.8.4.3.3 6.8.4.3.4 6.8.4.4.1 6.8.4.4.2 6.8.4.4.3 6.8.4.4.4 6.8 4.5.1 6.8.4.5.2 6.8.4.5.3 6.8.4.5.4 6.8.4.6.1 6.8.4.6.2 6.8.4.6.3 6.8.4.6.4 6.8.47.1 6.8.4.7.2 6.8.4.7.3 6.8.4.7.4 6.8.4.8.1 6.8.4.8.2 6.8.4.8.3 6.8.4.8.4

224

Table 1 - continued

7.1.1.1.1 7.1.1.1 2 7.1.1.1.3 7.1.1.1.4 7.1.1.2.1 7.1.1.2.2 7.1.1.2.3 7.1.1.2.4 7.1.1.3.1 7.1.1.3.2 7.1.1.3.3 7.1.1.3.4 7.7.1.4.1 7.1.1.4.2 7.1.1.4.3 7.1.1.4.4 7.1.1.5.1 7.1.1.5.2 7.1.1.5.3 7.1.1.5.4 7.1.1.6.1 7.1.1.6.2 7.1.1.6.3 7.1.1.6.4 7.1.1.7.1 7.1.1.7.2 7.1.1.7.3 7.1.1.7.4 7.1.1.8.7 7.1.1.8.2 7.1.1.8.3 7.7.1.8.4 7.1.2.1.1 7.1.2.1.2 7.1.2.1.3 7.1.2.1.4 7.1.2.2.1 7.1.2.2.2 7.1.2.2.3 7.1.2.2.4 7.1.2.3.1 7.1.2.3.2 7.1.2.3.3 7.1.2.3.4 7.1.2.4.1 7.1.2.4.2 7.1.2.4.3 7.1.2.4.4 7.1.2.5.1 7.1.2.5.2 7.1.2.5.3 7.1.2.5.4 7.1.2.6.1 7.1.2.6.2 7.1.2.6.3 7.1.2.6.4 7.1.2.7.1 7.1.2.7.2 7.1.2.7.3 7.1.2.7.4 7.1.2.8.1 7.1.2.8.2 7.1.2.8.3 7.1.2.8.4 7.1.3.1.1 7.1.3.1.2 7.1.3.1.3 7.1.3.1.4 7.1.3.2.1 7.1.3.2.2 7.1.3.2.3 7.1.3.2.4 7.1.3.3.1 7.1.3.3 7.1.3.3.3 7.1.3.3.4 7.1.3.4.1 7.1.3.4.2 7.1.34.3 7.1.3.4.4 7.1.3.5.1 7.1.3.5.2 7.1.3.5.3 7.1.3.5.4 7.1.3.6.1 7.1.3.6.2 7.1.3.6.3 7.1.3.6.4 7.1.3.7.1 7.1.3.7.2 7.1.3.7.3 7.1.3.7.4 7.1.3.8.1 7.1.3.8.2 7.1.3.8.3 7.1.3.8.4 7.1.4.1.1 7.1.4.1.2 7.1.4.1.3 7.1.4.1.4 7.1.4.2.1 7.1.4.2.2 7.1.4.2.3 7.1.4.2.4 7.1.4.3.1 7.1.4.3.2 7.1.4.3.3 7.1.4.3.4 7.1.4.4.1 7.1.4.4.2 7.1.4.4.3 7.1.4.4.4 7.1.4.5.1 7.1.4.5.2 7.1.4.5.3 7.1.4.5.4 7.1.4.6.1 7.1.4.6.2 7.1.4.6.3 7.1.4.6.4 7.1.4.7.1 7.1.4.7.2 7.1.4.7.3 7.1.4.7.4 7.1.4.8.1 7.1.4.8.2 7.1.4.8.3 7.7.4.8.4 7.2.1.1.1 7.2.1.1.2 7.2.1.1.3 7.2.1.1.4 7.2.1.2.1 7.2.1.2.2 7.2.1.2.3 7.1.1.2.4 7.2.1.3.1 7.2.1.3.2 7.2.1.3.3 7.2.1.3.4 7.2.1.4.1 7.2.1.4.2 7.3.1.4.3 7.2.1.4.4 7.2.1.5.1 7.2.1.5.2 7.2.1.5.3 7.2.1.5.4 7.2.1.6.1 7.2.1.6.2 7.2.1.6.3 7.2.1.6.4 7.2.1.7.1 7.2.1.7.2 7.2.1.7.3 7.2.1.7.4 7.2.1.8.1 7.2.1.8.2 7.2.1.8.3 7.2.1.8.4 7.2.2.1.1 7.2.2.1.2 7.2.2.1.3 7.2.2.1.4 7.2.2.2.1 7.2.2.2.2 7.2.2.2.3 7.2.2.2.4 7.2.2.3.1 7.2.2.3.2 7.2.2.3.3 7.2.2.3.4 7.2.2.4.1 7.2.2.4.2 7.2.2.4.3 7.2.2.4.4 7.2.2.5.1 7.2.2.5.2 7.2.2.5.3 7.2.2.5.4 7.2.2.6.1 7.2.2.6.2 7.2.2.6.3 7.2.2.6.4 7.2.2.7.1 7.2.2.7.2 7.2.3.7.3 7.2.2.7.4 7.2.2.8.1 7.2.2.8.2 7.2.2.8.3 7.2.2.8.4 7.2.3.1.1 7.2.3.1.2 7.2.3.1.3 7.2.3.1.4 7.2.3.2.1 7.2.3.2.2 7.2.3.2.3 7.2.3.2.4 7.2.3.3.1 7.2.3.3.2 7.2.3.3.3 7.2.3.3.4 7.2.3.4.1 7.2.3.4.2 7.2.3.4.3 7.2.3.4.4 7.2.3.5.1 7.2.3.5.2 7.2.3.5.3 7.2.3.5.4 7.2.3.6.1 7.2.3.6.2 7.2.3.6.3 7.2.3.6.4 7.2.3.7.1 7.2.3.7.2 7.2.3.7.3 7.2.3.7.4 7.2.3.8.1 7.2.3.8.2 7.2.3.8.3 7.2.3.8.4 7.2.4.1.1 7.2.4.1.2 7.2.4.1.3 7.2.4.1.4 7.2.4.2.1 7.2.4.2.2 7.2.4.2.3 7.2.4.2.4 7.2.4.3.1 7.2.4.3.2 7.2.4.3.3 7.2.4.3.4 7.2.4.4.1 7.2.4.4.2 7.2.4.4.3 7.2.4.4.4 7.2.4.5.1 7.2.4.5.2 7.2.4.5.3 7.2.4.5.4 7.2.4.6.1 7.2.4.6.2 7.2.4.6.3 7.2.4.6.4 7.2.4.7.1 7.2.4.7.2 7.2.4.7.3 7.2.4.7.4 7.2.4.8.1 7.2.4.8.2 7.2.4.8.3 7.2.4.8.4

225

Table 1 - continued

7,3.1.1.1 7.3.1 1.1.2 7.3.1.1.3 7.3.1 1.1.4 7.3.1.2.1 7.3.1.2.2 7.3.1.2.3 7.3.1.2.4 7.3.1.3.1 7.3.1.3.2 7.3.1.3.3 7.3.1.3.4 7.3.1.4.1 7.3.1.4.2 7.3.1.4.3 7.3.1.4.4 7.3.1.5.1 7.3.1.5.2 7.3.1.5.3 7.3.1.5.4 7.3.1.6.1 7.3.1.6.2 7.3.7.6.3 7.3.1.6.4 7.3.1.7.1 7.3.1 1.7.2 7.3.1.7.3 7.3.1 1.7.4 7.3.1.8.1 7.3.1.8.2 7.3.1.8.3 7.3.1.8.4 7.3.2.1.1 7.3.2.1.2 7.3.2.1.3 7.3.2.1.4 7.3.2.2.1 7.3.2.2.2 7.3.2.2.3 7.3.2.2.4 7.3.2.3.1 7.3.2.3.2 7.3.2.3.3 7.3.2.3.4 7.3.2.4.1 7.3.2.4.2 7.3.2.4.3 7.3.2.4.4 7.3.2.5.1 7.3.2.5.2 7.3.2.5.3 7.3.2.i.4 7.3.2.6.1 7.3.2.6.2 7.3.2.6.3 7.3.2.6.4 7.3.2.7.1 7.3.2.7.2 7.3.2.7.3 7.3.2.7.4 7.3.2.8.1 7.3.2.8.2 7.3.2.8.3 7.3.2.8.4 7.3.3.1.1 7.3.3.1.2 7.3.3.1.3 7.3.3.1.4 7.3.3.2.1 7.3.3.2.2 7.3.3.2.3 7.3.3.2.4 7.3.3.3.1 7.3.3.3.2 7.3.3.3.3 7.3.3.3.4 7.3.3.4.1 7.3.3.4.2 7.3.3.4.3 7.3.3.4.4 7.3.3.5.1 7.3.3.5.2 7.3.3.5.3 7.3.3.5.4 7.3.3.6.1 7.3.3.6.2 7.3.3.6.3 7.3.3.6.4 7.3.3.7.1 7.3.3.7.2 7.3.3.7.3 7.3.3.7.4 7.3.3.8.1 7.3.3.8.2 7.3.3.8.3 7.3.3.8.4 7.3.4.1.1 7.3.4.1.2 7.3.4.1.3 7.3.4.1.4 7.3.4.2.1 7.3.4.2.2 7.3.4.2.3 7.3.4.2.4 7.3.4.3.1 7.3.4.3.2 7.3.4.3.3 7.3.4.3.4 7.3.4.4.1 7.3.4.4.2 7.3.4.4.3 7.3.4.4.4 7.3.4.5.1 7.3.4.5.2 7.3.4.5.3 7.3.4.5.4 7.3.4.6.1 7.3.4.6.2 7.3.4.6.3 7.3.4.6.4 7.3.4.7.1 7.3.4.7.2 7.3.4.7.3 7.3.4.7.4 7.3.4.8.1 7.3.4.8.2 7.3.4.8.3 7.3.4.8.4 7.4.1.1.1 7.4.1.1.2 7.4.1.1.3 7.4.1 1.1.4 7.4.1.2.1 7.4.1.2.2 7.4.1.2.3 7.4.1.2.4 7.4.1.3.1 7.4.1.3.2 7.4.1.3.3 7.4.1.3.4 7.4.1.4.1 7.4.1.4.2 7.4.1.4.3 7.4.1.4.4 7.4.1.5.1 7.4.1.5.2 7.4.1.5.3 7.4.1.5.4 7.4.1.6.1 7.4.1.6.2 7.4.1.6.3 7.4.1.6.4 7.4.7.7.1 7.4.1.7.2 7.4.1.7.3 7.4.1.7.4 7.4.1.8.1 7.4.1.8.2 7.4.1.8.3 7.4.1.8.4 7.4.2.1.1 7.4.2.1.2 7.4.2.1.3 7.4.2.1.4 7.4.2.2.1 7.4.2.2.2 7.4.2.2.3 7.4.2.2.4 7.4.2.3.1 7.4.2.3.2 7.4.2.3.3 7.4.2.3.4 7.4.2.4.1 7.4.2.4.2 7.4.2.4.3 7.4.2.4.4 7.4.2.5.1 7.4.2.5.2 7.4.2.5.3 7.4.2.5.4 7.4.2.6.1 7.4.2.6.2 7.4.2.6.3 7.4.2.6.4 7.4.2.7.1 7.4.2.7.2 7.4.2.7.3 7.4.2.7.4 7.4.2.8.1 7.4.2.8.2 7.4.2.8.3 7.4.2.8.4 7.4.3.1.1 7.4.3.1.2 7.4.3.1.3 7.4.3.1.4 7.4.3.2.1 7.4.3.2.2 7.4.3.2.3 7.4.3.2.4 7.4.3.3.1 7.4.3.3.2 7.4.3.3.3 7.4.3.3.4 7.4.3.4.1 7.4.3.4.2 7.4.3.4.3 7.4.3.4.4 7.4.3.5.1 7.4.3.5.2 7.4.3.5.3 7.4.3.5.4 7.4.3.6.1 7.4.3.6.2 7.4.3.6.3 7.4.3.6.4 7.4.3.7.1 7.4.3.7.2 7.4.3.7.3 7.4.3.7.4 7.4.3.8.1 7.4.3.8.2 7.4.3.8.3 7.4.3.8.4 7.4.4.1.1 7.4.4.1.2 7.4.4.7.3 7.4.4.1.4 7.4.4.2.1 7.4.4.2.2 7.4.4.2.3 7.4.4.2.4 7.4.4.3.1 7.4.4.3.2 7.4.4.3.3 7.4.4.3.4 7.4.4.4.7 7.4.4.4.2 7.4.4.4.3 7.4.4.4.4 7.4.4.5.1 7.4.4.5.2 7.4.4.5.3 7.4.4.5.4 7.4.4.6.1 7.4.4.6.2 7.4.4.6.3 7.4.4.6.4 7.4.4.7.1 7.4.4.7.2 7.4.4.7.3 7.4.4.7.4 7.4.4.8.7 7.4.4.8.2 7.4.4.8.3 7.4.4.8.4

226

Table 1 - continued

7.5.7.1.1 7.5.1.1.2 7.5.1.1.3 7.5.1.1.4 7.5.7.2.1 7.5.1.2.2 7.5.1.2.3 7.5.1.2.4 7.5.1.3.1 7.5.1.3.2 7.5.1.3.3 7.5.1.3.4 7.5.1.4.1 7.5.1.4.2 7.5.1.4.3 7.5.1.4.4 7.5.1.5.1 7.5.1.5.2 7.5.1.5.3 7.5.1.5.4 7.5.1.6.1 7.5.1.6.2 7.5.1.6.3 7.5.1.6.4 7.5.1.7.1 7.5.1.7.2 7.5.1.7.3 7.5.1.7.4 7.5.1.8.1 7.5.1.8.2 7.5.1.8.3 7.5.1.8.4 7.5.2.1.1 7.5.2.1:2 7.5.2.1.3 7.5.2.1.4 7.5.2.2.1 7.5.2.2.2 7.5.2.2.3 7.5.2.2.4 7.5.2.3.1 7.5.2.3.2 7.5.2.3.3 7.5.2.3.4 7.5.2.4.1 7.5.2.4.2 7.5.2.4.3 7.5.2.4.4 7.5.2.5.1 7.5.2.5.2 7.5.2.5.3 7.5.2.5.4 7.5.2.6.1 7.5.2.6.2 7.5.2.6.3 7.5.2.6.4 7.5.2.7.1 7.5.2.7.2 7.5.2.7.3 7.5.2.7.4 7.5.2.8.1 7.5.2.8.2 7.5.2.8.3 7.5.2.8.4 7.5.3.1.1 7.5.3.1.2 7.5.3.1.3 7.5.3.1.4 7.5.3.2.1 7.5.3.2.2 7.5.3.2.3 7.5.3.2.4 7.5.3.3.1 7.5.3.3.2 7.5.3.3.3 7.5.3.3.4 7.5.3.4.1 7.5.3.4.2 7.5.3.4.3 7.5.3.4.4 7.5.3.5.1 7.5.3.5.2 7.5.3.5.3 7.5.3.5.4 7.5.3.6.1 7.5.3.6.2 7.5.3.6.3 7.5.3.6.4 7.5.3.7.1 7.5.3.7.2 7.5.3.7.3 7.5.3.7.4 7.5.3.8.1 7.5.3.8.2 7.5.3.8.3 7.5.3.8.4 7.5.4.1.1 7.5.4.1.2 7.5.4.1.3 7.5.4.1.4 7.5.4.2.1 7.5.4.2.2 7.5.4.2.3 7.5.4.2.4 7.5.4.3.1 7.5.4.3.2 7.5.4.3.3 7.5.4.3.4 7.5.4.4.1 7.5.4.4.2 7.5.4.4.3 7.5.4.4.4 7.5.4.5.1 7.5.4.5.2 7.5.4.5.3 7.5.4.5.4 7.5.4.6.1 7.5.4.6.2 7.5.4.6.3 7.5.4.6.4 7.5.4.7.1 7.5.4.7.2 7.5.4.7.3 7.5.4.7.4 7.5.4.8.1 7.5.4.8.2 7.5.4.8.3 7.5.4.8.4 7.6.1.7.1 7.6.1.1.2 7.6.1.1.3 7.6.1.1.4 7.6.1.2.1 7.6.1.2.2 7.6.1.2.3 7.6.1.2.4 7.6.1.3.1 7.6.1.3.2 7.6.1.3.3 7.6.1.3.4 7.6.1.4.1 7.6.1.4.2 7.6.1.4.3 7.6.1.4.4 7.6.1.5.1 7.6.1.5.2 7.6.1.5.3 7.6.1.5.4 7.6.1.6.1 7.6.1.6.2 7.6.1.6.3 7.6.1.6.4 7.6.1.7.1 7.6.1.7.2 7.6.1.7.3 7.6.1.7.4 7.6.1.8.1 7.6.1.8.2 7.6.1.5.3 7.6.1.8.4 7.6.2.1.1 7.6.2.1.2 7.6.2.1.3 7.6.2.1.4 7.6.2.2.1 7.6.2.2.2 7.6.2.2.3 7.6.2.2.4 7.6.2.3.1 7.6.2.3.2 7.6.2.3.3 7.6.2.3.4 7.6.2.4.1 7.6.2.4.2 7.6.2.4.3 7.6.2.4.4 7.6.2.5.1 7.6.2.5.2 7.6.2.5.3 7.6.2.5.4 7.6.2.6.1 7.6.2.6.2 7.6.2.6.3 7.6.2.6.4 7.6.2.7.1 7.6.2.7.2 7.6.2.7.3 7.6.2.7.4 7.6.2.8.1 7.6.2.8.2 7.6.2.8.3 7.6.2.8.4 7.6.3.7.1 7.6.3.1.2 7.6.3.1.3 7.6.3.1.4 7.6.3.2.1 7.6.3.2.2 7.6.3.2.3 7.6.3.2.4 7.6.3.3.1 7.6.3.3.2 7.6.3.3.3 7.6.3.3.4 7.6.3.4.1 7.6.3.4.2 7.6.3.4.3 7.6.3.4.4 7.6.3.5.1 7.6.3.5.2 7.6.3.5.3 7.6.3.5.4 7.6.3.6.1 7.6.3.6.2 7.6.3.6.3 7.6.3.6.4 7.6.3.7.1 7.6.3.7.2 7.6.3.7.3 7.6.3.7.4 7.6.3.8.1 7.6.3.8.2 7.6.3.8.3 7.6.3.8.4 7.6.4.1.1 7.6.4.1.2 7.6.4.1.3 7.6.4.1.4 7.6.4.2.1 7.6.4.2.2 7.6.4.2.3 7.6.4.2.4 7.6.4.3.1 7.6.4.3.2 7.6.4.3.3 7.6,4.3.4 7.6.4.4.1 7.6.4.4.2 7.6.4.4.3 7.6.4.4.4 7.6.4.5.7 7.6.4.5.2 7.6.4.5.3 7.6.4.5.4 7.6.4.6.1 7.6.4.6.2 7.6.4.6.3 76.4.6.4 7.6.4.7.1 7.6.4.7.2 7.6.4.7.3 7.6.4.7.4 7.6.4.8.1 7.6.4.8.2 7.6.4.8.3 7.6.4.8.4

227

Table 1 - continued

7.7.1.1.1 7.7.1.1.2 7.7.1.1.3 7.7.1.1.4 7.7.1.2.1 7.7.1.2.2 7.7.1.2.3 7.7.1.2.4 7.7.1.3.1 7.7.1.3.2 7.7.1.3.3 7.7.1.3.4 7.7.1.4.1 7.7.1.4.2 7.7.1.4.3 7.7.1.4.4 7.7.1.5.1 7.7.1.5.2 7.7.1.5.3 7.7.1.5.4 7.7.1.6.1 7.7.16.2 7.7.1.63 7.7.1.6.4 7.7.1.7.1 7.7.1.7.2 7.7.1.7.3 7.7.1.7.4 7.7.1.8.1 7.7.1.8.2 7.7.1.8.3 7.7.1.8.4 7.7.2.1.1 7.7.2.1.2 7.7.2.1.3 7.7.2.1.4 7,7.2.2.1 7.7.2.2.2 7.7.2.2.3 7.7.2.2.4 7.7.2.3.1 7.7.2.3.2 7.7.2.3.3 7.7.2.3.4 7.7.2.4.1 7.7.2.4.2 7.7.2.4.3 7.7.2.4.4 7.7.2.5.1 7.7.2.5.2 7.7.2.5.3 7.7.2.5.4 7.7.2.6.1 7.7.2.6.2 7.7.2.6.3 7.7.2.6.4 7.7.2.7.1 7.7.2.7.2 7.7.2.7.3 7.7.2.7.4 7.7.2.8.1 7.7.2.8.2 7.7.2.8.3 7.7.2.5.4 7.7.3.1.1 7.7.3.1.2 7.7.3.1.3 7.7.3.1.4 7.7.3.2.1 7.7.3.2.2 7.7.3.2.3 7.7.3.2.4 7.7.3.3.1 7,7.3.3.2 7.7.3.3.3 7.7.3.3.4 7.7.3.4.1 7.7.3.4.2 7.7.3.4.3 7.7.3.4.4 7.7.3.5.1 7.7.3.5.2 7.7.3.5.3 7.7.3.5.4 7.7.3.6.1 7.7.3.6.2 7.7.3.6.3 7.7.3.6.4 7.7.3.7.1 7.7.3.7.2 7.7.3.7.3 7.7.3.7.4 7.7.3.8.1 7.7.3.8.2 7.7.3.8.3 7.7.3.8.4 7.7.4.1.1 7.7 4.1.2 7.7: 4.1.3 7.7.4.1.4 7.7.4.2.1 7.7.4.2.2 7.7.4.2.3 7.7.4.2.4 7.7.4.3.7 7.7.4.3.2 7.7.4.3.3 7.7.4.3.4 7.7.4.4.1 7.7.4.4.2 7.7.4.4.3 7.7.4.4.4 7.7.4.5.1 7.7.4.5.2 7.7.4.5.3 7.7.4.5.4 7.7.4.6.1 7.7.4.6,2 7.7.4.6.3 7.7.4.6.4 7.7.4.7.1 7.7.4.7.2 7.7.4.7.3 7.7.4.7.4 7.7.4.8.1 7.7.4.8.2 7.7.4.8.3 7.7.4.8.4 7.8.1.1.1 7.8.1.1.2 7.8.1.1.3 7.8.1.1.4 7.8.1.2.I 7.8.1.2.2 7.8.1.2.3 7.8.1.2.4 7.8.1.3.1 7.8.1.3.2 7.8.1.3.3 7.8.1.3.4 7.8.1.4.1 7.8.1.4.2 7.8.1.4.3 7.8.1.4.4 7.8.3.5.1 7.8.1.5.2 7.8.1.5.3 7.8.1.5.4 7.8.1.6.1 7.8.1.6.2 7.8.1.6.3 7.8.1.6.4 7.8.1.7.1 7.8.1.7.2 7.8.1.7.3 7.8.1.7.4 7.8.1.8.1 7.8.1.8.2 7.8.1,8.3 7.8.1.8.4 7.8.2.1.1 7.8.2.1.2 7.8.2.1.3 7.8.2.1.4 7.8.2.2.1 7.8.2.2.2 7.8.2.2.3 7.8.2.2.4 7.8.2.3.1 7.8.2.3.2 7.8.2.3.3 7.8.2.3.4 7.8.2.4.1 7.8.2.4.2 7.8.2.4.3 7.8.2.4.4 7.8.2.5.1 7.8.2.5.2 7.8.2.5.3 7.8.2.5.4 7.8.2.6.1 7.8.2.6.2 7.8.2.6.3 7.8.2.6.4 7.8.2.7.1 7.8.2.7.2 7.8.2.7.3 7.8.2.7.4 7.8.2.8.1 7.82.8.2 7.8.2.8.3 7.8.2.8.4 7.8.3.1.1 7.8.3.1.2 7.8.3.1.3 7.8.3.1.4 7.8.3.2.1 7.8.3.2.2 7.8.3.2.3 7.8.3.2.4 7.8.3.3.1 7.8.3.3.2 7.8.3.3.3 7.8.3.3 7.8.3.4.1 7.8.3.4.2 7.8.3.4.3 7.8.3.4.4 7.8.3.5.1 7.8.3.5.2 7.8.3.5.3 7.8.3.5.4 7.8.3.6.1 7.8.3.6.2 7.8.3.6.3 7.8.3.6.4 7.8.3.7.1 7.8.3.7.2 7.8.3.7.3 7.8.3.7.4 7.8.3.5.1 7.8.3.8.2 7.8.3.8.3 7.8.3.S 4 7.8.4.1.1 7.8.4.1.2 7.8.4.1.3 7.8.4.1.4 7.8.4.2.1 7.8.4.2.2 7.8.4.2.3 7.8.4.2.4 7.8 4.3.1 7.8.4.3.2 7.8.4.3.3 7.8.4.3.4 7.8.4.4.1 7.8.4.4.2 7.8.4.4.3 7.8.4.4.4 7.5.4.5.1 7.8.4.5.2 7.8.4.5.3 7.8.4.5.4 7.8.4.6.I 7.8.4.6.2 7.8.4.6.3 7.8.4.6 4 7.8.4.7.1 7.8.4.7.2 7.8.4.7.3 7.8.4.7.4 7.8.4.8.1 7.8.4.8.2 7.8.4.8.3 7.8.4.S.4

228

Table 1 - continued

8.1.1.1.1 8.1.1.1.2 8.1.1.1.3 8.1.i.1.4 8.1.1.2.1 8.1.1.2.2 8.1.1.2.3 8.1.1.2.4 8.1.1.3.1 8.1.1.3.2 8.1.1.3.3 8.1.1.3.4 8.1.1.4.1 8.1.1.4.2 8.1.1.4.3 8.1.1.4.4 8.1.1.5.1 8.1.1.5.2 8.1.7.5.3 8.1.1.5.4 8.1.1.6.1 8.1.1.6.2 8.1.1.6.3 8.1.1.6.4 8.1.1.7.1 8.1.1.7.2 8.1.1.7.3 8.1.1.7.4 8.1.1.8.1 8.1.1.8.2 8.1.1.8.3 8.1.1.8.4 8.1.2.1.1 8.1.2.1.2 8.1.2.1.3 8.1.2.1.4 8.1.2.2.1 8.1.2.2.2 8.1.2.2.3 8.1.2.2.4 8.1.2.3.1 8.1.2.3.2 8.1.2.3.3 8.1.2.3.4 8.1.2.4.1 8.1.2.4.2 8.1.2.4.3 8.1.2.4.4 8.1.2.5.1 8.1.2.5.2 8.1.2.5.3 8.1.2.5.4 8.1.2.6.I 8.1.2.6.2 8.1.2.6.3 8.1.2.6.4 8.1.2.7.1 8.1.2.7.2 8.1.2.7.3 8.1.2.7.4 8.1.2.8.1 8.1.2.8.2 8.1.2.8.3 8.1.2.8.4 8.1.3.1.1 8.1.3.1.2 8.1.3.1.3 8.1.3.1.4 8.1.3.2.1 8.1.3.2.2 8.1.3.2.3 8.1.3.2.4 8.1.3.3.1 8.1.3.3.2 8.1.3.3.3 8.1.3.3.4 8.1.3.4.1 8.1.3.4.2 8.1.3.4.3 8.1.3.4.4 8.1.3.5.1 8.1.3.5.2 8.1.3.5.3 8.1.3.5.4 8.1.3.6.1 8.1.3.6.2 8.1.3.6.3 8.1.3.6.4 8.1.3.7.1 8.1.3.7.2 8.1.3.7.3 8.1.3.7.4 8.1.3.8.1 8.1.3.8.2 8.1.3.8.3 8.1.3.8.4 8.1.4.1.1 8.1.4.1.2 8.1.4.1.3 8.1.4.1.4 8.1.4.2.1 8.1.4.2.2 8.1.4.2.3 8.1.4.2.4 8.1.4.3.1 5.1.4.3.2 8.1.4.3.3 8.1.4.3.4 8.1.4.4.1 8.1.4.4.2 8.1.4.4.3 8.1.4.4.4 8.1.4.5.1 8.1.4.5.2 8.1.4.5.3 8.1.4.5.4 8.1.4.6.1 8.1.4.6.2 8.1.4.6.3 8.1.4.6.4 8.1.4.7.1 8.1.4.7.2 8.1.4.7.3 8.1.4.7.4 8.1.4.8.1 8.1.4.8.2 8.1.4.8.3 8.1.4.8.4 8.2.1.1.1 8.2.1.1.2 8.2.1.1.3 8.2.1.1.4 8.2.1.2.1 8.2.1.2.2 8.2.1.2.3 8.2.1.2.4 8.2.1.3.1 8.2.1.3.2 8.2.1.3.3 8.2.1.3.4 8.2.1.4.1 8.2.1.4.2 8.2.1.4.3 8.2.1.4.4 8.2.1.5.1 8.2.1.5.2 8.2.1.5.3 8.2.1.5.4 8.2.1.6.1 8.2.1.6.2 8.2.1.6.3 8.2.1.6.4 8.2.1.7.1 8.2.1.7.2 8.2.1.7.3 8.2.1.7.4 8.2.1.8.1 8.2.1.B.2 8.2.1.8.3 8.2.1.8.4 8.2.2.1.1 8.2.2.1.2 8.2.2.1.3 8.2.2.1.4 8.2.2.2.1 8.2.2.2.2 8.2.2.2.3 8.2.2.2.4 8.2.2.3.1 8.2.2.3.2 8.2.2.3.3 8.2.2.3.4 8.2.2.4.1 8.2.1.4.2 8.2.2.4.3 8.2.2.4.4 8.2.2.5.1 8.2.2.5.2 8.2.2.5.3 8.2.2.5.4 8.2.2.6.1 8.2.2.6.2 8.2.2.6.3 8.2.2.6.4 8.2.2.7.1 8.2.2.7.2 8.2.2.7.3 8.2.2.7.4 82.2.8.1 8.2.2.8.2 8.2.2.8.3 8.2.2.8.4 8.2.3.1.1 8.2.3.1.2 8.2.3.1.3 8.2.3.1.4 8.2.3.2.1 8.2.3.2.2 8.2.3.2.3 8.2.3.2.4 8.2.3.3.1 8.2.3.3.2 8.2.3.3.3 8.2.3.3.4 8.2.3.4.1 8.2.3.4.2 8.2.3.4.3 8.2.3.4.4 8.2.3.5.1 8.2.3.5.2 8.2.3.5.3 8.2.3.5.4 8.2.3.6.1 8.2.3.6.2 8.2.3.6.3 8.2.3.6.4 8.2.3.7.1 8.2.3.7.2 8.2.3.7.3 8.2.3.7.4 8.2.3.8.1 8.2.3.8.2 8.2.3.8.3 8.2.3.8.4 8.2.4.1.1 8.2.4.1.2 8.2.4.1.3 8.2.4.1.4 8.2.4.2.1 8.2.4.2.2 8.2.4.2.3 8.2.4.2.4 8.2.4.3.1 8.2.4.3.2 8.2.4.3.3 8.2.4.3.4 8.2.4.4.1 8.2.4.4.2 8.2.4.4.3 8.2.4.4.4 8.2.4.5.1 8.2.4.5.2 8.2.4.5.3 8.2.4.5.4 8.2.4.6. and 8.2.4.6.2 8.2.4.6.3 8.2.4.6.4 8.2.4.7.1 8.2.4.7.2 8.2.4.7.3 8.2.4.7.4 8.2.4.8.1 8.2.4.8.2 8.2.4.8.3 8.2.4.8.4

229

Table 1 - continued

8.3.1.1.1 8.3.1.1.2 8.3.1.1.3 8.3.1.1.4 8.3.1.2.1 8.3.1.2.2 8.3.1.2.3 8.3.1.2.4 8.3.1.3.1 8.3.1.3.2 8.3.1.3.3 8.3.1.3.4 8.3.1.4.1 8.3.1.4.2 8.3.1.4.3 8.3.1.4.4 8.3.1.5.1 8.3.1.5.2 8.3.1.5.3 8.3.1.5.4 8.3.1.6.1 8.3.1.6.2 8.3.1.6,3 8.3.1.6.4 8.3.1.7.1 8.3.1.7.2 8.3.1.7.3 8.3.1.7.4 8.3.1.8.1 8.3.1.8.2 8.3.1.8.3 8.3.1.8.4 8.3.2.1.1 8.3.2.1.2 8.3.2.1.3 8.3.2.1.4 8.3.2.2.1 8.3.2.2.2 8.3.2.2.3 8.3.2.2.4 8.3.2.3.1 8.3.2.3.2 8.3.2.3.3 8.3.2.3.4 8.3.2.4.1 8.3.2.4.2 8.3.2.4.3 8.3.2.4.4 8.3.2.5.1 8.3.2.5.2 8.3.2.5.3 8.3.2.5.4 8.3.2.6.1 8.3.2.b.2 8.3.2.6.3 8.3.1.6.4 8.3.2.7.1 8.3.2.7.2 8.3.2.7.3 8.3.2.7.4 8.3.2.8.1 8.3.2.8.2 8.3.2.8.3 8.3.2.8.4 8.3.3.1.1 8.3.3.1.2 8.3.3.1.3 8.3.3.1.4 8.3.3.2.1 8.3.3.2.2 8.3.3.2.3 8.3.3.2.4 8.3.3.3.1 8.3.3.3.2 8.3.3.3.3 8.3.3.3.4 8.3.3.4.1 8.3.3.4.2 8.3.3.4.3 8.3.3.4.4 8.3.3.5.1 8.3.3.5.2 8.3.3.5.3 8.3.3.5.4 8.3.3.6.1 8.3.3.6.2 8.3.3.6.3 8.3.3.6.4 8.3.3.7.1 8.3.3.7.2 8.3.3.7.3 8.3.3.7.4 8.3.3.8.1 8.3.3.8.2 8.3.3.8.3 8.3.3.8.4 8.3.4.1.1 8.3.4.1.2 8.3.4.1.3 8.3.4.1.4 8.3.4.2.1 8.3.4.2.2 8.3.4.2.3 8.3.4.2.4 8.3.4.3.1 8.3.4.3.2 8.3.4.3.3 8.3.4.3.4 8.3.4.4.1 8.3.4.4.2 8.3.4.4.3 8.3.4.4.4 8.3.4.5.1 8.3.4.5.2 8.3.4.5.3 8.3.4.5.4 8.3.4.6.1 8.3.4.6.2 8.3.4.6.3 8.3.4.6.4 8.3.4.7.1 8.3.4.7,2 8.3.4.7.3 8.3.4.7.4 8.3.4.8.1 8.3.4.8.2 8.3.4.83 8.3.4.8.4 8.4.1.1.1 8.4.1.1.2 8.4.1.1.3 8.4.1.1.4 8.4.1.2.1 8.4.1.2.2 8.4.1.2.3 8.4.1.2.4 8.4.1.3.1 8.4.1.3.2 8.4.1.3.3 8.4.1.3.4 8.4.1.4.1 8.4.1.4.2 8.4.1.4.3 8.4.1.4.4 8.4.1.5.1 8.4.1.5.2 8.4.1.5.3 8.4.1.5.4 8.4.1.61 8.4.1.6.2 8.4.1.6.3 8.4.1.6.4 8.4.1.7.1 8.4.1.7.2 8.4.1.7.3 8.4.1.7.4 8.4.1.8.1 8.4.1.8.2 8.4.1.8.3 8.4.1.8.4 8.4.2.1.1 8.4.2.1.2 8.4.2.1.3 8.4.2.1.4 8.4.2.2.1 8.4.2.2.2 8.4.2.2.3 8.4.2.2.4 8.4.2.3.1 8.4.2.3.2 8.4.2.3.3 8.4.2.3.4 8.4.2.4.1 8.4.2.4.2 8.4.2.4.3 8.4.2.4.4 8.4.2.5.1 8.4.2.5.2 8.4.2.5.3 8.4.2.5.4 8.4.2.6.1 8.4.2.6.2 8.4.2.6.3 8.4.2.6.4 8.4.2.7.1 8.4.2.7.2 8.4.2.7.3 8.4.2.7.4 8.4.2.8.1 8.4.2.8.2 8.4.2.8.3 8.4.2.8.4 8.4.3.1.1 8.4.3.1.2 8.4.3.1.3 8.4.3.1.4 8.4.3.2.1 8.4.3.2.2 8.4.3.2.3 8.4.3.2.4 8.4.3.3.1 8.4.3.3.2 8.4.3.3.3 8.4.3.3.4 8.4.3.4.1 8.4.3.4.2 8.4.3.4.3 8.4.3.4.4 8.4.3.5.1 8.4.3.5.2 8.4.3.5.3 8.4.3.5.4 8.4.3.6.1 8.4.3.6.2 8.4.3.6.3 8.4.3.6.4 8.4.3.7.1 8.4.3.7.2 8.4.3.7.3 8.4.3.7.4 8.4.3.8.1 8.4.3.8.2 8.4.3.8.3 8.4.3.8.4 8.4.4.1.1 8.4.4.1.2 8.4.4.1.3 8.4.4.1.4 8.4.4.2.1 8.4.4.2.2 8.4.4.2.3 8.4.4.2.4 8.4.4.3.1 8.4.4.3.2 8.4.4.3.3 8.4.4.3.4 8.4.4.4.1 8.4.4.4.2 8.4.4.4.3 84.4.4.4 8.4.4.5.1 8.4.4.5.2 8.4.4.5.3 8.4.4.5.4 8.4.4.6.1 8.4.4.6.2 8.4.4.6.3 8.44.6.4 8.4.4.7.1 8.4.4.7.2 8.4.4.7.3 8.4.4.7.4 8.4.4.8.1 8.4.4.8.2 8.4.4.8.3 8.4.4.8.4

230

Table 1 - continued

8.5.1.1.1 8.5.1.1.2 8.5.1.1.3 8.5.1.1.4 8.5.1.2.1 8.5.1.2.2 8.5.7.2.3 8.5.1.2.4 8.5.1.3.1 8.5.1.3.2 8.5.1.3.3 8.5.1.3.4 8.5.1.4.1 8.5.1.4.2 S.5.1.4.3 8.5.1.4.4 8.5.1.5.1 8.5.1.5.2 8.5.1.5.3 8.5.1.5.4 8.5.1.6.1 8.5.1.6.2 8.5.1.6.3 8.5.1.6.4 8.5.1.7.1 8.5.1.7.2 8.5.1.7.3 8.5.1.7.4 8.5.1.8.1 8.5.1.8.2 8.5.1.8.3 8.5.1.8.4 8.5.2.1.1 8.5.2.1.2 8.5.2.1.3 8.5.2.1.4 8.5.2.2.1 5.5.2.2.2 8.5.2.2.3 8.5.2.2.4 8.5.2.3.1 8.5.2.3.2 8.5.2.3.3 8.5.2.3.4 8.5.2.4.1 8.5.2.4.2 8.5.2.4.3 8.5.2.4.4 8.5.2.5.1 8.5.2.5.2 8.5.2.5.3 8.5.2.5.4 8.5.2.6.1 8.5.2.6.2 8.5.36.3 8.5.2.6.4 8.5.2.7.1 8.5.2.7.2 8.5.1.7.3 8.5.2.7.4 8.5.2.8.1 8.5.2.8.2 8.5.2.8.3 8.5.2.8.4 8.5.3.1.1 8.5.3.1.2 8.5.3.1.3 8.5.3.1.4 8.5.3.2.1 8.5.3.2.2 8.5.3.2.3 8.5.3.2.4 8.5.3.3.1 8.5.3.3.2 8.5.3.3.3 8.5.3.3.4 8.5.3.4.1 8.5.3.4.2 8.5.3.4.3 8.5.3.4.4 8.5.3.5.1 8.5.3.5.2 8.5.3.5.3 8.5.3.5.4 8.5.3.6.1 8.5.3.6.2 8.5.3.6.3 8.5.3.6.4 8.5.3.7.1 8.5.3.7.2 8.5.3.7.3 8.5.3.7.4 8.5.3.8.1 8.5.3.8.2 8.5.3.83 8.5.3.8.4 8.5.4.1.1 8.5.4.1.2 8.5.4.1.3 8.5.4.1.4 8.5.4.2.1 8.5.4.2.2 8.5.4.2.3 8.5.4.2.4 8.5.4.3.1 8.5.4.3.2 8.5.4.3.3 8.5.4.3.4 8.5.4.4.1 8.5.4.4.2 8.5.4.4.3 8.5.4.4.4 8.5.4.5.1 8.5.4.5.2 8.5.4.5.3 8.5.4.5.4 8.5.4.6.1 8.5.4.6.2 8.5.4.6.3 8.5.4.6.4 8.5.4.7.1 8.5.4.7.2 8.5.4.7.3 8.5.4.7.4 8.5.4.8.1 8.5.4.8.2 8.5.4.8.3 8.5.4.8.4 8.6.1.1.1 8.6.1.1.2 86.1.1.3 8.6.1.1.4 8.6.1.2.1 8.6.1.2.2 8.6.1.2.3 8.6.1.2.4 8.6.1.3.1 8.6.1.3.2 8.6.1.3.3 8.6.1.3.4 8.6.1.4.1 8.6.1.4.2 8.6.1.4.3 8.6.1.4.4 8.6.1.5.1 8.6.1.5.2 8.6.1.5.3 8.6.1.5.4 8.6.1.6.1 8.6.1.6.2 8.6.1.6.3 8.6.1.6.4 8.6.1.7.1 8.6.1.7.2 8.6.1.7.3 8.6.1.7.4 8.6.1.8.1 8.6.7.8.2 8.6.1.8.3 8.6.1.8.4 8.6.2.1.1 8.6.2.1.2 8.6.2.1.3 8.6.2.1.4 8.6.2.2.1 8.6.2.2.2 8.6.2.2.3 8.6.2.2.4 8.6.2.3.1 8.6.2.3.2 8.6.2.3.3 8.6.2.3.4 8.6.2.4.1 8.6.2.4.2 8.6.2.4.3 8.6.2.4.4 8.6.2.5.1 8.6.2.5.2 8.6.2.5.3 8.6 2.5.4 8.6.2.6.1 8.6.2.6.2 8.6.2.6.3 8.6.2.6.4 8.6.2.7.1 8.6.2.7.2 8.6.2.7.3 8.6.2.7.4 8.6.2.8.1 8.6.2.8.2 8.6.2.8.3 8.6.2.8.4 8.6.3.1.1 8.6.3.1.2 8.6.3.1.3 8.6.3.1.4 8.6.3.2.1 8.6.3.2.2 8.6.3.2.3 8.6.3.2.4 8.6.3.3.1 8.6.3.3.2 8.6.3.3.3 8.6.3.3.4 8.6.3.4.1 8.6.3.4.2 8.6.3.4.3 8.6.3.4.4 8.6.3.5.1 8.6.3.5.2 8.6.3.5.3 8.6.3.5.4 8.6.3.6.1 8.6.3.6.2 8.6.3.6.3 8.6.3.6.4 8.6.3.7.1 8.6.3.7.2 8.6.3.7.3 8.6.3.7.4 8.6.3.8.1 8.6.3.8.2 8.6.3.8.3 8.6.3.8.4 8.6.4.1.1 8.6.4.1.2 8.6.4.1.3 8.6.4.1.4 8.6.4.2.1 8.6.4.2.2 8.6.4.2.3 8.6.4.2.4 8.6.4.3.1 8.6.4.3.2 8.6.4.3.3 8.6.4.3.4 8.6.4.4.1 8.6.4.4.2 8.6.4.4.3 8.6.4.4.4 8.6.4.5.1 8.6.4.5.2 8.6.4.5.3 8.6.4.5.4 8.64.6.1 8.6.4.6.2 86.4.6.3 8.6.4.6.4 8.6.4.7.1 8.6.4.7.2 8.6.4.7.3 8.6.4.7.4 8.6.4.8.1 8.6.4.8.2 8.6.4.8.3 8.6.4.8.4

231

Examples of compounds of formula VII include, but are not limited to, pharmaceutically acceptable salts and prodrugs of the compounds listed in Tables viia and viib below:

Table viia

Table viia yellow- čeni- on the X ⁴ G ⁵ G ⁶ G ⁷ J ³ J ⁴ J ⁵ J ⁶ J ⁷ 1 found HPLC rt 1.13 L1 C C C H NO. H no ₂ H 313 5.30 ' 2.13 L1 C C C NH, NO; H NO. H 328 5. 58 ' 3.13 L1 C C C MeO H H CI H 287 5.71 ' 4.13 L1 C C C CI H H CI H 291/293 6.27 ' 5.13 L1 C C C SO, NH Me H H cf ₃ H 384 5.82 ' 13.6 L1 C C C SO ₂ NHMe H H CI H 350 5:43 ' 7.13 L1 C C C SO ₂ NHMe H H H H 316 5.25 ' 8.13 L1 C C C SO ₂ NH (n-Pr) H H H H 37: 6.12 ' 9.13 L1 C C C OH H H H H 239 3.97 ' 13:10 L1 C C C H Me H Me H 251 6 .10 ' 13:11 L1 C C C H br H H H 301/303 5.90 ' 13:12 L1 C C C H H NH, H H 238 4. 64 ' 13:13 L1 C C C MeO H CI MeO H 317 6:00 ' 13:14 L1 C C C C (O) NHCH ₁ - - (4-ClPh) H H H H 3 9 C 6.12 ' 13:15 L1 C C C C (0) NH-CH, - CH (4-ClPh) H H H H 404 6:42 ' 13:16 L1 C C C SO _; NHBn H H H H 392 6.17 ' 13:17 L1 C C C SO, NH, H H H H 302 4:44 ' 13:18 L1 C C C Me Me Me M e Me 293 5.8 ' 13:19 L1 C C C CO _: Et CO? E t H H H 367 6:00 ' 13:20 L1 C C C H Me NHAc H H 294 4. 12 ' 13:21 L1 C C C C H CI H Me 305/307 6.66 ' 13:22 L1 C C C WHAT, ME H OH H H 297 4 .71 ' 13:23 L1 C C C C (O) NH, H Me H H 280 6. 89 ' 13:24 L1 C C C CO ₂ Et H OH H H 311 5. 56 ' 13:25 L1 C C C H. H NO. H H 268 4 .81 '

232

Table viia compound X ⁴ G ⁵ G ⁶ G ⁷ J ³ J ⁴ J ⁵ J ⁶ J ⁷ M- í found HPLC rt 13:26 L1 C C C C (O) NH (2,4- -di fluoro-Ph) H H H H 378 5, 56 ' 13:27 L1 C C C H C1 H C1 H 291/293 6:43 ' 13:28 L1 C C C H OH H H H 239 4:41 ' 13:29 L1 C C C H co ₂ h H 3r H 345/347 5:37 ' 13:30 L1 C C C MeO MeO H CHO H 31 ' 5.12 ' 13:31 L1 C C C no ₂ H H H H 268 4 .78 ' 13:32 L1 C C C ph H H H H 299 6.75 ' 13:33 L1 C C C CO, Et H H H H 295 5:32 ' 13:34 L1 C C C H H br H H 301/303 1.6 ' 13:35 L1 C C C H C (O) Et, H H H 2 “9 4:54 ' 13:36 L1 C C C MeO H H CN H no. · C 5.18 ' 13:37 L1 C C C et H H H H 2 5 2 5.13 ' 13:38 L1 C C C no ₂ H H H Me 232 5.76 ' 13:39 L1 C C C H H nhac H H 28C 3.94 ' 13:40 L1 C C C Me Me Me Me H 279 7.7 ' 13:41 L1 C C C H ph H H H 299 2.7 ' 13:42 L1 C C C SO ₂ NH ₂ H H C1 H 336 5:37 ' 13:43 L1 C C C H H NHC (O) -CH ₂ -pyrrolidin-1-yl H H 349 5.6 ' 13 .44 L1 C C C H Me Me H H 2 o _ 5.10 ' 13:45 L1 C C C NO? H NO; H H 313 5:59 ' 13:46 L1 C C C H ch ₂ nh ₂ H H H 252 2. 35 ' 13:47 L1 C C C H F NH; H H 25c 5.8 ' 13:48 L1 C C C H ch ₂ oh H H H 253 4. 52 ' 13:49 L1 C r C br H H H H 301/303 5.72 ' 13:50 L1 C C C CH ₂ CH ₂ OH H H H H 2 5 5:51 ' 13:51 L1 C C C H H C (0) NH, H H 2 66 3. 61 ' 13:52 L1 C C C H H CN H H 248 3.64 ' 13:53 L1 C C C H CN H H H 248 3.98 ' 13:54 L1 C C C CN H H H H 248 4. 96 '

233

Table viia compound X ⁴ G ⁵ G ⁶ G ⁷ J ³ J ⁴ J ⁵ J ⁶ J ⁷ M-1 found HPLC rt 13:55 L1 C C C H NO. NH, H H 283 1.5 ' 13:56 L1 C C C iPr H H H H 265 6.8 6 ' 13:57 L1 N C C Cl null NH, H H 273 3.98 ' 13:59 L1 C C C nh. H H Cl H 272 5:44 ' 13.60 L1 C C C H Cl H F H 275 5.8 ' 13.61 L1 C C C MeO H H CN H 278 5:44 ' 13.62 L1 C C C Me H H no ₂ H 282 5.88 ' 13.63 L1 C C C H no ₂ H F H 286 4. 68 ' 13.64 L1 C C C NH, H H C0, Me H 296 5.18 ' 13.65 L1 C C C MeO H H NO; H 298 5:52 ' 13.66 L1 C C C Cl H H CF, H 325 5:42 ' 13.67 L1 C C C cf ₃ H H cf ₃ H 359 5.78 ' 1.14 L1 C C C H H F H H 241 5.9 ' 2.14 L1 C C C Cl H Cl n H 291/293 5:48 ' 3.14 L1 C C C H NH, H CO _: Me H 2.96 3:51 ' 1.15 L1 C C C H nh ₂ br H H 316/313 4. 72 '

Table viib

Table viib compound X ⁴ G ² G ³ G ⁴ J ³ J ⁴ J ⁵ J ⁵ M-I found HPLC rt 13:58 L1 C WITH C H null H CH _; . 2 4 3 5. 38

Insulin secretagogues

In one aspect, the preferred use of at least one FBPase inhibitor and at least one insulin secretagogue is described. Secretagogues are targeted to one of the three largest defects associated with diabetes, namely pancreatic β cell dysfunction. Insulin secretion agents are compounds that stimulate

234 release of insulin from pancreatic β cells and thereby increase glycemic control as seen in increased glucose tolerance and / or decreased blood glucose concentration and / or reduced hemoglobin Ale stage. These actions may include adjusting the whole body glucose supply, reducing hepatic glucose production, increasing insulin-mediated glycogenesis, reducing lipolysis, and / or other manifestations of increased insulin secretion. In some cases, the insulin release agents of the invention may also reduce circulating triglycerides and / or free fatty acids, may increase HDL cholesterol levels, may lower total cholesterol concentrations, may lower resting insulin concentrations, and may reduce insulin C-peptide levels, may decrease appetite meals and / or may delay the emptying of the digestive tract.

Examples of agents for insulin secretion are those that bind to ATP-dependent potassium channels in pancreatic β cells, causing channel closure and insulin secretion. These compounds include e.g. sulfonylureas and nonsulfonylureas.

sulfonylureas

Sulfonylureas have been widely used in clinical practice since the age of sixty. Although sulfonylureas represent the majority of NIDDM therapy for patients, four factors limit their overall success.

First, a large proportion of the population that has diabetes does not respond adequately to sulphonylurea therapy (i.e., therapy results in primary failure in 20-25% of patients) or patients treated with sulphonylurea therapy become resistant to therapeutic action (that is, therapy leads to secondary therapy). failure in about 5 to 10% of patients each year). It is understood that secondary failure leads to over stimulation of the pancreas by sulfonylurea, leading to the toxic effects of high

235 blood glucose concentrations and high lipid concentrations per β cells.

Second, sulfonylurea therapy is associated with an increased risk of severe hypoglycaemic episodes. Severe hypoglycaemic episodes are well known to pose a serious risk to the individual.

Third, chronic hyperinsulinemia is associated with increased cardiovascular disease. However, this bonding need not yet be demonstrated.

Fourth, sulfonylureas are associated with weight gain. Weight gain is undesirable in that it may lead to a deterioration of the pre-peripheral insulin sensitivity and thus to a faster progression of the disease.

The mechanism of action of sulfonylureas involves binding to a specific domain of adenosine triphosphate (ATP) -dependent potassium channels of β cells, the so-called. a sulfonylurea receptor or SURRI. By this binding, the sulfonylureas inhibit the flow of potassium ions.

Second, the key domain of the potassium channels, encoded by a separate protein subunit in the ion pore forming unit, Kirú.X. See e.g. Groop LC Diabetes Line 6: 737-754 (1992); Luna B. et al., Diabetes 26: 895-915 (1999); Babe.nk AP., Aguilar-Bryan L., Bryan J Annu. Rev. Physiol. 60: 667-87 (1998); and Aguilar-Bryan L. et al., Science 268: 423-6 (1995).

SURRI binding results in depolarization of the cell membrane and penetration of calcium ions into the cell. Calcium forms a complex with calmodulin, which then tends to act as a second mesenger that stimulates exocytosis of insulin-containing granules, ultimately leading to the release of insulin into the circulation. Two of the key metabolic effects of insulin are an increase in tissue glucose levels such as muscles and suppression of hepatic glucose production, the overall result of which is improved glycemic control.

236

Examples of sulfonylureas include compounds such as glyburide, glimeperide and glipizide. Sulfonylureas are well known and are described e.g. in U.S. Pat. U.S. Patents 2,968,158, 3,097,242, 3,454,635, 3,501,495, 3,654,357, 3,668,215, 3,669,966 and 3,708,486.

Particularly preferred sulfonylureas are compounds of formula XV:

ABOUT

II

SO ₂ NHCNH-B (XV)

A is selected from the group consisting of hydrogen, halogen, alkyl, alkanoyl, aryl, aralkyl, heteroaryl and cycloalkyl and B is selected from the group consisting of alkyl, cycloalkyl and heterocyclic alkyl.

Particularly preferred are the following sulfonylureas: glyburide, glisoxepide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, gliclazide, gliquidone, glyhexamide, fenbutamide, tolcyclamide and glimepiride.

Non-sulfonylureas

Short-acting non-sulfonylureas, nategliride and repaglinide from the benzoic and phenylpropionic series, stimulate the release of insulin from the pancreas by a mechanism similar to that of sulfonylureas. Panten li. et al.,

Biochem. Pharmacol. 38: 1217-1229 et al., J.

Med. Chem. 41: 5219-5246 (1998);

Priscilla A. et al

However, repaglinide diabetes is mediated by binding to a sulfonylurea receptor binding site other than

Fuhlendorff J. et al., Diabetes for Glyburide.

Another class of non-sulfonylureas that mediate insulin release through the closure of potassium imidazolines (e.g., midaglizole, BTS-67582, isaglidol, channels are deriglidol,

(Idazoxane, efaroxane and fluparoxane). Rustenbeck I. et al., Ann. NY Acad. Sci. 881: 229-240 (1999); Mourtada M. et al., Br. J. Phartiiacol. 127: 1279-1287 (1999); Le Brigand L. et al., Br. J. Pharmacol. 128: 1021-1026 (1999). These compounds are known to bind to the pore-forming group in the channels (Kirôx), rather than to the sulfonylurea binding site (SURI).

Examples of non-sulfonylureas include compounds such as benzoic acid derivatives (mitiglinide and repaglinide), phenylpropionic acid derivatives (e.g., nateglinide), and imidazoline derivatives (e.g., BTS-67582 (Knoll Pharmaceuticals, Co.), midaglizole, isaglidol, deriglidol, idazoxane, efaroxane and fluparoxane). Many of these non-sulfonylureas are described in the following patents and publications: WO 91/03247, WO 93/0337, WO 96/34870, WO 97/31019, WO 98/27078, WO 98/56378, WO 98/07681, WO 00/71117, WO 01126639, U.S. Pat 5,631,224 and U.S. Pat. Particularly preferred non-sulfonylureas include mitiglinide, BTS-67582, repaglinide, and nateglinide.

GLP-1 receptor agonists

Another class of secretagogues is represented by GLP-1 receptor agonists that include GLP-1 and GLP-1 fragments, including analogs and functional derivatives thereof, as well as peptidomimetics. These compounds act by binding to the GLP-1 receptor in pancreatic β cells and thereby increasing glucose-stimulated insulin release through a cAMP-dependent mechanism. This class of insulin secretion agents is described e.g. in U.S. Pat. Nos. 5,118,666, 5,120,712, 5,545,618, 5,512,549, 5,574,008, 5,614,492, 5,631,224, 5,705,483, 5,766,620, 5,908,830, 5,958,909, 5,977,071, 5 981 488 and PCT application no. WO 87/06941 and WO 99/25728. Examples of these types of secretagogues include NN-2211 (Scios Inc./Novo Nordisk A / S), exendin, and exedin agonists.

DPP-IV inhibitors

238

A third class of insulin secretagogues are those that prolong the half-life of GLP-1. These drugs include dipeptidyl peptidase (DPP) -IV inhibitors (e.g. NVP-DPP728, P32 / 98 (Probiodrug) and valine pyrrolidide), preventing DPP-IV mediated inactivation of GLP-1 and consequently prolonging its biological action. These compounds are described e.g. in the following patents and publications: German Patent Publication no. DE 2 9909208, DE 2 9909210 and DE 2 990921 1, U.S. Pat. Nos. 6,011,155, 6,107,317, 6,110,949 and 6,124,305 and PCT applications no. WO 97/40832, WO 98/19998, WO 99/61431, WO 99/67279 and WO 00/34241.

Other insulin secretagogues include glucagon-like peptide (GLP-1) receptor agonists, fragments and analogs thereof, and functional derivatives of GLP-1 and fragments thereof.

GLP-1 is incretin, which is generated by post-translational cleavage of proglucagon in L-cells of the lower gastrointestinal tract in response to food. The primary site of action associated with these insulin secretion agents is pancreatic β cells, after they bind to the GLP-1 receptor, which increases glucose-stimulated insulin release via a cAMP-mediated mechanism. Nauck M.A. et al., Diabetes Line 21: 1925-31 (1998). The duration of action of GLP-1 is short due to its rapid metabolism with DPP-IV.

GLP-1 analogs are described which increase resistance to metabolism and thereby increase the half-life in vivo. See e.g. Sturis J. et al., Diabetes 40 (suppl. 1) 943-P (2000). GLP-1 analogues that increase the binding affinity for the GLP-1 receptor are also known. See e.g. Xiao Q. et al., Diabetes 46 (Suppl. 1) 941-P (2000). Examples of GLP-1 agonists include NN-2211 (Ocios Inc./Novo Nordisk A / S) and exendin.

A third class of insulin secretagogues includes those compounds that enhance the pharmacodynamics of the half-life of GLP-1. DPP-IV inhibitors (e.g. NVP-DPP728) have been shown to increase plasma GLP-1 levels and thereby prolong the stimulatory effect on insulin secretion.

239

See e.g. Holst JJ, Deacon CF Diabetes 47: 1663-70 (1998), and Hughes T.E. et al., Biochemistry 38: 11597-603 (1999).

Examples of preferred DPP-IV inhibitors include valine pyrrolidide, NVP-DPP728 and P32 / 98 (Probiodrug).

Preferred insulin secretagogues are the compounds disclosed in the following publications and patents:

1. Sulfonylureas:

U. U.S. Pat. 2,968,158, 3,097,242, 3,454,635, 3,501,495,

654,357, 3,668,215, 3,669,966 and 3,708,486.

2. Non-sulphonylureas:

U. Nos. 5,631,224 and 5,741,926; PCT Publication no. WO 91/03247, WO 93/00337, WO 96/34870, WO 97/31019, WO 98/07681, WO 98/27078, WO 98156378, WO 00171117 and WO 01/26639.

3. GLP-1 receptor agonists:

U. U.S. Pat. 5,118,666, 5,120,712, 5,512,549, 5,545,618,

(+420) 574 008, 5 614 492, 5 631 224, 5 705 483, 5 766 620,

908 830, 5 958 909, 5 977 071 and 5 981 488 and PCT application no.

WO 87/06941 and WO 99/25728.

4. DPP-IV Inhibitors:

Germán patent Publication no. DE 2 9909208. DE 2 9909210 and DE 2 9909211; U. U.S. Pat. 6 011 155 6 107 317 6 110,949 a 6 124 305, a PCT Publication Nos. . WO 97/40832, WO 98/19998,

WO 99/61431, WO 99/67278, WO 99/67279 and WO 00/34241.

While these publications disclose a large number of insulin secretory agents, the present invention is not limited thereto and any insulin secretagogue may be used.

The insulin secretagogues used in this invention typically exhibit activity in assays that are known to be useful in characterizing compounds that function as insulin secretagogues. Assays include, but are not limited to,

240 which are e.g. to identify the following activities: (a) release of insulin from pancreatic islets of β cell lines (Example H), (b) insulin secretion in rats (Example L), (c) lowering the glucose concentration in non-feeding rats (Example I) (d) intravenous or oral glucose tolerance in non-feeding rats (Examples J and K), (e) inhibition of ATP-dependent potassium channels in pancreatic β cells (Example M), (f) binding to sulfonylurea receptors ( Example N), (g) binding to the GLP-1 receptor and (h) inhibition

DPP-IV (Example Q). Other assays include those described by Bergsten P. et al., J. Biol. Chem. 269: 1041-45 (1994); Frodin M. et al., J. Biol. Chem. 270: 7882-89 (1995);

Dickinsori K. et al., Eur. J. Pharmacol. 339: 69-76 (1997);

Ladriere L. et al., Eur. 3. Pharmacol. 335: 227-234 (1997);

Edwards G., Weston A. H., Ann. Rev. Pharmacol. Toxicol. 33:

597-637 (1993); Aguilar-Bryan L. et al., Science 268: 423-6 (1995); Thorens B. et al., Diabetes 42: 1678-82 (1993); Deacon

C.F., Hughes T.E., Holst J.J. Diabetes 47: 764-9 (1998).

Particularly preferred insulin secretagogues are glyburide, glipizide and glimepiride, mitiglinide, BTS-67582, repaglinide and nateglinide.

As expected from their mechanism of action, insulin secretagogues are primarily effective in the early stages of NIDDM, during which all or part of the ability of insulin to secrete in the pancreas is protected. The efficacy of the sulfonylureas is e.g. significantly reduced in advanced stages of NIDDM, which is associated with severely impaired β cell function and thus the disappearance of insulin secretion. Groop LC Diabetes Line 15: 737-54 (1992). The dependence of these drugs on the functioning of β cells is reflected in their percentage primary and secondary failure (about 20 to 25% and about 5 to 10% per year). Gerich JE N. Engl. J. Med. 321: 1231-45 (1989).

Insulin secretion therapy generally fails to restore euglycemia or normalize hemoglobin Ale (HbA1c) concentrations in patients. For example, it has been shown that the second gene

241 ration sulfonylureas decreases hemoglobin Ale values by an average of 0.8 to 1.7% except for lower blood glucose values of 50-70 mg / dl. See e.g. Dills DT et al., Horm. Metab. Res. 28: 426-9 (1996); Mooradian AD et al., Diabetes Line 19: 883-4 (1996); Simonson DC et al., Diabetes Line 20: 597-606 (1997). In advanced NIDDM patients, the mean reduction is greater than 140 mg / dl, and in more than 3%, these parameters are typically needed to restore these parameters to normal levels.

Unlike insulin secretagogues, FBPase inhibitors are effective in both the early and advanced stages of diabetes. In animal studies, FBPase inhibitors significantly reduce blood glucose concentration in hyperinsulinemic db / db mice (early diabetes model (Example V), as well as in advanced diabetes models: insulinopenic streptozocin-induced diabetic mice). This model was also extensively used as a model for type I diabetes, suggesting the potential utility of FBPase receptors in this case. In ZDF rats, FBPase inhibitors are effective as in early stage diabetes (8-9 weeks old, Example W) as well as in advanced stage diabetes (16 weeks old).

Based on the pharmacological profile of the insulin secretagogues and FBPase inhibitors described above, therapy using insulin secretagogues combined with FBPase inhibitors is effective for a wide range of patients. In the early stages of diabetes, both FBPase inhibitors and insulin secretion agents are effective. Notwithstanding the well-characterized action of insulin on hepatic glucose performance, combined treatment with insulin secretagogues and FBPase inhibitors, not only provides improved glycemic diabetes (Example X), but also the failure observed with monotherapy early stage control reduces the incidence of secondary with insulin secretion agents (insulin secretion). Examples). In advanced diabetes, insulin secretagogues have a high percentage of primary failure and are only partially effective, while FBPase inhibitors retain a large

242 efficiency. The advantage of the combination in advanced diabetes is in a significant reduction in the number of inadequate therapy and in an overall increase in the degree of glycemic control. While the initial response of combination therapy in advanced diabetes may be largely due to treatment with FBPase inhibitors, a reduction in blood glucose adjusts pancreatic function and allows insulin secretion agents to become more effective over time and thus provide improved response to secretory agents in the long term. insulin and improved glycemic control.

A further significant improvement in the combination treatment with insulin secretion agents and FBPase inhibitors is the unexpectedly beneficial effect on the metabolism of sugars and / or lipids and / or proteins.

A further improvement in the combination treatment with insulin secretagogues and FBPase inhibitors is to alleviate the side effects associated with insulin secretagogue therapy and vice versa. A key consequence of insulin secretagogue therapy is hyperinsulinemia, which leads to undesirable side effects such as weight gain, worsening of insulin resistance and predisposing patients to hypoglycaemic episodes. Hyperinsulinemia may also be associated with an increased risk of macrovascular disease. Insulin secretagogues may also overstimulate the pancreas and subsequently induce β-cell degradation and thus secondary failure. Similarly, FBPase inhibitors may have undesirable side effects in humans. FBPase inhibitors may e.g. cause a transient increase in blood lactate concentration. As described in Example X, combination treatment with an FBPase inhibitor and an insulin secretagogue (glyburide) leads to an unexpected attenuation of the elevated blood lactate concentration caused by FBPase inhibitor monotherapy.

Insulin / insulin analogs

243

In another aspect of the invention, the use of an FBPase inhibitor and an insulin or insulin analog is preferred. Insulin is a polypeptide hormone (molecular weight of about 6000) that is released into the circulation from pancreatic β cells in response to key metabolic fuels such as amino acids, triangular sugars such as glyceraldehyde and most importantly glucose. The key physiological role of insulin is to regulate glucose homeostasis. Once eliminated, insulin binds to specific receptors present in cell surfaces and regulates many processes through a complex signaling cascade, including tissue glucose consumption such as muscle and fat, and inhibition of hepatic glucose production (hepatic glucose production or HGO). Insulin is believed to inhibit primarily HGO by reducing the reaction pathway of de novo glucose production or gluconeoaesis. Its action on gluconeogenesis is mediated by a multiple mechanism: (a) reducing stocks of key precursors such as glycerin, lactate and amino acids, (b) increasing the concentration of liver fructose-2,6-bisphosphate, fructose-1,6-bisphosphatase inhibitor, and ( c) decreased expression of 3 key gluconeogenic enzymes, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase and glucose-6-phosphatase. Diabetes Mellitus, eds. LeRoith D, Taylor SI, Olefsky GM, Lippincott-Raven Publishers, Philadelphia (1996).

Insulin is typically the basis for IDDM therapy. In addition, insulin is probably one of the best treatments for NIDDM. Its use has been evaluated in a number of important clinical trials conducted by random sampling. For example, insulin therapy has been shown to be effective monotherapy in the early stages of diabetes (UKPDS test) as well as in advanced stages of diabetes (VACSDM test). UK Prospective Diabetes Study group, Diabetes 44: 1249 (1995); Colwell JA Ann. Intern. Med. 124: 131 (1996). The UKPDS test found that early insulin intervention was associated with a reduction in microvascular complications and a strong trend to reduce macrovascular complications.

244

However, regular or intensive insulin therapy was unable to maintain glycemic control during the six years of the study due to a progressive increase in insulin resistance. In the VACSDM test, which included patients who failed sulfonylurea therapy, a third of patients did not achieve glycemic control and generally, the remainder required massive and multiple doses of insulin to control blood glucose. Insulin treatment causes a significant increase in body weight, which is associated with an increase in insulin resistance, hypertension and dyslipidemia, all of which are risk factors for cardiovascular disease.

Insulin is traditionally produced by purifying bovine and porcine pancreas. Advances in recombinant technology have recently enabled the production of human insulin in vitro. It is currently common practice in the United States to prescribe recombinant human insulin to all patients who start insulin therapy. A wide variety of purified insulin and insulin analogs are prescribed. Formulations with rapid, medium or long-term effects are available, as are many mixtures of the above formulations. Insulin preparations useful in the present invention include: Humulin N, Humulin N NPH, Humulin N NPH Pen, Novolin N Human Insulin Vial, Novolin N PenFill Caruridges, Novolin N Prefilled Syringe Disposable Insulin Delivery System, Humulin R Regular, Humulin R Regular Humur 50/50, Humulin 70/30, Humulin 70/30, Humulin 70/30, Humulin 70/30, Humulin 70/30, Humulin 70/30, Humulin 70/30, Humulin 70/30 Pen, Novolin 70130 Human Insulin Vials, N Novolin 70/30 Penfill Cartridges, Novolin 70/30 Pre-Disposable Insulin Delivery System, Humulin L, Humulin U, Novolin L Human Insulin Vials, IPHP II, PPH, Purified Pork NPH Isophani Insulin, Iletter III Regular (Pork), Purified Pork Regular Insulin, Iletter III, Lente (Pork), Purified Pork Lente Insulin. Other insulins

245 useful according to the invention are described in US 5 149 716, WO 92/00321 and WO 99/65941. The invention is not limited to these particular formulations, but any insulin or insulin analog administered by injection, inhalation, transdermally, orally, by an implanted pump, or by any other means may be used. Insulin analogs useful in the present invention include, but are not limited to, the following: insulin lispro, insulin aspart, insulin glargine. Some of the more recent analogs / formulations include inhaled insulins (e.g. AERx, Spiros, Aerodose) and oral insulins (e.g. Oralin, Macrulin, M2). These analogs are described in the following publications / patents: Heller SR, Amiel SA, Mansell P Diabetes Line 22: 1607-1611 (1999); Raskin P, Guthrie RA, Leiter L, Riis A, Jovanovic L. Diabetes Line 23: 583-588 (2000); Heinemann L, Linkesch R, Rave K et al.,

Diabetes Line 23: 644-649 (2000); EP-00622376; US 5,681,811 and US 5,438,040.

Preferred insulins bind to the soluble recombinant insulin receptor with a dissociation constant between 0.3 nM and 300 nM in the assay described in Kristensen C, Wiberg FC, Schaffer L, Andersen AS, J. Biol. Chem. 273: 1778-1786 (1998).

More preferably, the dissociation constants are between 0.3 nM and 30 nM.

The FBPase inhibitors of the invention are also useful in patients who have been implanted with artificial pancreas (i.e., pancreatic, e.g., recombinant human pancreatic β cells or other cells capable of producing insulin in response to elevated glucose concentrations). Methods used to identify insulin and insulin analogs with insulin-like activity are well known to those of skill in the art and include, for example, insulin receptor binding, insulin receptor tyrosine kinase activation, insulin receptor substrate phosphorylation, and interaction of these substrates with downstream signaling molecules.

Notwithstanding the known inhibitory action of insulin on gluconeogenesis, the association of an FBPase inhibitor and insulin or insulin

Surprisingly, it results in a significantly higher glycemic control than administration of only one of the agents alone. This is demonstrated in a key model of obese NIDDM patients, db / db mice as well as in the lean NIDDM patient model, Goto-Kakizaki rats (Examples Z, AA, BB and CC). In addition, glycemic control was achieved by a combination of drugs using reduced doses of insulin. Thus, the present invention allows for a safer and more effective treatment of diabetes.

A further advantage of combination therapy is that FBPase inhibitors may reduce the side effects associated with insulin therapy or insulin analogues and vice versa. A key consequence of insulin therapy and therapy with insulin analogues is hyperinsulinemia, leading to undesirable side effects such as weight gain. Increasing body weight is known to impair insulin resistance, leading to worsening of hyperinsulinemia and to the development of hypertension and dyslipidemia. Hyperlipidemia may also be associated with an increased risk of macrovascular disease. As illustrated in Examples AA and BB, combination therapy significantly reduces the weight gain observed with insulin monotherapy. Examples AA and BB also illustrate the surprising fact that co-administration of FBPase inhibitors allows a significant reduction in insulin dosages while maintaining the same glycemic control as insulin monotherapy. This insulin-saving effect is likely to reduce the risks of the aforementioned side effects associated with insulin therapy.

A further significant improvement in the combination therapy of FBPase inhibitors and insulin is an unexpected advantageous effect on the metabolism of sugars and / or lipids and / or proteins.

biguanides

Biguanidines are a series of compounds that include metformin, phenformin and buformin. These compounds have the general formula:

247 (F 1 R ² ) NC (NH) NHC (NH) NH 2. Where R ¹ and R ² include hydrogen, alkyl, aryl, aralkyl or the like, including salt and standard forms of the prodrug. Metformin has been used on the US market for the treatment of NIDDM since 1995. The mechanism of action of this class of compounds is unclear, but the main mode of action is thought to be to inhibit hepatic glucose production. Inzucchi SE, Maggs DG, Spollett GR et al., N. Engl. J. Med. 338: 867-872 (1998). All compounds of the class of biguanidines having this readily detectable activity are useful in the present invention. Preferred biguanides inhibit lactone gluconeogenesis in rat hepatocytes in the presence of insulin with IC50 values of 10 nM to 100 μΜ in the assay described in Wollen N, Bailey CJ, Biochem. Pharmacol. 37: 4353-4358 (1998). More preferred are those having an IC ₅₀ in the range of 1 μΜ and 30 μΜ. Preferred biguanides also counteract glucagon stimulated glucose production from lactate in rat hepatocytes. Yu B, Pugazhenthi S, Khandlewal RL, Biochem. Pharmacol. 48: 949-9S4 (1994). Preferred compounds have an IC _{50 of} from 0.1 to 5000 μaj. Most preferably, the compounds have an IC _{50 of} from 0.1 to 500 μΜ.

In another aspect, the use of FBPase inhibitors and biguanide is preferred. Metformin is a biguanide that has been used to treat NIDDM since 1957. For many years, it has been believed that the glucose lowering effect of metformin results from improved peripheral insulin sensitivity and decreased postprandial sugar absorption. It is now known that metformin primarily functions by reducing endogenous glucose production. Inzucchi SE, Maggs DG, Spollett GR et al., N. Engl. T. Med. 335: 867-872 (1998). There is ample evidence that the action of metformin on endogenous glucose production results from inhibition of hepatic glucogenesis. Studies in isolated infused liver and animal hepatocytes have shown that metformin reduces gluconeogenesis from a number of substrates including lactate, pyruvate, alanine, glutamine and glycerin through a mechanism that is synergistic with insulin. Wiernsperger NF and Bailey CJ Dru with S8 (suppl. 1): 31-39 (1999). Recent studies of type 2 diabetes have also suggested that

Metformin inhibits endogenous glucose production by reducing gluconeogenesis. Hundal RS, Krassak M, Laurent D et al. Diabetes 49 (suppl. 1) 154 OR (2000). The mechanism by which this inhibitory effect is exerted is still unclear and has been postulated to include a reduction in hepatic consumption of gluconeogenic precursors and / or stimulation of pyruvate kinase and thus counteract the glycolysis reaction pathway.

Metformin is one of the therapies included in the US K. Prospective Diabetes study (UKPDS), which studied whether intensive glycemic control of type 2 diabetic patients reduced the incidence of clinical complications. The results of this major three-centered study were published in 1998 and showed that while metformin initially provides adequate glycemic control, there was a gradual loss of efficacy over a six-year study period; only 41% of patients were adequately controlled at the end of the study. The results of intensive insulin and sulfonylurea therapy were similarly worrying. This research has underlined the need for new antidiabetic treatments. U.K. Prospective Diabetes Study Group Diabetes 44: 1249-1258 (1995).

Metformin (hydrochloride salt) is currently prescribed in the United States in oral tablet form (Glucophag, Bristol-Myers Squibb). Metformin is a preferred biguanide. Other biguanides useful in the present invention include phenformin and buformin. Other metformin formulations useful in the present invention include, but are not limited to, those described in the following patents / applications:

U. U.S. Pat. No. 3,174,901 discloses the phosphate, sulfate, hydrobromide, salicylate, maleic, benzoate, succinate, ethanesulfonate, fumarate, and glycolate salts of metformin;

U. U.S. Pat. No. 4,835,184 discloses a salt of p-chlorophenoxyacetic acid and metformin;

U. U.S. Pat. 6,031,004 discloses fumarate salt of merformin;

U. U.S. Pat. No. 4,028,402 discloses a salt of dichloroacetic acid and metformin;

249

French Patent no. 2320735 and 2037002 disclose metformin pamoate salt;

French Patent no. No. 2264539; 66008075 disclose the metformin orotate salt;

French Patent no. 2275199 discloses metformin (4-chlorophenoxy) isobutyrate salt;

U. U.S. Pat. No. 4,080,472 discloses the clofibrate salt of metformin;

U. U.S. Pat. No. 3,957,853 discloses metformin acetylsalicylate salt;

French Patent no. 2220256 discloses theophylline-7-acetate salt of metformin;

German patent no. 2357864 and 1967138 disclose a salt of nicotinic acid and metformin;

U. U.S. Pat. No. 3,903,141 discloses metformin adamantoate salt;

Japanese Patent no. No. 69008566 discloses a zinc-chlorophyllin salt with metformin;

Japanese Patent no. 64008237 describes a salt of hydroxy acids with metformin, including salts of hydroxy aliphatic dicarboxylic acids such as tartaric acid, tartaric acid, mesoxalic acid, and oxidized maleates;

Japanese Patent no. 63014942 discloses a salt of tannic acid and metformin;

Japanese Patent no. 87005905 and 61022071 disclose 3-methylpyrazole-5-carboxylic acid (or other 5-membered heterocyclic carboxylic acid) salt and metformin;

Romanian Patent no. 82052 discloses sulfamido aryloxyalkyl carboxylic acid salts and metformin;

Soviet Patent No. No. 992512 discloses a trimethoxybenzoic acid salt of metformin;

WO99 / 29314A1, WO99 / 47128A1, WO98 / 10786A2, EP-00976395,

WO 99/55320; WO 96/08243.

Although it is believed that metformin is used to reduce glucose in patients who have type 2 diabetes by inhibiting gluconeogenesis, combined treatment with FBPase inhi

Surprisingly, 250 bitor and metformin results in significantly higher glycemic control than when administered alone with individual agents (Example DD).

Another important advantage of the combination treatment with an FBPase inhibitor and metformin is the unexpectedly beneficial effect on the metabolism of sugars and / or lipids and / or protein.

A further advantage of combination therapy is that FBPase inhibitors can reduce the side effects associated with metformin therapy and vice versa. One of the major metabolic complications that may occur during treatment with metformin is lactic acidosis. The incidence of this side effect is about 0.03 per 1000 patients per year. Structurally close biguanide, phenformin, has been found to be associated with an increased risk of cardiovascular complications in well-reported cases (UGDP study). FBPase inhibitors may also have undesirable side effects in humans.

Α-glucosidase inhibitors

In another aspect, the preferred use of FBPase inhibitors and α-glucosidase inhibitors is described. α-Glucosidases are a family of enzymes responsible for digesting sugars in the gastrointestinal tract. Elbein AD FASEB J. 5: 3055 (1991). It is well established that inhibition of α-glucosidases decreases large onslaughts of post-prandial glucose characteristics in NIDDM and thereby improves glucose tolerance. Reaven GM, Lardinois CK, Greenfield MS et al. Diabetes Line 13: 32-36 (1990). Normally, complex sugars are digested in the proximal small intestine and low complex sugars reach the distal intestine. Treatment with α-glycosidase inhibitors prevents the digestion of complex sugars in the proximal intestine and thus delays the absorption of sugars until the complex sugars are digested by the glucosidases in the distal intestine (ileum). This delay in digestion of sugars leads to blunting

251 postprandial blood glucose and insulin peaks after meals and to smooth out daily glucose and insulin profiles.

Hillebrand I Boehme K

Frank G. et al.

Res. Exp. Med. 175: 81

The most developed of α-glucosidase inhibitors is acarbose (Beyer), a pseudotetrasaccharide of microbial origin, which has been confirmed worldwide for clinical use. Most preferred α-glucosidase inhibitors include: miglitol, voglibos, emiglitate, MDL-25,637, camiglibos, and MDL-73,945.

Preferred α-glucosidase inhibitors inhibit sucrose and maltose with an IC _{50 of} 1 nM to 10 μΜ (Example P). More preferred are substances having an IC ₅₀ in the range of 1 nM and 1 µΜ.

Other preferred α-glucosidase inhibitors used in the present invention are described in the following patents:

WO 98/57635, WO 99/29327, WO 98/09981, WO 97/09040, ' EP 0713873 A2, EP • 00056194, DE- 02758025, EP • 410953-A, EP -427 694-A, EP A-406211, EP 409 812-A, US 5,017,563, US 5,025,098, WO U2 / 03978, US 4 013 510 US 5,028,614, US 5,097,023, US 5 157 116 US 5,504,078, US 5 840 705 US 5 844 102 JP 08040998A2, JP 08289783A2, J P 09048735A2, JP 11236337A2, JP 11286449A2, JP 11029472A2, JP 10045588A2, JP 09104624A2. While these opi Suju large quantities / o a -glukozidá-

The present invention is not limited thereto and may use any α-glucosidase inhibitor. Methods used to identify and characterize α-glucosidase inhibitors are well known and are widely described.

Surprisingly, the combined treatment with FBPase inhibitor and α-glucosidase inhibitor results in significantly increased postprandial glycemic control compared to administration of the agent alone in the lean NIDDM model, Goto-Kakizaki rats (Example

252

ΕΕ). The results suggest that intestinal carbohydrate absorption and gluconeogenesis are both key contributors to postprandial blood glucose concentrations.

A further advantage of the combination therapy is in the unexpectedly beneficial effect on the metabolism of sugars, lipids and proteins.

A further advantage of combination therapy is that FBPase inhibitors can reduce the side effects associated with α-glucosidase treatment and vice versa. Α-glucosidase inhibitors are known to have gastrointestinal side effects in humans and to increase serum transamination. Similarly, FBPase inhibitors may have side effects in humans.

Inhibitors of glucose production in the liver

In another aspect, the use of an FBPase inhibitor and an inhibitor of hepatic glucose production (e.g., a glycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, a glucagon antagonist, an amylin agonist, or a fatty acid oxidation inhibitor) is preferred. The glucose production in the liver proceeds by two reaction schemes: gluconeogenesis (de novo glucose synthesis) and glycogenolysis (cleavage of glycogen stores). Although glucose overproduction by glyconeogenesis is the primary cause of NIDDM-associated hyperglycemia, glycogenolysis is nevertheless a key component of HGO and hence an important target for the treatment of hyperglycemia. The rate-determining step for the degradation of glycogen is catalyzed by glycogen α-phosphorylase, a well-studied enzyme that is regulated by multiple covalent, substrate, and allosteric effectors. Newgard CB, Hwang PK, Fletzerick RJ, Crit. Rev. Biochem. Mol. Biol. 24: 6999 (1989). Glycogen phosphorylase catalyzes the cleavage of glycogen into glucose-1-phosphate. Two additional enzymatic steps for the release of glucose into the circulation are required: glucose-6-phosphate isomerase and glucose-6-phosphatase.

Two types of glycogen-phosphorylase inhibitors are described:

253 glucose analogs that bind near the active site of the enzyme and caffeine and other heteroaromatic analogs that bind to the regulatory site, the I-site. Indole-2-carboxamides have been reported to function as inhibitors of glycogen phosphorylase in the human liver and reduce blood glucose following oral administration to diabetic ob / ob mice. Hoover DJ, Leflcowitz-Snow S, Burgess-Henry JL et al., J. Med. Chem. 41: 2934-2938 (1998). Piperidine and pyrrolidine inhibitors are also described to reduce both basal and glucagon-induced glucose production in rat hepatocytes (WO 97/09040).

Preferred glycogen phosphorylase inhibitors have 1C50 values from 1 nM to 10 μΜ in the human recombinant glycogen phosphorylase assay (Example Q). More preferred are compounds having an IC 50 in the range of 1 nM and 1 µΜ.

Preferred glycogen phosphorylase inhibitors used in the present invention include CP-91149, CP-316819 and CP-368296. Tieco and other inhibitors are described in the following publications and patents:

Hoover DJ, Lefkowitz-Snow S, Burgess-Henry, JL et al., J. Med.

Chem. 41: 2934-2938 (1998);

Martin JL, Veluraja K, Ross K et al., Biochemistry 30 10101-10116 (1991); Watson KA, Mitchell EP, Johnson LN et al., Biochemistry y 33 5745-5758 (1994); Bichard CJF, Mitchell EP, Wormald MR et al., Tetrahedror. Lett

36: 2145-2148 (1995);

Krulle TM, Watson KA, Gregorious M. a et al., Tetrahedron Lert 36 8291-8294 (1995 ); Kasvrnsky PJ, Madsen, Sygusch J. Biol. Chem. 253 3343-3351 (1978 ); Ercan-Fang N and Nuttall FQ, J. Pharmacol. Exp. Ther 280 1312-1318 (1997 ); Kasvins ky PJ, Fletterick dating in RJ, Madsen NB, Can. J. Biochem. 59

254

387-395 (1981);

Waagpetersen HS, Westergaard N., Schousboe A., Neurochem. Int. 36:

435-440 (2000);

Oikonomakos NG, tsitsanis KE, Zographos SE et al., Protein Sci. 8: 1930-1945 (1999); WO 95/24391, WO 97/09040, WO 98/50359, WO 96/03984, WO 96/03985, WO 98/40353, WO 97/09040, WO 96/39384, WO 96/39385, WO 98/50359, US 5,998,463 US-05998463 EP 00978279, EP 00832066; 00832065, EP 01088824, EP 00,978,279th

While these documents disclose a number of glycogen phosphorylase inhibitors, the present invention is not limited thereto and any glycogen phosphorylase inhibitor may be used. Methods used to identify and characterize glycogen phosphorylase inhibitors are well known and are widely described.

Although glycogen phosphorylase inhibitors exert their glucose lowering effect by inhibiting hepatic glucose production, the combination treatment with FBPase inhibitors and a glycogen phosphorylase inhibitor surprisingly results in a significantly increased glycemic control as with the administration of individual agents alone (Example FF).

Another important advantage of the combination treatment with FBPase inhibitors and glycogen phosphorylase inhibitors is an unexpectedly beneficial effect on the metabolism of sugars and / or lipids and / or proteins.

Another advantage of the combination treatment with FBPase inhibitors and glycogen phosphorylase inhibitors is that FBPase inhibitors can reduce the side effects associated with glycogen phosphorylase therapy and vice versa.

Glucose-6-phosphatase catalyzes the dephosphorylation of glucose-6-phosphate to glucose. Since glucose-6-phosphate is a common end product of both hepatic gluconeogenesis and glycogenolysis, inhibition of this enzyme directly reduces hepatic glucose production. Glu255 goat-6-phosphatase is associated with a multienzyme complex in the endoplasmic reticulum. The enzyme complex consists of specific translocases in the membrane of the endoplasmic reticulum, a phosphatase located on the luminal side of the membrane, and a phosphate translocase. Burchell A and Waddell ID, Biochim. Biophys. Acta 1092: 129-137 (1990). The activity of this multienzyme complex is enhanced under observation conditions, leading to increased blood glucose in animals (e.g., streptozocin treatment). In addition, it has been demonstrated by clinical studies that the increased glucose production observed in NIDDM is associated with increased glucose-6-phosphatase activity. Clore, JN, Stillman, J, Sugerman, H, Diabetes 49 (6): 969-74 (2000).

Preferred glucose-6-phosphatase inhibitors used in this method include compounds that inhibit the dephosphorylation of glucose-6-phosphate through interactions with glucose-6-phosphatase alone or other essential components of the glucose-6-phosphatase multi-enzymatic complex (i.e., translocase or phosphatase). Methods used to identify and characterize glucose-6-phosphatase inhibitors are well known and are widely described. Chlorogenic and benzic acid from Hoecht have been reported to inhibit glucose-6-phosphatase, Novo Disk described active tetrahydrothienylpyridine derivatives, and Pfizer described selective chlorogenic acid derivatives. Examples of such compounds include S-0034 and S-4048. Representative glucose-6-phosphonate inhibitors are described in the following publications and patents:

Arion WJ, Canfield WK, Ramoc FC et al., Ar. Biochem. Biophys.

15: 279-285 (1998); Heriing AW, Burger HJ Schwab D et al., Am. J. · Physiol. 274: G1087-1093 (1998); Parker JC, Van Volkenburg MA, Levy CB et al., Diabetes 47: 1630-1636 ( 1998); EP 93114260 .0, EP 93114261.6, US 5 567 725, EP 816329,

EP 0682024A1, WO 98/40385.

256

While these documents disclose a number of glucose-6-phosphatase inhibitors, the present invention is not limited thereto, and any glucose-6-phosphatase inhibitor may be employed.

Although glucose-6-phosphatase inhibitors exert their glucose-lowering effect by inhibiting hepatic glucose production, combination treatment with FBPase inhibitors and glucose-6-phosphatase inhibitors results in a surprisingly significantly increased glycemic control compared to administration of the agents alone (Example) YGG).

Another significant advantage of the combination treatment with FBPase inhibitors and glucose-6-phosphatase inhibitors lies in the surprisingly beneficial effect on the metabolism of sugars and / or lipids and / or proteins.

Another advantage of combination therapy is that FBPase inhibitors can reduce the side effects associated with glucose-6-phosphatase therapy and vice versa.

Glucagon is a polypeptide hormone produced by post-translational processing of pro-glucagon in pancreatic α-cells. The primary physiological role of glucagon, in accordance with insulin, is to ensure the acute and long-term maintenance of blood glucose concentrations. Low blood glucose concentrations trigger glucagon secretion, which then stimulates the production of glucose in the liver by increasing both the rate of glycogenolysis and gluconeogenesis. These effects are mediated by the binding of glucagon to a specific receptor that is positively associated with adenyl cyclase via the Gs protein. There is strong evidence to suggest that excess glucagon concentrations contribute to the hyperglycemic characteristic of NIDDM in both non-fed and non-fed conditions. It has also been demonstrated that removal of circulating glucagon by selective antibodies results in a glycemic control. These observations provide a strong basis for the use of glucagon antagonists in the treatment of NIDDM. Scheen AJ,

257

Drugs 54: 355-368 (1997); Brand CL, Jorgensen PN, Knigge

U et al., Am. J. Physiol. 269: E469-477 (1995). Johnson DG,

Goebel CU, Hruby VJ et al., Physiol. 269: E469-477 (1995). Johnson DG, Goebel CU, Hruby VJ et al., Science 215: 1115-11-16 (1982). Baron AD, Schaeffer L, Shragg P, Kolterman OG, Diabetes 36: 274-283 (1987).

In addition to glucagon receptor antibodies, there are two classes of antagonists: peptide-derived antagonists and non-peptide compounds. Examples of peptide-derived antagonists are described in the following U.S. Pat. U.S. Patent Nos. 4,879,273, 5,143,902, 5,480,867, 5,665,705, 5,408,037, and 5,510,459. Examples of non-peptide antagonists are described, e.g. in the following publications and patents:

Collins JL; Dambek PJ; Goldstein SW; Faraci WS; Bioorg. Med. Chem. Lett 2: 915-918 (1992);

Guillon J, Dallemagne P, Pfeiffer B et al., Eur. J. Med. Chem. 33: 293-308 (1998);

De Laszlo SE, Hacker C, Li B et al., Bioorg. Med. Chem. Lett. 9: 641-646 (1999);

Cook JH, Doherty EM, Ladouceur G et al., ACS National Meeting. Boston, MA, USA, Poster no. MEDI 285 (August 1998);

WO 97/16442, WO 97/35598, WO 98/04528, WO 98/21957, WO 98/22108, WO 98/22109, WO 98/24780, WO 99101423, U.S. Pat. 5,508,304 and U.S. Pat. 5,677,334.

While a large number of glucagon antagonists are described in these patents, the present invention is not limited thereto and may use any glucagon antagonists. Examples of known glucagon antagonists include ALT-3000 (Alteon, Inc.), BAY-27-9955 (Bayer, AG), CP-99711, Skyrin, and NNC-92-1687. Methods used to identify and characterize glucagon antagonists are also well known (e.g., Example S) and are widely described.

Glucagon antagonists inhibit the binding of glucagon to the kidney cells of hamster pups transfected with the human glucagon receptor (Example S). Preferred antagonists have an IC ₅₀ in the range of 0.1 nM and 100 µΜ. More preferred are compounds having inhibitory IC50 binding in the range of 0.1 nM and 1 μΜ.

Although glucagon antagonists function primarily by inhibiting hepatic glucose production, combination therapy with FBPase inhibitors and glucagon antagonists results in significantly higher glycemic control than administration of the agents alone.

Another important advantage of the combination treatment with an FBPase inhibitor and a glucagon antagonist is the unexpectedly beneficial effect on the metabolism of sugars and / or lipids and / or proteins.

Another advantage of the combination therapy is that FBPase inhibitors may reduce the side effects associated with glucagon antagonist treatment and vice versa.

As described above, glucagon is an important regulator of glucose production in the liver. Basal glucagon concentrations are higher in NIDDM than in control subjects, despite competing basal hyperglycemia and hyperinsulinemia, two factors known to suppress glucagon secretion. Reaven GM, Chen YD, Golay A, Swislocki AL, Jaspan JB, J Clin Endocrinol Metab 64: 106-110 (1987). A direct relationship between plasma glucagon concentration and blood glucose concentration has been found in NIDDM patients. In addition, glucagon has been shown to be responsible for maintaining up to a 60% increase in hepatic glucose production, which is evident in NIDDM patients. Baron AD, Schaeffer L, Shragg P, Kolterman OG, Diabetes 36: 274-283 (1987). Glucagon secretion from pancreatic and cells is inhibited by insulin from β cells.

Amylin, amylin agonists

Amylline is a peptide hormone comprising 37 amino acids which

259 is produced and secreted together with insulin by pancreatic β cells in response to nutritional stimuli. The action of amylin involves reducing food intake, controlling gastric motility, and suppressing postprandial glucagon secretion, which may reduce hepatic glucose production. Amylin secretion is believed to be delayed and attenuated at a later stage of NIDDM. The use of amylin agonists, including amylin alone, for the treatment of diabetes is described in U.S. Pat. Patente no. 5,175,145. Pramlintide, a synthetic analogue of human amylin, has been shown to improve metabolic control in NIDDM patients receiving insulin. RG Thompson, L Pearson, SL Schoenfeld, OG Kolterman, Diabetes Line 21: 987-993 (1998). Significant reductions in the two serum glycemic control indicators, fructosamine and hemoglobin Ale, were observed in multi-center clinical research. Methods for identifying and characterizing amylin antagonists are well known and are described e.g. in WO 92/11863; 5,264,372.

Amylin agonists inhibit the binding of 125-1-labeled amylin to a membrane preparation isolated from the nucleus accumbens of the basal forebrain of the rat (Example T). Preferred aconists have Ki values between 0.001 nM and 1 μΜ. More preferably, the compounds inhibit binding with Ki 'constants between 0.001 nM and 10 nM. Alternative assays in which amylin agonists exhibit activity include the petane calf muscle assay described in Leighton B and Cooper GJS, Nature 335: 632-635 (1988). In this assay, insulin stimulation of glycogen synthesis is measured in the absence and presence of amylin or amylin agonist. Preferred agonists have EC50 values from 0.1 nM dc to 1 μΜ. Most preferred amylin agonists have EC values in the range of 0.1 nM to 100 nM.

Amylin is a partner hormone to insulin, “metallised in response to nutritional stimuli. It has been demonstrated that amylline is a potent inhibitor of glucagon secretion. Gedulin BR, Rink TJ, Young AA, Metabolism 46: 67-70 (1997). Amylin and amylin are expected

260 agonists reduce hepatic glucose production and thus can be used in the treatment of hyperglycemia that is characteristic of diabetes. By clinical evaluation, pramlintide, an amylin agonist, has been shown to improve glycemic control in NIDDM patients. RG Thompson, L Pearson, SL Schoenfeld, OG Kolterman, Diabetes Line 21: 30, 987-993 (1998). Pharmaceutical formulations of amylin peptide agonists containing pramlintide are claimed in WO 99/34822. The present invention is not limited to pramlintide, but any amylin agonist may be used.

Although amylin agonists are believed to inhibit glucose production, combination treatment with an FBPase inhibitor and an amylin agonist surprisingly results in significantly higher glycemic control compared to administration of the agents alone (Example HH).

Another significant advantage of the combination treatment with an FBPase inhibitor and an amylin agonist is the unexpectedly beneficial effect on the metabolism of sugars and / or lipids and / or proteins.

Another advantage of the combination therapy is that FBPase inhibitors may reduce the side effects associated with amylin agonist therapy and vice versa.

Fatty acid oxidation inhibitors

Under normal conditions, a reduction in free fatty acid (FFA) concentration after a meal provides a liver signal to reduce hepatic glucose production. In NIDDM patients, FFA concentrations are elevated and their oxidation is known to lead to over-regulation of gluconeogenesis and consequently to increased hepatic glucose production. Reberin K, Steil Gm, Getcy L, Bergman RN, Diabetes 44: 1038-1045 (1995); Foley JE, Diabetes Line 15: 773-784 (1992). One approach to reducing blood glucose concentrations in NIDDM patients is to reduce excessive fatty acid oxidation, an enzymatic process by which fatty acids are metabolized in the mitochondrial matrix to produce a reduction equivalent of ace

261 tylCoA. The rate-determining step in the oxidation of long-chain fatty acids is the transport of FFA to mitochondria by carnitine palmitoyltransferase I (CPT I). Inhibition of CPT I has been shown to reduce hepatic glucose production and blood glucose concentration in NIDDM patients. Ratheiser K, Schneeweiss B, Waldhaus IW et al., Metabolism 40: 1185-90 (1991).

CPT I inhibitors useful in the present invention include 2-tetradecylglycidic acid (methyl palmoxirate), etomoxir, clomoxir, ST1326 and SDZ-CPI-975. These and other inhibitors are described in the following:

Tutwiler GF, Kirsch T, Bridi G, Washington F, Diabetes 27: 856 (1978),

Tutwiler GF, Dellevigne P. J. Biol. Chem. 254: 2935 (1979), Koundakian PP, Tumbull DM, Bone AJ Biochem Pharmacol 33: 465 (1984),

Deems RO, Anderson RC, Foley JE, Am. J. Physiol. 274: R 524-528 (1998).

The present invention is not limited to the CPT I inhibitors described above, but any compounds that inhibit fatty acid oxidation can be used. The methods used to identify and characterize fatty acid oxidation inhibitors are well known and widely described.

Preferred fatty acid oxidation inhibitors have IC 50 values from 10 nM to 300 μΜ when determining palmitate oxidation in rat hepatocytes (Example U). More preferably, the inhibitors have IC ₅₀ values in the range of 10 nM and 30 μΜ.

Although fatty acid oxidation inhibitors are known to inhibit hepatic glucose production, combination treatment with FBPase inhibitor and fatty acid oxidation inhibitor surprisingly results in significantly higher glycemic control than when administered alone (Example JJ).

Another important advantage is that the combination treatment

262

The FBPase inhibitor and the fatty acid oxidation inhibitor have surprisingly beneficial effects on the metabolism of sugars and / or lipids and / or proteins.

Another advantage of the combination therapy is that FBPase inhibitors can reduce the side effects associated with fatty acid inhibitor therapy and vice versa. It is known that inhibitors of fatty acid oxidation are e.g. associated with cardiac hypertrophy. Bressler R, Gay R, Copeland G et al., Life Sci 44: 1897-1906 (1989).

FBPase inhibitors reduce blood glucose levels both in the non-eating state (Examples E-G) and in the free eating state (Example W) and in the postprandial states (Example X). This provides a wide range of therapies in combination with insulin secretagogues, insulin, biguanides, α-glucosidase inhibitors, glucagon antagonists, amylin agonists or fatty acid oxidation inhibitors. The combination may be administered e.g. with food and provides increased glycemic control compared to the agent alone. Other dosing regimens may include administration of an insulin, insulin, biguanide, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon antagonist, amylin agonist or fatty acid oxidation inhibitor, and administration of the FBPase inhibitor separately overnight. A number of other dosage regimens are possible.

While the combination of FBPase inhibitors with insulin secretagogues, insulin, biauanics, α-glucosidase inhibitors, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon agonists, amylin agonists or fatty acid oxidation inhibitors is primarily predicted for NON-NON-BREAKING HYPHEN (8209) acid and , retinal, micro- and macrovascular and metabolic complications, the treatment of other diseases that respond to increased glycemic control and / or increased insulin sensitivity are also possible.

263

Patients with impaired glucose tolerance (IGT) are minimally hyperglycaemic under normal conditions but may become hyperglycaemic after taking a large dose of glucose. IGT is a predictor of future diabetes, and patients with these predispositions have become the target of attempts to prevent diabetes these years. Combined treatment of these patients, especially during meals, restores normal glucose response and reduces the risk of developing diabetes. Another distinct group of subjects at higher risk of developing NIDDM are women suffering from polycystic ovarian syndrome (POCS). Combination therapy is advantageous for these patients, also because these patients are typically insulin resistant and may suffer from IGT. Combination therapy is also useful in the treatment of renal dysfunction and hypertension, particularly obesity, in insulin resistant patients with IGT. Other applications of combination therapy include pregnancy diabetes, poorly controlled IDDM, obesity, and dyslipidemia.

formulations

In accordance with the present invention, novel antidiabetic combinations are disclosed, including FBPase inhibitors in combination with another agent that can be administered orally or by injection.

The FBPase inhibitors of the invention can be used in weight ratios to sulfonylurea or non-sulfonylurea insulin secretagogues in the range of about 1000: 1 to about 50: 1, preferably from about 250: 1 to 75: 1.

The FBPase inhibitors of the invention can be used in weight ratios to metformin ranging from about 10: 1 to 0.1: 1, preferably from 3: 1 to about 0.1: 1.

The FBPase inhibitors of the invention can be used in weight ratios to the α-glucosidase inhibitor in the range of about 300: 1 to about 2: 1, preferably from about 200: 1 to about 25: 1.

The FBPase inhibitors of the invention may be used

264 in weight ratios to the glycogen phosphorylase inhibitor in the range from about 100: 1 to about 0.01: 1, preferably from 10: 1 to 0.1: 1.

The FBPase inhibitors of the invention may be used in weight ratios to the glucose-6-phosphatase inhibitor in the range of 1000: 1 to about 0.01: 1, preferably from 100: 1 to 0.1: 1.

The FBPase inhibitors of the invention may be used in weight ratios to the glucagon antagonist in the range of about 1000: 1 to about 0.01: 1, preferably from 100: 1 to 0.1: 1.

The FBPase inhibitors of the invention may be used in weight ratios to the amylin agonist in the range of 1000: 1 to about 0.01: 1, preferably from 100: 1 to 0.1: 1.

The FBPase inhibitors of the invention may be used in weight ratios to the fatty acid oxidation inhibitor in the range of 1000: 1 to about 0.1: 1, preferably from 100: 1 to 0.1: 1.

In addition, in accordance with the present invention, there is provided a method of treating diabetes and related diseases, wherein a therapeutically effective amount of an FBPase inhibitor, optionally in combination with another antidiabetic agent, is administered to a patient in need of such treatment.

Where present, sulfonylureas such as glyburide, glimepride, glipyride, glipizide, chlorpropamide and glicazide and α-glucosidase inhibitors or miglitol and biguanides such as metformin may be used in the formulations in amounts and dosages as described in the medical reference manual.

Where present, GLP-1 or GLP-1 analogs may be administered in oral buccal formulations, nasal administration or parenterally as described in US 5,346,701, US 5,614,492 and US 5,631,224.

Where present, insulin may be used in the formulations, amounts and dosages as indicated in the medical reference.

265.

Where present, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists, amylin agonists or fatty acid oxidation inhibitors are administered in daily doses of from 0.5 mg to 2500 mg, preferably from 10 to 100 mg. Inhibitors may be administered in daily doses or in corresponding portions of the daily dose (e.g., two or three times daily).

The FBPase inhibitors of the invention alone or in combination with another antidiabetic agent may be incorporated into conventional systemic dosage forms such as tablets, capsules, elixir or injectable formulations. The above dosage forms will also include the necessary physiologically acceptable carrier materials, excipient, lubricant, buffers, antibacterial agent, bulking agent (such as mannitol), antioxidants (ascorbic acid or sodium bisulfite) and the like. Oral dosage forms are preferred, although parenteral forms are equally satisfactory.

The doses to be administered must be carefully adjusted according to the age, weight and condition of the patient, as well as the route of administration, dosage form and administration regimen and the desired result. In general, the dosage form of the FBPase inhibitor may be administered in daily doses of 5 to 2500 mg. Preferably, dosage forms from 100 mg to 1000 mg are used. FBPase inhibitors may be administered in a daily dose or in corresponding portions of the daily dose (e.g., two or three times). The administration of the FBPase inhibitor may occur over or near the time of administration of the other antidiabetic agent or at different times.

The combination of an FBPase inhibitor of the invention and another antidiabetic agent may be formulated separately or, where possible, in a single formulation using conventional formulation procedures.

266

The various compositions of the invention may optionally contain one or more fillers or excipients in amounts ranging from about 0 to 90% by weight and preferably from 1 to about 80% by weight such as lactose, sugar, corn starch, modified corn starch, mannitol, sorbitol , inorganic salts such as calcium carbonate and / or cellulose derivatives such as wood pulp and microcrystalline cellulose.

One or more binders may be present in addition to or in place of the filler in amounts ranging from 0 to about 35%, and preferably in amounts ranging from 0 to about 35%.

0.5 to about

30% by weight of the composition.

Examples of such binders suitable for use in the present invention include polyvinylpyrrolidone (molecular weight ranging from about

5000 to about 80000 and preferably about

Lactose, starches such as cereal starch, modified cereal starch, sugars, gum acacia and the like, as well as wax binders in finely ground form (less than carnauba wax, paraffin, spermacet such as 500 microns) polyethylene or microcrystalline wax.

When the composition is to be in the form of a tablet, it will comprise one or more disintegrants in from about 0.5 to 10% and preferably from about 2 to an amount of

8% by weight of a composition such as sodium croscarmellose, povidone, crospovidone, sodium starch glycolate, cereal as well as single or microcrystalline cellulose, more lubricants in amounts ranging from starch or preferably from 0.5 to about 2% by weight of the composition such as magnesium stearate, acid stearic acid, palmitic acid, calcium stearate, talc, carnauba wax and the like. Optionally, other conventional ingredients such as preservatives, stabilizers, antiadherents or silicone flow modifiers or talc flours such as Syloid brand silica as well as FD&C dyes may be included.

The tablets of the present invention may also include a coating layer containing from 0 to 15% by weight of the tablet compositions.

267 cie. The coating layer which is used for the tablet core may contain one or more film-forming agents such as hydrophilic polymers such as hydroxypropylmethyl cellulose and hydrophobic polymers such as ethylcellulose, cellulose acetate, polyvinyl alcohol-maleic anhydride copolymers, β-pinene polymers, glycerin esters resins and the like, and one or more plasticizers such as triethyl citrate, diethyl phthalate, polypropylene glycol, glycerin, butyl phthalate, castor oil and the like. Both the tablet core and the coating layer may contain aluminum lacquers for color.

The film former is applied from a solvent system comprising one or more solvents including water, alcohols such as methanol, ethanol or isopropyl alcohol, ketones such as acetone or ethyl methyl ketone, chlorinated hydrocarbons such as methylene chloride, dichloroethane and 1,1,1-trichloroethane.

Where a paint is used, the paint will be applied together with the film-forming agent, the plasticizer and the dissolved formulation.

A preferred composition of the tablet compositions of the invention will comprise from 90 to about 97.5% by weight of the FBPase inhibitor, from 2 to about 8% by weight of povidone, and from 0.5 to about 2% by weight of magnesium stearate.

The pharmaceutical compositions of the invention may be prepared as follows. The drug / fraction mixture (less than 50%; fillers, if present (such as lactose), with or without dye) are mixed together and passed through a # 12 to # 40 screen. for example microcrystalline cellulose, a disintegrant (such as povidone), and mixed together, a lubricant (such as magnesium stearate) is added with stirring until a homogeneous mixture is obtained, and the mixture can then be compressed into tablets up to 2 g in size. if desired, the tablets of the invention may be formulated by the wet granulation technique as described in US Patent No. 5,030,447, which

268 is incorporated herein by reference.

Examples of synthetic schemes

Compounds of formula (VI) are prepared according to literature procedures using modifications and enhancements readily apparent to those skilled in the art. In general, these compounds are synthesized by the methods described in Srivastava, J. Med. Chem. (1976). Other procedures are described in Wood et al., J. Med. Chem. 28: 1198-1203 (1985); Sagi et al., J: Med. Chem. 35: 4549-4556 (1992); Paul, Jr. J. Med. Chem. 28: 1704-1716 (1985); Cohen et al., J. Am. Chem. Soc. 95: 4619-4624 (1973).

Compounds of formula (II-IV) are prepared according to the procedures published in PCT no. WO 98/39344, WO 98/39343 and WO 98/39342.

Section 1

Synthesis of compounds of formula 1

Synthesis of compounds of the invention typically involves several or all of the following steps: (1) preparation of a phosphonate prodrug, (2) deprotection of a phosphonate ester, (3) modification of a heterocycle, (4) coupling of a heterocycle with a phosphonate component, (5) 6) ring closure to form a heterocycle with a phosphonate group; and (7) preparation of useful intermediates. These steps are illustrated in the following scheme for a compound of formula 2 wherein R ⁵ is a five membered heteroaromatic ring. Compounds of formula 2 wherein R ⁵ is a six membered heteroaromatic ring or another heteroaromatic ring are prepared in a similar manner.

269

Formula V or

Formula V-A

s Íl

R ⁵ —X — P — OH I

OH

J (3) 1 J ¹ A \ / // * L 0 II M-P-OR ' OR ^A \ n ⁽⁴⁾ ° ---- iCJl — xP-OR ' ^B f OR' B ² B ² 6 5 4 t (5) f P) f (6)

O I ¹¹ P x OR-I OR '(Ia) Preparation of a phosphonate prodrug

Prodrugs can be introduced at various stages of the synthesis. Most often, these prodrugs are prepared from the phosphonic acids of Formula 2 for their stability. Advantageously, these prodrugs may be introduced at an earlier stage, provided that they can overcome the reaction conditions of the subsequent steps.

Compounds of formula 2 can be alkylated with electrophiles (such as alkyl halides, alkylsulfonates, and the like) under conditions of a nucleophilic substitution reaction to form phosphonate esters. For example, compounds of formula I wherein R * is acyloxyalkyl can be synthesized by direct alkylation of compounds of formula 2 with the appropriate

270 acyloxyalkyl halides (e.g., Cl, Br, I; Elhaddadi, et al.

Phosphorus Sulphur, 1990, 54 (1-4): 143; Hoffmann, Synthesis,

1988, 62) in the presence of a base (e.g., N, N'-dicyclohexyl-4-morpholinecarboxamidine, Hunigs base, etc.) in suitable solvents such as 1,1-dimethylformamide (DMF) (Starrett, et al., J. Med. Chem., 1994, 1857). The carboxylate component of these acyloxyalkyl halides includes, but is not limited to, acetate, propionate, isobutyrate, pivalate, benzoate, and other carboxylates. If necessary, further modifications are possible after formation of these acyloxyalkyl phosphate esters such as nitro reduction. For example, compounds of formula 3 wherein A is NO ₂ can be converted to compounds of formula 3 wherein A is NH ₂ - under suitable reducing conditions (Dickson, et al., J.

Med. Chem., 1996, 39: 661; Iyer, et al., Tetrahedron Lett.,

1989, 30: 7141; Srivastva, et al., Bioorg. Chem., 1984, 12:

118). These methods can be extended to the synthesis of other types of prodrugs, such as compounds of formula 1, wherein R ¹ is phthalyl and 2-oxo-4,5-didehydro-1,3-dioxolanemethyl or 2-oxotetrahydrofuran-5-yl (Biller et al., US 5,157,027; Serafinowska et al., J.

Med. Chem. 1995, 38: 1372; Starrett et al.,

1857; Martin et al., J. Plzarm. Sci.

J. Med. Chem. 1994, 37:

1987 76: 180; Alexander et al. 1994 59: 1853; EPO 0632048A1). Taly the they can also used on (Alexander , P ·, et al., Collect.

1853)

Collect. Czech. Chem. Commun, N, N-Dimethylformamide dialkylacealkylation of phosphonic acids. Chem. Commun. 1994, 59,

Alternatively, these phosphonate prodrugs can also be synthesized by reacting the corresponding dichlorophosphonates with an alcohol (Alexander et al., Collect. Czech. Chem. Commun., 1994, 59: 1853). For example, reaction of a dichlorophosphonate with substituted phenols and aralkyl alcohols in the presence of a base (e.g., pyridine, triethylamine, etc.) provides compounds of formula V wherein R ¹ is an aryl group (Khamnei et al., J. Med. Chem., 1996, 39 Serafinowska et al., J. Med. Chem., 1995,

271

38: 1372; De Lombaert et al., J. Med. Chem., 1994, 37: 498) or an arylalkyl group (Mitchell et al., J. Chem. Soc. Perkin Trans. 1, 1992, 38: 2345). Disulfide-containing prodrugs (Puech et al., Antivira. 1 Res., 1993, 22: 155) can also be prepared from dichlorophosphonate and 2-hydroxyethyl disulfide using standard conditions.

These reactive dichlorophosphonates can be generated from the corresponding phosphonic acids with a chlorinating agent (e.g., thionyl chloride: Starrett et al., J. Med. Chem., 1994, 1857, oxalyl chloride: Stowell et al., Tetrahedron Lett., 1990, 31: 3261 and phosphoropentachloride: Quast et al., Synthesis, 1974, 490). Alternatively, the dichlorophosphonate can be generated from the corresponding disulfosphonate esters (Bhongle et al., Synth. Commun., 1987, 17: 1071) or dialkyl phosphonate esters (Still et al., Tetrahedron Lett., 1983, 24: 4405; Patois et al. Bull. Soc. Chim. Fr., 1993, 130: 485).

In addition, these products can be prepared using Mitsunobu reactions (Mitsunobu, Synthesis, 1981, 1; Campbell, J. Org. Chem., 1992, 52: 6331) and other coupling reactions (e.g., using carbodiimides: Alexander et al. Chem. Commun., 1994, 59: 1853; Casara et al., Bioorg. Med. Chem. Lett., 1992, 2: 145; Ohashi et al., Tetrahedron Lett., 1988, 29 : 1189 and benzotriazolyloxytris (dimethylamino) -phosphonium salts: Campagne et al., Tetrahedron Lett., 1993, 34: 6743). A compound of formula I wherein R ¹ is a cyclic carbonate, lactone or phthalidyl group can also be synthesized by direct alkylation of the free phosphonic acid with the corresponding halides in the presence of a suitable base (e.g. NaH or diisopropylethylamine, Biller et al., US 5,157) Serafinowska et al., J. Med. Chem. 1995, 38: 1372; Starrett et al., J. Med. Chem. 1994, 37: 1857; Martin et al., J. Pharm. Sci. 1987, 76: 180; Alexander et al., Collect. Czech. Chem. Commun, 1994, 59: 1853; EPO 0632048A1).

272

R ¹ may also be introduced at an earlier stage of the synthesis, provided that it is compatible with subsequent reaction steps. For example, compounds of Formula I wherein R ¹ is an aryl group may be prepared by metallization of a 2-furanyl heterocycle (e.g., using LDA) followed by capture of the anion with diarylchlorophosphate.

It will be appreciated that compounds of Formula V may be mixed phosphonate esters (e.g., phenyl and benzyl esters or phenyl and acyloxy esters) including chemically combined mixed esters such as phenyl and benzyl combined prodrugs described in Meier, et al., Bioorg. Med. Chem. Lett., 1997, 7: 99.

(1b) Preparation of Bisamidate Phosphonate

General synthesis of bisphosphoramidate prodrugs:

In general, bisphosphoramidates of formula I wherein both -NR ¹⁵ R ¹⁶ and -N (R ¹⁸ ) - (CR ¹² R ¹³ ) n C (O) -R ¹⁴ are from the same amino acid residues can be prepared from activated phosphonates, e.g. dichlorophosphonate, by condensation with an amino acid ester such as e.g. glycine ethyl ester with or without a base e.g. N-methyl imidazole. The reactive dichloridates can be prepared as described above in the general section on prodrugs.

Alternatively, these bisphosphoramidates can be prepared by reacting the corresponding phosphonic acids with amino acid esters such as e.g. glycine ethyl ester in the presence of PPh ₃ and 2,2'-dipyridyl disulfide in pyridine as described in WO 95/07920 or Mukaiyama T. et al., I. Arn. Chem. Soc., 1972, 94, 8528.

Synthesis of mixed bisphosphoramidates of formula IA wherein -NR ¹⁵ R ¹⁶ and -N (R ¹⁸ ) - (CR ¹² R ¹³ ) n C (O) -R ¹⁴ are different amino acid esters or a combination of an amino acid ester and a substituted amine may be prepared by direct synthesis. by treatment with the dichloridate of the above, followed by separation of the desired product description (sequential additions) by column chromatography or HPLC. Alternatively, these mixed bisphosphoroamidates may be prepared starting from an appropriate phosphonate monoester such as a phenyl or benzyl ester to produce the mixed phosphonoesteramide via the chloridate stage, followed by ester hydrolysis under conditions where the amine bond is stable. The resulting monoamide can be converted to the mixed bisamide by condensation with a second amino acid ester or substituted amine as described above through the chlorideidate stage. The synthesis of these monoesters can be carried out using the published procedure (EP 481 214).

Substituted cyclic propyl phosphonate esters can be synthesized by reacting the corresponding dichlorophosphonates with substituted 1,3-propanediol. Some of the methods useful for preparing substituted 1,3-propanediol are described below.

Synthesis of 1,3-propanediol

Various synthetic methods can be used to prepare multiple types of 1,3-propanedioles: (i) 1-substituted, (ii) 2-substituted, (iii) 1,2- or 1,3-annulled 1,3-propanediols. The substituents on the prodrug moiety of the compounds of formula I (i.e., the substituents on the 1,3-propanediol group) may be introduced or modified either during the synthesis of these diols or after condensation of these diols to the compounds of formula 2.

(i) 1-Substituted 1,3-propanediols

1,3-Propanediols useful in the synthesis of the compounds of this invention can be prepared using a variety of synthetic procedures. Addition of the aryl Grignard reagent to 1-hydroxypropan-3-one affords 1-aryl-substituted 1,3-propanediols (reaction route a). This method is suitable for the conversion of various aryl halides to 1-aryl-substituted 1,3-propanediols (Coppi et al., J. Org. Chem., 1988, 53, 911). Conversion of aryl halides to

274

1-substituted 1,3-propanediols can be achieved using a Heck reaction (e.g., condensation with 1,3-diox-4-ene) followed by reduction and subsequent hydrolysis reaction (Sakamoto et al., Tetrahedron Lett., 1992, 33, 6845). The various aromatic aldehydes can also be converted to 1-substituted 1,3-propanediols using an addition reaction of alkenyl Grignard reagents followed by a hydroboration reaction (reaction route b). The addition of metallized tert-butyl acetate to aromatic aldehydes followed by ester reduction (reaction route e) is also useful in the synthesis of 1,3-propanedioles (Turner., J. Org. Chem. 1990, 55 4744). In another method, the cinnamyl alcohol epoxidation is performed using known methods (e.g., Sharpless epoxidation and other asymmetric epoxidation reactions) followed by a reduction reaction (e.g., using Red-Al), resulting in different

1,3-propanediols (reaction route c). Alternatively, enantiometry of pure 1,3-propanediols can be obtained using reduction reactions of chiral boranes of hydroxyethylaryl ketone derivatives (Ramachandran et al., Tetrahedron Lett., 1997, 38 761). Propan-3-oles with a 1-heteroaryl substituent (e.g. pyridyl, quinolinyl or isoquinolinyl) can be oxygenated to form 1-substituted 1,3-propanediols using a reaction to form an N-oxide followed by a rearrangement in acetic anhydride (reaction route d) (Yamamoto et al., Tetrahedron, 1981, 37, 1871).

275

(ii) 2-substituted 1,3-propanediols

Various 2-substituted 1,3-propanedioyl compounds of formula I may be useful for the synthesis of

2- (hydroxymethyl) -1,3-propanedioles using known procedures

Comprehensive Organic Transformations, VCH

New York,

For example, reduction of trialkyloxycarbonylmethane under known conditions (reaction night gives triol via complete path a) or bis (hydroxymethyl) acetic acid by reduction of selective hydrolysis of one of the ester groups, followed by reduction of the remaining two also known to provide trioles via reduction elimination b) (Latour et al., Synthesis, 1987, 8,

742). In addition, 2- (hydroxymethyl) -1,3-propanediol can be converted to a monoacylated derivative (e.g., acetyl, methoxycarbonyl) using acyl chloride or an alkyl chloroformate (e.g., acetyl chloride or methyl chloroformate) (reaction route d) using known procedures (Greene). et al., Protective Grooups In Organic Synthesis; Wiley, New York, 1990). Others may be used

Functional group manipulations to prepare 1,3-propanediols, such as e.g. oxidation of one hydroxymethyl group in 2- (hydroxymethyl) -1,3-propanediol to an aldehyde, followed by an addition reaction with a Grignard reagent (reaction route c). The aldehydes can be converted to alkylamines via a reductive amination reaction (reaction route e).

(iii) Annulated 1,3-propanediols

Compounds of formula I wherein V and Z or V and W are linked by four carbon atoms to form a ring can be prepared from the corresponding 1,3-cyclohexanedioles. For example, cis, cis-1,3,5-cyclohexanetriol may be modified as described for 2-substituted 1,3-propanediols. It is understood that these modifications can be made either before or after formation of the cyclic phosphonate 1,3-propanediol ester. Various 1,3-cyclohexanediols can also be prepared using (e.g., using a pyrone as a diene: Posner et al., Tetrahedron Lett., 1991, 32, 5295). 1,3-Cyclohexanediol derivatives are also prepared by pros

277 through other cycloaddition methodologies. For example, cycloadiation of nitriloxide to olefin followed by conversion of the resulting cycloaduct to a 2-ketoethanol derivative that can be converted to a 1,3-cyclohexanediol derivative using known chemistry (Curran et al., J. Am. Chem. Soc., 1985, 107, 6023). Alternatively, precursors for 1,3-cyclohexanediols can be prepared from quinic acid (Rao et al., Tetrahedron Lett., 1991, 32, 547).

2) Deprotection of phosphonate esters

Compounds of formula I wherein R ¹ is hydrogen can be prepared from phosphonate esters using known cleavage conditions for phosphate and phosphonate esters. In general, silyl halides are used to cleave various phosphonate esters, using mild hydrolysis conditions of the resulting silyl phosphonate esters to produce the desired phosphonic acids. If desired, acid scavengers (e.g., acid scavengers) may be used to synthesize acid labile compounds.

1,1,1,3,3,3-hexamethyldisilazane, 2,6-lutidine and the like). These silyl halides include chlorotrimethylsilane (Rabinowitz, J. Org. Chem., 1963, 28: 2975) and bromotrimethylsilane (McKenna et al., Tetrahedron Lett., 1977, 155) and iodotrimethylsilane (Blackburn et al.,

J. Chem. Soc., Chem. Commun., 1978, 870). Alternatively, phosphonate esters may be cleaved under strongly acidic conditions (e.g., HBr or HCl, Moffatt et al., US Patent 3,524,846, 1970). These esters can also be cleaved through the dichlorophosphonate stage, prepared by reaction of esters with halogenating agents (e.g. phosphoropentachloride, thionyl chloride, BBr ₃ : Pelchowicz et al., J. Chem. Soc., 1961, 238) followed by aqueous hydrolysis to produce phosphonic acids . Aryl and benzyl phosphonate esters can be cleaved under hydrogenolysis conditions (Lejczak et al., Synthesis, 1982, 412; Elliott et al., J. Med. Chem., 1985, 28: 1208; Baddiley et al., Nature, 1953, 171: 76) or under metal reduction conditions (Shafer et al., J. Am. Chem. Soc., 1977, 99:

278

5118). Electrochemical (Shono et al., J. Org. Chem., 1979, 44: 4508) and pyrolysis conditions (Gupta et al., Synth. Commun., 1980, 10: 299) were also used to cleave various phosphonate esters.

(3) Modification of an existing heterocycle

The synthesis of the heterocycles contained in the compounds of this invention has been studied extensively as described in several review articles (see Section 4). Although it is preferred that the desired heterocycle be present prior to the synthesis of the compound of Formula 4, in some cases the desired substituents are not compatible with the following reactions and hence modifications of the existing heterocycle later in the synthetic scheme using known chemical procedures are required, Larock, Comprehensive organic transformations , VCH, New York, 1989; Trost, Comprehensive Organic Synthesis; Pergamon Press, New York, 1991). For example, compounds of Formula I wherein A and A or B are halogen or cyano may be prepared from the corresponding amino group by conversion to a diazonium salt and reaction with various copper salts (e.g., CuI, CuBr, CuCl, CuCN). Halogens can also be introduced by direct halogenation of various heterocycles. For example, 5-unsubstituted 2-aminothiazoles can be converted to 2-amino-2-halothiazoles using various reagents (e.g., NIS, NBS, NCS). Heteroaryl halides are also useful intermediates and are also readily converted to other substituents (such as A, A, B, B, C, D, D ', E and E) by transition metal mediated coupling reactions such as Suzuki, Heckova or Stille reaction (Farina et al., Organic Reactions, Vol. 50; Wiley, New York, 1997; Mitchell, Synthesis, 1992, 808; Suzuki, Pure App. Chem., 1991, 63, 419); Heck Palladiurn Reagents in Organic Synthesis; Academic Press: San Diego, 1985). Compounds of formula I wherein A is a carbamoyl group can be prepared from the corresponding alkyl carboxylate esters by aminolysis with various amines and conventional

279 modifications of alkyl carboxylate ester functional groups are useful for the synthesis of compounds of formula I wherein A is -CH ₂ OH or -CH ₂ -halogen. The substitution reaction of halogen heterocycles (e.g. 2-bromothiazole, 5-bromothiazole) with various nucleophiles (e.g. HSMe, HOMe, etc.) represents other methods of introducing substituents such as A, A ', B and B. For example, substitution of 2-chlorothiazole with methanethiol provides the corresponding 2-methylthiothiazole.

Obviously, when alkylation of a nitrogen atom in a heterocycle (e.g., imidazoles, 1,2,4-triazoles and 1,2,3,4-tetrazoles) is required, this can be easily accomplished using standard alkylation reactions (with an alkyl halide, aralkyl halide, alkylsulfonate or aralkylsulfonate) or by Mitsunobu reaction (with alcohol).

(4) Coupling of a heterocycle with a phosphonate component

If desired, the compounds described in this invention can be prepared in a preferred manner via a synthetic route involving coupling of a heterocycle with a phosphonate diester.

Cross-coupling reactions catalyzed by transition metal complexes such as Stille or Suzuki reactions are particularly useful for the synthesis of compounds of formula I. The cross-coupling reaction between a heteroaryl halide or triflate (e.g. 2-bromopyridine) and M-PO ₃ R ', where M is 2- (5-tributylstanyl) furanyl or 2- (5-boronyl) furanyl group under palladium catalysis conditions (Farina et al., Organic Reactions, Vol. 50; Wiley, New York, 1997; Mitchell, Synthesis, 1992, 808; Suzuki (Pure App. Chem., 1991, 63, 419) provides a compound of formula I wherein X is a furan-2,5-diyl group. Obviously, the kind of coupling partners for these reactions can also be reversed (e.g., coupling of trialkylstanyl or boronyl heterocycles with halogen-XP (O) (O-alkyl) ₂ ). Other coupling reactions between organostananes and alkenyl halides or alkenyl triflates are also described

280 and may be used to prepare compounds of formula I wherein X is alkenyl. The Heck reaction can be used to synthesize compounds of formula V wherein X is alkynyl (Heck Palladium Reagents in Organic Synthesis; Academic Press: San Diego, 1985). These reactions are particularly suitable for the synthesis of various heteroaromatic compounds such as R ⁵ for compounds of formula I, given that several halogenated heterocycles are available and these reactions are particularly suitable for parallel synthesis (e.g., combinatorial solid phase synthesis (Bunin, BA). , The Combinatorial Index; Academic Press: San Diego, 1998) or in solution (Flynn DL et al., Curr. Op. Drug. Disc. Dev., 1998, 1, 1367)) to generate large combinatorial libraries. For example, ethyl 5-iodo-2-furanyl phosphonate can be coupled onto Wang resin under suitable reaction conditions. The reagent resin, 5-iodo-2- [5-ethyl-O-Wang resin) phosphono] furan, may then be subjected to a transition metal-catalysed Suzuki or Stille reaction (see above) with organoboranes and organotin reagents in a parallel manner, wherein to form a library of compounds of formula 3 wherein X is furan-2,5-diyl.

The substitution reactions are suitable for coupling a heterocycle with a phosphonate diester component. For example, cyanuryl chloride may be substituted with dialkylmercaptoalkylphosphonates or dialkylaminoalkylphosphonates to give compounds of formula 2 wherein R ³ is 1,3,5-triazine, X is alkylthio or alkylamino. Alkylation reactions are also useful for coupling a heterocycle with a phosphonate diester component. For example, a heteroaromatic thiol (e.g., 1,3,4-thiadiazole-2-thiol) may be alkylated with a dialkylmethylphosphonate derivative (e.g., ICH ₂ P (O) (OEt) ₂ , TsOCH ₂ P (O) (OEt) ₂ , TfOCHP (O) (OEt) ₂ ) to give compounds of formula I wherein X is alkylthio. In another aspect, an alkylation reaction of a heteroaromatic carboxylic acid (e.g., thiazole-4-carboxylic acid) with a dialkylmethylphosphonate derivative (e.g., ICH ₂ P (O) (OEt) ₂ , TsOCH ₂ P (O) (OEt) 2, TfOCH ₂ P (O) (OEt) ₂ )

281 show compounds of formula I wherein X is an alkoxycarbonyl group while the alkylation reaction of heteroaromatic thiocarboxylic acids (e.g., thiazole-4-thiocarboxylic acid) with dialkylmethylphosphonate derivatives (e.g., ICH ₂ P (0) (OEt) ₂ , TsOCH ₂ P (O) (OEt) ₂ , TfOCH ₂ P (O) (OEt) ₂ ), leads to compounds of formula I wherein X is an alkylthiocarbonyl group. Substitution of halo heterocycles (e.g., 4-haloalkylthiazole) with nucleophiles containing a phosphonate group (diethylhydroxymethylphosphonate) are useful for the preparation of compounds of formula I wherein X is alkyloxyalkyl or alkylthioalkyl. For example, compounds of formula I wherein X is -ΟΗ ΟΟΗ _2-2 may pripraviťz 2-chloromethylpyridine or 4-chloromethylthiazole using dialkylhydroxymetylfosfonátov a suitable base (e.g. sodium hydride). It is possible to reverse the nature of nucleophiles and electrophiles in substitution reactions, i.e. haloalkyl and / or sulfonylalkylphosphonate esters may be substituted with nucleophile-containing heterocycles (e.g., 2-hydroxyalkylpyridine, 2-mercaptoalkylpyridine or 4-hydroxyalkyloxazole).

Reactions known for amide bond construction (e.g., acyl halide method, mixed anhydride method, carbodiimide method) can also be used for coupling a heteroaromatic carboxylic acid with a phosphonate diester component to give compounds of formula 4 wherein X is an alkylaminocarbonyl or alkoxycarbonyl. For example, condensation of a thiazole-7-carboxylic acid with a dialkylaminoalkylphosphonate or a dialkylhydroxyalkylphosphonate provides compounds of formula 4 wherein R ⁵ is thiazole and X is alkylaminocarbonyl or alkoxycarbonyl. Alternatively, the nature of the coupling partnership may be reversed to give compounds of Formula 4 wherein X is an alkylcarbonylamino group. For example, 2-aminothiazoles can be condensed with (RO) ₂ ? (O) -alkyl-CO ₂ H (e.g. diethylphosphonoacetic acid) to provide under these conditions compounds of formula 4 wherein R ⁵ is thiazole and X is alkylcarbonylamino. These reactions are also useful for

282 parallel synthesis of compound libraries through combinatorial chemistry on solid support or in solution. For example, HOCH ₂ P (O) (OEt) (O-resin), NH ₂ CH ₂ P (0) (OEt) (O-resin) and HOOCCH ₂ P (O) - (OEt) (O-resin) ( prepared using known methods) may be condensed with various heterocycles using the above reactions to form a library of compounds of formula 3 wherein X is -C (O) OCH ₂ - or -C (O) NHCH ₂ - or NHC (0) _CH2 -.

The rearrangements may also be used to prepare the compounds of this invention. For example, the Curtius rearrangement of thiazole-4-carboxylic acid in the presence of a dialkyl hydroxyalkylphosphonate or a dialkylaminoalkylphosphonate leads to compounds of formula 4 wherein X is an alkylaminocarbonylamino group or an alkoxycarbonylamino group. These reactions can also be used for the combinatorial synthesis of various libraries of compounds of formula 3. For example, a Curtius rearrangement between a heterocyclic carboxylic acid and HOCH ₂ P (0) (OEt) (O-resin) or NH ₂ CH ₂ P (0) (OEt) (O-resin) may result in libraries of compounds of formula I wherein X is -NHC (O) OCH ₂ - or -NHC (O) NHCH ₂ -.

For compounds of formula V wherein X is an alkyl group, phosphonate groups can be introduced using other conventional methods of forming a phosphonate group such as e.g. Michaelis-Arbuz reaction (Bhattac'narya et al., Chem. Rev., 1981, 81: 415), Michaelis-Becker reaction (Blackburn et al., J. Organomet. Chem., 1988, 348: 55) and addition reactions phosphorus to electrophiles (such as aldehydes, ketones, acyl halides, imines and other carbonyl derivatives).

The phosphonate component can also be introduced through a lithiation reaction. For example, lithiation of 2-ethynylpyridine using a suitable base followed by capture of the thus generated anion with dialkyl chlorophosphonate leads to compounds of formula 3 wherein R ⁵ is pyridyl and X is 1- (2-phosphono) ethynyl.

283 (5) Heterocycle Construction

While existing heterocycles are suitable for the synthesis of compounds of Formula V, if desired, heterocycles can also be constructed to provide compounds of the invention, and in some cases, these methods may be useful for preparing certain compounds. Heterocyclic constructs are well described in the literature using a variety of reaction conditions (Joule et al., Heterocyclic Chemistry; Chapman Hall, London, 1995; Boger, Weinreb, Hetero Diels Alder Methodology In Organic Synthesis; Academic Press, San Diego, 1987; Padwa, 1,3-Dipolar Cycloaddition Chemistry; Wiley, New York, 1984; Katritzsky et al., Comprehensive Heterocyclic Chemistry; Pergamon press,

Oxford; Newkome et al., Contemporary

Heterocyclic Chemistry:

Syntheses, Reaction and Applications;

Wiley, New

York, 1982;

Syntheses of Heterocyclic Compounds;

Consultants

Bureau, New

York). Some of these methods, which are suitable for the preparation of the compounds of the present invention, are exemplified in the examples below. (I) Construction of a thiazole ring system

Thiazoles suitable according to the invention can be readily prepared using a number of well-described cycle-forming reactions (Metzger, Thiazole and its derivatives, Part I and Part 2; Wiley & Sons, New York, 1979). The cyclization reactions of thioamides (e.g., thioacetamide, thiourea) and α-halocarbonyl compounds (such as α-halo ketones, α-haloaldehydes) are particularly suitable for the construction of the thiazole ring system. For example, cyclization reactions between thiourea and 5-diethylphosphono-2 - [(- 2-bromo-1-oxo) alkyl] furans are useful for the synthesis of compounds of formula 2 wherein R ⁵ is thiazole, A is amino and X is furan -2,5-diyl, cyclization reactions between thiourea and bromopyruvate alkyl ester to give 2-amino-4-alkoxycarbonylthiazole useful for the preparation of compounds of formula 2 wherein R ⁵ is thiazole and X is alkylaminocarbonyl, alkoxy

284 a carbonyl and alkylaminocarbonylamino or alkoxycarbonylamino group. Thioamides can be prepared using the reactions described in the literature (Trost, Comprehensive organic synthesis, vol. 6; Pergamon press, New York 1991, pages 419-434) and α-halocarbonyl compounds are readily prepared by conventional reactions (Larock, Comprehensive organic transformations (VCH, New York, 1989). For example, amides can be converted to thioamides using Lawesson's reagent or P ₂ S ₅ , ketones can be halogenated using various halogenating agents (e.g., NBS, CuBr ₂ ).

(ii) Construction of the oxazole ring system

Oxazoles useful in the present invention can be prepared using various methods described in the literature (Turchi, Oxazales; Wiley & Sons, New York, 1986). Reactions between isocyanides (e.g., tosylmethylisocyanides) and carbonyl compounds (e.g., aldehydes and acyl halides) can be used to construct the oxazole ring system (van Leusen et al., Tetrahedron Lett., 1972, 2369). Alternatively, cyclization reactions of amides (e.g., urea, carboxamides) and α-halocarbonyl compounds are commonly used to construct the oxazole ring system. For example, the reactions of urea and 5-diethylphosphono-2- [2-bromo-1-oxo) alkyl] furans are suitable for the synthesis of compounds of formula 2 wherein R ⁵ is oxazole, A is amino and X is furan-2,5- a diyl group. Reactions between amines and imidates are also useful in the construction of the oxazole ring system (Meyers et al., J. Org. Chem., 1986, 51 (26), 5111).

(iii) Construction of the pyridine ring system

Pyridines useful for the synthesis of compounds of formula

I may be prepared using known synthetic procedures (Klingsberg, Pyridine and Its Derivatives; Irterscience Publishers, New York, 1960-1984). The 1,5-dicarbonyl compounds or their equivalents can be reacted with ammonia or ammonia-generating compounds to produce 1,4-dihydropyri unsaturated 1,5-dicarbonyl compounds or (e.g., pyrylium salts) for reaction with ammonia, ginseng which are readily dehydrogenated to pyridines. When their equivalents are used, pyridines can be generated directly. The 1,5-dicarbonyl compounds of the lent can be prepared using conventional 1,5-diketones are achievable in many ways or their equivalents. For example, such as Michael addition of an enolate to an enone (or precursor

Mannich principles

Am. Chem. Soc., 1952, 74, cyclopentene precursors, or by reaction of silylenol ethers with

3-methoxyalyl alcohols (Duhamel et al.,

Tetrahedron 1986

42, 4777). When one of the carbonyl carbons is in the oxidation state of the acid, then this type of reaction produces 2-pyridones which can be easily converted to

2-halopyridines (Isler et al.,

Helv.

Chim.

Acta, 1955,

38

1033) or 2-aminopyridines (Vorbruggen et al., Chem. Ber., 1984, 117, 1523). Alternatively, pyridine can be prepared from an aldehyde, a 1,3-dicarbonyl compound, and ammonia et al.,

Angew.

by classical Hantsch synthesis (Bossart

1981, 20, 762). reactions

Chem. Int. Ed. Engl. .

1,3-dicarbonyl compounds (or equivalents) p

3-aminoenones or 3-aminonitriles have also been used to prepare pyridines (such as Guareschi synthesis, Mariella, Org.

Synth. Coli. Vol. IV, 1963, 210). The 1,3-dicarbonyl compounds may be prepared by the corresponding oxidation reactions

1,3-diols or aldol reaction products (Mukaiyama, Org.

Reactions,

Cycloaddition reactions have also been used to synthesize a cycloaddition reaction between oxazoles of alkenes (Naito et al., Chem. Pharm. Bull.,

Diels-Alder reactions between 1,2,4-triazines and enamines (Boger et al., J. Org. Chem., 1981, 46, 2179).

(iv) Construction of the pyrimidine ring system

Pyrimidine ring systems for the synthesis of compounds of formula V-2 are readily available (Brown, The pyrimidines, Wiley, New

286

York, 1994). One method for pyrimidine synthesis involves the condensation of a 1,3-dicarbonyl component (or equivalent) with an N-C-N fragment. Selection of NCN component-urea (Sherman et al., Org. Synth., Coll. Vol. 11; 1963, 247), amidine (Kenner et al., J. Chem. Soc., 1943, 125) or guanidine (Burgess, J. Org. Chem., 1956, 21, 97; VanAllan, Org. Synth., Coll. Vol. IV; 1963, 245) - directs substitution on C-2 pyrimidine products. This method is particularly effective for the synthesis of compounds of formula V-2 with different A groups. In another method, pyrimidines can be prepared by a cycloaddition reaction such as an aza-Diels-Alder reaction between 1,3,5-triazine and enamine or ynamine) ( Boger et al., J. Org. Chem., 1992, 57, 4331 and references herein).

(v) Construction of the imidazole ring system

Imidazoles useful for the synthesis of compounds of Formula V-1 are readily prepared using a variety of synthetic methodologies. Various cyclization reactions are generally used for the synthesis of imidazoles, such as the reaction of amides and α-haloketones (Mallick et al., J. Am. Chem. Soc., 1984, 106 (23), 7252) or α-hydroxyketones (Shi et al. , Synthetic Somm., 1993, 23 (18), 2623), the reaction between urea and α-haloketones and the reaction between aldehydes and 1,2-dicarbonyl compounds in the presence of amines.

(vi) Construction of the isoxazole ring system

The isoxazoles useful for the synthesis of compounds of formula VI are readily synthesized using a variety of methodologies (such as cycloaddition reactions between nitriloxides and alkynes or active methylene compounds, oximation of 1,3-dicarbonyl compounds or α, β-acetylenic carbonyl compounds or α, β-dihalocarbonyl compounds, etc., can be used to synthesize an isoxazole ring system (Grunanger et al.,

287

Izoxazoles; Wiley & Sons, New York, 1991). For example, reactions between alines and 5-diethylphosphono-2-chlorooximidofuran in the presence of a base (e.g., triethylamine, Hunig's base, pyridine) are useful for the synthesis of compounds of formula 2 wherein R ⁵ is oxazole and X is furan-2,5-diyl group.

(vii) Construction of a pyrazole ring system

Pyrazoles useful for the synthesis of compounds of Formula VI are readily prepared using a variety of methods (Wiley, Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles and Condensed Rings; Interscience Publishers, New York, 1967) such as reactions between hydrazines and 1,3-dicarbonyl compounds. or 1,3-dicarbonyl equivalents (e.g., one of the carbonyl groups is masked as enamine or ketal or acetal) and the addition of hydrazines to acrylonitriles followed by cyclization reactions (Dorn et al., Org. Synth., 1973, Coli. Vol. 1) ; 39). reactions

2- (2-alkyl-3-N, N-dimethylamino) acryloyl-5-diethylphosphonofuran with hydrazines are useful for the synthesis of compounds of formula I wherein R ⁵ is pyrazole, X is furan-2,5-diyl and B is alkyl group.

(vii) Construction of a 1,2,4-triazole ring system

1,2,4-triazoles useful for the synthesis of compounds of formula V-1 are readily available using a variety of methodologies (Morgonomers, 1,2,4-Triazoles; Wiley, New York, 30, 1981). For example, reactions between hydrazides and imidates or thioimidates (Sui et al., Bioorg. Med. Chem. Lett., 1998, 8, 1929; Catarzi et al., J. Med. Chem., 1995, 38 (2), 2196 ), reactions between 1,3,5-triazine and hydrazines (Grundmann et al., J. Org. Chem., 1956, 21, 1037) and reactions between aminoguanidine and carboxylic esters (Ried et al., Chem. Ber., 1968, 101, 2117) are used for the synthesis of 1,2,4-triazoles.

(6) Ring closure in the construction of a heterocycle with a phosphonate

288

Compounds of formula 4 may also be prepared using ring closure reactions to construct a heterocyclic precursor containing a phosphonate component. For example, cyclization reactions between thiourea and 5-diethylphosphono-2- [2-bromo-1-oxo) alkyl] furans are useful for the synthesis of compounds of formula 2 wherein R ⁵ is thiazole, A is amino and X is furan-2, 5-diyl. The oxazoles of the invention may also be prepared using cyclization reactions. In this case, the reactions of urea and 5-diethylphosphono-2- [2-bromo-1-oxo) alkyl] furans are useful for the synthesis of compounds of formula I wherein R ⁵ is oxazole, A is amino and X is furan-2, 5-diyl. Reactions between 5-diethylphosphono-3-furanaldehyde, alkylamine, 1,2-diketone and ammonium acetate are useful for the synthesis of compounds of formula 2 wherein R ⁵ is imidazole and X is furan-2,5-diyl. These types of cyclization reactions may also be useful for the synthesis of pyridines or pyrimidines useful in the present invention. For example, reaction of 5-diethylphosphono-2- [3-dimethylamino-2-alkyl · acryloyl] furans and cyanoacetamide in the presence of a base gives 5-alkyl-3-cyano-6- [2- (5-diezylphosphono) furanyl] -2 pyridones (Jain et al., Tetrahedron Lett., 1995, 36, 3307). Subsequent conversions of these 2-pyridones to the corresponding 2-halopyridines (see references cited in section 3 for heterocycle modifications) will lead to compounds of formula I wherein R ⁵ is pyridine, A is halogen, X is furan-2,5-diyl, and B is an alkyl group. Reaction of 5-diethylphosphono-2- [3-dimethylamino-2-alkyl) acryloyl] furans and amides in the presence of a base affords 5-alkyl-6- [2- (5-diethylphosphono) furanyl] pyrimidines to give compounds of formula 2 wherein R ³ is pyrimidine, X is furan-2,5-diyl and B is alkyl.

(7) Preparation of various precursors useful in cyclization reactions

The intermediates required for the synthesis of the compounds of this invention are generally prepared using either existing ones

289 methods described in the literature or modifications of existing methods. The synthesis of some intermediates useful in the synthesis of the compounds of this invention is described herein.

Various arylphosphonate dialkyl esters are particularly useful for the synthesis of compounds of formula I. For example, compounds of formula 3 wherein X is a furan-2,5-diyl group may be prepared from various furanyl precursors. It is understood that synthesis of other precursors may be carried out using all or only some of the reaction steps, and some modifications of these reactions may be required for various precursors. 5-Dialkylphosphono-2-furancarbonyl compounds (e.g., 5-diethylphosphono-2-furaldehyde, 5-diethylphosphono-2-acetylfuran) will be very suitable for the synthesis of compounds of formula I wherein X is furan-2,5-diyl. These intermediates are prepared from furan or furan derivatives using conventional chemistry such as lithiation reactions, carbonyl group protection and carbonyl group deprotection. For example, furan lithiation using a known method (Gschwend Org. React. 1979, 26: 1) followed by addition of a phosphorylating agent (e.g., CIPO 3 R 2) affords 2-dialkylphosphonofurans (e.g., 2-diethylphosphonofuran). This method can also be applied to 2-substituted furans (e.g., 2-furoic acid) to give 5-dialkylphosphono-2-substituted furan (e.g., 5-diethylphosphono-2-furoic acid). It is understood that other arylphosphonate esters may also be prepared using this procedure or by modifying this approach. Alternatively, other methods may also be used to prepare aryl phosphonates, e.g. transition metal complex catalyzed reactions of aryl halides and criflates (Balthazar et al. J. Org. Chem., 1980, 45: 5425; Petrakis et al., J. Am. Chem. Soc., 1987, 109: 2831; Lu et al. Synthesis, 1987, 726). Arylphosphonate esters can also be prepared from arylphosphates under anionic rearrangement conditions (Melvin, Tetrahedron Lett., 1981, 22: 3375; Casteel et al., Synthesis, 1991, 691). N-alkoxyaryl salts with alkali metal dialkyl phosphonate derivatives provide

290, another general method for the synthesis of heteroaryl-2-phosphate esters (Redmore J. Org. Chem., 1970, 35: 4114).

The second casting step can be used to introduce a second group into an arylphosphonate dialkyl ester such as an aldehyde, a trialkylstanyl or a halogen group, although other known methods for generating these functional groups (e.g., aldehydes) (e.g., Vismeier-Hack reaction or Reimer-Teiman reaction for the synthesis of aldehydes). In the second casting step, the lithium aromatic ring is reacted either directly with the reagent to generate the desired functional group (e.g., for an aldehyde using DMF, HCO2R, etc.) or with the reagent leading to the group which is subsequently converted to the desired functional group using known chemistry (e.g. alcohols, esters, nitriles, alkenes can be converted to aldehydes). For example, lithiation of 2-dialkylphosphonofuran (e.g., 2-diethylphosphonofuran) under normal conditions (e.g., LDA in THF) followed by capture of the thus generated anion by an electrophile (e.g., tributyltin chloride or iodine) to give 5-functionalized 2-dialkylphosphonofuran (e.g. -tributylstanyl-2-diethylphosphonofuran or 5-iodo-2-diethylphosphonofuran). It will also be appreciated that the order of these reactions may be reversed, i.e., the aldehyde group may first be introduced and then the phosphorylation reaction may be carried out. The order of reactions will depend on the reaction conditions and the presence of the protecting groups. Obviously, it may be advantageous to protect some of the functional groups from phosphorylation using a number of well known reactions (e.g., protection of aldehydes in the form of acetals, amines, protection of ketones in the form of ketals). Protected functional groups are unmasked after phosphorylation (Protective groups in Organic Synthesis, Greene, T.W., 1991, Wiley, New York). For example, protection of 2-furanaldehyde as 1,3-propanedioacetal followed by a lithiation step (using e.g. LDA) and capture of an anion with a dialkyl phosphate (e.g. diethyl chlorophosphate) followed by deprotection of the acetal group under normal deprotection conditions provides

291

5-dialkylphosphono-2-furaldehyde (e.g. 5-diethylphosphono-2-furaldehyde). Another example is the preparation of 5-keto-2-dialkylphosphonofuran, which comprises the following steps: acylation of furan under Friedel-Crafts reaction conditions to form 2-ketofuran, followed by protection of the ketone as an acetal (e.g., 1,3-propanediol cyclic ketal) followed by The lithiation step described above provides 5-dialkylphosphono-2-furanketone which is protected as a cyclic ketal with 1,3-propanediol and the final ketal deprotection in e.g. acidic conditions afford 2-keto-5-dialkylphosphonofurans (e.g., 2-acetyl-5-diethylphosphonofuran). Alternatively, 2-ketofurans can be synthesized by palladium catalyzed reactions between 2-trialkylstanylfuran (e.g., 2-tributylstanylfuran) and acyl chloride (e.g., acetyl chloride, isobutyryl chloride). It is preferred to have a phosphonate group present in 2-trialkylstanylfuran (e.g., 2-tributylstanyl-5-diethylphosphonofuran). 2-Keto-5-dialkylphosphonofurans can also be prepared from 5-dialkylphosphono-2-furoic acid (e.g., 5-diethylphosphono-2-furoic acid) by converting the acid to the corresponding acyl chlorides followed by addition of Grignard reagent.

Some of the above intermediates may also be used to synthesize other useful intermediates. For example, 2-keto-5-dialkylphosphonofuran can be further converted to a 1,3-dicarbonyl derivative which is useful for the preparation of pyrazoles, pyridines or pyrimidines. Reaction of 2-keto-5-dialkylphosphonofuran (e.g. 2-acetyl-5-diethylphosphonofuran) with dialkylformamide diakyl acetal (e.g. dimethylformamide dimethylacetal) affords

1,3-dicarbonyl equivalent such as 2- (3-dialkylamino-2-alkyl-acryloyl) -5-dialkylphosphonofuran (e.g. 2- (3-dimethylaminoacryloyl) -5-diethylphosphonofuran).

It will be appreciated that the previously described methods for synthesizing furan derivatives may be applied directly or with some modifications to the synthesis of various other useful intermediates such as arylphosphonate esters (e.g., thienylphosphonate esters, phenylphosphonate esters or pyridylphosphonate esters).

292

It is possible for the previously described synthetic methods to be applied as a parallel synthesis either in solid phase or in solution to rapidly detect the SAR (structure-activity relationship) of the FBPase inhibitors involved in the present invention, provided that the above methods are capable of such a reaction. .

Section 2

Synthesis of compounds of formula X

The synthesis of compounds encompassed by this invention typically involves some or all of the following steps: (1) preparation of phosphonate prodrugs, (2) deprotection of phosphonate ester, (3) construction of heterocycle, (4) introduction of phosphonate component, (5) synthesis of aniline derivative. Step (1) and step (2) are discussed in section 1 and a discussion of steps (3), (4) and (5) is given below. These methods are generally applicable to compounds of formula X.

293 (3) Heterocycle Construction (i) Benzothiazole ring system

Compounds of formula 3 wherein G = S, i.e. benzothiazoles, can be prepared using various methods described in the literature. Two of these methods are exemplified in the following discussion. One method is to modify commercially available benzothiazole derivatives to provide the corresponding functionality on the benzothiazole ring. Another method is the annulment of various anilines (e.g., compounds of Formula 4) to form the thiazole moiety of the benzothiazole ring. For example, compounds of formula 3 wherein G = S, A = NH ₂ , 1, E ² , J ² = H, X ² = CH ₂ O and R 1 = Et can be prepared from commercially available 4-methoxy- 2-aminothiazoles via a two-step sequence: conversion of 4-methoxy-2-aminobenzothiazole to 4-hydroxy-2-aminobenzothiazole with agents such as BBr ₃ (Node M. et al., J. Org. Chem., 45, 2243-2246, 1980) or AlCl ₃ in the presence of thiols (e.g., EtSH) (McOmie JFW et al., Org. Synth. Collect. Vol. V, 412, 1973) followed by alkylation of the phenol group with diethylphosphonomethyl trifluoromethylsulfonate (Phillion DP et al., Tetrahedron). Lett., 27, 1477-1484, 1986) in the presence of a suitable base (e.g. NaH) in polar aprotic solvents (e.g. DMF) provides the desired compound.

Several methods can be used to convert various anilines into benzothiazoles (Sprague JM; Land AH, Heterocycle, Compd. 5, 506-13, 1957). For example, 2-aminobenzothiazoles (Formula 3 wherein A = NH ₂ ) can be prepared by annulment of compounds of Formula 4 wherein W ⁴ = H, using various conventional methods. One method involves reacting suitable substituted anilines with a mixture of KSCN and CuSCl in methanol to give substituted 2-aminobenzothiazole (Ismail IA; Sharp DE; Chedekel MR, J. Org. Chem. 45, 2243-2246, 1980). Alternatively, 2-aminobenzothiazole can also be prepared by reaction with Br ₂ in the presence

294

KSCN in acetic acid (Pattil DG; Chedekel MR; J. Org. Chem. 49: 997-1000, 1984). This reaction can also be performed in a two step sequence. For example, reaction of substituted phenylthioureas with Br ₂ in chloroform provides substituted 2-aminobenzothiazoles (Pattil DG; Chedekel MR; J. Org. Chem., 49, 997-1000, 1984). 2-Aminobenzothiazoles can also be prepared by condensing ortho iodoanilines with thiourea in the presence of a Ni catalyst (NiCl ₂ (PPh ₃ ) ₂ ) (Takagi K., Chem. Lett., 265-266, 1986).

Benzothiazoles can undergo electrophilic aromatic substitution to form 6-substituted benzothiazoles (Sprague, JM; Land AH; Heterocycle. Compd. 5, 606-13 (1957). For example, bromination of Formula 3 wherein G = S, A = NH ₂ , L ² , E ¹ , J ² = hydrogen, X ² = CH ₂ O and R 1 -Et, with bromine in polar solvents such as acetic acid, provides a compound of formula 3 wherein E ² = Br.

In addition, compounds of formula 3 wherein A is halogen, hydrogen, alkoxy, alkylthio or alkyl may be prepared from the corresponding amino compound (Larock, Comprehensive Organic Transformations, VCH, New York, 1989; Trost, Comprehensive Organic Synthesis; Pergamon press, New York, 1991).

(ii) Benzoxazoles

Compounds of formula 3 wherein G = O, i.e. benzoxazoles, can be prepared by annealing ortho aminophenols with a suitable reagent (e.g. cyanogen halide (A = NH ₂ , Alt KO et al., J. Heterocyclic Chem. 12, 775, 1975)) or acetic acid (A = CH ₃ ; Saa JM; J. Org. Chem. 57, 589-594, 1992) or trialkyl orthoformate (A = H; Org. Prep. Proced. Int., 22, 613, 1990).

(4) Introduction of the phosphonate component

Compounds of Formula 4 (wherein X ² = CH ₂ O and R '= alkyl)

295 can be prepared by a variety of routes (e.g., using alkylation and nucleophilic substitution). Typically, compounds of formula 5 wherein M '= OH can be reacted with a suitable base (e.g. NaH) in a polar aprotic solvent (e.g. DMF, DMSO) and the resulting phenoxide anion can be alkylated with a suitable electrophile, preferably a phosphonate component present (e.g., diethyl iodomethylphosphonate, diethyl trifluoromethylsulfonomethyl phosphonate, diethyl p-methyltoluenesulfonomethylphosphonate). The alkylation methods can also be applied to precursor compounds to form compounds of formula 5 wherein a phenol group is present and can be alkylated with a phosphonate-containing component. Alternatively, compounds of formula 4 may also be made by nucleophilic substitution of the precursor compounds of formula 5 (where a halogen group, preferably fluorine or chlorine, is present in the ortho position against the nitro group. For example, a compound of formula 4 (where X ² = CH ₂ O) and R '= Et) can be prepared from a 2-chloro-1-nitrobenzene derivative by reaction with NaOCH ₂ P (O) (OEt) ₂ in DMF Similarly, compounds of formula 4 wherein X ² = -alkyl can be prepared -S- or -alkyl-N-.

(5) Synthesis of aniline derivatives

Several methods of synthesizing aniline derivatives are described, and these methods can be applied to the synthesis of useful intermediates that can lead to compounds of formula X. For example, various alkenyl or aryl groups can be introduced on the benzene ring by transition metal catalyzed reactions (Kasibhatla SR, et al., WO 98/39343 and references herein), anilines can be prepared from the corresponding nitro derivatives by reduction reactions (e.g., hydrogenation reaction in the presence of 10% Pd / C or a reduction reaction using SnCl ₂ in HCl (Pätil DG; Chedekel); MR, J. Org. Chem., 49, 997-1000, 1984).

Section 3

296

Synthesis of Compounds of Formula VII

The synthesis of compounds encompassed by this invention typically involves some or all of the following general steps represented by the following scheme: (a) coupling of a phosphonate fragment (Ia or 1b) with an aryl or heteroaryl ring fragment (2a or 2b), (b) as appropriate, ( c) deprotection to form a phosphonic acid prodrug.

modification of the coupled phosphonate diester molecule (3), at (4) and (d) preparation of a phosphonate

(C)

ABOUT

HO --- P --- X ⁴ —R ⁵⁵ ( ^d )

I --------------

1 ---------------- r'y — P — x ⁴ - OH l 4 YR ¹ J ³ J ³ in n r ¹⁵ = ₆ , C-Gt. _s a: J ^{6 J 1} e '| 6

(a) Coupling of a phosphonate fragment (1) with an aryl group (2)

If appropriate, the compounds encompassed by this invention are preferably prepared by convergent synthetic procedures involving coupling of a phosphonate component with an aryl or het

297 roaryl ring fragment.

Transition catalysed reactions such as the Stille reaction or the Suzuki reaction are particularly useful for the synthesis of compounds of formula VII (Farina et al., Organic Reactions, vol. 50, Wiley, New York, 1997, Suzuki in Metal Catalysed Cross-Coupling Reactions, Wiley. (1998, pp. 49-97). The coupling reaction between compound I (where B is preferably Bu ₃ Sn) and compound 2 (where A is e.g. iodine, bromine or trifluoromethylsulfonate) under palladium catalysis provides compounds of formula 3 wherein X ⁴ is e.g. 2,5-furanyl. The same type of coupling reaction between compound 1 (where B is preferably iodine) and compound 2 (where A = B (OH) 2 or Bu ₃ Sn) can also be used to synthesize a compound of formula 3 wherein X ⁴ is e.g. 2,5-furanyl.

The reactants 2, which are substituted aryl or heteroaryl compounds, are either commercially available or can be readily prepared by known methods. Binding agents 1 are prepared using well known chemistry. For example, when X ⁴ is

2,5-furanyl, coupling agent 1 is prepared starting from furan using an organolithium technique. Furan lithiation using known methods (e.g., n-BuLi / TMEDA, Gschwend Org. React. 1979, 26, 1), followed by addition of a phosphorylating agent (e.g., C1PO ₃ R ₂ ) affords 2-dialkylphosphonofurans (e.g., 2-diethylphosphonofuran) . Synthesis of 2,5-disubstituted furan building blocks can be accomplished by lithiation of 2-dialkylphosphonofuran (e.g., 2-diethylphosphonofuran) with a suitable base (e.g., LDA) followed by capture of the resulting anion with an electrophile (e.g., tributylcin chloride, triisopropylborate or iodine). -functionalized 2-dialkylphosphonofuran (e.g. 5-tributylstanyl-2-diethylphosphonofuran, 2-diethylphosphonofuran-5-boronic acid or 5-iodo-2-diethylphosphonofuran).

It will be appreciated that the previously described methods for synthesizing furan derivatives may be applied, directly or with modifications, to the synthesis of various other useful intermediates such as arphosphonate

298 esters (e.g., thienylphosphonate esters, phenylphosphonate esters or pyridylphosphonate esters).

The reactions known to form an amide bond may be used to condense phosphonate diester building blocks 1 with an aryl or heteroaryl ring intermediate 2, resulting in compounds of formula VII wherein X ⁴ is an alkylaminocarbonyl or alkylcarbonylamino group. For example, coupling of an arylcarboxylic acid preferably with diethylaminomethylphosphonate may result in a compound of formula VII wherein the ring fragment included from intermediate 2 is aryl and the X ⁴ fragment is -CH 2 NHC (O) -. Similarly, substitution of diethylalkylaminoalkylphosphonates in this method may result in a compound wherein the fragment X ⁴ represents the group -R'C (R) NRC (O) -. Alternatively, for example, arylamine coupling with preferably diethylphosphonoacetic acid may provide a compound of formula VII wherein the ring fragment introduced from intermediate 2 is aryl and the X ⁴ fragment is -CH 2 C (O) NH-. Compounds with the X ⁴ fragment -R'C (R) N (R) C (O) - can be prepared by extending this method.

Methods known to form an ester linkage can be used to prepare compounds of formula VII wherein X ⁴ is an alkylcarboxy or alkoxycarbonyl group (e.g., -CH 2 C (O) O- or -CH 2 OC (O) -). For example, when the fragment of compound 2 is a hydroxy-substituted aryl (e.g., a phenol derivative), it can be acylated with diethylphosphonoacetyl chloride in the presence of sterically bulky amines such as triethylamine to form compounds wherein X ⁴ is -CH 2 C (O) O-. In addition, arylacyl halides (e.g., arylacyl chlorides) can be coupled with dialkyl (hydroxy) phosphonates (e.g., diethyl (hydroxy) methylphosphonate) to form compounds wherein X ⁴ is -alkoxycarbonyl- (e.g., -CH ₂ OC (O) - ).

Reactions known to form an ether bond may be used to prepare compounds of formula VII wherein X ⁴ is an alkylene-O or alkylene-O-alkylene group. For example, the phenol sodium may be alkylated with diethyl (iodomethyl) phosphonate or preferably

299 diethylphosphonomethyl triflate to form compounds of formula VII wherein X ⁴ is -alkylene-O. Similarly, alkylation of the aryl methyl alcohol sodium with diethyl (iodomethyl) phosphonate or preferably diethyl phosphonomethyl triflate may result in compounds of formula VII wherein X ⁴ is -alkylene-O-alkylene-. Alternatively, the reaction of diethyl hydroxymethylphosphonate with sodium hydride and the reaction of the sodium salt thus generated with a haloalkylaryl compound can lead to compounds of formula VII wherein X ⁴ is -alkylene-O-alkylene-.

For compounds of formula VII wherein X ⁴ is an alkyl group, a phosphonate group may be introduced using conventional phosphonate formation methods such as e.g. Michaelis-Arbuz reaction (Bhattacharya et al., Chem. Rev., 981, 81: 415), Michaelis-Becker reaction (Blackburn et al., J. Organomet. Chem., 1988, 348: 55) and phosphorus addition reactions to electrophiles (such as aldehydes, ketones, acyl halides, imines and other carbonyl derivatives).

If necessary and sometimes preferred, the compounds of formula 3 can also be prepared from the aryl compounds 2b by introducing a phosphonate group such as a dialkylphosphono group (e.g., a diethylphosphono group). For example, compounds of formula VII wherein X ⁴ is 1,2-ethynyl can be prepared by lithium terminal arylalkine followed by reaction of the anion with a phosphorylating agent (e.g., CIPO 3 R 2) to form arvlalkynyl phosphonate. The desired arylalkines are used using conventional chemical procedures.

easy to prepare with

For example, arylalkines (e.g. iodides, bromides) or triflates with trimethylsilylacetylene using the Sonogashira reaction (Sonogashira in Comprehensive

Organic

Synthesis

Pergamon Press: New York, 1991, vol. 3, p.

521-549), followed by deprotection of the trimethylsilyl group, resulting in terminal arylalkines.

wherein (b) Modification of the coupled molecules

300

The coupled molecule 3 can be modified in many ways. Aryl halides (J ³ -J ⁷ each optionally Br, I or O-triflate) are useful intermediates and are often readily converted to other substituents such as aryls, olefins, alkyls, alkynyls, arylamines and aryloxy groups by transition metal catalysis reactions ( Farina et al., Organic Reacticns, vol. 50; Wiley, New York, 1997; Mitchell, Synthesis, 1992, 808; Suzuki in Metal Catalytic Cross Coupling Reactions; Wiley VCH, 1998, pp. 49-97; Heck Palladium Reagents in Organic Synthesis, Academic Press: San Diego, 1985; Sonogashira in Comprehensive Organic Synthesis, Pergamon Press: New York, 1991, vol. 3, pp. 521-549, Buchwald J. Am. Chem. Soc. 1999, 121, 4369- 4378; Hartwig, J. Am. Chem. Soc. 1999, 121, 3224-3225; Buchwald Acc. Chem. Res. 1998, 31, 805).

Compounds of formula VII wherein J ³ -J ⁷ is each optionally a carboxamido group can be prepared from the corresponding alkyl carboxylate esters by aminolysis using various amines or by reaction of carboxylic acids with amines under standard amide bond forming conditions (e.g. DIC / HOBt mediated amide bond formation).

Compounds of formula VII wherein J ³ -J ⁷ is each optionally a carboxylate ester can be prepared from the corresponding carboxylic acids by standard esterification reactions (e.g. DIEA / DMF / alkyl iodide or EDCI, DMAP and alcohol) or from the corresponding aryl halides / triflates by means of standard esterification reactions. transition metal-catalyzed carbonylation reactions.

Compounds of formula VII wherein J ³ -J ⁷ is each optionally an alkylaminoalkyl or arylaminoalkyl group may be prepared from the corresponding aldehydes by standard reductive amination procedures (e.g., aryl or alkylamine, TMCF, AcOH, DMSO, NaBH ₄ ).

(c) Deprotection of phosphonate and phosphoramidate esters

301

Compounds of formula 4 may be prepared from phosphonate esters using known phosphonate ester cleavage conditions as discussed in Section 1.

(d) Preparation of phosphonate and phosphoramidate prodrugs

The prodrug substitution can be introduced at various stages of the synthesis. Most often, the prodrug is prepared from a phosphonic acid of formula 4 due to the instability of some prodrugs. Preferably, the prodrugs are introduced at an earlier stage, provided that the reaction conditions of the subsequent steps can persist.

Bis-phosphoramidates, compounds of formula (VII) wherein Y 'is nitrogen and R' are identical amino acid groups may be prepared from the corresponding compounds of formula (4) by coupling a suitably activated phosphonate (e.g. dichlorophosphonate) with an amino acid ester (e.g. alanine ethyl ester) ) with or without the presence of a base (e.g., N-methylimidazole, 4-N, N-dimethylaminopyridine). Alternatively, bis-phosphoramidates can be prepared by reactions between compounds of Formula 4 with amino acid esters (e.g., glycine ethyl ester) in the presence of triphenylphosphine and 2,2'-dipyridyldisulfide in pyridine as described in WO / 07920 or Mukaiyama T. et al., J. Am. Chem. Soc., 1972, 94, 8528.

Mixed bis-phosphoramidates, compounds of formula VII wherein both Y 1 are nitrogen and R ¹ are different groups with one R ¹ derived from an amino acid and the other R ¹ derived from either amino acids or from other groups (e.g. alkyl, aryl, arylalkylamines) , can be prepared by the methods described above, but with successive addition of various amines (e.g., glycine ethyl ester and alanine ethyl ester) to activated phosphonates (e.g., dichlorophosphonate). It will be appreciated that the mixed bis-phosphoramidates may be separated from other products (e.g., compounds of formula VII wherein both Y 'are nitrogen and R ¹ are identical groups) using appropriate

302 purification techniques such as column chromatography, MPLC or crystallization methods. Alternatively, the mixed bis-phosphoramidates can be prepared as follows: coupling of the appropriate phosphonate monoester (phenyl or benzyl esters) with an amine (e.g. alanine ethyl ester or morpholine) by the above described chloridate method, followed by removal of the phosphonate ester (e.g. phenyl ester or benzyl ester) wherein the phosphoramidate linkage is stable (e.g., suitable hydrogenation conditions) and the resulting monophosphoramidate can be coupled with a second amine (e.g., glycine ethyl ester) to form a mixed bisphosphoramidate by the above-described chloridate method. Phosphonic acid monoesters can be prepared using conventional methods (e.g., hydrolysis of phosphonate diesters or the procedure described in EP 481 214).

Monophosphoramidate monoesters, compounds of formula VII wherein one Y is O and the other Y is N can be prepared using the sequential addition methods described above. For example, the dichloridate generated from compounds of Formula 4 can be reacted with 0.7 to 1 equivalent of an alcohol (e.g. phenol, benzyl alcohol, 2,2,2-trifluoromethanol) preferably in the presence of a suitable base (e.g. Hunig's base, triethylamine). Upon completion of the above reaction, 2 to 10 equivalents of amine (e.g., alanine ethyl ester) are added to the reaction to give compounds of formula VII wherein one Y is O and the other Y is N. Alternatively, selective hydrolysis (e.g. using lithium hydroxide). The phosphonate diester (e.g. diphenylphosphonate) can lead to a phosphonate monoester (e.g. phosphonate monophenyl ester) and the phosphonate mono ester can be condensed with an amine (e.g. alanine ethyl ester) using the above described chloridate method to prepare mixed bis-phosphoramidates.

Compounds of formula 4 may be alkylated with electrophiles (such as alkyl halides, alkylsulfonates, and the like) under conditions of a nucleophilic substitution reaction to form phosphonate esters. For example, compounds of formula VII wherein R ¹

303 are cycloalkyl groups, can be synthesized by direct alkylation of compounds of Formula 4 with a suitable acyloxy halide (e.g., Cl, Br, I, Elhaddadi et al., Phosphorus Sulfur, 1990, 54 (1-4), 143, Hoffmann, Synthesis, 1998 62) in the presence of a suitable base (e.g., N, N'-dicyclohexyl-4-morpholinecarboxamidine, Hunig's base) (Starrett et al., J. Med. Chem., 1994, 1857). The carboxylate component of these acyloxyalkyl halides may be, but is not limited to, acetate, propionate, 2-methylpropionate, pivalate, benzoate, and other carboxylates. If desired, further modifications are possible after formation of the acyloxyalkyl phosphonate esters such as reduction of the nitro group. For example, compounds of formula 5 wherein J ³ to J ⁷ are each optionally nitro can be converted to compounds of formula 5 wherein J ³ to J ⁷ are each optionally amino under the conditions of a suitable reduction reaction (Dickson et al. , J. Med. Chem., 1996, 39: 661; Iyer et al., Tetrahedron Lett., 1989, 30: 7141; Srivastva et al., Bioorg. Chem., 1984, 12: 118). Compounds of formula VII wherein R ¹ is a cyclic carbonate, lactone or phthalidyl group may be synthesized by direct alkylation of compounds of formula 4 with appropriate electrophiles (e.g. halides) in the presence of a suitable base (e.g. NaH or diisopropylethylamine, Biller et al., U.S. 5,157,027, Serafinowska et al., J. Med. Chem. 1995, 38: 1372; Starrett et al., J. Med. Chem. 1994, 37: 1857; Martin et al., J. Pharm. Sci. 1987, 76: 180; Alexander et al., Collect. Czech. Chem. Commun. 1994, 59: 1853; EPO 0632048A1). Other methods can also be used to alkylate compounds of Formula 4 (e.g., using N, N-dimethylformamide dialkyl acetals as alkylating agents: (Alexander P. et al., Collect. Czech. Chem. Commun., 1994, 59, 1853)) .

Alternatively, these phosphonate prodrugs can be synthesized by the reaction of the corresponding dichlorophosphonates with an alcohol (Alexander P., et al., Collect. Czech. Chem. Cmmmm., 1994, 59, 1853). For example, the reaction of a dichlorophosphonate with substituted phenols, arylalkyl alcohols in the presence of a suitable base.

304 of the kit (e.g. pyridine, triethylamine, etc.) provides compounds of formula VII wherein R ¹ is an aryl group (Khamnei et al. J. Med. Chem., 1996, 39: 4109; Serafinowska et al., J. Med. Chem., 1995, 38: 1372; De Lombaert et al., J. Med. Chem., 1994, 37: 498) or an arylalkyl group (Mitchell et al., J. Chem. Soc. Perkin Trans. 1, 1992 , 38: 2345) and Y is oxygen. Disulfide-containing prodrugs (Puech et al., Antiviral Res., 1993, 22: 155) can also be prepared from dichlorophosphonate and 2-hydroxyethyl disulfide under standard conditions. If possible, these methods may be extended to the synthesis of other types of prodrugs such as compounds of formula VII wherein R ¹ is 3-phthalidyl, 2-oxo-4,5-didehydro-1,3-dioxolane methyl or 2-oxotetrahydrofuran -5-yl.

Dichlorophosphonate or monochlorophosphonate derivatives of compounds of Formula 4 may be generated from the corresponding phosphonic acids using chlorinating agents (e.g., thionyl chloride: Starrett et al., J. Med. Chem., 1994, 1857, oxalvl chloride: Stowell et al., Tetrahedron Lett. 1990, 31: 3261 and phosphoropentachloride: Quast et al., Synthesis, 1974, 490). Alternatively, the dichlorophosphonate may also be generated from the corresponding disilyl phosphonate ester (Bhongle et al., Synth. Commun., 1987, 17: 1071) or dialkyl phosphonate esters (Still et al., Tetrahedron Lett., 1983, 24: 4405; Patois et al. et al., Bull. Soc. Chim. Fr., 1993, 130: 485).

In addition, where possible, prodrugs can be prepared using the Mitsunobu reaction (Mitsunobu, Synthesis, 1981, 1; Campbell, J. Org. Chem. 1992, 52: 6331) and other coupling reactions (e.g., using carbodiimides: Alexander et al., Collect., Czech. Chem. Commun., 1994, 59: 1853; Casara et al., Bioorg. Med. Chem. Lett., 1992, 2: 145; Ohashi et al., Tezrahedron Lett., 1988 , 29: 1189 and benzotriazolyloxytris (dimethylamino) phosphonium salt: Campagne et al., Tetrahedron Lett., 1993, 34: 6743). In some cases, R ¹ may be introduced preferably at an early stage of the synthesis, provided that it is compatible

305 with subsequent reaction steps. For example, compounds of formula VII, wherein R ¹ is an aryl group, can be prepared by a metallation reaction of a 2-furanyl-substituted heterocycle (e.g., using LDA) followed by anion capture with diaryl chlorophosphate.

It will be appreciated that compounds of Formula VII may be mixed phosphonate esters (e.g., phenyl and benzyl esters, or phenyl and acyloxy esters) including chemically combined esters such as phenyl and benzyl combined prodrugs described in Meier et al., Bioorg. Med. Chem. Lett., 1997, 7: 99.

Substituted cyclic propyl phosphonate or phosphoramidate esters can be synthesized by reacting the corresponding dichlorophosphonates with substituted 1,3-propanediol, 1,3-hydroxypropylamine or 1,3-propanediamine. Some methods useful for preparing substituted e.g. 1,3-propanedioles are described below.

Synthesis of 1,3-propanediol, 1,3-hydroxypropylamine and 1,3-propanediamine

Various synthetic methods can be used to prepare several types of 1,3-propanedioles: (i) 1-substituted, (ii) 2-substituted, (iii) 1,2- or 1,3-annulled 1,3-propanediols, ( iv)

1,3-hydroxypropylamine and 1,3-propanediamine. The general approach for preparing these compounds is discussed above.

Synthesis of chiral substituted 1,3-hydroxyamines and 1,3-diamines

Enantiomerically pure 3-aryl-3-hydroxypropan-1-amines are synthesized by CBS enantioselectively catalyzed reaction of 3-chloropropiophenone followed by halogen substitution to give the desired secondary or primary amine (Corey et al., Tetrahedron Lett., 1989, 30, 5207) . The chiral 3-aryl-3-aminopropanol type prodrug group can be obtained by 1,3-dipolar addition of a chiral-pure olefin and a substituted nitrone aryl

306 of the aldehyde, followed by reduction of the resulting isoxazolidine (Koizumi et al., J. Org. Chem., 1982, 47, 4005). Chiral induction at 1,3-dipolar additions to give substituted isoxazilidines is also achieved by the chiral palladium phosphine complexes produced by the enantioselective formation of δ-aminoalcohol (Hori et al., J. Org. Chem., 1999, 64, 5017). Alternatively, optically pure 1-aryl-substituted amino alcohols are obtained by selective ring opening of the corresponding chiral epoxy alcohol with the desired amine (Canas et al., Tetrahedron Lett., 1991, 32, 6931).

Several methods for diastereoselective synthesis are known

1,3-disubstituted amino alcohols. For example, reaction of (E) -N-cinamyltrichloroacetamide with hypochlorous acid results in trans-dihydrooxazine which is readily hydrolyzed to erythro-β-chloro-α-hydroxy-β-phenylpropanamine with high diastereoselectivity (Conunercon et al., Tetrahedron Lett., 1990, 31, 3871). Diastereose-selective formation of 1,3-aminoalcohols is also achieved by reductive amination of optically pure 3-hydroxyketones (Haddad et al., Tetrahedron Lett., 1997, 38, 5981). In an alternative approach, 3-aminoketones are transformed into 1,3-disubstituted amino alcohols with high stereoselectivity by selective hydride reduction (Barluenga et al., J. Org. Chem., 1992, 57, 1219).

All of the above methods can also be applied to the preparation of the corresponding V-Z, V-W or V2-Z2 nullified chiral amino alcohols. In addition, these optically pure amino alcohols are also a source for obtaining optically pure diamines by the procedures described above.

Section 4

Mechanism of prodrug cleavage in cyclic 1,3-propanyl esters

Cyclic 1,3-propanyl ester prodrugs are rapidly cleaved in the presence of liver microsomes in rats and humans, freshly

307 isolated rat hepatocytes and cytochrome P450 inhibitors. The CYP3A4 isoenzyme cytochrome is believed to be responsible for oxidation based on ketoconosole inhibition of drug formation. Cytochrome P450 family 1 and / or family 2 inhibitors appear to inhibit prodrug cleavage. In addition, although these prodrug particles appear to be cleaved by CYP3A4, other prodrugs in this class may be substrates for other P45C.

Although the cyclic 1,3-propanyl esters of the present invention are not limited by the mechanisms described above, generally each ester contains a group or atom susceptible to microsomal oxidation (e.g., alcohol, benzyl methine proton), which in turn generates intermediates that cleave to the parent compound. in aqueous solution by β-elimination of the phosphonate or phosphcramidate diacid.

Class 1 prodrugs easily undergo P450 oxidation because they have Z '= hydroxyl or hydroxyl equivalent with a side (geminal) acidic proton. D 'is hydrogen for the final reduction to give phenol.

Class 2 generally has V selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl. This class of prodrugs easily undergoes P450 oxidation at the benzylic proton (proton on carbon, to

308 appended V). The allyl proton behaves similarly for 1-alkenyl and 1-alkynyl. There must be hydrogen geminal to V in order for this oxidation mechanism to take place. Since Z, W and W 'are not oxidation sites in this class of prodrugs, a wide variety of substitutions are possible. In one aspect, Z may be an electron donor moiety that may reduce the mutagenicity or toxicity of aryl vinyl vinyl ketone, which is a by-product of oxidation of this class of prodrugs. Thus, in this aspect, Z is -OR ² , -SR ^2, or -NR ² ₂ .

In this class of prodrugs V and W may be cis to one another or trans to one another.

The class 2 mechanism generally describes an oxidation mechanism for cyclic 1,3-propanyl esters wherein V and Z are connected through an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, wherein said cyclic group is fused to an aryl group in position β and γ to Y attached to V.

Class 3 includes compounds wherein Z ² is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² CC (S) R ³ , -CHR ² OC (S) OR ³ , -CHR ² OC (O) SR ³ , -CHR'OCO ₂ R ³ , -SR ² , -CHR ² N 3, -CH ² aryl, -CH (aryl) OH, -CH (CH = CR ² 2) OH, -CH (C ¹ -C ² ) OH and -CH ₂ NHaryl.

Class 3 prodrugs readily undergo P450 oxidation, since Z contains a hydroxyl or hydroxyl equivalent (e.g., -CHR ² OC (O) R ³ , -CHR ² N 3) with a side (geminal) acidic proton. Of the ² groups, they can easily undergo P450 oxidation because they have a benzylic methine proton or equivalent (e.g., -CH 2 NHaryl, -CH (CH = CR ² 2) OH). When Z ² is -SR ² , it is believed to be oxidized to a sulfoxide or sulfone that will enhance the β-elimination step. Where Z ² is -CH2NHaryl, the carbon next to nitrogen is oxidized to form a hemiaminal which hydrolyses to the aldehyde (-C (O) H), as shown above for class 3. As in ^2,

309

W ² and W are not an oxidation site in this class of compounds, a wide range of substituents V ² , W ² and W are possible.

The class 3 mechanism mentioned above generally describes the oxidation mechanism for cyclic 1,3-propanyl esters wherein V ² and Z ² are joined together through an additional 3 to 5 atoms to form a cyclic group containing 5-7 atoms, optionally containing 1 heteroatom, substituted with a hydroxy group, an acyloxy group, an alkoxycarbonyloxy group or an aryloxycarbonyloxy group attached to a carbon which is three atoms from the Y group attached to the phosphorus. This class of prodrugs undergoes P450 oxidation and is oxidized by a mechanism analogous to the class 3 described above. A wide range of groups W and W 'are possible.

The cleavage mechanism could follow the following mechanisms. Further evidence for these mechanisms is suggested by the byproducts of cleavage. Class 1 prodrugs where Y is O- generate phenol, while type 2 prodrugs where Y is -O- generate phenyl vinyl ketone.

Cyclic phosphoramidates, where Y is nitrogen rather than oxygen, can serve as prodrugs, since intermediate phosphoramidates can generate transient phosphonates or phosphoramidates by similar mechanisms. The phosphoramidate (-P (O) (NH ₂ ) O-) is then converted to a phosphonate (-PO ₃ ² -).

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise stated, all chemical agents discussed herein, including exemplary embodiments, are generally available from Aldrich Chemical Company, Milwaukee, WI.

Section 1

Example 1

310

Preparation of 5-diethylphosphono-2-furaldehyde (1)

Step A. A solution of 2-furaldehyde diethyl acetal (1 mmol) in THF (tetrahydrofuran) was treated with BuLi (1 mmol) at -78 ° C. After 1 hour, diethyl chlorophosphate (1.2 mmol) was added and the reaction mixture was stirred for 40 minutes. Extraction and evaporation gave a brown oil.

Step B. The resulting brown oil was treated with 80% acetic acid at 90 ° C for 4 hours. Extraction and chromatography gave Compound 1 as a clear yellow oil. Alternatively, the aldehyde may be prepared from furan as described below.

Step C. A solution of furan (1 mmol) in diethyl ether was treated with TMEDA (N, N, N ', N'-tetramethylenediamine) (1 mmol) and BuLi (2 mmol) at -78 ° C for 0.5 h . Diethyl chlorophosphate (1.2 mmol) was then added to the reaction mixture and stirred for an additional hour. Extraction and distillation gave diethyl 2-furanphosphate as a clear oil.

Step D: A solution of diethyl 2-furanphosphonate (1 mmol) in THF was treated with LDA (1.12 mmol, lithium N, N-diisopropylamide) at -78 ° C for 20 minutes. Then methyl chloroformate (1.5 mmol) was added to the reaction mixture and stirred for an additional 1 hour. Extraction and chromatography gave Compound 1 as a clear yellow oil. Preferably, the aldehyde can be prepared from 2-furaldehyde as described above.

Step E: A solution of 2-furaldehyde (1 mmol) and N, N'-dimethylethylenediamine (1 mmol) in toluene was heated to boiling while the resulting water was removed by an azeotropic extender. After 12 hours the solvent was evaporated in vacuo and the residue was distilled to give furan-2- (N, N'-dimethylimidazolidine) as a clear colorless oil. Boiling point 59-61 ° C (3 mm Hg).

Step F. A solution of furan-2- (N, N'-dimethylimidazolidine) (1 mmol) and TMEDA (1 mmol) in THF was treated with nBuLi (1.3 mmol) at -40 to -48 ° C. The reaction was stirred at 0 ° C for 1.5 h

It was then cooled to -55 ° C and then treated with diethyl chlorophosphate (1.1 mmol) in THF. After stirring at 25 ° C for 12 hours, the reaction mixture was evaporated and subjected to extraction to give 5-diethylphosphonofuran-2- (N, N'-dimethylimidazolidine) as a brown oil.

Step G. A solution of 5-diethylphosphonofuran-2- (N, N'-dimethylimidazolidine) (1 mmol) in water was treated with concentrated sulfuric acid until pH = 1. Extraction and chromatography gave compound 1 as a clear yellow oil.

Example 2

Preparation of 5-diethylphosphono-2 - [(1-oxo) alkyl] furans and 6-diethylphosphono-2 - [(1-oxo) alkyl] pyridines]

Step A. A solution of furan (1.3 mmol) in toluene was treated with 4-methylpentanoic acid (1 mmol), trifluoroacetic anhydride (1.2 mmol), and boron trifluoride etherate (0.1 mmol) at 56 ° C for 3 days. 5 hours. The cooled reaction mixture was quenched with aqueous sodium bicarbonate solution (1.9 mmol), filtered through a pad of celite. Extraction, evaporation and distillation gave 2 - [(4-methyl-1-oxo) pentyl] furan as a brown oil (bp 65-77 ° C, 0.1 mm Hg).

Step B. A solution of 2 - [(4-methyl-1-oxo) pentyl] furan (1 mmol) in benzene was treated with ethylene glycol (2.1 mmol) and p-toluenesulfonic acid (0.05 mmol) at reflux for 60 hocin, water was removed with an azeotropic extension. Triethyl orthoformate (0.6 mmol) was then added and the resulting mixture was heated to reflux for an additional hour. Extraction and evaporation gave 2- (2-furanyl) -2 - [(3-methyl) butyl] -1,3-dioxolane as an orange liquid.

Step C. A solution of 2- (2-furanyl) -2 - [(3-methyl) butyl] -1,3-dioxolane (1 mmol) in THF was treated with TMEDA (1 mmol) and nBuLi (1.1 mmol). ) at -45 ° C and the resulting mixture was stirred at -5 to 0 ° C for 1 hour. The resulting reaction mixture was cooled to -45 ° C and poured into a solution of diethyl chlorophosphate in THF at

312

-45 ° C. The reaction mixture was gradually warmed to room temperature over 1.25 hours. Extraction and evaporation gave 2- (2- (5-dieylphosphono) furanyl] -2 - [(3-methyl) butyl] -1,3-dioxolane as a dark oil.

Step D. A solution of 2- [2- (5-diethylphosphono) furanyl] -2 - [(3-methyl) butyl] -1,3-dioxolane (1 mmol) in methanol was treated with 1N hydrochloric acid (0.2 mmol) for 18 hours at 60 ° C. Extraction and distillation gave 5-diethylphosphono-2 - ((4-methyl-1-oxo) pentyl] furan (2.1) as a light orange oil (bp 152-156 ° C, 0.1 mm Hg).

The following compounds were prepared using a similar procedure:

(2.2) 5-diethylphosphono-2-acetylfuran: boiling point 125-136 ° C, 0.1 mm Hg, (2.3) 5-diethylphosphono-2 - [(1-oxo) butyl] furan: boiling point 130 145 ° C , 0.08 mm Hg.

Alternatively, these compounds may be prepared using the following procedures:

Step E. A solution of 2 - [(4-methyl-1-oxo) pentyl] furan (1 mmol) prepared in Step A) in benzene was treated with N, N-dimethylhydrazine (2.1 mmol) and trifluoroacetic acid ( 0.05 mmol) at reflux for 6 hours. Extraction and evaporation gave 2 - ((4-methyl-1-oxo) pentyl] furan N, N-dimethylhydrazone as a brown liquid.

Step F. 2 - [(4-Methyl-1-oxo) pentyl] furan N, N-dimethylhydrazone was subjected to Step C to give 2 - [(4-methyl-1-oxo) pentyl] -5-diethylphosphonofuran N, N-dimethylhydrazone as a brown liquid and treated with copper (I) chloride (1.1 equivalents) in ethanol-water at 25 ° C for 6 hours. Extraction and distillation gave compound 2.1 as a light orange oil.

Some of the 5-diethylphosphono-2 - [(1-oxo) alkyl] furans are at

313 modified using the following procedures:

Step G. A solution of compound 1 (1 mmol) and 1,3-propanedithiol (1.1 mmol) in chloroform was treated with boron trifluoride etherate (0.1 mmol) at 25 ° C for 24 hours. Evaporation and chromatography gave 2- (2- (5-diethylphosphono) furanyl) -1,3-dithiane as a pale yellow oil.

A solution of 2- (2- (5-diethylphosphono) furanyl) -1,3-dithiane (1 mmol) in THF was cooled to -78 ° C and treated with nBuLi (1.2 mmol). After 1 hour at -78 ° C, the mixture was treated with cyclopropanemethyl bromide and the reaction mixture was stirred at -78 ° C for an additional hour. Extraction and chromatography gave 2- (2- (5-diethylphosphono) furanyl) -2-cyclopropanomethyl-1,3-dithiane as an oil.

A solution of 2- (2- (5-diethylphosphono) furanyl) -2-cyclopropanomethyl-1,3-dithiane (1 mmol) in acetonitrile-water was treated with [bis (trifluoroacetoxy) iodo] benzene (2 mmol) at 25 ° C. ° C for 24 hours. Extraction and chromatography gave 5-diethylphosphono-2- (2-cyclopropylacetyl) furan as a pale orange oil.

The following compounds were prepared using a similar procedure:

(2.4) 5-Diethylphosphono-2- (2-ethoxycarbonylacetyl) furan, (2.5) 5-Diethylphosphono-2- (2-methylthioacetyl) furan, (2.6) 6-Diethylphosphono-2-acetylpyridine.

Example 3

Preparation of 4- (2- (5-phosphono) furanyl) thiazoles, 4- [2- (6-phosphono) pyridyl] thiazoles and 4- [2- (5-phosphono) furanyl] selenazoles

Step A. A solution of compound 2.1 (1 mmol) in ethanol was treated with copper (I) bromide (2.2 mmol) at reflux for 3 hours. The cooled reaction mixture was filtered and the filtrate was evaporated to

314 sucha. The resulting dark oil was purified by chromatography to give 5-diethylphosphono-2 - [(2-bromo-4-methyl-1-oxo) pentyl] furan as an orange oil.

Step B. A solution of 5-diethylphosphono-2 - [(2-bromo-4-methyl-1-oxo) pentyl] furan (1 mmol) and thiourea (2 mmol) in ethanol was heated to reflux for 2 hours. The cooled reaction mixture was evaporated to dryness and the resulting yellow foam was suspended in saturated sodium bicarbonate solution and water (pH = 8). The resulting material was collected by filtration to give 2-amino-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] thiazole.

Step C. A solution of 2-amino-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] thiazole (1 mmol) in methylene chloride was treated with bromotrimethylsilane (10 mmol) at 25 ° C for 8 hours. The reaction mixture was evaporated to dryness and the residue was suspended in water. The resulting solid was filtered to give 2-amino-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole (3.1) as an off-white solid. Mp> 250 ° C. Anal calcd for C ₁₁ H ₁₅ N ₂ O ₄ PS + 1.25 HBr: C: 32.75; H, 4.06; N: 6.94. Found: C: 32.39; H, 4.33; N: 7.18.

The following compounds were prepared according to the above described procedure or with minor modifications of the above described procedure using conventional chemistry:

(3.2) 2-Methyl-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole, Anal, calcd for C H NO? PS + HBr + 0.1 CH ₂ C1 _2: C: 37 , 20; H, 4.44; N: 3.58. Found: C: 37.24; H, 4.56; N: 3.30.

(3.3) 4- [2- (5-Phosphono) furanyl] thiazole, Anal. Calcd. for C ₇ H ₆ NO ₄ PS + 0.65 HBr, C: 29.63; H, 2.36; N: 4.94. Found: C: 29.92; H, 2.66; N: 4.57.

(3.4) 2-Methyl-4- [2- (5-phosphono) furanyl] thiazole, m.p. 235-236 ° C, Anal. Calcd. For C ₈ H ₈ NChPS + 0.25 H ₂ O: C: 38 , 48; H, 3.43; N: 5.61. Found: C: 38.68; H, 3.33; N: 5.36.

(3.5) 2-Phenyl-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole, Anal, calculated for C ₁₇ H ₁₈ NO ₄ PS + HBr: C: 45.96; H, 4.31; N: 3.15. Found: C: 45.56; H, 4.26; N: 2.76.

315 (3.6) 2-Isopropyl-4- [2- (5-phosphono) furanyl] thiazole, m.p. 194-197 ° C, Anal. Calcd. For C ₁₀ H ₁₂ NO ₄ PS: C: 43, 96; H, 4.43; N: 5.13. Found: C: 43.70; H, 4.35; N: 4.75.

(3.7) 5-Isobutyl-4- [2- (5-phosphono) furanyl] thiazole, m.p. 164-166 ° C, Anal. Calcd. For C 14 H 14 NO 4 PS: C: 45.99; H, 4.91; N: 4.88. Found: C: 45.63; H, 5.01; N: 4.73.

(3.8) 2-Aminothiocarbonyl-4- [2- (5-phosphono) furanyl] thiazole, m.p. 189-191 ° C, Anal. Calcd. For C 8 H 7 N 2 O 4 PS 2: C: 33.10; H, 2.43; N: 9.65. Found: C: 33.14; H, 2.50; N: 9.32.

(3.9) 2- (1-Piperidyl) -5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole, Anal, calculated for C ₁₆ H ₂ 3 N ₂ O iPS + 1.3 HBr: C : 40.41; H: 5.15; N: 5.89. Found: C: 40.46; H: 5.36; N: 5.53.

(3.10) 2- (2-Thienyl) -5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole, Anal. Calcd. For C 15 H 16 NO 4 PS 2 + 0.75 H ₂ O: C: 47.05; H, 4.61; N: 3.66. Found: C: 47.39; H, 4.36; N, 3.28.

(3.11) 2- (3-Pyridyl) -5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole, Anal. Calcd. For CuH 2 O 3 O 2 PS + 3.75 HBr: C: 28, 78; H, 3.13; N, 4.20. Found: C: 28.73; H, 2.73; N: 4.53.

(3.12) 2-Acetamido-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole, m.p. 179-181 ° C, Anal. Calcd. For C 13 H 17 N ₂ O 5 PS + 0.25 H ₂ 0: C: 44.76; H, 5.06; N: 8.03. Found: C: 44.73; H, 5.07; N: 7.89.

(3.13) 2-Amino-4- [2- (5-phosphono) furanyl] thiazole, Anal calcd for C 7 H 7 N 2 O 4 PS: C: 34.15; H, 2.87; N: 11.38. Found: C: 33.88; H, 2.83; N: 11.17.

(3.14) 2-Methylamino-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole, m.p .: 202-205 ° C, Anal. Calcd. For C 12 H 17 N ₂ O ₄ PS + 0.5 H ₂ O: C: 44.30; H: 5.58; N: 8.60. Found: C: 44.67; H: 5.27; N: 8.43.

(3.15) 2- (N-amino-N-methyl) amino-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole, m.p. 179-181 ° C, Anal. Calcd. For C ₁₂ Hi8N ₃ 0 ₄ PS + 1.25 HBr: C: 33.33; H, 4.49; N: 9.72. Found: C: 33.46; H, 4.81; N: 9.72.

316 (3.16) 2-Amino-5-methyl-4- [2- (5-phosphono) furanyl] thiazole, m.p. 200-220 ° C, Anal. Calcd. For C 8 H 9 N 2 O 4 PS + 0.65 HBr: C: 30, 72; H, 3.11; N: 8.96. Found: C: 30.86; H, 3.33; N: 8.85.

(3.17) 2,5-Dimethyl-4- [2- (5-phosphono) furanyl] thiazole, m.p. 195 ° C (dec.), Anal. Calcd. For C 9 H 11 ONO 4 PS + 0.7 HBr: C: 34.22; H, 3.41; N: 4.43. Found: C: 34.06; H, 3.54; N: 4.12.

(3.18) 2-Aminothiocarbonyl-5-isobutyl-4- [2- (5-phosphono) -furanyl] -thiazole, Anal, calcd for C 12 H 15 N 2 O 4 PS 2 + 0.1 HBr + 0.3 EtOAc: C: 41.62; H, 4.63; N: 7.35. Found: C: 41.72; H, 4.30; N: 7.17.

(3.19) 2-Ethoxycarbonyl-4- [2- (5-phosphono) furanyl] thiazole, m.p. 163-165 ° C, Anal. Calcd. For C ₁₀ H ₁₀ N06PS + 0.5 H ₂ 0: C: 38 , 47; H, 3.55; N: 4.49. Found: C: 38.35; H, 3.30; N: 4.42.

(3.20) 2-Amino-5-isopropyl-4- [2- (S-phosphono) furanyl] thiazole, Anal. Calcd. For C 10 H 13 N 2 O 4 PS + 1 HBr: C: 32.53; H, 3.82; N: 7.59. Found: C: 32.90; H, 3.78; N: 7.65.

(3.21) 2-Amino-5-ethyl-4- [2- (5-phosphono) furanyl] thiazole, m.p. > 250 ° C, Anal calcd for C 9 H _for N ₂ O ₄ PS: C: 39.42; H, 4.04; N: 10.22. Found: C: 39.02; H, 4.15; N: 9.92.

(3.22) 2-Cyanomethyl-4- [2- (5-phosphono) furanyl] thiazole, mp 204-206 ° C, Anal. Calcd. For C 9 H 7 N 2 O 4 PS: C: 40.01; H, 2.61; N: 10.37. Found: C: 39.69; H, 2.64; N, 10.03.

(3.23) 2-Aminothiocarbonylamino-5-isobutyl-4- [2- (5-phosphonc) furanyl) thiazole, m.p. 177-182 ° C, Anal. Calcd. for C 12 H 16 N 3 O 4 PS 2 + 0.2 hexane + 0.3 HBr: C: 39.35; H, 4.78; N: 10.43. Found: C: 39.61; H, 4.48; N: 10.24.

(3.24) 2-Amino-5-propyl-4- [2- (5-phosphono) furanyl] 11a zole, m.p. 235-237 ° C, Anal. Calcd. For C ₁₀ H 13 N ₂ O ₄ PS + 0.3 H 2 O : C: 40.90; H, 4.67; N: 9.54. Found: C: 40.91; H, 4.44; N: 9.37.

(3.25) 2-Amino-5-ethoxycarbonyl-4- [2- (5-phosphono) furanyl] thiazole, m.p. 248-250 ° C Anal, calcd for C Hi _0, N, 0 ₆ PS + 0. 1 HBr: C: 36.81; H, 3.43; N: 8.58. Found: C: 36.99; H, 3.35; N: 8.84.

(3.26) 2-Amino-5-methylthio-4- [2- (5-phosphono) furanyl] thiazole, m.p. 181-184 ° C, Anal. Calcd. For C ₈ H ₉ N ₂ O ₄ PS2 + 0.4 H ₂ C: C: 32.08; H, 3.30; N: 9.35. Found: C: 32.09; H, 3.31; N: 9.15.

317 (3.27) 2-Amino-5-cyclopropyl-4- [2- (5-phosphono) furanyl] thiazole, Anal. Calcd. For C 10 H 11 N ₂ O ₄ PS + 1 H ₂ O + 0.75 HBr: C: 32.91; H, 3.80; N: 7.68. Found: C: 33.10; H, 3.80; 20 N: 7.34.

(3.28) 2-Amino-5-methanesulfinyl-4- [2- (5-phosphono) furanyl] thiazole, m.p.> 250 ° C, Anal. calcd for C ₈ H ₉ N ₂ O = PS ₂ +

0.35 NaCl: C: 29.23; H, 2.76; N: 8.52. Found: C: 29.37; H, 2.52; N: 8.44.

(3.29) 2-Amino-5-benzyloxycarbonyl-4- [2- (5-phosphono) furanyl] thiazole, Anal, calculated for C ₁₅ H ₃ N ₂ 0 ₆ PS + 0.2 H ₂ O: C: 46 93; H: 3.52; N: 7.30. Found: C: 46.64; H, 3.18; N: 7.20.

(3.30) 2-Amino-5-cyclobutyl-4- [2- (5-phosphono) furanyl] thiazole, Anal. Calcd. For C 11 H ₁₃ N ₂ O 4 PS + 0.15 HBr + 0.15 H ₂ O: C: 41.93; H, 4.30; N: 8.89. Found: C: 42.18; H, 4.49; N: 8.53.

(3.31) 2-Amino-5-cyclopropyl-4- [2- (5-phosphono) furanyl] thiazole hydrobromide, Anal. calcd for C ₁₀ H 11 N ₂ O ₄ PSBr + 0.73 HBr +

0.15 MeOH + 0.5 H ₂ O: C: 33.95; H, 3.74; N: 7.80; S: 8.93; Br: 16.24. Found: C: 33.72; H, 3.79; N: 7.65; S: 9.26; Br: 16.03.

(3.32) 2-Amino-5 - [(N, N-dimethyl) aminomethyl] -4- [2- (5-phosphono) furanyl] thiazole dihydrobromide. Anal, calcd for C Hi ₀ N _{3 S} C> 4 Br ₂ PS + 0.8 CH ₂ Cl ₂ : C: 24.34; H, 3.33; N: 7.88. Found: C: 24.23; H, 3.35; N: 7.64.

(3.33) 2-Amino-5-methoxycarbonyl-4- [2- (5-phosphono) furanyl] thiazole, m.p. 227 ° C (dec.), Anal. Calcd. For C ₉ H ₉ N ₂ 0 ₆ PS + 0, 1 H ₂ O + 0.2 HBr: C: 33.55; H, 2.94; N: 8.69. Found: C: 33.46; H, 3.02; N: 8.49.

(3.34) 2-Amino-5-ethylthiocarbonyl-4- [2- (5-phosphono) furanyl] thiazole, m.p. 245 ° C (dec.), Anal. Calcd. For C ₁₀ H _for N ₂ O ₂ PS ₂ : C: 35.93; H, 3.32; N: 8.38. Found: C: 35.98; 10 H: 3.13; N: 8.17.

(3.35) 2-Amino-5-propyloxycarbonyl-4- [2- (5-phosphono) furanyl] thiazole, m.p. 245 ° C (dec.), Anal. Calcd. for C ₁₁ H ₁₃ N ₂ O ₆ PS: C: 39.76; H, 3.94; N: 8.43. Found: C: 39.77; H, 3.72; N: 8.19.

(3.36) 2-Amino-5-benzyl-4- [2- (5-phosphono) furanyl] thiazole, Anal calcd for C ₁₄ H ₁₃ N ₂ O ₄ PS + H ₂ O: C: 47.46; H, 4.27; N: 7.91. naj

318 d: C: 47.24; H, 4.08; N: 7.85.

(3.37) 2-Amino-5 - [(N, N-diethyl) aminomethyl] -4- [2- (5-phosphono) furanyl] thiazole dihydrobromide, Anal. Calcd. For C ₁₂ H ₂ N ₃ O ₄ Br ₂ PS + 0.1 HBr + 1.4 MeOH: C: 29.47; H, 4.74; N: 7.69. Found: C: 29.41; H, 4.60; N: 7.32.

(3.38) 2-Amino-5 - [(N, N-dimethyl) carbamoyl] -4- [2- (5-phosphono) furanyl] thiazole, Anal, calculated for C10H12N3O5PS + 1.3 HBr + 1.0 H ₂₀ + 0.3 acetone: C: 28.59; H, 3.76; N: 9.18. Found: C: 28.40; H, 3.88; N: 9.01.

(3.39) 2-Amino-5-carboxyl-4- [2- (5-phosphono) furanyl] thiazole, Anal, calculated for C 8 H 15 N 4 ePS + 0.2 HBr + 0.1 H ₂ O: C: 31.18 ; H, 2.42; N: 9.09. Found: C: 31.11; H, 2.42; N: 8.83.

(3.40) 2-Amino-5-isopropyloxycarbonyl-4- [2- (5-phosphono) furanyl] thiazole, mp: 240 ° C (dec.), Anal. Calcd. For C ₁₁ H ₁₃ N ₂ 0 ₆ PS: C: 39, 76; H, 3.94; N: 8.43. Found: C, 39.42; H, 3.67; N: 8.09.

(3.41) 2-Methyl-5-ethyl-4- [2- (5-phosphono) furanyl] thiazole, Anal, calculated for C ₁₀ H ₁₂ O ₄ PNS + 0.75 HBr + 0.35 H ₂ O: C: 36 , 02; H, 4.13; N, 4.06. Found: C: 36.34; H, 3.86; N: 3.69.

(3.42) 2-Methyl-5-cyclopropyl-4- [2- (5-phosphono) furanyl] thiazole, Anal, calculated for ChH ₁₂ NO ₄ PS + 0.3 HBr + 0.5 CHCl 3: C: 37.41 ; H, 3.49; N: 3.79. Found: C: 37.61; H, 3.29; N: 3.41.

(3.43) 2-Methyl-5-ethoxycarbonyl-4- [2- (5-phosphono) furanyl] thiazole, Anal, calcd for C ₁₁ H ₁₂ MO ₆ PS: C: 41.64; H, 3.81; N: 4.40. Found: C: 41.61; H, 3.78; N: 4.39.

(3.44) 2 - [(N-acetyl) amino] -5-methoxymethyl-4- [2- (5-phosphono) furanyl] thiazole, Anal, calculated for C ₁₁ H ₁₃ N ₂ O ₆ PS + 0.15 HBr: C: 38.36; H, 3.85; N: 8.13. Found: C: 38.74; H, 3.44; N: 8.13.

(3.45) 2-Amino-5- (4-morpholinyl) methyl-4- [2- (5-phosphono) furanyl] thiazole dihydrobromide, Anal. Calcd. for C 19 H 18 Br 3 N 3 O 5 PS + 0.25 HBr: C: 27.33; H, 3.49; N: 10.97. Found: C: 27.55; H, 3.75; N: 7.62.

(3.46) 2-Amino-5-cyclopropylmethoxycarbonyl-4- [2- (5-phosphono) furanyl] thiazole, m.p. 238 ° C (dec.), Anal. Calcd. For C ₁₂ H ₁₃ N ₂ 06PS: C: 41.86; H, 3.81; N: 8.14. Found: C: 41.69;

319

Η: 3.70; N: 8.01.

(3.47) 2-Amino-5-methylthio-4- [2- (5-phosphono) furanyl] thiazole N, N-dicyclohexylammonium salt, m.p.> 250 ° C, Anal. Calcd. For C 8 H 9 N 2 O 4 PS 2 + 1.15 : 52.28; H: 7.13; N: 8.81. Found: C: 52.12; H: 7.17; N: 8.81.

(3.48) 2 - [(N-Dansyl) amino] -5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole, Anal, calculated for C ₂₃ H ₂₆ N ₃ O ₆ PS2 + 0.5 HBr: C: 47.96; H, 4.64; N: 7.29. Found: C: 48.23; H, 4.67; N: 7.22.

(3.49) 2-Amino-5- (2,2,2-trifluoroethyl) -4- [2- (5-phosphono) furanyl] thiazole, Anal calcd for C 9 H 8 N 2 FO 4 PS: C: 32.94, H: 2, 46, N: 8.54. Found: C: 32.57, H: 2.64, N: 8.14.

(3.50) 2-Methyl-5-methylthio-4- [2- (S-phosphono) furanyl] thiazole, Anal calcd for C 9 H ₁₀ NO ₄ PS ₂ : C: 37.11; H, 3.46; N: 4.81. Found: C: 36.72; H, 3.23; N: 4.60.

(3.51) 2-Amino-5-methylthio-4- [2- (5-phosphono) furanyl] thiazole ammonium salt. Anal. Calcd for CBH ₁₂ N ₃ O ₄ PS2: C: 31.07; H, 3.91; N: 13.59. Found: C: 31.28; H, 3.75; N: 13.60.

(3.52) 2-Cyano-5-ethyl-4- [2- (5-phosphono) furanyl] thiazole, Anal calcd for C 10 H 9 N 2 O 4 PS: C: 42.26; H, 3.19; N, 9.86. Found: C: 41.96; H, 2.95; N: 9.76.

(3.53) 2-Amino-5-hydroxymethyl-4- [2- (5-phosphono) furanyl] thiazole, Anal calcd for C 8 H 9 N 2 O 5 PS: C: 34, 79; H, 3.28; N: 10.14. Found: C: 34.57; H, 3.00; N, 10.04.

(3.54) 2-Cyano-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole, Anal, calcd for C12H13N2O4SP + 0.09 HBr: C: 46.15; H, 4.20; N:

8.97. Found: C: 44.81; H, 3.91; N: 8.51.

(3.55) 2-Amino-5-isopropylthio-4- [2- (5-phosphono) furanyl] thiazole hydrobromide, Anal, calcd for C Hi _{0 4} BRN2 _s! PS2 C: 29.94; H: 3.52; N, 6.98. Found: C: 30.10; H, 3.20; N: 6.70.

(3.56) 2-Amino-5-phenylthio-4- [2- (5-phosphono) furanyl] thiazole, Anal calcd for C 13 H ₁₁ N ₂ O ₄ PS ₂ : C: 44.07; H, 3.13; N: 7.91. Found: C: 43.83; H, 3.07; N: 7.74.

(3.57) 2-Amino-5-tert-butylthio-4- [2- (5-phosphono) furanyl] thiazole, Anal calcd for C ₁₁ H ₁₅ N ₂ O ₄ PS ₂ + 0.6 CH 2 Cl 2: C: 36.16; H, 4.24; N: 7.27. Found: C: 36.39; H, 3.86; N: 7.21.

320 (3.58) 2-Amino-5-propylthio-4- [2- (5-phosphono) furanyl] thiazole hydrobromide, Anal. Calcd. For C ₁₀ H ₄ BrN ₂ O ₄ PS ₂ : C: 29, 94; H: 3.52; N:

6.98. Found: C: 29.58; H, 3.50; N: 6.84.

(3.59) 2-Amino-5-ethylthio-4- [2- (5-phosphono) furanyl] thiazole, Anal, calcd for CGH _n N ₂ O4PS ₂ + 0.25 HBr: C: 33.11; H, 3.47; N: 8.58. Found: C: 33.30; H, 3.42; N: 8.60.

(3.60) 2 - [(N-tert-butyloxycarbonyl) amino] -5-methoxymethyl-4- [2- (5-phosphono) furanyl] thiazole, Anal, calculated for ChH ₁₉ N-O-PS: C: 43 , 08; H, 4.91; N: 7.18. Found: C: 42.69; H, 4.58; N: 7.39.

(3.61) 2-Hydroxyl-4- [2- (5-phosphono) furanyl] thiazole, Anal calcd for C 7 H 6 NO 5 PS: C: 34.02; H, 2.45; N: 5.67. Found: C: 33.69; H, 2.42; N: 5.39.

(3.62) 2-Hydroxyl-5-ethyl-4- [2- (5-phosphono) furanyl] thiazole, Anal calcd for C 9 H 10 NO 5 PS: C: 39.28; H, 3.66; N: 5.09. Found: C: 39.04; H, 3.44; N: 4.93.

(3.63) 2-Hydroxyl-5-isopropyl-4- [2- (5-phosphono) furanyl] thiazole, Anal, calculated for C ₁₀ H ₁₂ NO ₅ PS + 0.1 HBr: C: 40.39; H, 4.10; N: 4.71. Found: C: 40.44; H, 4.11; N: 4.68.

(3.64) 2-Hydroxyl-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole, Anal calcd for C 11 H 14 NO 5 PS: C: 43, 57; H, 4.65; N: 4.62. Found: C: 43.45; H, 4.66; N: 4.46.

(3.65) 5-Ethoxycarbonyl-4- [2- (5-phosphono) furanyl] thiazole, Anal calcd for C ₁₀ H ₁₀ NO ₅ PS: C: 39.61; H, 3.32; N: 4.62. Found: C: 39.60; H, 3.24; N: 4.47.

(3.66) 2-Amino-5-vinyl-4- [2- (5-phosphono) furanyl] thiazole, Anal calcd for C ₉ H ₉ N ₂ O ₄ PS + 0.28 HCl: C: 37.66; H, 3.26; N: 9.46. Found: C: 37.96; H, 3.37; N: 9.10.

(3.67) 2-Amino-4- [2- (6-phosphono) pyridyl] thiazole hydrobromide, (3.68) 2-Methylthio-5-isobutyl-4- [2- (5-phosphono) furanylitiazole, Anal, calculated for C ₁₂ H ₁₆ NO ₄ PS ₂ : C: 4.22; H, 4.84; N, 4.20. Found: C: 43.55; H, 4.63; N: 4.46.

(3.69) 2-Amino-5-isobutyl-4- [2- (3-phosphono) furanyl] thiazole, Anal, calculated for C ₁₁ H ₁₅ N ₂ O ₄ PS + 0.1 H ₂ O: C: 43.45; H, 5.04; N: 9.21. Found: C: 43.68; H: 5.38; N: 8.98.

(3.70) 2-Amino-5-isobutyl-4- [2- (S-phosphono) furanyl] selenazole,

321

Anal calcd for C 11 H 15 N 4 PSe + 0.14 HBr + 0.6 EtOAc: C: 38.93; H, 4.86; N: 6.78. Found: C: 39.18; H, 4.53; N: 6.61.

(3.71) 2-Amino-5-methylthio-4- [2- (5-phosphono) furanyl] selenazole, Anal, calculated for C ₈ H ₈ N ₂ O ₄ PSSe + 0.7 HBr + 0.2 EtOAc: C: 2S, S7 ; H, 2.75; N: 6.78. Found: C: 25.46; H, 2.49; N: 6.74.

(3.72) 2-Amino-5-ethyl-4- [2- (5-phosphono) furanyl] selenazole, Anal, calculated for C ₈ H ₁₁ N ₂ O ₄ PSe + HBr: C: 26.89; H, 3.01; N: 6.97. Found: C: 26.60; H, 3.16; N: 6.81.

Example 4

Preparation of various 2- and 5-substituted 4- [2- (5-phosphono) furanyl] thiazoles

Step A. A solution of 2-bromo-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] thiazole (1 mmol) prepared by reaction of a solution of 2-amino-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] thiazole (prepared in Step B of Example 3) (1 mmol) in acetonitrile with copper bromide (1.2 mmol) and isoamylnitrite (1.2 mmol) at 0 ° C for 20 hours, followed by extraction and chromatography, whereby a brown solid formed, in DME was treated with tributyl (vinyl) tin (5 mmol) and palladium bis (triphenylphosphine) dichloride (0.05 mmol) at 100 ° C under a nitrogen atmosphere. After 5 hours, the reaction mixture was evaporated to dryness and the residue was chromatographed to give 2-vinyl-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] thiazole as a yellow solid.

Step B, 2-Vinyl-S-isobutyl-4- [2- (5-diethylphosphono) furanyl] thiazole was subjected to Step C of Example 3 to give 2-vinyl-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole (4.1) as a yellow solid. Anal calcd for C 13 H ₁₆ NO ₄ PS + 1 HBr + 0.1 H ₂ O: C: 39.43; H, 4.38; N: 3.54. Found: C: 39.18; H, 4.38; N: 3.56.

This method was also used to prepare various 5-substituted 4- [2- (5-phosphono) furanyl] thiazoles from their corresponding halides.

Step C. 2-Amino-5-bromo-4- [2- (5-diethylphosphono) furanyl] thiazole

322 was subjected to Step A using 2-tributylstanylfuran as the coupling partner to give 2-amino-5- (2-furanyl) -4- [2- (5-diethylphosphono) furanyl] thiazole.

Step D. 2-Amino-5- (2-furanyl) -4- [2- (5-diethylphosphono) furanyl] thiazole was subjected to Step C of Example 3 to give 2-amino-5- (2-furanyl) - 4- [2- (5-phosphono) furanyl] thiazole (4.2), m.p. 190-210 ° C, Anal calcd for CHH 9 N 2 O 5 PS + 0.25 HBr: C: 39.74; H, 2.80; N: 8.43. Found: C: 39.83; H, 2.92; N: 8.46.

The following compound was prepared according to the following procedure:

(4.3) 2-Amino-5- (2-thienyl) -4- [2- (5-diethylphosphono) furanyl] thiazole, Anal. Calcd. + 0.3 EtOAc + 0.11 HBr: C: 40.77; H, 3.40; N: 7.79. Found: C: 40.87; H, 3.04; N: 7.45.

Example 5

Preparation of 4- [2- (5-phosphono) furanyl] oxazoles and 4- [2- (5-phosphono) furanyl] imidazoles

Step A. A solution of 5-diethylphosphono-2 - [(2-bromo-4-methyl-1-oxo) pentyl] furan (1 mmol) in t-BuOH was treated with urea (10 mmol) at reflux for 72 hours. Filtration, evaporation and chromatography gave 2-amino-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] oxazole and 2-hydroxy-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] imidazole .

Step B. 2-Amino-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] oxazole was subjected to Step C of Example 3 to give 2-amino-5-isobutyl-4- [2- (5- phosphono) furanyl] oxazole (5.1), mp 250 ° C (dec.), Anal calcd for C 11 H 15 N 2 O 5 P: C: 46.16; H, 5.28; N: 9.79. Found: C: 45.80; H: 5.15; N: 9.55.

Step C. 2-Hydroxy-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] imidazole was subjected to Step C of Example 3 to give 2-hydroxy-5-isobutyl-4- [2- (5 -phosphono) furanyl] imidazole (5.14), mp 205 ° C (dec.), Anal calcd for C 18 H 18 N 3 O 5: C: 46.16; H, 5.28; N: 9.79. Found: C: 45.80; H, 4.90; N: 9.73.

323

Alternatively, 4- [2- (5-phosphono) furanyl] oxazoles and 4- [2- (5-phosphono) furanyl] imidazoles may be prepared as follows:

Step D. A solution of 5-diethylphosphono-2 - [(2-bromo-4-methyl-1-oxo) pentyl] furan (1 mmol) in acetic acid was treated with sodium acetate (2 mmol) and ammonium acetate (2 mmol). ) at 100 ° C for 4 hours. Evaporation and chromatography gave 2-methyl-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] oxazole, 2-methyl-4-isobutyl-5- [2- (5-diethylphosphono) furanyl] oxazole and 2- methyl-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] imidazole.

Step E. 2-Methyl-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] oxazole, 2-methyl-4-isobutyl-5- [2- (5-diethylphosphono) furanyl] oxazole and 2-methyl -5-Isobutyl-4- [2- (5-diethylphosphono) furanyl] imidazole was subjected to Step C of Example 3 to give the following compounds:

(5.18) 2-Methyl-4-isobutyl-5- [2- (5-phosphono) furanyl] oxazole hydrogen bromide, m.p. > 230 ° C; Anal. Calcd for C ₁₂ H ₁₇ BrNO ₅ P + 0.4 H ₂ O: C: 38.60; H, 4.81; N: 3.75. Found: C: 38.29; H, 4.61; N: 3.67.

(5.19) 2-Methyl-5-isobutyl-4- [2- (5-phosphono) furanyl] oxazole nydrogen bromide, Anal. Calcd. For C 14 H 15 BrNO 5 P: C: 39, 36; H, 4.68; N: 3.83. Found: C: 39.33; H, 4.56; N: 3.85.

(5.21) 2-Methyl-5-isobutyl-4- [2- (5-phosphono) furanyl] imidazole hydrogen bromide, Anal, calculated for C ₁₂ H ₁₈ BrN ₂ O ₄ P + 0.2 NH 3r: C: 37 , 46; H, 4.93; N: 8.01. Found: C: 37.12; H, 5.11; N: E, 28.

Alternatively, 4- [2- (5-phosphono) furanyl] imidazoles may be prepared as follows:

Step F. A solution of 5-diethylphosphono-2- (bromoacetyl) furan (1 mmol) in ethanol was treated with trifluoroacetamidine (2 mmol) at 80 ° C for 4 hours. Evaporation and chromatography gave 2-trifluoromethyl-4- [2- (5-diethylphosphono) furanyl] imidazole as an oil.

Step G. 2-Trifluoromethyl-4- [2- (5-diethylphosphono) furanylimidazole was subjected to Step C of Example 3 to give 2-trifluoromethyl-4- [2- (5-phosphono) furanyl] imidazole (5.22), temperature copenia

324

188 ° C (dec.); Anal calcd for C 9 H 9 F 1 N 2 P + 0.5 HBr: C:

29.79; H, 2.03; N: 8.68. Found: C: 29.93; H, 2.27; N: 8.30.

Alternatively, 4,5-dimethyl-1-isobutyl-2- [2- (5-phosphono) furanyl] imidazole can be prepared as follows:

Step H. A solution of 5-diethylphosphon-2-furaldehyde (1 mmol), ammonium acetate (1.4 mmol) and 3,4-butanedione (3 mmol) and isobutylamine (3 mmol) in glacial acetic acid was heated to 100 ° C. for 24 hours. Evaporation and chromatography gave 4,5-dimethyl-1-isobutyl-2- [2- (5-diethylphosphono) furanyl] imidazole as a yellow solid.

Step I. 4,5-Dimethyl-1-isobutyl-2- [2- (5-diethylphosphono) furanyl] imidazole was subjected to Step C of Example 3 to give

4,5-dimethyl-1-isobutyl-2- [2- (5-phosphono) furanyl] imidazole (5.23); Anal calcd for C 13 H 19 N 2 O 4 P + 1.35 HBr: C: 38.32; H, 5.03; N, 6.87. Found: C: 38.09; H, 5.04; N: 7.20.

Following the above procedures or in some cases, the following compounds were prepared by introducing some minor modifications:

(5.2) 2-Amino-5-propyl-4- [2- (5-phosphono) furanyl] oxazole, m.p. 250 ° C (dec.); Anal calcd for C 10 H 13 N 2 O 5 P: C: 44.13; H, 4.81; N: 10.29. Found: C: 43.74; H, 4.69; N: 9.92.

(5.3) 2-Amino-5-ethyl-4- [2- (5-phosphono) furanyl] oxazole, Anal calcd for C 9 H ₁₁ N ₂ O 5 P 0.4 H ₂ O: C: 40.73; H, 4.48; N: 10.56.

Found: C: 40.85; H, 4.10; N: 10.21.

(5.4) 2-Amino-5-methyl-4- [2- (5-fluoro) furanyl] oxazole, Anal calcd for C 8 H ₈ N ₂ O ₂ O + 0.1 H ₂ O: C: 39.07; H, 3.77; N: 11.39. Found: C: 38.96; H, 3.59; N: 11.18.

(5.5) 2-Amino-4- [2- (5-phosphono) furanyl] oxazole, Anal. Calcd for C ₇ H ₇ N ₂ O ₅ P + 0.6 H ₂ O: C, 34.90; H, 3.43; N: 11.63. Found: C: 34.72; H, 3.08; N: 11.35.

(5.6) 2-Amino-5-isobutyl-4- [2- (5-phosphono) furanyl] oxazole hydrogen bromide, Anal calcd for C ₁₁ H ₁₆ N ₂ O ₅ Br + 0.4 H ₂ O: C: 35.29;

325

Η: 4.52; N: 7.48. Found: C: 35.09; H, 4.21; N: 7.34.

Example 6

Preparation of various phosphoramides as prodrugs

Step A. A solution of 2-methyl-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole (1 mmol) in thionyl chloride (5 mL) was heated to reflux for 4 hours. The cooled reaction mixture was evaporated to dryness and the resulting yellow residue was dissolved in dichloromethane and treated with a solution of the corresponding benzyl alcohol (4 mmol) and pyridine (2.5 mmol) in methylene chloride. The mixture was stirred at 25 ° C for 24 hours and the reaction mixture was then subjected to extraction and chromatography to give the title compound.

Step B. A solution of 2-methyl-5-isopropyl-4- [2- (5-phosphono) furanyl] thiazole dichloridate (generated in Step A) (1 mmol) in dichloromethane (5 mL) was cooled to 0 ° C and treated with a solution of benzyl alcohol (0.9 mmol) in dichloromethane (0.5 mL) and pyridine (0.3 mL). The resulting solution was stirred at 0 ° C for 1 hour and then a solution of ammonia (excess) in THF was added. The mixture was stirred at room temperature for 16 hours, the reaction mixture was evaporated to dryness and the residue purified by chromatography to give 2-methyl-5-isopropyl-4- [2- (5-phosphonomonoamido) furanyl] thiazole (6.1) as a solid. yellow gum and 2-methyl-5-isopropyl-4- [2- (5-phosphorothiamido) furanyl] thiazole (6.2) as a yellow solid gum.

(6.1) 2-Methyl-5-isopropyl-4- [2- (5-phosphonomonamido) furanyl] thiazole: MS m / e 299 (M-H).

(6.2) 2-Methyl-5-isopropyl-4- [2- (5-phosphorodiamido) furanyl] thiazole: MS m / e 298 (M-H).

Alternatively, another method was used to prepare phosphoramides other than those shown in the following procedure:

Step C. A solution of 2-amino-5-methylthio-4- [2- (5-phosphono) furanyl] thiazole dichloridate (generated in Step A) (1 mmol) in dichloromethane (5 mL) was cooled to 0 ° C and ammonia (excess) with

326 was bubbled through the reaction mixture for 10 minutes. After stirring for 16 hours at room temperature, the reaction mixture was evaporated to dryness and the residue was purified by chromatography to give 2-amino-5-methylthio-4- [2- (5-phosphorodiamido) furanyl] thiazole (6.3) as a form. foam. Anal calcd for C ₈ H ₁₁ N ₄ O ₂ PS ₂ + 1.5 HCl + 0.2 EtOH: C: 28.48; H, 3.90; N: 15.82. Found: C: 28.32; H, 3.76; N: 14.21.

The following compounds were prepared according to the above procedures or in some cases with some minor modifications introduced:

(6.4) 2-Amino-5-isobutyl-4- [2- (5-phosphonomonoamido) furanyl] thiazole, m.p. 77-81 ° C, Anal. Calcd. For C 11 H 11 N ₃ O 3 PS + H ₂ O + 0.8 Et ₂ N: C: 47.41; H, 7.55; N: 13.30. Found: C: 47.04; H, 7.55; N: 13.67.

(6.5) 2-Amino-5-isobutyl-4- [2- (5-phosphorodiamido) furanyl] thiazole, Anal, calculated for C 11 H 17 N ₄ O ₂ PS + 0.5 H ₂ O + 0.75 HCl: C: 39.24 '; H: 5.61; N: 16.64. Found: C: 39.05; H, 5.43; N: 15.82.

(6.28) 2-Amino-5-isobutyl-4- {2- [5 - (N, N-diisobutyl) fosfcrodiamido] furanyl} thiazole, mp 182-183 ° C Anal, calcd for C ₄ H _L9 H33N ₂ PS: C: 55.32; H, 8.06; N: 13.58. Found: C: 54.93; H, 7.75; N: 13.20.

(6.29) 2-Amino-5-isobutyl-4- {2- [S- (N, N '- (1,3-bis (ethoxycarbonyl) -1-propyl) phosphoryl) diamido] furanyl] thiazole, Anal, calculated for C ₂₉ H _{4 5} N ₄ O ₁₀ PS: C: 51.78: H: 6.74; N: 8.33. Found: C: 51.70; H, 6.64; N: 8.15.

(6.30) 2-Amino-5-isobutyl-4- {2- [5- (N, N '- (1-benzyloxycarbonyl) -1-ethyl) phosphorodiamido] furanyl} thiazole, Anal. Calcd. for C ₃₂ H ₃₇ N ₆ O ₆ PS: C: 59.60; H, 5.97; N: 8.97. Found: C, 59.27; H: 5.63; N: 8.74.

(6.31) 2-Amino-5-isobutyl-4- {2- [5-bis (2-methoxycarbonyl-1-azirdinyl) phosphorodiamido] furanyl) thiazole, Anal. Calcd for C ₁₉ H ₂₅ N ₄ O ₆ PS + 0.3 CH ₂ Cl ₂ : C, 46.93; H, 5.22; N: 11.34. Found: C: 58.20; H: 5:26; N: 9.25.

327 (6.39) 2-Amino-5-isobutyl-4- {2- [5- (N, N'-2- (1-ethoxycarbonyl) propyl) phosphorodiamido] furanyl} thiazole, Anal. Calcd. for C 23 H 37 N 4 O 6 PS + 0.6 EtOAc + 0.1 CH ₂ Cl ₂ : C: 51.91; H: 7.18; N: 9.50. Found: C: 51.78; H: 7.17; N: 9.26.

The monophenyl monophosphonamide derivatives of the compounds of formula I may also be prepared according to the above procedures:

Step D. A solution of 2-amino-5-isobutyl-4- [2- (5-diphenylphosphono) furanyl] thiazole (1 mmol) in acetonitrile (9 mL) and water (4 mL) was treated with lithium hydroxide (1 L, 1 mL, 5 mmol) at room temperature for 4 hours. The reaction solution was evaporated to dryness and the residue was dissolved in water (10 mL), cooled to 0 ° C and the pH of the solution was adjusted to 4 by addition of 6N HCl. The resulting white solid was collected by filtration to give 2-amino-5-isobutyl-4- [2- (5-phenylphosphono) furanyl] thiazole.

Step E. A suspension of 2-amino-5-isobutyl-4- [2- (5-phenylphosphono) furanyl] thiazole (1 mmol) in thionyl chloride (3 mL) was heated to reflux for 2 hours. The reaction solution was evaporated to dryness and the residue was dissolved in anhydrous dichloromethane (2 mL) and the resulting solution was added to a solution of L-alanine methyl ester hydrochloride (1.2 mmol) in pyridine (0.8 mL) and dichloromethane (3 mL) at temperature 0 ° C. The resulting reaction solution was stirred at room temperature for 14 hours. Evaporation and chromatography gave 2-amino-5-isobutyl-4- {2- [5- (O-phenyl-N- (1-methoxycarbonyl) ethyl) phosphonamido] furanyl) thiazole (6.6) as an oil. Anal, calcd for C ₂ H 6 N ₂ O _{3 5} PS: C: 54, 42; H: 5.65; N: 9.07. Found: C: 54.40; H, 6.02; N: 8.87.

The following compounds were prepared according to the above procedures:

(6.7) 2-amino-5-isobutyl-4- {2- [5- (O-phenylphosphonamido)] - furanyl} thiazole, m.p. 205 ° C (dec.), Anal. Calcd. For C ₁₇ H ₂₀ N ₃ 0 ₃ PS + 0.3 H ₂ O + 0.3 HCl: C: 51.86; H: 5.35; N: 10.67.

Found: C: 51.58; H, 4.93; N: 11.08.

(6.8) 2-Amino-5-isobutyl-4- {2- [5- (O-phenyl-N-ethoxycarbonylmethyl)]

328 phosphonamido] furanyl} thiazole, Anal calcd for C 21 H 26 N 3 O 5 PS: C: 54.42; H: 5.65; N: 9.07. Found: C: 54.78; H: 5.83; N: 8.67.

(6.9) 2-amino-5-isobutyl-4- {2- [5- (O-phenyl-N-isobutyl) phosphonamido] furanyl} thiazole, m.p. 151-152 ° C, Anal. Calcd. For C 21 H 28 N 3 O 3 PS: C : 58.18; H, 6.51; N: 9.69. Found: C: 58.12; H, 6.54; N: 9.59.

(6.18) 2-Amino-5-isobutyl-4- (2- [5- (O-phenyl-N- (1- (1-ethoxycarbonyl-2-phenyl) ethyl) phosphonamido)] furanyl) thiazole, Anal. for C ₂₈ H ₃₂ N 3 O 5 PS: C: 60.75; H: 5.83; N: 7.59 Found: C: 60.35; H: 5.77; N: 7.37.

(6.19) 2-Amino-5-isobutyl-4- {2- [5- (O-phenyl-N- (1- (1-ethoxycarbonyl-2-methyl) propyl) phosphonamido)] furanyl} thiazole, Anal. Calcd. for C 23 H 30 N 3 O 5 PS: C: 56.20; H: 6.15; N: 8.55. Found: C: 55.95; H: 5.80; N: 8.35.

(6.20) 2-amino-5-isobutyl-4- {2- [5- (O-phenyl-N- (1- (1,3-bis (ethoxycarbonyl) propyl) phosphonamido)] furanyl) thiazole, Anal. Calcd. for C 26 H 34 N 3 O 7 PS + 0.2 CH ₂ Cl ₂ : C: 54.20; H, 5.97; N: 7.24. Found: C, 54.06; H: 5.68; N: 7.05.

(6.21) 2-amino-5-isobutyl-4- {2- [5- (O- (3-chlorophenyl) -N- (1- (1-methoxycarbonyl) ethyl) propyl) phosphonamido)] furanyl} thiazole, Anal . Calcd. for C 21 H 25 N 3 O 5 PSCl: C: 50.65; H, 5.06; N: 8.44. Found: C: 50.56; H, 4.78; N: 8.56.

(6.22) 2-amino-5-isobutyl-4- {2- [5- (O- (4-chlorophenyl) -N- (1- (1-methoxycarbonyl} ethyl) phosphonamido)] furanyl} thiazole, Anal. for C 21 H 25 N 3 O 5 PSCl + 1 HCl + 0.2 H ₂ O: C: 46.88; H: 4.95; N: 7.81. Found: C: 47.33; H: 4.71; N: 7.36 .

(6.23) 2-Amino-5-isobutyl-4- (2- [5- (O-phenyl-N- (1- (1-bis (ecoxycarbonyl) methyl) phosphonamido) methyl) phosphonamido)] furanyl} thiazole, Anal calcd for C 24 H 30 N 3 O 7 PS H: 5.65; N: 7.85 Found: C: 53.54 H: 5.63; N: 7.77.

(6.24) 2-amino-5-isobutyl-4- {2- [5- (O-phenyl-N- (1-morpholinyl) phosphonamido)] furanyl} thiazole, Anal calcd for C 21 H 26 N 3 O 4 PS: C: 56.37; H: 5.86; N: 9.39. Found: C: 56.36; H: 5.80; N: 9.20.

(6.25) 2-Amino-5-isobutyl-4- (2- [5- (O-phenyl-N- (1- (1-benzyloxycarbonyl) ethyl) phosphonamido)] furanyl) thiazole, Anal. calculated for

329

C27H30N3O5PS: C: 60.10; H: 5.60; N: 7.79. Found: C, 59, 80; H, 5.23; N: 7.53.

(6.32) 2-Amino-5-isobutyl-4- {2- [5- (O-phenyl-N-benzyloxycarbonylmethyl) phosphonamido)] furanyl} thiazole, Anal. Calcd for C ₂ H ₅ 6H28N ₃ PS: C: 59, 42; H: 5.37; N: 8.00. Found: C: 59.60; H: 5.05; N: 7.91.

(6.36) 2-amino-5-isobutyl-4- {2- [5- (O- (4-methoxyphenyl) -N- (1- (1-methoxycarbonyl) ethyl) phosphonamido)] furanyl (thiazole, Anal. for C ₂ H 28 N ₃ O ₆ PS + 0.1 CHCl ₃ + 0.1 MeCN: C: 52.56; H: 5.62; N: 8.52 Found: C: 52.77; H: 5.23: N: 8.87.

(6.37) 2-Amino-5-isobutyl-4- {2- [5- (O-phenyl-N-2-methoxycarbonyl) propyl) phosphonamido]] furanyl} thiazole, Anal. Calcd. for C ₂₂ H ₂₈ N ₃ O ₅ PS + 0.6 H ₂ O: C: 54.11; H, 6.03; N: 8.60. Found: C: 53.86; H, 5.97; N: 8.61.

(6.38) 2-Amino-5-isobutyl-4- {2- [5- (O-phenyl-N- (2- (1-ethoxycarbonyl) propyl) phosphonamido)] furanyl} thiazole, Anal. Calcd. for C ₂₃ H ₃₀ N ₃ O ₅ PS: C: 56.20; H: 6.15; N: 8.55. Found: C: 55.90; H, 6.29; N: 8.46.

Reaction of the dichlorophosphonate with 1-amino-3-propanol in the presence of a suitable base (e.g. pyridine, triethylamine) can also be used to prepare cyclic phosphoramidates as prodrugs of phosphonates. The following compounds were prepared as follows:

(6.10) 2-Methyl-5-isobutyl-4- {2- [5- (1-phenyl-1,3-propyl) phosphonamido] furanyl} thiazole minor isomer, Anal. Calcd for C ₂₁ H ₂₅ N ₂ O ₃ PS - 0.25 H ₂ O + 0.1 HCl: C: 59.40; H, 6.08; N: 6.60. Found: C: 59.42; H: 5.72; N: 6.44.

(6.11) 2-Methyl-5-isobutyl-4- {2- [5- (1-phenyl-1,3-propyl) phosphonamido] furanyl} thiazole major isomer, Anal. Calcd for C ₂ H ₂₅ N ₂ O ₃ S + 0.25 H ₂ O: C: 59.91; H, 6.11; N: 6.65. Found: C: 60.17; H: 5.81; N: 6.52.

(6.12) 2-Amino-5-isobutyl-4- {2- [5- (1-phenyl-1,3-propyl) phosphonamido] furanyl) thiazole major isomer, Anal. Calcd for C ₂₀ H ₂₄ N ₃ O ₃ PS + 0.25 H ₂ O 0.1 CH ₂ Cl ₂ : C: 55.27; H: 5.72; N: 9.57.

330

Found: C: 55.03; H, 5.42; N: 9.37.

(6.13) 2-Amino-5-isobutyl-4- (2- [5- (1-phenyl-1,3-propyl) phosphonamido] furanyl} thiazole minor isomer, Anal calcd for C ₂₀ H ₂₄ N 3 O 3 PS + 0.15 CH ₂ Cl ₂ : C: 56.26; H: 5.69; N: 9.77 Found: C: 56.36; H: 5.46; N: 9.59.

(6.14) 2-Amino-5-methylthio-4- {2- [5- (1-phenyl-1,3-propyl) phosphonamido] furanyl} thiazole less polar isomer, Anal, calculated for C ₁₇ H ₁₈ N3O3PS2 + 0 .4 HCl: C: 48.38; H, 4.39; N: 9.96. Found: C: 48.47; H, 4.21; N: 9.96.

(6.15) 2-Amino-5-methylthio-4- {2- [5- (1-phenyl-1,3-propyl) phenylphenamido] furanyl) thiazole multiple polar isomer, Anal. Calcd. for C 17 H 18 N 3 O 3 PS 2: C: 50.11; H, 4.45; N: 10.31. Found: C, 49.94; H, 4.19; N: 10.13.

(6.16) 2-Amino-5-methylthio-4- {2- [5- (N-methyl-1-phenyl-1,3-propyl) phosphonamido] furanyl) thiazole, Anal, calculated for C ₁₈ H ₂ NO. ₃ PS ₂ + 0.25 HCl: C, 50.21; H, 4.74; N: 9.76. Found: C: 50.31; H, 4.46; N: 9.79.

(6.17) 2-Amino-5-methylthio-4- {2- [5- (1-phenyl-3-propyl) -N-acetylfosfónamido] furanyl} thiazole, Anal, calcd for C22H2ÍN3O4PS + 1.25 H ₂ O: C: 54.82; H, 5.96; N: 8.72. Found: C: 55.09; n: 5.99; N: 8.39.

(6.26) 2-Amino-5-isobutyl-4- {2- [5- (1-oxo-1-phospha-2-oxa-7-aza-3,4-benzocycloheptan-1-yl)] furanyl} thiazole , major isomer, m.p. 233-234 ° C, Anal calcd for C 21 H 24 N ₃ O ₅ PS + 0.2 CHCl ₃ : C: 52.46; H, 5.03; N: 8.66. Found: C, 52.08; H, 4.65; N: 8.58.

(6.27) 2-Amino-5-isobutyl-4- {2- [5- (1-oxo-1-phospha-2-oxa-7-aza-3,4-benzocycloheptan-1-yl)] furanyl} thiazole , minor isomer, MS calcd for C 21 H 24 N 3 O 5 PS + H: 462, Found 466.

(6.34) 2-amino-5-isobutyl-4- (2- [5- (3- (3,5-dichlorophenyl) -1,3-propyl) phosphonamido] furanyl} thiazole, Anal calcd for C 20 H 22 N 3 O 3 PSCl 2: C: 49: 39; H: 4.56; N: 8.64 Found: C: 49.04; H: 4.51; N: 8.37.

(6.35) 2-Amino-5-isobutyl-4- {2- [5- (4,5-benzo-1-oxo-1-phospha-2-oxa-6-aza) cyclohexan-1-yl] furanyl} thiazole, Anal, calculated for

331

C18H20N3O3PS + 0.7 _H2O: C, 53.78; Η: 5.37; N: 10.45. Found: C, 53.63; H: 5.13; N: 10.36.

Section 2

Synthesis of compounds of formula X

Example 7

Preparation of 2-amino-4-phosphonomethyloxy-6-bromobenzothiazole

Step A. A solution of AlCl ₃ (5 mmol) in EtSH (10 mL) was cooled to 0 ° C and treated with 2-amino-4-methoxybenzothiazole (1 mmol). The mixture was stirred at 0 ° C for 2 hours. Evaporation and extraction afforded 2-amino-4-hydroxybenzothiazole as a white solid.

Step B. A mixture of 2-amino-4-hydroxybenzothiazole (1 mmol) and NaH (1.3 mmol) in DMF (5 mL) was stirred at 0 ° C for 10 min and then treated with diethylphosphonomethyltrifluoromethylsulfonate (1, 2). 2 mmol). The mixture was stirred at room temperature for 8 hours, then subjected to extraction and chromatography to give 2-amino-4-diethylphosphonomethyloxybenzothiazole as an oil.

Step C. A solution of 2-amino-4- (diethylphosphonomethyloxy) benzothiazole (1 mmol) in AcOH (6 mL) was cooled to 10 ° C and treated with bromine (1.5 mmol) in AcOH (2 mL). After 5 minutes, the reaction mixture was stirred for an additional 2.5 hours at room temperature. The yellow precipitate was filtered and washed with CH 2 Cl 2 to give 2-amino-4-diethylphosphonomethyloxy-6-bromobenzothiazole.

Step D. A solution of 2-amino-4-diethylphosphonomethyloxy-6-bromobenzothiazole (1 mmol) in dichloromethane (4 (10 mmol) at 0 ° C.) Mixture at room temperature, evaporate to (5 mL). After stirring for 8 hours at room temperature, the residue was taken up in water filtered and washed with water to give 2-amino-4-phosphonomethyloxy-6-bromobenzothiazole (7.1) as a white solid. Mp> 220 ° C (dec.), Anal. Calcd. For C ₈ H ₈ N ₂ O ₄ PSBr: C: 28.34; H, 2.38; N: 8.26. found:

332

C: 28.32; H, 2.24; N: 8.06.

The following compounds were prepared using similar procedures:

(7.2) 2-Amino-4-phosphonomethyloxybenzothiazole, m.p. > 250 ° C, Anal. Calcd. For C 8 H ₈ N 2 OPS + 0.4 H ₂ O: C: 35, 93; H, 3.69; N: 10.48. Found: C: 35.90; H, 3.37; N: 10.37.

Example 8

Preparation of 2-amino-4-phosphonomethyloxy-6-bromo-7-chlorobenzothiazole

Step A. A solution of 1- (2-methoxy-5-chlorophenyl) -2-thiourea (mmol) in chloroform (10 mL) was cooled to 10 ° C and treated with bromine (2.2 mmol) in chloroform (10 mL). 10 ml). The reaction mixture was stirred at 10 ° C for 20 minutes and then at room temperature for 20 minutes. The resulting suspension was heated to reflux for 30 minutes. The precipitate was filtered (washed with dichloromethane) to give 2-amino-4-methoxy-7-chlorobenzothiazole, which was subjected to steps A, B, C and D of Example 34 to give 2-amino-4-phosphonomethoxy-6. -bromo-7-chlorobenzothiazole (8.1), m.p. > 220 ° C (dec.): Anal calcd for C ₆ H ₇ N ₂ O ₄ PSCl ₃ r: C: 25.72; H, 1.89; N: 7.50. Found: C: 25.66; H, 1.67; N: 7.23.

The following compounds were prepared in a similar manner to the above procedures:

(8.2) 2-Amino-4-phosphonomethoxy-6-bromo-7-methyl-benzothiazole, m.p. > 220 ° C (dec.). Anal calcd for C 8 H 15 N 2 O 4 PSBr: C: 30.61; H, 2.85; N: 7.93. Found: C: 30.25; H, 2.50; N: 7.77.

(8.3) 2-Amino-4-phosphonomethoxy-7-methylbenzothiazole, m.p. > 220 ° C (dec.). Anal calcd for C 9 H 11 N 4 PS - 1.0 H ₂ O: C: 36.99; H, 4.48; N: 9.59. Found: C: 36.73; H, 4.23; N: 9.38.

(8.4) 2-Amino-4-phosphonomethoxy-7-chlorobenzothiazole, m.p. > 220 ° C (dec.). Anal. Calcd for C 8 H ₈ N 2 OPSCl · 0.1 H ₂ O: C: 32.41; H, 2.79; N: 9.45. Found: C: 32.21; H, 2.74;

333

N: 9.22.

Example 9

Preparation of 2-amino-7-ethyl-6-thiocyano-4-phosphonomethoxy benzothiazole

Step A. A solution of 2-diethylphosphonomethyloxy-5-bromonitrobenzene (1 mmol) prepared in Example 7, Step B) in DMF (5 mL) was treated with tributyl (vinyl) tin (1.2 mmol) and palladium bis (triphenylphosphine) ) with dichloride (0.1 mmol) and the mixture was then heated at 60 ° C under a nitrogen atmosphere for 6 hours. Evaporation and chromatography gave 2-diethylphosphonomethyloxy-5-vinylnitrobenzene as an oil.

A solution of SnCl ₂ (4 mmol) in freshly prepared methanolic HCl (10 mL) was added to a cold (0 ° C) solution of 2-diethylphosphonomethyloxy-5-vinylnitrobenzene (1 mmol) in MeOH (5 mL). The mixture was warmed to room temperature and stirred for 3 hours at room temperature. Evaporation, extraction and chromatography gave 2-diethylphosphonomethyloxy-5-vinylaniline.

A solution of KSCN (16 mmol) and CuSO4 (7.7 mmol) in MeOH (10 mL) was treated with a solution of 2-diethylphosphonomethyloxy-5-vinylaniline (1 mmol) in MeOH (5 mL) at room temperature. The mixture was heated to reflux for 2 hours. Filtration, extraction and chromatography gave the product that was subjected to Step D of Example 7 to give 2-amino-7-ethyl-6-thiocyano-4-phosphonomethoxybenzothiazole (9.1). Melting point> 167 ° C (dec.), Anal. Calcd. For C ₁₁ H ₁₂ N ₃ O ₄ PS ₂ : C: 38.26; H, 3.50; N: 12.17. Found: C: 37.87; H, 3.47; N: 11.93.

Example 10

Preparation of various benzothiazole prodrugs

Step A. A suspension of 2-amino-4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole (1 mmol) in DMF (10 mL) was treated with DCC (3 mmol) followed by 3 min. - (3,5-dichloro) phenyl-1,3-propanedio

334 fracture (1.1 mmol). The resulting mixture was stirred at 80 ° C for 8 hours. Evaporation followed by column chromatography gave 2-amino-4 - {[3- (3,5-dichlorophenyl) propane-1,3-diyl] phosphonomethoxy} -5,6,7,8-tetrahydronaphtho [1,2-d] thiazole (10.1) as a solid. Melting point> 230 ° C, Anal. Calcd. For C 21 H ₂₁ N ₂ O ₂ S ₂ O ₂ : C: 50.51; H, 4.24; N: 5.61. Found: C: 50.83; H: 4.34; N: 5.25.

Step B. A solution of 4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole dichloridate (generated in Step A, Example 6) (1 mmol) in dichloromethane (5 mL) was cooled to 0 ° C and treated with a solution of benzyl alcohol (0.9 mmol) in dichloromethane (0.5 mL) and pyridine (0.3 mL). The resulting reaction solution was stirred at 0 ° C for 1 hour and then a solution of ammonia (excess) in THF was added. The mixture was stirred at room temperature for 16 hours, the reaction was evaporated to dryness and the residue purified by chromatography to give 4-phosphonomonoamidomethoxy-5,7,7,8-tetrahydronaphtho [1,2-d] thiazole.

Alternatively, various methods for preparing other phosphoramides are exemplified in the following procedures:

Step C. A suspension of 4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole dichloridate (generated in Step A, Example 6) (1 mmol) in dichloromethane (5 mL) was cooled to 0 ° C and ammonia (excess) was bubbled through the mixture for 10 minutes. The mixture was stirred at room temperature for 16 hours, the mixture was evaporated to dryness and the residue was purified by column chromatography to give 4- (phosphorodiamido) methoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole.

The above-mentioned procedures can also be used to prepare monophenyl monophosphonamide derivatives of compounds of formula X:

Step D. A solution of 4-diphenylphosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole (1 mmol) in acetonitrile (9 mL) and water (4 mL) was treated with lithium hydroxide (1 N, 1.5 mmol) at room temperature for 24 hours. The reaction solution was evaporated to dryness and the residue was dissolved in water (10 mL), cooled to 0 ⁼ C and pH.

335 of the solution was adjusted to 4 by adding 6N HCl. The resulting white solid was filtered to give 4-phenylphosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole.

Step E. A suspension of 4-phenylphosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole (1 mmol) in thionyl chloride (3 mL) was heated to reflux for 2 hours. The reaction solution was evaporated to dryness and the residue was dissolved in anhydrous dichloromethane (2 mL) and the resulting solution was added to a solution of L-alanine ethyl ester hydrochloride (1.2 mmol) in pyridine (0.8 mL) and dichloromethane (3 mL) at temperature 0 ° C. The resulting reaction solution was stirred at room temperature for 14 hours. Evaporation and chromatography gave 4- [O-phenyl-N- (1-ethoxycarbonyl) ethylphosphonamido] methoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole.

Step F. A solution of 4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole (1 mmol) in DMF was treated with N, N'-dicyclohexyl-4-morpholinecarboxamidine (5 mmol) and ethyl propyloxycarbonyloxymethyl iodide (5 mmol) prepared from chloromethyl chloroformate according to the procedure described (Nis'nimura et al., J. Antibiotics, 1987, 40, 81). The reaction mixture was stirred at 25 ° C for 24 hours.

Evaporation and chromatography gave 4-bis (ethoxycarbonyloxymethyl) phosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole.

4- (dipivaloyloxymethyl) phosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole and 4-bis (isobutyryloxymethyl) phosphonomethoxy-5,6,7, -

8-Tetrahydro-naphtho [1,2-d] thiazole was also prepared in a similar manner.

Example 11

General method for preparing bis-phosphoramide prodrugs

Formation of dichloridate

To a suspension of 1 mmol of phosphonic acid in 5 mL of dichloroethane was added 0.1 mmol of pyridine (or 0.1 mmol of DMF) followed by 6 mmol of thionyl chloride and the mixture was heated to reflux for 2.5 hours. The solvent and excess thionyl chloride were removed under reduced pressure

The reaction mixture was concentrated under reduced pressure and the residue was dried to give the dichloridate.

Binding reaction:

Method A: The crude dichloridate was dissolved in 5 mL of dry dichloromethane and 8 mmol of the amino acid ester was added at 0 ° C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was subjected to water treatment and chromatography.

Method B: The crude dichloridate was dissolved in 5 mL of dry dichloromethane and a mixture of 4 mmol of amino acid ester and 4 mmol of N-methylimidazole was added at 0 ° C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was subjected to water treatment and chromatography.

The following compounds were prepared as follows:

(11.1) 2-Amino-5-isobutyl-4- [2- (5-N, N'-bis (diethyl-L-glutamic acid diethyl ester) phosphonoamido) furanyl] thiazole, Anal, calculated for C ₂ 9 H _{4 5} N <10 ₁₀ PS: C: 51.78; H, 6.74; N: 8.33. Found: C: 51.70; H, 6.64; N: 8.15.

(11.2) 2-Amino-5-isobutyl-4- [2- (5-N, N'-bis (L-alanic acid dibenzyl ester) phosphonoamido) furanyl] thiazole, Anal, calculated for C31H37N4O6PS: C: 59.60 ; H, 5.97; N: 8.97. Found: C: 59.27; H: 5.63; N: 8.74.

(11.3) 2-Amrno-5-isobutyl-4- (2- [S- (N, N'-bis (benzyloxycarbonylmethyl) phosphonodiamido] furanyl) thiazole) Anal calcd for C ₁₉ H ₂₅ N ₄ O ₆ PS + 0 , 3 CH ₂ C1 _2: C: 46.93, H: 5.22, N: 11.34. Found: C: 46.92, H: 5.00, N: 11.22.

(11.4) 2-Amino-5-isobutyl-4- (2- [5- (N, N'-bis (benzyloxycarbonylmethyl) phosphonodiamido] furanyl) thiazole, Anal Calcd for C ₂₉ H ₃₃ N 4 O _with PS: C: 58.38 H: 5.57; N: 9.39 Found: C: 53.20; H: 5.26; N: 9.25.

(11.5) 2-Amino-5-isobutyl-4- (2- [5- (N, N'-bis ((R) -1-methoxycarbonyl) ethyl) phosphonamido] furanyl} thiazole, Anal.

337

C ₁₉ H ₂₉ N ₄ O ₆ PS + 0.6 CH ₂ Cl ₂ : C: 44.97; H: 5.82; N, 10.70. Found: C: 44.79; H: 5.46; N: 10.48.

(11.6) 2-Amino-5-isobutyl-4- {2- [5- (N, N'-bis ((S) -1-ethoxycarbonyl) ethyl) phosphonamido] furanyl] thiazole, m.p .: 164-165 ° C: Anal calculated for C ₂₁ H ₃₃ N ₄ O ₆ PS + 0.61 CH ₂ Cl ₂ : C: 46, 99; H, 6.24; N: 10.14. Found: C: 47.35; H: 5.85; N: 9.85.

(11.7) 2-Amino-5-isobutyl-4- (2- [5- (N, N'-bis ((tert-butoxycarbonyl) methyl) phosphonamido] furanyl) thiazole) Anal calcd for C ₂₃ H ₃₇ N ₄ O ₆ PS + 0.15 CH ₂ C1 _2: C: 51.36, H: 6.94, N: 10.35. Found: C: 51.34; H: 6.96; N: 10.06.

(11.8) 2-Amino-5-isobutyl-4- {2- [5- (N, N'-bis (ethoxycarbonyl) methyl) phosphonamido)] furanyl) thiazole, Anal, calculated for C19H29N4OSPS + 0.1 EtOAc + 0 47 CH ₂ C1 _2: C, 45.79; H: 5.94; N: 10.75. Found: C: 46.00; H, 5.96; N: 10.46.

(11.9) 2-Amino-5-isobutyl-4- {2- [5- (N, N'-bis (1-methyl-1-ethoxycarbonyl) ethyl) phosphonamido] furanyl] thiazole, m.p .: 142-145 ° C; Anal calcd for C ₂₃ H ₃₇ N ₄ O ₆ PS: C: 52.26; H, 7.06; N: 10.60 '. Found: C: 52.21; 6.93; 10.62.

(11.10) 2-Amino-5-isobutyl-4- {2- [5- (N, N'-bis (ethoxycarbonylmethyl) -N, N'-dimethylphosphonamido)] furanyl} thiazole, Anal. Calcd for C ₂ H ₃₃ N4O ₆ PS: C: 50.39; H, 6.65; N: 11.19. Found: C: 50.57; H, 6.56; N: 11.06.

(11.11) 2-Amino-5-isobutyl-4- (2- [5- (N, N'-bis ((S) -1-benzyloxycarbonyl-2-methyl) propyl) phosphonamido] furanyl} thiazole, Anal. for C ₃₅ H 45 N ₄ O ₆ PS + 0.5 H ₂ O: C: 60.94; H: 6.72; N: 8.12 Found: C: 61.01: H: 6.48; 7.82.

(11.12) 2-Amino-5-isobutyl-4- (2- [5- (N, N'-bis ((S) -1-methoxycarbonyl-3-methyl) butyl) phosphonamido] furanyl) thiazole, Anal calcd for C25H41N4O6PS N: 10.06 Found: C: 54.12, H: 7.62, N: 9.82.

(11.13) 2-Amino-5-isobutyl-4- (2- [5- (N, N'-bis ((R) -1-ethoxycarbonyl-2- (5-benzyl)) ethyl) phosphonamido] furanyl} thiazole Anal. calcd for _C3 5H4 ₅ N4O ₆ PS ₃ + 0.4 toluene: C: 58.07; H: 6.21; N: 7.17. Found: C: 57.87; H: 6.14 N: 6.81.

338 (11.14) 2-Amino-5-isobutyl-4- {2- [5- (N, N'-bis ((S) -1-ethoxycarbonyl-

-3- (5-methyl) (butyl) phosphonamido] furanyl} thiazole, Anal calcd for C 23 H 37 N 4 O 6 PS 3: C: 46.61; H, 6.92; N: 9.45. Found: C: 46.26; H, 6.55; N: 9.06.

(11.15) 2-Amino-5-propylthio-4- {2- [5- (N, N '- (1- (S) ethoxycarbonyl) ethyl) phosphonamido] furanyl} thiazole, Anal. Calcd. For C ₂₀ H ₃₁ N4O _with PS ₂ : C: 46.32; H, 6.03; N: 10.80. Found: C: 46.52; H: 6.18; H, 10.44.

(11.16) 2-Amino-5-isobutyl-4- {2- [5- (N, N'-bis ((S) -1-benzyloxycarbonyl-2-methyl) isobutyl) phosphonamido] furanyl} thiazole, Anal. Calcd. for C37H49N4O6PS: C, 62.69; H, 6.97; H, 7.90. Found: C: 62.85; h 7.06; 7.81.

(11.17) 2-Amino-5-isobutyl-4--2- [5- (N, N'-bis ((S) -1-ethoxycarbonyl-3-methyl) butyl) phosphonamido] furanyl} thiazole, Anal, calculated for C 27 H 45 N 4 O 6 PS: C: 55, 46; H, 7.76; N: 9.58. Found: C: 55.35; H, 7.94; N: 9.41.

(11.18) 2-Amino-5-isobutyl-4- {2- [5- (N, N'-bis ((S) -1-ethoxycarbonyl-2-methyl) propyl) phosphonamido] furanyl} thiazole, Anal. Calcd. for C 25 H 41 N 4 O 6 PS: C: 53.94; H, 7.42; N, 10.06. Found: C: 54.01; H, 7.58; N: 9.94.

(11.19) 2-Amino-5-isobutyl-4- (2- [5- (N, N'-bis ((S) -1-ethoxycarbonyl-2-phenyl) ethyl) phosphonamido] furanyl} thiazole, Anal. the C ₃ H ₆ 3H4iN ₄ PS + 0.15 CH ₂ C1 _2: C: 59.83; H: 6.26; H, 8.42. Found: C: 59.88; H: 6.28 H : 8,32.

(11.20) 2-Amino-5-propyl-thio-4- (2- [5- (N, N '- (1-methyl-1-ethoxycarbonyl) ethyl) phosphonamido] furanyl} thiazole, m.p. 110-115 ° C: Anal, calculated for C ₂₂ H 35 N ₄ O ₆ PS ₂ + 0.4 HCl + 0.5 Et ₂ O: C: 48.18; H: 6.81; N: 9.36. 48.38, H: 6.60, H: 8.98.

(11.21) 2-Amino-5-methylthio-4- {2- [S- (N, N'-bis (1-methyl-1-ethoxycarbonyl) ethyl) phosphonamido] furanyl} thiazole, Anal. Calcd. for C ₂₀ H ₃₁ N ₄ O 5 PS ₂ + 0.5 H ₂ O: C: 45.53; H, 6.11; N: 10.62. Found: C: 45.28; H: 5.85; N: 10.56.

Alternatively, compound 11.6 was prepared using a modified procedure. A suspension of compound 3.1 (1 mmol), oxalyl chloride (3.2 mmol) and DMF (1.1 mmol) in anhydrous toluene was heated to reflux for 1 hour. The resulting solution was concentrated under reduced pressure to 80% of the original volume, cooled to 0 ° C and triethylamine (3 mmol) and L-alanine ethyl ester (2.2 mmol) were added. The mixture was stirred at 0 ° C for 2 hours and then at room temperature for 6 hours. Acetic acid (9.5 mmol) and ethanol (21 mmol) were added to the reaction mixture and the resulting mixture was heated to boiling for 16 hours. Extraction and crystallization gave compound 11.6 as an off-white solid.

Example 12

General procedure for the preparation of mixed bis-phosphoramidate prodrugs

To a suspension of the crude dichloridate (1 mmol, prepared as described in Example 40) in 5 mL of dry dichloromethane was added an amine (1 mmol) followed by 4-dimethylaminopyridine (3 mmol) at 0 ° C. The resulting mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was cooled to 0 ° C before addition of the amino acid ester (2 mmol) and left at room temperature for 16 hours. The reaction mixture was treated with water and the mixed bis-phosphoramidate prodrug was purified by column chromatography.

The following compounds were prepared in a similar manner:

(12.1) 2-Amino-5-isobutyl-4- (2- [S- (N-morpholino-N '- (1-methyl-1-ethoxycarbonyl) ethyl) phosphonamido] furanyl) thiazole, temperature m.p .: 182-183 ° C: Anal calcd for C 21 H 33 N 4 O 5 PS: C: 52.05; H, 6.86; N: 11.56. Found: C: 51.66; H: 6.68; N: 11.31.

(12.2) 2-Amino-5-isobutyl-4- {2- [5- (N-pyrrolidino-N '- (1-methyl-1-ethoxycarbonyl) ethyl) phosphonamido) furanyl} thiazole, m.p .: 189-190 ° C: Anal calcd for C 21 H 33 N 4 O 4 PS: C: 53.83; H, 7.10; N: 11.96. Found: C: 54.15; H, 7.48; N: 12.04.

340

Synthesis of Compounds of Formula VII

Example 13

Preparation of 5- (3,5-dinitrophenyl) -2-furanephosphonic acid (Compound No. 13.01).

1) A solution of furan (1 mmol) in 1 mL diethyl ether was treated with N, N, N ', N'-tetramethylethylenediamine (TMEDA) (1 mmol) and nBuLi (1.1 mmol) at -78 ° C for 0 , 5 hours. The resulting solution was added via cannula to a solution of diethyl chlorophosphate (1.33 mmol) in 1 mL diethyl ether at -60 ° C and the reaction mixture was allowed to warm to room temperature and stirred at this temperature for an additional 16 hours. Extraction and distillation at 75 ⁼ C / 0.2 mm Hg gave diethyl 2-furanphosphonate as a clear oil.

2) A solution of diethyl 2-furanphosphonate (1 mmol) in 2 mL THF was cooled to -78 ° C and a solution of lithium diisopropylamide (LDA) (1 mmol) in 5 mL THF was added at -78 ° C over 20 minutes. The resulting mixture was stirred at -78 ° C for 20 minutes and a solution of tributyltin chloride (1 mmol) in THF was added at -78 ° C over 20 minutes. The mixture was stirred at -78 ° C for 15 minutes and then at 25 ° C for 1 hour. Extraction and chromatography gave diethyl 5-tributylstanyl-2-furanphosphonate as a colorless oil.

3) A mixture of diethyl 5-t-butylstanyl-2-furanphosphonate (1 mmol),

1-Iodo-2,4-dinitrobenzene (1 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.05 mmol) in 6 mL dioxane were heated at 80 ° C for 16 h. Evaporation of the solvent and chromatography gave diethyl 5- (3,5-dinitrophenyl) -2-furanphosphonate as a rigid foam.

4) A mixture of diethyl 5- (3,5-dinitrophenyl) -2-furanphosphonate (1 mmol) and TMSBr (6 mmol) in 10 mL of dichloromethane was stirred at room temperature for 16 h and evaporated. The residue was dissolved in 85/15 acetonitrile / water and the solvent was then evaporated. The residue was suspended in dichloromethane and the resulting compound (# 13.01) was collected as a pale yellow solid: HPLC

341

_Rc = 5.30 min., Negative ion electrospray MS M-found 313.

The following reagents were coupled with diethyl 5-tributylstanyl-2-furanphosphonate and converted to the corresponding compounds (compound numbers are shown in brackets) using steps C and D as described in Example 13: 2-bromo-4,6-dinitroaniline ( to compound 13.02); chloro-2-iodoanisole (to compound 13.03); 2,5-dichloro-1-iodobenzene (to compound 13.04); N ¹ -methyl-2-iodo-4- (trifluoromethyl) benzene-1-sulfonamide (to compound 13.05); N ^1- methyl-4-chloro-2-iodobenzene-1-sulfonamide (to compound 13.06); N ^1- methyl-2-iodobenzene-1-sulfonamide (to compound 13.07); N ¹ -propyl-4-chloro-2-iodobenzene-1-sulfonamide (to compound 13.08); 2-iodophenol (to compound 13.09); 5-iodo-m-xylene (to compound 13.10); 1-bromo-3-iodobenzene (to compound 13.11); 4-iodoaniline (to compound 13.12); 2,5-dimethoxy-4-iodo-chlorobenzene (to compound 13.13); N ^1- (4-chlorobenzyl) -2-iodobenzamide (to compound 13.14); N ^1- (4-chlorophenethyl) -2-iodobenzamide (to compound 13.15); N ¹ -benzyl-2-iodobenzene-1-sulfonamide (to compound 13.16); 2-iodobenzenesulfonamide (to compound 13.17); 1-iodo-2,3,4,5,6-pentamethylbenzene (to compound 13.18); 3-iodophthalic acid (iodoethane and diisopropylamine included in step C, to compound 13.19); 4-iodo-2-methyl-acetanilide (to compound 13.20); 3,5-dichloro-2-iodotoluene (to compound 13.21); methyl 5-hydroxy-2-iodobenzoate (to compound 13.22);

2-iodo-5-methylbenzanilide (to compound 13.23); 5-hydroxy-2-iodobenzoic acid (iodoethane and diisopropylamine included in step C, to compound 13.24); 1-iodo-4-nitrobenzene (to compound 13.25); N ^1- (2,4-difluorophenyl) -2-iodobenzamide (to compound 13.26); 3,5-dichloro-1-iodobenzene (to compound 13.27); 3-iodophenol (to compound 13.28); 3-bromo-5-iodobenzoic acid (to compound 13.29);

3-bromo-4,5-dimethoxybenzaldehyde (to compound 13.30); 1-iodo-2-nitrobenzene (to compound 13.31); 2-iodo-biphenyl (to compound 13.32); 2-iodobenzoic acid (iodoethane and diisopropylamine included in step C, to compound 13.33); 1-bromo-4-iodobenzene (to compound 13.34); 3'-bromopropiophenone (to compound 13.35); 3-bromo-4-methoxybenzonitrile (to compound 13.36); 1-ethyl-2-iodobenzene (na

342

2-bromo-3-nitrotoluene (to compound 13.38);

zene (to compound 13.39); 2,3,4,5-tetrametyljódben13.40); 3-bromobiphenyl (to compound 13.41);

4-chloro-2-iodobenzenesulfonamide (per compound nyl) -2-tetrahydro-1H-pyrrol-1-ylacetamide (per compound 13.43);

3,4-dimethyl-iodobenzene (to compound 13.44);

2,4-dinitroiodobenzene (to compound 13.45); 3-iodobenzylamine (to compound 13.46);

2-fluoro-4-iodoaniline (to compound 13.47); 3-iodobenzyl alcohol (to compound 13.48);

2-bromo-1-iodobenzene (na

2-bromophenethyl alcohol (to compound 13.50);

4-iodobenzamide (to compound 13.51);

4-bromobenzonitrile compound 13.52);

3-bromobenzonitrile (to compound 13.53); 2-bromobenzonitrile (to compound 13.54);

4-bromo-2-nitroaniline

2-iodoisopropylbenzene (to compound 13.56); 6-amino-2-chloro-3-bromopyridine (derived from the reaction of 6-amino-2-chlorobenzene (1 mmol) with bromine (1 mmol) in acetic acid (4 mL) for 2 hours at room temperature, followed by evaporation and chromatography, to give 6-amino-2-chloro-3-bromopyridine) (to the compound

3-bromo-4-methylthiophene (to compound 13.58); 2-bromo-4-chloroaniline (to compound 13.59); 1-bromo-3-chloro-5-fluoroaniline (per compound

13.60); 2-bromo-4-cyanoanisole (to compound 13.61); 2-bromo-4-nitrotoluene (to compound 13.62); 3-nitro-5-fluoro-1-iodobenzene (to compound 13.63); 2-iodo-4-carbomethoxyaniline (per compound

13.64); 2-bromo-4-nitroanisole (to compound 13.65);

2-chloro-1-iodo-5-trifluoromethylbenzene (to compound 13.66) and 1-bromo-2,5-bis- (trifluoromethyl) benzene (to compound 13.67).

Example 14

Preparation of 5- (4-fluorophenyl) -2-furanphosphonic acid (Compound No. 14.01)

1) A solution of diethyl 2-furanephosphonate (prepared as described in Step A, Example 13) (1 mmol) in 2 mL THF was cooled to -78 ° C and a solution of lithium isopropylcyclohexylamide (LCA) (1 mmol) in 2 mL THF was added. -78 ° C over 20 minutes. The resulting

The 343 mixture was stirred at -78 ° C for 20 minutes and a solution of iodine (1 mmol) in 1 mL THF was added over 20 minutes at -78 ° C. The mixture was then stirred at -78 ° C for 20 minutes. Extraction and chromatography gave diethyl 5-iodo-2-furanphosphonate as a yellow oil.

2) A mixture of diethyl 5-iodo-2-furanphosphonate (1 mmol), 4-fluorophenylboronic acid (2 mmol), diisopropylethylamine (4 mmol) and bis (acetonitrile) dichloropalladium (II) (0.05 mmol) in 6 mL of DMF was added. The mixture was heated at 75 ° C for 16 hours. Extraction and chromatography gave diethyl 5- (4-fluorophenyl) -2-furanphosphonate as an oil.

Use of Step D, Example 13 on this material afforded the title compound (No. 14.01) as a white solid. HPLC R _t = 5.09 min, negative ion-electrospray MS M1 found: 241.

The introduction of 2,4-dichlorophenylboronic acid into this method gave compound no. 2.14 The introduction of 3-amino-5-carbomethoxyphenylboronic acid into this method gave compound no. 3.14

Example 15

Preparation of 5- (4-Bromo-3-aminophenyl) -2-furanphosphonic acid (Compound No. 15.01)

Reaction of 3-aminophenylboronic acid hydrochloride with diethyl 5-iodo-2-furanphosphonate as described in Step B of Example 14 afforded diethyl 5- (3-aminophenyl) -2-furanphosphonate as an oil.

A mixture of diethyl 5- (3-aminophenyl) -2-furanphosphonate (1 mmcl), NBS (0.9 mmol) and AIBA (0.1 mmol) in 30 mL of CCl 4 was stirred at room temperature for 2 hours. Extraction and chromatography gave diethyl 5- (4-bromo-3-aminophenyl) -2-furanphosphonate as an oil.

Applying Step D of Example 13 to this material afforded the final compound No. 1. 15.01 in the form of a white solid. HPLC R _t = 4.72 min, negative ion-electrospray MS M / found: 316/318.

344

Biological examples

The following examples can be used to identify compounds that 1) inhibit FBPases and gluconeogenesis in cell and animal models of diabetes, or 2) increase insulin sensitivity in cell or animal models of diabetes, or

3) exhibit better pharmacological activity than a combination of FBPase inhibitors and insulin secretion agents compared to the individual agents alone.

The following compounds A-K are used in some biological examples which are as follows:

ABOUT

Compound B

Compound D

Compound C

Compound E

Compound F

345

Compound I

Compound H

Compound J

Compound K

Compound F was prepared in Example 5.6, Compound G was prepared in Example 3.26, Compound H was prepared in Example 3.69, Compound I was prepared in Example 3.58, Compound J was prepared in Example 11.6, and Compound K was prepared in Example 11.2.

Example A: Inhibition of human liver FBPase

The E. coli strain BL21 transformed with a plasmid encoding human liver FBPase was obtained from Dr. M. R. El-Maghrabi of Stony Brook State University of New York. hlFBPase was typically purified from 10 liters of E. coli culture as described by M. Gidh-Jain et al., J. Biol. Chem. 269, 27732-27738 (1994). Enzymic activity was measured spectrophotometrically in reactions that combine product formation (fructose-6-phosphate) with reduction of dimethylthiazoldiphenyltetrazolium bromide (MTT) by NADP and phenazine.

346 tosulfate (PMS), using phosphoglucose isomerase and glucose-6-phosphate dehydrogenase as capping enzymes. Reaction mixtures (200 μΐ) were prepared in a 96 well microtiter plate and consisted of 50 mM Tris-HCl, pH 7.4, 100 mM KCl, 5 mM EGTA, 2 mM MgCl ₂ , 0.2 mM NADP, 1 mg / ml. ml BSA, 1 mM MTT, 0.6 mM PMS, 1 unit / ml phosphoglucose isomerase, 2 units / ml glucose-6-phosphate dehydrogenase and 0.150 mM substrate (fructose-1,6-bisphosphate). Inhibitor concentrations varied from 0.01 μ 0,01 to 10 μΜ. Reactions were started by adding 0.002 units of pure hEBPase and monitored for 7 minutes at 590 nm in a Moiecular Devices Plate Reader (37 ° C).

The efficacy of selected compounds against human liver FBPase is shown in the table below:

Table 1

compound IC50 / μΜ AM P 1.3 E 0,055 D 1.0 B 5.0 C 30 F 0, 12 G 0,015 H 0,025 I 0,018

Example B: Inhibition of rat liver and mouse liver FBPase

E. coli strain BL21 transformed with a plasmid encoding rat liver FBPase was obtained from Dr. E. coli. M. R. El-Macnrabi of Stony Brook State University of New York and purified as described (El-Maghrabi, M.R. and Pilkis S.J., (1991) Biochem. Siophys. Res. Commun. 176: 137-144). Mouse liver FBPase was obtained by homogenizing freshly isolated mouse liver in 10C mM Tris-HCl buffer, pH 7.4, containing 1 mM EGTA and 10% glycerin. Homo

The 347 genate was clarified by centrifugation and a 45-75% ammonium sulfate fraction was prepared. This fraction was redissolved in homogenization buffer and desalted on a PD-10 gel filtration column (Biorad) eluted with the same buffer. This partially purified fraction was used for enzyme assays. Both rat and mouse liver FBPase were determined as described for human liver FBPase in Example A. In general, as reflected by higher IC ₅₀ values, rat and mouse liver enzymes are less effective at inhibiting test compounds than the human liver enzyme.

The following table shows IC ₅₀ values for several compounds prepared in the examples:

Table 2

Compound AMP IC ₅₀ rat liver (μΜ) 25 IC ₅ o mouse liver (μΜ) 15 B 140 33 D 1.25 55 C > 100 > 100 E 0.4 1.1 F 2.0 G 0.25 H 0, 175 I 0.05

Example C: Inhibition of gluconeogenesis by FBPase inhibitor in rat hepatocytes

Hepatocytes were prepared from food-treated Sprague-Dawley rats (250-300 g) according to the procedure described in Berry and Friend (Berry MN, Friend DS, 1969, J. Cell. Biol. 43, 506-520) modified in Groen (Groen, AK, Sips, HJ, Vervoorn RC, Tager, JM, 1982, Eur. J. Biochem. 122, 87-93). Hepatocytes (75 mg wet weight / ml) were incubated in 1 ml Krebs bicarbonate buffer containing 10 mM lactate, 1 mM

348 pyruvate, 1 mg / ml BSA and test compound concentrations from 0 to 500 μΜ. Incubation was performed in a 95% oxygen atmosphere and 5% carbon dioxide in a 50 ml sealed Falcon tube immersed in a rapidly shaken water bath (37 ° C). After 1 hour, an aliquot (0.25 ml) was removed, transferred to an Eppendorf tube and centrifuged. 50 μΐ of the supernatant was then determined for glucose content using the Sigma Glucose Oxidase kit according to the manufacturer's instructions.

The following table shows IC50 values for several compounds prepared in the examples:

Table 3

Compound IC ₅₀ ( _μΜ )

compound A 50 compound D 4.5 compound E 2.5 compound C > 100 compound F 15 compound G 10 compound H 2.5 compound I 2.0 compound J 2.0 compound The 2, 1

FBPase from rat liver is less sensitive to AMP than FBPase from human liver. Values of ΙΟ ₅₀ are higher than in rat hepatocytes as would be expected in human hepatocytes.

It is particularly advantageous to screen compounds of formula I on hepatocytes as described in Examples C and D, since these compounds are phosphorylated by hepatocytes and thereby become FBPase inhibitors.

Example D: Inhibition of glucose production and increase in fructose-1,6-bisphosphate concentration in FBP-treated rat hepatocytes

349 withase inhibitors

Rat hepatocytes were isolated and incubated as described in Example C. Cell extracts were analyzed for glucose content as described in Example C as well as for fructose-1,6-bisphosphate. Fructose-1,6-bisphosphate was determined spectrophotometrically by combining its enzymatic conversion to glycerol-3-phosphate to oxidize NADH, which is monitored at 340 nm. The reaction mixture (1 ml) consists of 200 mM Tris-HCl, pH 7.4, 0.3 mM NADH, 2 units / ml glycerol-3-phosphate dehydrogenase, 2 units / ml triosephosphate isomerase and 50-100 μΐ cell extract . After a 30 minute preincubation at 37 ° C, 1 unit / ml aldolase was added and a change in absorbance was obtained up to a stable value. 2 moles of NADH were oxidized in this reaction to the mole of fructose-1,6-bisphosphate present in the cell extract.

Compound A and Compound E inhibit glucose production in a dose-dependent manner with IC ₅₀ values of 50 and 2.5 µΜ. Consistent with FBPase inhibition, a cd dose-dependent increase in intracellular fructose-1,6-bisphosphate was observed for both compounds.

Example E: Analysis of drug metabolite concentration in liver and plasma, blood glucose and hepatic fructose-1,6-bisphosphate concentration after oral administration of Compound A to rats on a normal diet

Compound A was administered orally to Sprague Dawley rats (250-300 g), which were freely fed. The compound was prepared as a suspension in carboxymethylcellulose and administered at doses of 250 mg / kg. To determine liver metabolites, rats were sacrificed serially within 24 hours of drug administration. The liver was crumbled, homogenized in perchloric acid, neutralized, and then analyzed for compound B by anion exchange HPLC.

To determine plasma metabolites, rats were fitted with a cervical artery catheter prior to oral dosing. Blood samples are collected

350 µl through the catheter at some point within 8 hours of drug administration. Plasma was prepared from blood samples by centrifugation and plasma proteins were precipitated by the addition of methanol to 60%. Metabolites of Compound A were quantified by reverse phase HPLC on protein-free plasma samples. The C18 column (1.4 cm x 250) was equilibrated with 10 mM sodium phosphate, pH 5.5, and eluted with a gradient from this buffer to acetonitrile. Detection was performed at 254 nm.

The effect of Compound A on blood glucose and liver fructose-1,6-bisphosphate concentration was determined in 18 hours of Sprague-Dawley (250-300 g) fed rats. At some point after drug administration, the rats were anesthetized with halothane and a liver biopsy (approximately 1 g) was performed, as well as a blood sample (2 ml) was taken from the vena cava posterior. A syringe and needles rinsed with heparin were used to collect the blood. The liver sample was immediately homogenized in ice-cooled 10% perchloric acid (3 mL), centrifuged, and the supernatant was neutralized with 1/3 volume of 3 M KOH / 3 M KH 2 CO 3. After subsequent centrifugation and filtration, the neutralized extract was analyzed for fructose-1,6-bisphosphate content as described for isolated hepatocytes in Example C. Blood glucose was measured using a Hemocue analyzer (Hemocue Inc., Mission Viejo, CA).

Analysis of liver metabolites revealed that Compound A was effectively converted to Compound B with intrahepatic concentrations of Compound B reaching 3 μιηοΐ / g tissue within 1 hour. Although the concentrations slowly declined over time, Compound B could be measured until the end, 24 hours after administration. 5-Bromo-1-3D-ribofuranosylimidazolecarboxamide was detected in plasma, but not Compound A, suggesting that Compound A was rapidly decelvated at all three positions.

A single 250 mg / kg dose of Compound A significantly reduced blood glucose levels for about 8 hours, at which time the concentration in treated animals slowly compared to the

351 ciou in a control sample (vehicle only). Drug administration resulted in increased fructose 1,6-bisphosphate concentrations in the liver. The time course of increase in this gluconeogenic intermediate correlates well with the time course of glucose lowering. The maximum increase was observed near the glucose reduction maximum and as the blood glucose gradually returns to normal, the fructose-1,6-bisphosphate concentration slowly returns to normal. These observations are consistent with the inhibition of gluconeogenesis by Compound A to fructose-1,6-bisphosphatase concentration.

Example F: Analysis of drug concentrations in liver and plasma following administration of compounds D, E, F, and G intraperitoneally to rats on a normal diet

Sprague-Dawley rats (250-300 g) were not fed for 18 hours and then dosed intraperitoneally with saline or an FBPase inhibitor. One hour after injection, rats were anesthetized with halothane and liver and blood samples were taken and processed as described in Example E. Neutralized liver extracts were analyzed for FBPase inhibitor by HPLC. A reverse phase YMC ODS AQ column (250 x 4.6 cm) was used and eluted with a gradient from 10 mM sodium phosphate pH 5.5 to 75% acetonitrile. Absorbance was monitored at 310 nm. Glucose was measured on blood samples as described in Example C. Plasma was prepared by centrifugation and extracted by adding methanol to 60% (v / v). The methanolic extract was clarified by centrifugation and filtration and then analyzed by HPLC as described above.

The results for the selected compounds in the samples are summarized in the following table:

352

Table 4

compound Glucose reduction,% concentration in plasma (μΜ) concentration in the liver (nmol / g) D 31 WHAT WHAT 27.2 E 44.4 79.2 38.4 F 51 18 35 G 73 56, 1

Example G: Determination of oral bioavailability of compounds G, H, I and J and oral glucose lowering activity of compounds G and J

The oral bioavailability of prodrugs and maternal compounds was determined in the rat by the urinary excretion method. The prodrugs were dissolved in 10% ethanol / 90% polyethylene glycol (MW 400) and administered orally at doses of 10 to 40 mg / kg equivalents of the parent compound to Sprague Dawley rats (220-240 g) which were not fasted for 6 hours. The parent compounds were typically dissolved in deionized water, neutralized with sodium hydroxide, and then administered orally at doses of 10-40 mg / kg or intravenously about 10 mg / kg.

The rats were subsequently placed in metabolic cages and their urine collected for 24 hours. The amount of parent compound excreted into the urine was determined by the HPLC analysis described in Example F. The analysis was performed as in Example F. For prodrugs, the percent oral bioavailability was estimated by comparing the amount of parent urinary compound derived from the orally administered prodrugs with that corresponding to the parent. compounds obtained after intravenous administration. For parent compounds, the percent oral bioavailability is estimated by comparing the parent compound obtained from urine on oral administration with the compound obtained on intravenous administration.

The estimated% oral bioavailability of selected prodrugs and parent compounds is shown in the following table.

353

Table 5A

compound Oral bioavailability,% G 18 H 4 I 5 J 21

The oral efficacy of Compound J was determined in overnight fasted Sprague Dawley rats. Compounds G or J were administered orally as a suspension in 0.1% carboxymethylcellulose at 0, 10 or 30 mg / kg. At 1.5 hours or 4 hours after administration, blood samples were collected from the tail artery and analyzed for blood glucose using an automatic glucose analyzer (HemoCue, HemoCue Inc, Mission Viejo, CA). The results are as follows:

Table 5B

Dose, mg / kg reduction glucose,% Compound G (4 hours) Compound J (1.5 hr) 0 0 0 10 48 66% 30 > 70 85%

Example H: Release of insulin from pancreatic islets (insulin secretagogues)

Pancreatic islets from normal or diabetic rats or normal or diabetic mice were isolated by digestion of collagenase. Islets were used either directly or after preparation or cultured in modified RPMI 1640 medium containing 5.5 mM glucose and 10% calf serum. Test compounds were added to the cell medium at a concentration range of 0 to 100 pmol. Insulin secretion was measured in fresh single islets using a microperfusion system [Bercscen P. and Hellman B., Diabetes 42: 670-674 (1993)] and in cultured islets as described by Frodin et al., J. Biol. Chem. 270:

354

7882-7889 (1995). Insulin was determined by radioimmunoassay using e.g. Amerlex Magnetic Separation Procedure (Amersham Life Science) with rat or mouse insulin as standard, as appropriate. Preferred insulin secretagogues used according to the invention increase insulin secretion in the presence of physiological glucose concentrations by at least 20% and preferably by more than 100% at concentrations < 10 micromoles, preferably < 1 micromoles.

Example I: Glucose reduction in fasting rats (insulin secretagogues)

Adult Sprague-Dawley or Wistar rats (200-220 g) were fed ad libitum with standard rat food and behaved on a 12/12 hour light / dark life cycle (lights on at 7am, off at 7pm). Food was removed 24 hours before the start of the study, which was generally performed starting at 8 hours. morning. The compounds were suspended in methylcellulose or another vehicle and administered orally by gavage. Blood samples were taken from conscious animals at the time of drug administration and then at hourly intervals by cutting the tail artery. Blood glucose was analyzed using standard manual or automatic methods. The maximum percentage of blood glucose lowering was observed within 4 hours of measuring the blood glucose lowering activity of the test compounds. LD ₅₀ values were calculated for the active compounds and defined as the dose that produced half the maximal effect of the compound. Statistical significance was determined using Student's t-test. Preferred insulin secretagogues used in the present invention have ED ₅₀ values <30 mg / kg (preferably <5 mg / kg) and lower blood glucose by more than 10% at the ED ₅₀ dose.

Typical assay results are given below (Grell W. et al., J. Med. Chem. 41: 5219-5246 (1998).

355

Table β

dose Glucose reduction,% ED50, mg / kg glibenclamide 0.3 -25 0.255 (2 hours) glimepiride 0.1 -18 0.182 (2 hours) repaglinide 0.01 -21 0.01 (2 hours)

Example J: Intravenous glucose tolerance in fasting rats (insulin secretion agents)

Adult Sprague-Dawley or Wistar rats (200-220 g) were fed ad libitum with standard rat food and behaved on a 12/12 hour light / dark life cycle (lights on at 7am, off at 7pm). Food was removed 24 hours before the start of the study, which was generally performed starting at 8 am. Rats were anesthetized with intraperitoneally administered pentobarbital (60 mg / kg) and anesthesia was maintained with additional doses (15 mg / kg) as needed. Drug cannulas were inserted into the right jugular vein and a blood cannula was inserted into the left jugular vein. Rats received intravenous glucose pills (0.5 g / kg in 20% w / v solution) with or without test compound (0-100 mg / kg). Blood samples were taken immediately before glucose / compound administration and then at 2, 5, 10, 20, 30, 40 and 60 minutes after administration. Blood glucose was measured by standard manual or automatic methods. Preferred insulin secretion agents used in the present invention reduce blood plasma AUC versus time by more than 5%.

Example K: Oral glucose tolerance in fat rats with diaoetes mellitus (insulin secretagogues)

Fat rats with diabetes mellitus (9.5 weeks old) (Zucker diabetic fatty rats, ZDF) were fasted 6 hours prior to the 8 o'clock in the morning. Glucose (1 g / kg) and test compound (0.01-100 mg / kg) were administered simultaneously by oral gavage. Control animals were dosed only with glucose. Blood samples were obtained by cutting the jugular vein and taken before

356 administration of glucose / test substance and then at hourly intervals up to 6 hours. Blood glucose was determined by manual or automatic assays. Plasma was prepared from samples and assayed for insulin. Insulin was determined by radioimmunoassay using e.g. Amerlex Magnetic Separation Procedure (Amersham Life Science) with rat insulin as standard. The active compounds decrease glucose AUC versus time and temporarily increase plasma insulin concentrations. Preferred insulin secretion agents used in the present invention reduce glucose versus time AUC by> 5% (preferably> 10%) and increase insulin concentrations by> 20% (preferably> 50%).

Example L: Insulin secretion in rats (insulin secretion agents)

Adult Sprague-Dawley or Wistar rats (200-220 g) were fed ad libitum with standard rat food and behaved for a 12/12 hr life cycle. light / dark (lights on at 7 in the morning, off at 7 in the evening). Food was removed 24 hours before the start of the study, which was generally performed starting at 8 am. Rats were anesthetized with intraperitoneally administered pentobarbital (60 mg / kg) and anesthesia was maintained with additional doses (15 mg / kg) as needed. The right jugular vein was cannulated for drug administration and the left throat was cannulated for blood sampling. The arterial blood glucose concentration was maintained at 6 mM by intravenous infusion of a 10% (w / v) glucose solution using a syringe pump. Drug (0-100 mH / kg) or vehicle was administered intravenously once blood glucose had stabilized and blood samples were taken at 2, 5, 10, 20, 30, 40 and 60 minutes after administration. Plasma insulin was determined by radioimmunoassay using e.g. Amerlex Magnetic Separation Technique (Amersham Life Science) with rat insulin as standard. Insulin responses were calculated as the area of increase over basal response for arterial plasma insulin concentration at time 0-10 (1.

357 phase), 10-60 (Phase 2) and 0-60 (total). Preferred insulin secretion agents according to the present invention increase the insulin concentration in the first or second phase or the total insulin concentration by more than 10%, preferably more than 50%.

Example M: Inhibition of KATP channels in mouse pancreatic β-cells (insulin secretion agents)

Mouse β-cells were isolated by digesting collagen and culturing in modified RPMI 1640 medium containing 5.5 mM glucose and 10% fetal calf serum. Cell cuts were made and electrophysiological evaluation was performed using a micro-flow measurement device as described in [Schwanstecher et al. Br. J. Pharmacol. 113: 903-911 (1999)]. The membrane potential was set to -50 mV and the reverse currents flowing through the KATP channels were measured. KATP channel activity was normalized to channel activity during the control period (ADP presence, absence of drug) before and after drug administration (0-100 μΜ) in each study. Preferred insulin secretion agents used in the present invention inhibit channel activity with an IC 50 of less than 10 µΜ, preferably less than 100 nM.

Example N: Binding of a sulfonylurea receptor (insulin secretion agents)

The sulfonyl receptor SURI was cloned and transfected into Cos-7 cells as described [Aguilar-Bryan et al., Science 268: 423-426 (1995)]. The membrane was prepared from cells 60-72 hours after transfection. To measure binding to SURI, resuspended membranes were incubated in the presence of a fixed concentration of [3H] glibenclamide (or other appropriate standard) and various concentrations of the test compound. Non-specific binding is defined using 100 nM unlabeled standard. Incubation was performed for 1 hour at room temperature and terminated by rapid filtration of aliquots through Whatman GF / B filters. Filters up

358 were washed and the 3H content was determined by liquid scintillation counting. Binding to the receptor is indicated by a decrease in the number, i.e. by replacement of the labeled standard. Preferred insulin secretion agents used in the present invention have K d values (dissociation constant) of less than 10 µΜ, preferably less than 100 nM.

Example 0: Inhibition of Dipeptidyl Peptidase IV (DPP-IV Inhibitors)

This assay was performed as described in Deacon CF, Hughes TE, Holst JJ Diabetes 47: 764-769 (1999) using H-glycinproline-7-amino-4-methylcoumarin as a synthetic substrate and human plasma as an enzyme source. Preferred DPP-IV inhibitors will inhibit an enzyme with an IC _{50 of} less than 10 µΜ, preferably less than 500 nM.

Example P: Determination of α-glucosidase

Sucrose and maltose, prepared from sterile small intestinal membranes of adult Sprague Dawley rats, were determined by measuring glucose production from sucrose and maltose. Samulitis BK, Goda T, Lee SM, Koldovsky O, Drugs Exp Clin Res 13: 517-524 (1987). The glucose produced was quantified using a commercial assay kit (glucose oxidase method, Sigma Chemical Co.). Preferred α-glucosidase inhibitors inhibit enzyme activity with an IC ₅₀ in the range of 1 nM to 10 μΜ. More preferably, the IC ₅ s between 1 nM and 1 μΜ).

Example Q: Determination of glycogen phosphorylase

Glycogen phosphorylase prepared from human liver was determined during glycogen synthesis by releasing glucose-1-phosphate in a buffered reaction mixture containing 0.5 mM glucose-1-phosphate and 1 mg / ml glycogen. Phosphate was measured by addition of hydrochloric acid containing ammonium molybdate and malachite green. Absorbance was measured at 620 nm. The test compound was added in DMSO. Martin WH, Hoover DJ, Armento SJ et al.,

359

PNAS 95: 1776-1781 (1998). Preferred glycogen phosphorylase inhibitors have an IC ₅₀ in the range of 1 nM to 10 μΜ. More preferred are inhibitors having an IC ₅ in the range of 1 nM to 1 µΜ.

Example R: Determination of glucose-6-phosphatase inhibitors

Glucose-6-phosphatase activity was measured by monitoring phosphate release from glucose-6-phosphate. Microsomes prepared from fasting rats were incubated at room temperature in a buffer containing 1 mM glucose-6-phosphate. The liberated phosphate was measured by the addition of hydrochloric acid containing ammonium molybdate and malachite green. Absorbance was measured at 620 nm. Test compounds were added in DMSO prior to enzyme addition. Parker JC, van Volkenburg A, Levy CB et al., Diabetes 47: 1630-1636 (1998). Preferred glucose-6-phosphatase inhibitors have IC50 values ranging from 0.1 nM to 10 μΜ. More preferably, the inhibitors have an IC ₅₀ in the range of 0.1 nM and 300 nM.

Example S: Determination of glucagon antagonists

Glucagon antagonist activity was determined by measuring the replacement of iodinated glucagon from hamster kidney plasma cell membrane preparations expressing the cloned human receptor. Madsen P, Knudsen LB, Wiberg FC, Carr RD, J. Med. Chem. 41: 5150-5157 (1998). The assay was performed on filter microtiter plates. The test compound at various concentrations and a fixed amount of glucagon tracer isotope and buffer were added to each well. Non-specific binding was determined in the presence of a large amount of unlabeled ligand. Bound and unbound tracer isotope separated by vacuum filtration. Plates were washed and filters were analyzed using a γ counter. Non-specific binding values were subtracted from the counts obtained. To determine binding constants, Scatchard saturation curves were generated and analyzed by standard methods. Antagonism was measured as

360 ability of compounds to replace labeled glucagon tracer isotope from filters. Preferred antagonists have IC ₅₀ values _between 0.1 nM and 100 μΜ. More preferably, the compounds inhibit binding with IC 50 values between 0.1 nM and 1 µΜ.

Example T: Amylin agonist assay

Membranes were prepared from nuclear accumbens and surrounding areas of the basal forebrain of the rat. Amylin agonist activity was determined by measuring the replacement of iodinated human amylin from membrane preparations. The assay was performed on filter microtiter plates. The test compound at various concentrations and a fixed amount of amylin tracer isotope and buffer were added to each well. Non-specific binding was determined in the presence of a large amount of unlabeled ligand. Bound and unbound tracer isotopes were separated by vacuum filtration. Plates were washed and filters were analyzed using a γ counter. Non-specific binding values were subtracted from the counts obtained. To determine binding constants, Scatchard saturation curves were generated and analyzed by standard methods. Preferred agonists have Ki values between 0.001 nM and 1 μΜ. More preferably, the compounds inhibit binding with Ki constants between 0.001 nM and 10 nM.

Example U: Determination of fatty acid oxidation inhibitors

Isolated hepatocytes were prepared from fasting rats using the collagen digestion method of Berry and Chalk. Cells were incubated in Krebs bicarbonate buffer in the absence or presence of inhibitors over a concentration range. The reactions are started by adding ¹⁴ C-labeled palmitate, 0.05 Ci / mol, 0.5 mM final concentration bound to albumin. After 10 minutes of incubation, reactions were stopped with chloric acid and the oxidation products were extracted. Guzman M, Geelen MJH, Biochem J. 287: 487-492 (1992). Total oxidation of the products was calculated as are

361 platelet acid-soluble products (ketone moiety) and released CO ₂ . Preferred fatty acid oxidation inhibitors block fatty acid oxidation with an IC50 in the range of 10 nM to 300 μΜ. More preferably, the inhibitors have an IC 50 in the range of 10 nM to 30 μΜ.

Example V: Glucose Reduction in db / db Mice (FBPase Inhibitors)

Male db / db mice, a widely used model for NIDDM, were obtained at 8 weeks of age from Jackson Labs (Bar Harbor, Maine). Mice were kept in a vivarium under standard conditions (25 ° C, 12 hour light cycle, 12 hour dark) and were given Purina 5008 powder feed and water ad libitum. At 10 weeks of age, animals with blood glucose concentrations greater than 400 mg / dl and less than 900 mg / dl were divided into 2 groups (n = 5-6 / group). The experiment was run for 18 days. Blood glucose concentrations were measured in the tail vein samples using a HemoCue glucose analyzer (HemoCue Inc., Mission Viejo, CA). Values are expressed as mean plus or minus standard error of the mean. Differences between groups were expressed using Student's t-test. Results are considered significant with p <0.05.

As shown in the table below, on the last day of the experiment (day 18), blood glucose concentrations for Compound G were significantly lower than for the control group:

Table 1

Treatment Blood glucose, mg / dl Day 0 Day 18 inspection 707 ± 65 870 ± 32 Compound G 708 ± 55 646 ± 37

Example W: Glucose Reduction in ZDF Rats (Compounds G and J)

Fat rats with diabetes mellitus (ZDF) are widely used as a model of human NIDDM because of the development of the disease in these

362 rodents are similar to those described for 1983 human patients. Adult ZDF rats not only exhibit obesity, hyperglycemia, insulin resistance, and accelerated hepatic glucose production, but also develop some of the common macro- and microvascular complications associated with NIDDM. Clark JB, Palmer CJ (1982) Diabetes 30: 126A. Terrettaz J, Jeanrenaud B (1983) Endocrinology 112: 1346-1351.

a) Compound G protocol: Male ZDF rats were obtained at 8 weeks of age from Genetics Models Inc. (Indianapolis, Ind.). The rats were kept in a vivarium under standard conditions (25 ° C, 12 hours light, 12 hours dark) and received powdered Purina 5008 food and water ad libitum. At eleventh week of age, animals with a blood glucose concentration > 500 mg / dl were selected and divided into 2 groups (n = 8 / group). One group was control and the other was treated with Compound G (administered as 0.2% feed additive for 14 days). Blood glucose concentrations were measured in the tail vein samples using a HemoCue glucose analyzer (HemoCue Inc., Mission Viejo, CA). Values are expressed as the mean plus or minus standard error. The difference between the groups was expressed using Student's t-test. Results are considered significant with p <0.05.

(b) Protocol of Compound J:

This study was performed in exactly the same way as the compound G protocol with two modifications: the experiment time was 21 days and the dose of compound J used was 0.4%.

(c) Results:

Table 8: 14 day study, Compound G (0.2% feed additive)

Treatment Blood glucose, mg / dl Day 0 Day 14 inspection 655 ± 39 762 ± 31

363

Compound G 653 ± 55 530 ± 48 *

* p <0.05 vs. control

Table 9: 21-day study, Compound J (0.4% added to feed)

Treatment Blood glucose, mg / dl Day 0 Day 14 inspection 678 ± 19 815 ± 34 Compound J 674 ± 20 452 ± 40

* p <0.05 vs. control

Both compounds G and J significantly improve glycemic control in ZDF rats. The results indicate that FBPase inhibitors will be useful in the clinical treatment of NIDDM.

Example X: Acute combination treatment with insulin secretion agent and FBPase inhibitor (Compound J) in ZDF rats

Experimental protocol: ZDF rats (9.5 weeks old) were fasted for 5 hours starting at 8 am. The animals were divided into four groups with a statistically similar baseline blood glucose concentration. Test compounds were administered orally by gavage. The treatment was as follows:

Table 10

Group Treatment dose 1 saline on the 2 glyburide 100 mg / kg 3 Compound J 300 mg / kg 4 glyburide + Compound J 100 + 300 mg / kg

An hour after saline or drug administration, all animals received a simulated meal as an oral glucose tablet (1 g / kg). Blood glucose was then monitored at regular time intervals for 3 hours. Test compounds were prepared as a suspension in 0.1% carboxymethylcellulose. Blood samples were obtained by cutting the tail vein. Blood glucose is

364 was measured using a HemoCue glucose analyzer according to the manufacturer's instructions (HemoCue Inc., Mission Viejo, CA). Results are expressed as the mean plus or minus standard error for all values.

Results: In a pilot study, glyburide and compound J were found to be maximally effective in this model at doses of 100 and 300 mg / kg. In this study, both glyburide and Compound J suppressed increases in blood glucose levels induced by orally received glucose, with Compound J lowering blood glucose below baseline (see Figure 1). Combination therapy was better than monotherapy as seen from increased suppression in the area under the blood glucose (AUC) within the initial 4 hours after drug administration.

Table 11:

Treatment AUC glucose, mg / dl * inspection 1463 ± 99 glyburide 1324 ± 132 Compound J 1121 ± 82 combination 895 ± 74

The combination treatment also attenuates the increase in blood lactate concentration observed in the Compound J monotherapy group (p = 0.01 for time point 0, Figure 2).

This study suggests that the combination treatment with insulin secretion agents and FBPase inhibitors provides significantly improved glycemic control compared to the individual agents alone. Improved glycemic control is probably the result of a reduced incidence of NIDDM-related complications. In addition, this acute combination treatment reduces the side effects associated with FBPase inhibitor therapy, such as an increase in blood lactate concentration. In chronic settings, this reduction is even more pronounced.

365

Vehicle (n-23) ♦-Glyburide ( _n = 20) Compound ^J (n = 22)

- combination (n = 22) * p <0.05 vs all groups: ANOVA with Dunnett post hoc test tp <0.05 vs vehicle: ANOVA with Dunnett post hoc test

Figure 2: OGTT in ZDF rats

- □ - vehicle (n-23) - ♦ - Glyburide (n = 20)

- α - Compound J (n = 22) - * - combination (n = 22) time, hours

Example Y: Chronic Combined Treatment with Insulin Secretion Agent and FBPase Inhibitor in ZDF Rats

Male ZDF rats were obtained at 8 weeks of age by cc Genetics Models Inc. (Indianapolis, Ind.). The rats were maintained under standard vivarium conditions (25 ° C, 12 hours light, 12 hours dark) and received powdered Purina 5008 food and water ad libitum. At eight weeks of age, animals were divided into 4 groups (n = 8 / group). One group was control, the other was treated

366 Compound J, a third glyburide was administered, and a fourth was subjected to a combination treatment with Compound J and a glyburide. Compound J and glyburide were administered at maximum doses either orally via gavage, in drinking water, or as a feed additive for 2 to 12 weeks. Blood glucose concentrations were measured in the tail vein samples using a HemoCue glucose analyzer (HemoCue Inc., Mission Viejo, CA). Other measured parameters included: lactate, glycerin, alanine, triglycerides, free fatty acids, ketones, liver and muscle glycogen, cholesterol, VLDL, HDL, hemoglobin Ale, body weight, food and water intake, as well as further measurement of carbohydrate, fat and proteins. Values were expressed as the mean plus or minus standard error. The differences between groups were evaluated by ANOVA using the corresponding post hoc test. Results were considered significant with p <0.05.

The control group of animals became progressively more hyperglycemic during the study, while there was a significantly improved glycemic control in all three treatment groups. The combination treatment group showed a significantly higher glucose reduction compared to the Compound J or glyburide monotherapy group. Due to the progressive worsening of pancreatic β-cells and thus worsening insulin secretion, glyburide therapy becomes less and less effective over time and the animals become significantly hyperglycemic, i.e., secondary failure occurs. Compound J treatment is more effective than glyburide as pancreatic function decreases. However, the combination treatment results in significantly better glycemic control throughout the study period.

Example Z: Acute combination treatment with insulin and FBPase inhibitor (compound G) in db / db mice

Male C57BL / KsJ db / db mice were obtained at 5 weeks of age from Clea Japan Inc. (Tokyo, Japan). The mice were kept in a tent

367 dard conditions in the vivarium (24-26 ° C, 12 hours light, 12 hours dark) and received standard feed and water ad libitum. At 20 weeks of age, the animals were divided into four groups (n = 6 / group). The groups were control, treated with Compound G, insulin, and a combination of Compound G and insulin. Compound G was administered orally at doses of 200 mg / kg. Insulin (human recombinant insulin, Penfill R300, Novo Nordisk, Denmark) was injected subcutaneously at doses of 1.5 µ / kg. The feed was removed after compound application. Blood glucose concentrations were measured using Glucoloader-F, an automatic glucose analyzer (AT&T Co., Ltd., Tokyo, Japan). Values were expressed as standard plus or minus standard error.

The following table shows the blood glucose concentration compared to pre-treatment values:

Table 12: Blood glucose concentration before and after treatment

Treatment Plasma glucose (mg / dl) before P ° 0 hrs 1 hour 2,5 hr. 4 hours inspection 761.5 ± 41.9 (100.0 ± 0.0) 667.7 ± 50.1 (87.2 ± 2.9) 549.5 ± 47.5 (71.6 ± 3.5) 609.3 ± 52.6 (79.3 ± 3.7) Compound G 774.0 ± 18.3 (100.0 ± 0.0) 650.8 ± 14.8 (84.2 ± 1.9) 459.7 ± 11.5 (59.6 ± 2.3) 373.7 ± 24.7 (48.6 ± 4.0) insulin 756.2 ± 15.2 (100.0 ± 0.0) 410.8 ± 34.4 (54.2 ± 4.1) 463.2 ± 40.2 (61, 1 ± 4.9) 540.3 ± 35.9 (71.4 ± 4.1) combination 728.0 ± 29.8 (100, C ± 0.0) 378.0 ± 43.8 (51.9 ± 5.5) 243.0 ± 60.5 (33.7 ± 8.5) 130.8 ± 53.9 (18.3 ± 7.5) () mean% of value before treatment

Blood plasma concentrations in control animals improved to some extent with respect to fasting. Insulin treatment improved hyperglycemia within 2.5 hours after administration. However, there is no difference between the plasma glucose concentration in con

368 trolley and insulin-treated groups after 4 hours. Compound G progressively decreases plasma glucose concentration and exhibits a higher glucose lowering rate than insulin at 4 hours. The combination treated group exhibited significantly higher glucose lowering than those treated with compound G or insulin monotherapy.

Example AA: Advantageous effect of chronic insulin combination therapy with FBPase inhibitor (Compound G) in db / db mice

Male C57BL / KsJ db / db mice were obtained at 5 weeks of age from Clea Japan Inc. (Tokyo, Japan). Mice were maintained under standard vivarium conditions (24-26 ° C, 12 hours light, 12 hours dark) and received standard food and water ad libitum. At 16 weeks of age, animals were divided into two groups (n = 5 or 9-10 / group). Both groups were injected daily subcutaneously with human recombinant insulin (Penfill N300, Novo Nordisk, Denmark) to adjust the plasma glucose concentration to a final level of 250-300 mg / dl. One group was given compound G as a feed additive containing 0.2% compound G. Blood glucose concentrations in the tail vein samples were measured using Glu-test-ace, an automatic glucose analyzer, (Sanwa Kagaku Kenkyusho Co., Ltd., Nagoya , Japan). Values are expressed as the mean plus or minus standard error.

As shown in the table, plasma glucose concentrations were maintained in the range of 250 to 300 mg / dl.

Table 13 Plasma glucose concentration before and after treatment

Treatment Plasma glucose (mg / dl) before after 0 week 1 week 2 weeks 3 zýždne insulin very 736.5 ± 17.0 297.1 ± 46.0 375.6 ± 53.5 282.4 ± 43.1 combination 693.8 ± 44.7 290.8 ± 64.1 274.6 ± 50.3 273.3 ± 55.9

369

The following table shows the change in body weight.

Table 14 Body weight before and after treatment

Treatment Body weight (g) before AFTER 0 week 1 week 2 weeks 3 weeks insulin very 43.4 ± 2.2 50.7 ± 1.5 54.3 ± 1.2 57.4 ± 1.6 combination 42.7 ± 1.8 48.1 ± 1.3 51.1 ± 0.8 53.8 ± 0.6

While insulin treatment significantly increases body weight, the rate and extent of weight gain has greatly decreased in the combination treatment group.

The following table shows the insulin doses in each group required to adjust the plasma glucose to a final concentration (250-300 mg / dl).

Table 15

Treatment Insulin doses (D / kg) before after 0 week 1 week 2 weeks 3 weeks insulin very 548 ± 18 753 ± 72 492 ± 68 306 ± 67 combination 501 ± 47 494 ± 108 252 ± 78 114 ± 37

In the combination treatment group, co-administration of Compound G significantly reduces the insulin doses required to lower plasma glucose to a final concentration.

Example BB: Advantageous effect of chronic combination therapy with insulin and FBPase inhibitor (Compound J) in db / db mice

Male C57BL / KsJ db / db mice were obtained at 5 weeks of age from Clea Japan Inc. (Tokyo, Japan). Mice were maintained under standard vivarium conditions (24-26 ° C, 12 hours light, 12 hours dark) and received standard food and water ad libitum.

370

At 19 weeks of age, animals were divided into two groups (n = 6 / group). Both groups were injected daily subcutaneously with human recombinant insulin (Penfill · N300, Novo Nordisk, Denmark) to adjust the plasma glucose concentration to a final level of 300 mg / dl. One group was given Compound J as a feed additive containing 0.2% Compound G. Blood glucose concentrations in the tail vein samples were measured using Glucoloader-F, an automatic glucose analyzer, (AT&T Co., Ltd., Tokyo, Japan). Values are expressed as the mean plus or minus standard error.

The following table shows plasma glucose concentrations.

Table 16 Plasma glucose concentrations before and after treatment

Treatment Plasma glucose (mg / dl) before AFTER 0 week 1 week 2 weeks 3 weeks 4 weeks insulin very 617.2 ± 28.1 408.8 ± 15.3 447.7 +17.6 396.3 ± 39.3 316, ^Ί ± 17.2 combination 611.8 + 30.8 360.8 ± 37.3 335, 2 + 31.5 266.0 ± 18.5 281.6 ± 24.9

The plasma glucose concentration in both groups was maintained at about 300 mg / dl for 4 weeks of treatment.

The following table shows the changes in body weight for each treatment group.

Table 17 Body weight before and after treatment

Treatment body weight (g) before After 0 week 1 week 2 weeks 3 weeks 4 weeks insulin very 54.9 ± 1.4 57.9 ± 1.3 59.7 ± 1.3 61.4 ± 1.2 64.2 ± 1.0 combination 55.5 ± 1.7 56.4 +0.9 58.3 ± 1.0 60.0 ± 1.2 61.8 ± 1.1

While insulin treatment leads to an increase in body weight, 371 combination therapy with insulin and Compound J significantly reduces weight gain at 4 weeks of treatment.

As shown in the table below, Compound J significantly reduces the insulin doses required to maintain plasma glucose at the desired level by nearly 40% in the combination group.

Table 18 Insulin doses required to achieve a final blood glucose concentration

Treatment Insulin doses (g) before AFTER 0 week 1 week 2 weeks 3 weeks 4 weeks insulin very 0 ± 0 495 ± 32 699 ± 63 760 ± 95 802 ± 129 combination 0 ± 0 303 ± 31 411 ± 62 440 ± 80 491 ± 112

Example CC: Acute combination treatment with insulin and FBPase inhibitor in Goto-Kakizaki rats

Male Goto-Kakizaki rats were obtained at 9 weeks of age from Charles River Japan Inc. (Tokyo, Japan). Rats were maintained under standard vivarium conditions (24-26 ° C, 12 hours light, 12 hours dark) and received standard feed and water ad libitum. At 48 weeks of age, the animals were divided into four groups (n = 6 / group) after fasting overnight. The groups are as follows: a control group, a compound treated group J, an insulin treated group, and a group treated with a combination of compound J and insulin. Compound J was administered at a dose of 50 mg / kg. Insulin (human recombinant insulin, Penfill N300, Novo Nordisk, Denmark) was injected subcutaneously at a dose of 1.5 U / kg. Blood glucose concentrations in the tail vein samples were measured using Glucoloader-F, an automatic glucose analyzer, (AT&T., Ltd., Tokyo, Japan). Values are expressed as the mean plus or minus standard error.

372

The following table shows the glucose concentrations in each plasma group before and after treatment.

Table 19 Plasma glucose concentrations before and after treatment, mg / dl or (% of baseline)

Treatment plasma glucose (mg / dl) before AFTER 0 week 2 hrs 4 hours 6 hours inspection 160.5 ± 16.3 (100.0 ± 0.0) 189.5 ± 15.8 (119.1 ± 2.9) 187.5 ± 20.4 (116.6 ± 4.3) 186.0 ± 16.3 (116.8 ± 3.6) Compound J 161.8 ± 6.6 (100.0 ± 0.0) 106.3 ± 11.0 (65.6 ± 6.6) 79.6 ± 4.9 (51.0 ± 2.7) 35.4 ± 0.8 (22.6 ± 6.7) insulin 163.7 ± 5.8 (100.0 ± 0.0) 88.8 ± 16.8 (55.0 ± 11.0) 71.3 ± 20.9 (43.9 ± 13.3) 90.7 ± 19.7 (55.4 ± 12.4) combination 151.3 ± 4.4 (100.0 ± 0.0) 47.5 ± 4.0 (31.6 ± 3.0) 1.8 ± 1.0 (1.3 ± 0.7) (ND) (ND) ( ), % before. ND is not determined) .0.

The plasma glucose concentration in the control animals did not change during the study. Compound J and insulin reduce plasma glucose concentrations within 2 hours after administration. There is no difference between the plasma glucose concentration of Compound J treatment and the insulin group after 2 or 4 hours. Compound J progressively decreases plasma glucose concentration and shows a more effective hypoglycaemic effect than insulin after 6 hours. The group exposed to the combination treatment showed a significantly higher glucose reduction than the compound J or insulin monotherapy group after two hours. The magnitude of the effect suggests that significantly lower insulin doses could be used. Compound J is likely to have a gentle effect on insulin when used in combination therapy with insulin. Smaller doses of insulin are likely to reduce the incidence and severity of side effects associated with insulin monotherapy (eg weight gain).

Example DD: Acute combination treatment with biguanide and FBPase inhibitor in db / db rats

373

Male C57BL / KsJ db / db mice were obtained at 5 weeks of age from Clea Japan Inc. (Tokyo, Japan). Mice were maintained under standard vivarium conditions (24-26 ° C, 12 hours light, 12 hours dark) and received standard food and water ad libitum. At 10 weeks of age, the animals were divided into four groups (n = 6 / group). The groups are as follows: a control group, a group treated with compound J, a group treated with metformin, and a group treated with a combination of compound J and metformin. Compound J and / or metformin (Sigma) were orally administered at a dose of 150 mg / kg. Food was removed after administration. Blood glucose concentrations in the tail vein samples were measured using Glucoloader-F, an automatic glucose analyzer, (AT&T, Co., Ltd., Tokyo, Japan). Values are expressed as the mean plus or minus standard error.

As shown in the table below, plasma glucose concentration in control animals progressively decreases over the fasting period. Metformin monotherapy and monotherapy with compound J significantly reduced glucose concentration relative to the control group. The strongest decrease in blood glucose concentration was observed in the combination therapy group. It is surprising that, regardless of the usual mechanism of action (inhibition of gluconeogenesis), the combination therapy with metformin and an FBPase inhibitor provides a markedly improved glycemic control compared to drug treatment alone.

Table 20

Lieče- glucose / plasma (mg / dl) not before AFTER 0 hrs 2 hrs 4 hours 6 hours 8 hours A horse- 541.3 ± 10.0 465.5 ± 23.2 468.8 ± 21.6 4 60.5 ± 29.3 495.8 ± 28.1 troll (100.0 ± 0.0) (85.8 ± 3.2) (86.5 ± 3.3) (85.0 ± 5.0) (91.5 + 4.6) Zlúče- 514.3 ± 23.0 4 4 8, 6 ± 4 2.5 376.7 ± 39.9 357.7 ± 4 0.4 38c, 43.1 ± 5 nina J (100.0 ± 0.0) (70.2 ± 14.6) (72.4 ± 5.0) (68.7 ± 5.5) (74.2 ± 5.8)

374

Met 515.7 ± 37.0 347.0 ± 21.2 346.5 ± 34.6 348.3 ± 30.7 407.8 ± 40.0 formin (0.0 + 100.0) (67.7 ± 1.9) (66.4 ± 3.1) (67.7 ± 4.1) (79.1 ± 5.6) combination 538.4 ± 20.2 317.2 ± 21.0 265.4 ± 31.0 253.4 ± 32.7 28 9.2 ± 4 9.3 broach (100.0 ± 0.0) (59.9 ± 2.1) (49.3 ± 3.3) (45.9 ± 3.6) (53.4 ± 5.5)

() mean% pre-treatment values

Example EE: Acute combination treatment with α-glucosidase inhibitor and FBPase inhibitor in Goto-Kakizaki rats

Goto-Kakizaki rats, an NIDDM animal model, were obtained at 5 weeks of age from Charles River Japan Inc. (Tokyo, Japan). Rats were maintained under standard vivarium conditions (24-26 ° C, 12 hours light, 12 hours dark) and received standard feed and water ad libitum. At 18 weeks of age, the animals were divided into four groups (n = 5 / group). The groups are as follows: a control group, a group treated with compound J, an acarbose (Bayer, Japan) treated group, and a group treated with a combination of Compound J and acarbose. All animals were given cereal starch 1 g / kg orally by gavage. Compound J was administered orally 1 hour before starch administration at a dose of 10 mg / kg. Acarbose was administered orally at a dose of 1 mg / kg simultaneously with starch. Blood glucose concentrations in the tail vein samples were measured using Glucoloader-F, an automatic glucose analyzer, (AT&T Co., Ltd., Tokyo, Japan). Values are expressed as mean plus or minus error.

The following table shows the time profile of plasma glucose values for each treatment group.

Table 21 Plasma glucose concentration before and after treatment

Lie- Time after starch administration Čepan -60 min. 0 min 30 min. 60 min. 120 min. 240 min. not Plasma glucose (mg / dl) or relative value (%) A horse- troll 148.6 ± 8.1 (100,010,0) 211.4 ± 9.6 (2.2 + 142.6) 291.0 ± 10.4 (197.0 ± 7.4) 342.4 + 4.0 (233.7 ± 15.1) 248.6 ± 9.8 (9.8 + 168.9) 165.4 ± 9.5 (5.8 + 111.9)

375

Compound J 179.8 ± 15.2 (100.0 ± 0.0) 218.4 ± 19.9 (121.8 ± 8.0) 245.2 ± 29.9 (135.2 ± 9.2) 251.0 ± 28.6 (138.5 ± 6.2) 182.8 ± 18.0 (101.8 ± 7.2) 144.6 ± 9.8 (81.7 + 6.7) Acar- barefooted 175.4 ± 5.9 (100.0 ± 0.0) 226.4 ± 5.3 (2.8 + 129.4) 243.8 ± 8.5 (139.5 ± 6.0 247.2 ± 8.2 (141.3 ± 4.9) 209.4 ± 5.9 (119.9 ± 4.9) 164.2 ± 10.7 (93.5 + 4.7) wagon broach 164.4 ± 3.6 (100.0 ± 0.0) 198.2 ± 9.7 (4.4 + 120.4) 150.0 ± l, 2 (91.1 + 6.0) 129.4 ± 9.6 (78.6 + 5.3) 103.0 ± 9 l (62.7 ± 5.5) 111.2 + 12.1 (67.8 ± 7.7)

(),% of pre-treatment value

In control animals, plasma glucose concentrations are increased up to 1.6 fold after starch administration. The increase in plasma glucose following starch administration was reduced in the Compound J group and in the acarbose group. The combination treatment group showed a significantly higher glucose reduction than the treatment group alone. Thus, the combination of an FBPase inhibitor and an α-glucosidase inhibitor provides a significantly improved glycemic control in the postprandial state. Both gluconeogenesis and sugar absorption appear to be important determinants of glucose concentration after ingestion of food.

Example FF: Acute combination treatment with glycogen-phosphorylase inhibitor and FBPase inhibitor in db / db or ob / ob mice

Db / db or ob / ob mice were obtained at 5 weeks of age from Jackson Laboratories (Bar Harbor, Maine). Mice were maintained under standard vivarium conditions (24-26 ° C, 12 hours light, 12 hours dark) and received standard food and water ad Ubi t. More than 10 weeks of age, the animals were divided into four groups (n = 5 to 7 / group). The groups are as follows: the control group, the compound treated group J, the CP-91149 (Pfizer) group, and the combination of compound J and CP-91149. After 0 to 48 hours of the fasting period, compounds J and / or CP-91149 were administered orally at a dose of 0.5 to 300 mg / kg. Feeding was allowed after administration. Blood glucose concentrations in the tail vein samples were measured using standard manual or automatic methods. Values were expressed as mean plus

376 or minus standard error.

Both Compound J and CP-91149 monotherapy significantly reduced blood glucose concentration compared to the control group. Glucose reduction in combination therapy is significantly higher than that of any monotherapy.

Example GG: Acute combination therapy with glucose-6-phosphatase inhibitor and FBPase inhibitor in db / db or ob / ob mice

Db / db or ob / ob mice were obtained at 5 weeks of age from Jackson Laboratories (Bar Harbor, Maine). Mice were maintained under standard vivarium conditions (24-26 ° C, 12 hours light, 12 hours dark) and received standard food and water ad libitum. More than 10 weeks of age, the animals were divided into four groups (n = 5 to 7 / group). The groups are as follows: a control group, a compound treated group J, a glucose-6-phosphatase inhibitor administration group, and a combination of a compound J and glucose-6-phosphatase inhibitor. After 0 to 48 hours of the fasting period, Compound J and / or the glucose-6-phosphatase inhibitor were administered orally at a dose of 0.5 to 300 mg / kg. Following administration, either feeding was removed and / or allowed to feed. Blood glucose concentrations in the tail vein samples were measured using standard manual or automatic methods. Values were expressed as the mean plus or minus standard error.

Both Compound J monotherapy and glucose-6-phosphatase inhibitor monotherapy significantly reduced blood glucose concentration compared to the control group. Glucose reduction in combination therapy is significantly higher than that of any monotherapy.

Example HH: Acute combination treatment with an FBPase inhibitor and an amylin antagonist

Two to three weeks after the incubation of diabetes with 65 mg / kg of intravenous streptozocin, Sprague Dawley rats were allowed to

377 was fasted overnight and then saline or pramlintide (10 micrograms) was injected intravenously or compound J (300 mg / kg) was administered orally by gavage. The animals were then gavaged with 1 ml of 50% glucose and given any access to feeding. Blood glucose samples were collected from the tail vein at 0, 30, 60, 120, 180 and 240 minutes after glucose administration. Both pramlintide and compound J reduced postprandial glucose elevation. Combination therapy resulted in significantly better postprandial glycemic control than treatment with agents alone.

Example JJ: Chronic Combined Treatment with Fatty Oxidation Oxidation Inhibitor and FBPase Inhibitor in Streptozotocin-Induced Diabetes Rats

Male Sprague-Dawley rats (Charles Rivers Laboratories) weighing about 120 g at the start of the study were housed under standard vivarium conditions and fed a standard diet (Purina 5001). Rats were induced by diabetes by injection of 55 mg / kg body weight of streptozotocin (STZ) in citrate buffer, pH 4.7. Blood glucose concentrations in non-fasted animals were measured three days later and rats with a glucose concentration greater than 250 mg / dl were divided into 4 groups: a control group, a group treated with etomoxir, a group treated with Compound J, and a combination therapy group with etomoxir + Compound J. was administered (3-300 mg / kg) once daily by subcutaneous injection. Compound J was administered as a feed additive (0.2% w / w). Drug administration was continued for 2 to 6 weeks. Blood glucose concentrations were monitored at regular intervals throughout the duration of the experiment. At the end of the study, rats were anesthetized and catheters were inserted into the carotid artery and jugular vein. Liver glucose production was measured using a constant ( ³ H) -6-glucose infusion. Blood samples were taken after two hours and specific glucose activity was measured by GC-MS instrument. Liver glucose production was calculated by standard methods.

378

The control group was progressively hyperglycemic throughout the study. Blood glucose concentration decreased significantly with etomoxir monotherapy or Compound J. The combination therapy group showed a higher glycemic control adjustment than with etomoxir monotherapy or Compound J alone.

None of the references herein are accepted as a priority with respect to this application, and all references are incorporated herein by reference in their entirety. Various modifications and embodiments of the invention, in addition to those specifically specified in the invention, are known to those skilled in the art.

Although descriptions of various embodiments and methods have been provided in the invention, the scope of the invention is not limited thereto. Modifications and changes to the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Thus, it is preferable that the scope of the invention be defined by the appended claims, rather than by the calculation of specific examples, which serve only as examples of embodiments of the invention.

Claims (12)

PATENT CLAIMS A pharmaceutical composition comprising a pharmaceutically effective amount of at least one insulin secretagogue and a pharmaceutically effective amount of at least one FBPase inhibitor. The pharmaceutical composition according to claim 1, wherein the insulin secretagogue is a sulfonylurea antidiabetic agent. The pharmaceutical composition of claim 2, wherein said sulfonylurea antidiabetic agent is a compound of Formula XV: SO ₂ NHCNH-B (XV) where A is selected from the group consisting of hydrogen, halogen, alkyl, alkanoyl, aryl, aralkyl, heteroaryl and cycloalkyl, and B is selected from the group consisting of alkyl, cycloalkyl, and heterocyclic alkyl. The pharmaceutical composition of claim 2, wherein said sulfonylurea antidiabetic agent is selected from the group consisting of glyburide, glisoxepide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, gliclazide, gliquidone, glyhexamide, fenbutamide, tolcepiramide, tolcepiramide. 380 5. Pharmaceutical composition according to claim 1 n and no u j ú - c, that stated secretagogue insulin is a non -sulfo- -sulfinylurea. 6. Pharmaceutical composition according to claim 5 n and no u j ú - wherein said non-sulfonylurea agent is selected from the group consisting of mitiglinide, BTS-67582, repaglinide, and nateglinide. 7. Pharmaceutical composition by claim 1 confesses Hear ú - c, that the secretagogue insulin is a inhibitor dipepti- dylpeptidázy-IV (DPP-IV). 8. Pharmaceutical composition by claim 7 confesses Hear ú - c) wherein said dipeptidyl peptidase-IV (DPP-IV) inhibitor is selected from the group consisting of NVP-DPP728 and P32 / 98. The pharmaceutical composition of claim 1, wherein said insulin secretagogue is a clucagon-like peptide-1 (GLP-1) receptor agonist. The pharmaceutical composition of claim 9, wherein said glucagon-like peptide-1 receptor (GLP-1) agonist is NN-2211, exendin or exendin agonist. The pharmaceutical composition of claim 1, wherein said FBPase inhibitor is a compound selected from Formula I and IA, and pharmaceutically acceptable salts thereof, wherein Formula I and IA are as follows: 0 R ¹ YP - M I R ¹⁸ ---- R ¹⁴ C (O) --- (CR ¹² R ⁿ⁾ _n -N 0 II -P — M I I, YR ¹ nr ¹³ r ¹ ® I IA 381 wherein the compounds of Formula I and IA are transformed in vivo or in vitro to M-PO ₃ ² , which inhibits FBPase, and wherein: Y is independently selected from -O- and -NR ⁶ , with the proviso that: when Y is -O-, R ¹ attached to -O- is independently selected from the group consisting of hydrogen, alkyl, optionally substituted aryl, optionally substituted alicyclic, wherein the cyclic group comprises carbonate or thiocarbonate, optionally substituted -arylalkyl, -C (R ² ) 20 C (O) NR ² 2, -NR ² -C (O) -R ³ , -C (R ² ) ² -OC (O) R ³ , -C (R ² ) 2-OC (O) OR ³ , -C (R ² ) 20 C (O) SR ³ , -alkyl-SC (O) R ³ , -alkyl-SS-alkylhydroxy and -alkyl-SSS-alkylhydroxy; when Y is -NR ⁶ -, R ¹ attached to NR ⁶ is independently selected from hydrogen, - [C (R ² ) 2] q -COOR ³ , -C (R ⁴ ) 2 COOR ³ , - [ C (R ² ) ₂ ] q -C (O) SR and a -cycloalkylene-COOR ³ group wherein q is 1 or 2; when only one Y is -O-, wherein -O- is not part of a cyclic group containing a second Y, then the other Y is a group -N (R ⁱ⁾ - (CR ¹² R ¹³⁾ -C (0) -R ^14; and when Y is independently selected from -O- and -NR ⁰ , R ¹ and R ¹ together are alkyl-SS-alkyl- and form a cyclic group, or R ¹ and R * together form: wherein selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl, or V and Z are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group being fused to an aryl group at the β and γ position to Y attached to V; or Z is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OC (S) OR ³ , -CHR ² OC (0) SR ³ , -CHR ² OCO ² R ³ , -OR ² , -SR ² , -CHR ² N 3, -CH ² aryl, -CH (aryl) OH, -CH (CH = CR ² 2) OH, -CH (CsCR ² ) OH, -R ² , -NR ² 2, -OCOR ³ , -OCO2R ³ , -SCOR ³ , -SCO2R ³ , -NHCOR ² , - NHCO ² R ³ , -CH ₂ NHaryl, - (CH ₂ ) _p -OR ^2, and - (CH ₂ ) _p -SR ² , wherein p is an integer of 2 or 3; or Z and W are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, and V must be an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group; or W and W 'are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or W and W ¹ are joined together via an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V must be an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group; b) V ² , W ² and W are independently selected from the group consisting of hydrogen, 383 alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; Z ² is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OCO ² R ³ , -CHR ² OC (S) OR ^3, -CHR ² OC (0) SR ^3, -CH (aryl) OH, -CH (CH = CR ² 2) OH, -CH (C ^ CR ²⁾ OH, -SR ^2, -CH ₂ NHaryl, -CH ₂ aryl; or V ² and Z ² are joined together via an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 ring atoms, optionally containing 1 heteroatom and substituted with hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom which is three atoms from a group Y attached to phosphorus; c) Z 'is selected from the group consisting of -OH, -OC (O) R ³ , -OCO ₂ R ^3, and -OC (O) SR ³ ; D 'is hydrogen; D is selected from the group consisting of hydrogen, alkyl, -OR ² , -OH, and -OC (O) R ³ ; each W ³ is independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; with the proviso that: a) V, Z, W, W 'are not all hydrogen and V ² , Z ² , W ² , W''are not all hydrogen; R ² is selected from R ³ and hydrogen; 384 R ³ is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; each R ⁴ is independently selected from the group consisting of hydrogen, alkylene, alkylenearyl and aryl, or together R ⁴ and R ⁴ are joined via 2 to 6 atoms, optionally containing one heteroatom selected from O, N and S; R ⁶ is selected from the group consisting of hydrogen, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl; n is an integer from 1 to 3; R ¹⁸ is independently selected from the group consisting of hydrogen, lower alkyl, aryl, aralkyl or R ¹² and R ¹⁸ are joined together via 1 to 4 carbon atoms to form a cyclic group; each R ¹² and each R ¹³ are independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, lower aralkyl, all of which may be optionally substituted, or R ¹² and R ¹³ are joined together via 2 to 6 carbon atoms, optionally containing 1 heteroatom selected from O, N and S to form a cyclic group; each R ¹⁴ is independently selected from the group consisting of -OR ¹ ', -N (R ¹⁷ ) 2, -NHR ¹⁷ , -SR ^17, and -NR ^: R ²⁰ ; R ¹⁵ is selected from the group consisting of hydrogen, lower alkyl, lower aryl, and lower aralkyl, or, together, R ¹⁵ and R ¹⁶ are connected via 2 to 6 atoms to form a cyclic group wherein the cyclic group optionally includes one heteroatom selected from 0, N and S; R ¹⁶ is selected from the group consisting of - (CR ¹² R ¹³ ) _n ^- 385 -C (O) -R ¹⁴ , hydrogen, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ¹⁶ are joined together via 2 to 6 atoms to form a cyclic group wherein the cyclic group optionally includes one heteroatom selected from 0, N and S; each R ¹⁷ is independently selected from the group consisting of lower alkyl, lower aryl and lower aralkyl, or when R ¹⁴ is -N (R ¹⁷ ) ₂ , both R ¹⁷ are joined via 2 to 6 atoms to form a cyclic group wherein the cyclic group optionally comprises one heteroatom selected from O, N and S; ? C T R is selected from-H, lower R, -C (O) -lower R ^3rd 12th The pharmaceutical composition is: where U ⁶ and V ⁶ independently according to ca and m are selected from hydrogen, groups containing or together, U ° and V ° hydroxy and acyloxy, a lower cyclic ring containing at least one oxygen; W ^c is selected to form a lower alkylamino group; Z ⁶ is selected from the group consisting of alkyl and halogen. 386 13. The pharmaceutical composition of claim 11, wherein said insulin secretagogue is a sulfonylurea antidiabetic agent. Pharmaceutical composition according to claim 11, characterized in that: A ² is selected from the group consisting of -NR ³ 2, -NHSO ² R ³ , -OR ²⁵ , -SR ²⁵ , halogen, lower alkyl, -CON (R ⁴ ) 2, guanidino, amidino, hydrogen and a perhaloalkyl group; E ² is selected from the group consisting of hydrogen, halogen, lower alkylthio, lower perhaloalkyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, -CN, and -NR ⁷ ₂ ; X ³ is selected from the group consisting of -alkyl (hydroxy) -, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl- -. -alkythio-, nylamino-, -alkyloxy-, -alkythioalkyl-, -alkylaminocarbonyl-, -alkylcarbo -alicyclic-, -aralkyl-, -alkylaryl · -, -alkoxycarbonyl · -, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino-, all optionally substituted, with the proviso that X ³ is not substituted with -COOR ² , -SO ₃ H or group -PO ₃ R ₂ ; Y ³ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C (O) R ³ , -S (O) 2 R ^3, -C (O) R ^the group -CONHR ^3, -NR ² 2, and -OR ^3, all except H are optionally substituted; each R ⁴ is independently selected from the group consisting of hydrogen and alkyl, or together R ⁴ is a cyclic alkyl group; R ²⁵ is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic; each R ⁷ is independently selected from the group consisting of hydrogen, lower alkyl, lower alicyclic, lower aralkyl, lower aryl and -C (O) R ¹⁰ ; each R ⁸ is independently selected from the group consisting of hydrogen, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, -C (O) R ^10, or together both R ⁸ form a bidendate alkyl; R ¹⁰ j ^E selected from-H, lower alkyl, -NH _2, lower aryl, and lower perhaloalkyl, and R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ² ; and pharmaceutically acceptable prodrugs and salts thereof. The pharmaceutical composition of claim 14, wherein said insulin secretagogue is a sulfonylurea antidiabetic agent. A pharmaceutical composition according to claim 11 388 where: A, E, and L are independently selected from -NR ⁸ 2, -N02 group, hydrogen, -OR ^7, -SR ^7, -C (O) NR ⁴ 2, halo, -COR ^U, -SO ² R ³ , guanidine, amidine, -NHSO ² R ²⁵ , -SO ₂ NR ⁴ ₂ , -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C5 alkynyl and lower alicyclic, or, together, A and L form a cyclic group or, together, L and E form a cyclic group or, together, E and J form a cyclic group selected from the group consisting of aryl, cyclic alkyl and heterocyclic groups ; J is selected from the group consisting of -NR ⁸ 2, -N0 ₂ group, hydrogen, -OR ^7, -SR ^7, -C (O) NR ⁴ 2, halo, -C ^(O) R, -CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or together J and Y are selected from Y and Y; from the group consisting of aryl, cyclic alkyl and heterocyclic; X ³ is selected from the group consisting of -alkyl (hydroxy) -, -alkyl · -, -alkynyl, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkythioalkyl-, -alkythio-, -alkylaminocarbonyl-, -alkylcarbo- 389 nylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino-, all optionally substituted, with the proviso that X ³ is not substituted with -COOR ^2, -SO 3 H or a group -po3r ² 2; Y ³ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C (O) R ³ , -S (O) 2 R ³ , -C (O) -R ^n, a group -CONHR ^3, -NR ² 2, and -OR ^3, all except H are optionally substituted; each R ⁴ is independently selected from the group consisting of hydrogen and alkyl, or both R ⁴ together form a cyclic alkyl group; R ²⁵ is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic; each R ⁷ is independently selected from the group consisting of hydrogen, lower alkyl, lower alicyclic, lower aralkyl, lower aryl and -C (O) R ¹⁰ ; each R ⁸ is independently selected from the group consisting of hydrogen, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, and -C (O) R ¹⁰ ; or two R ⁸ together form a bidendátnu alkyl; R ¹⁰ is selected from the group consisting of hydrogen, lower alkyl, -NH ₂ , lower aryl and lower perhaloalkyl; and R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ² ; 390 and pharmaceutically acceptable prodrugs and salts thereof. The pharmaceutical composition of claim 16, wherein said insulin secretagogue is a sulfonylurea antidiabetic agent. The pharmaceutical composition of claim 17, wherein said sulfonylurea antidiabetic agent is selected from the group consisting of glyburide, glisoxepide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, gliclazide, gliquidone, glyhexamide, fenbutide, fenbutamide, fenbutamide, fenbutamide, fenbutamide, fenbutamide, fenbutamide, fenbutamide, fenbutamide, fenbutamide. The pharmaceutical composition of claim 16, wherein said insulin secretagogue is selected from the group consisting of mitiglinide, BTS-67582, repaglinide, nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitors and glucagon-like peptide-1 receptor (GLP) agonists. -1). 20. The pharmaceutical composition of claim 11, wherein M is: And where B ⁵ is a selected from groups -NH-, -N = and -CH =; C _h ... -U 4- D ⁵ is a selected from groups oosahujucej a Q ⁵ is a selected from groups -C = and -N-; with the proviso that: 391 when B ⁵ is -NH-, Q ⁵ is -C = and D ⁵ is T when B ⁵ is -CH =, Q ⁵ is -N- and D ⁵ is 1 when B ⁵ is -N =, 1 D ⁵ is ^N and Q ⁵ is -C, A, E, and L are selected from the group consisting of -NR ⁸ 2, -NO 2 radical, hydrogen, -OR ^7, -SR ⁷ group -CÍOINR ^, halogen, -COR ^n, -SO 2 R ³ group, a guanidino amidino, -NHSO ² R ²⁵ , -SO ₂ NR ⁴ ₂ , -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C 1 -C 5 alkyl, C ₂ -C ₅ alkenyl, C ₂ -C 5 alkynyl a group and a lower alicyclic group, or, together, A and L form a cyclic group or, together, L and E form a cyclic group or, together, E and J form a cyclic group selected from the group consisting of aryl, cyclic alkyl and heterocyclic groups; J is selected from the group consisting of -NR ⁸ 2, -N02 group, hydrogen, -OR ^7, -SR ^7, -C (O) NR ⁴ 2 <halo, -C ^(O) R group, -CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or together with Y are selected from the group consisting of Y; containing an aryl, cyclic alkyl and heterocyclic group; X ³ is selected from the group consisting of -alkyl (hydroxy) -, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkythio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyal 392-kyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted, with the proviso that X ³ is not substituted with -COOR ² , -SO 3 H, or -PO ³ R ² 2; Y ³ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C (O) R ³ , -S (O) 2 R ^3, -C (O) -R ^n, a group -CONHR ^3, -NR ² _2, and -OR ^3, all except H are optionally substituted; R ⁴ is independently selected from the group consisting of hydrogen and alkyl or R ⁴ and R ⁴ together form a cyclic alkyl group; R ²⁵ is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic; R ⁷ is independently selected from the group consisting of hydrogen, lower alkyl, lower alicyclic, lower aralkyl, lower aryl and -C (O) R ¹⁰ ; R ⁸ is independently selected from the group consisting of hydrogen, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, -C (O) R ¹⁰ ; or together form a bidendate alkyl group; R ¹⁰ is selected from the group consisting of hydrogen, lower alkyl, -NH ₂ , lower aryl and lower perhaloalkyl; R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ² , and pharmaceutically acceptable prodrugs and salts thereof. 393 The pharmaceutical composition of claim 20, wherein said insulin secretagogue is a sulfonylurea antidiabetic agent. A pharmaceutical composition according to claim 11, wherein M is -XR ⁵ , wherein R ⁵ is selected from: I D each G is independently selected from C, N, O, S and Se and wherein no more than one G is O, S or Se and no more than one G is N; each G 'is independently selected from C and N and wherein no more than two G' groups are N; A is selected from the group consisting of hydrogen, -NR ⁴ 2, -CONR ⁴ 2, -CO ² R ³ , halogen, -S (O) R ³ , -SO ² R ³ , alkyl, alkenyl, alkynyl, perhaloalkyl, haloalkyl, aryl, -CH 2 OH, -CH 2 NR ⁴ 2, -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , - N 3, -NHC (S) NR ⁴ 2, -NHAc group, a is zero; each B and D are independently selected from-H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, -C ^(O) R, -C (O) SR ³ , -SO 2 R ⁿ , -S (O) R ³ , -CN, -NR ⁹ 2, -OR ³ , -SR ³ , perhaloalkyl, halogen, -NO _2, and zero, all except hydrogen , -CN groups, perhaloalkyl groups, -NO ₂ and halogen groups are optionally substituted; E is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, -C (O) OR ³ , -CONR ⁴ 2, -CN,. -NR ⁹ 2 group, -NO _2, -OR ^3, -SR ^3, perhaloalkyl, halo, and null, all except-H, -CN, perhaloalkyl, and halo are optionally substituted; J is selected from hydrogen or zero; X is an optionally substituted linking group that connects R ⁵ to the phosphorus atom via 2 to 4 atoms, including 0 to 1 heteroatom selected from N, O and S, except that when X is urea or carbamate, then there are 2 heteroatoms between R ⁵ and the phosphorus atom, measured by the shortest route, and wherein the atom attached to the phosphorus atom is a carbon atom and wherein X is selected from the group consisting of furan-2,5-diyl, -alkyl (hydroxy) -, -alkynyl - group, -heteroaryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkythioalkyl-, -alkythio-, -alkylaminocarbonyl-, -alkylcarbonylamino-- , -alkoxycarbonyl, -carbonyloxyalkyl, -alkoxycarbonylamino, and -alkylaminocarbonylamino, all optionally substituted, with the proviso that X is not substituted with -COOR ² , -SO 3 H, or PO 3 R ² 2; R ² is selected from R ³ and hydrogen; R ³ is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; each R ⁴ is independently selected from the group consisting of hydrogen and alkyl or R ⁴ and R ⁴ together form a cyclic alkyl group; 395 each R ⁹ is independently selected from hydrogen, alkyl, aralkyl and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl or heterocyclic group wherein the heteroatom is selected from O, S and N; R ¹¹ is selected from. containing an alkyl group, an aryl group, an -NR ' ₂ group and -OR ² group; with the proviso that: 1) when G 'is N, then the corresponding A, B, D or E is zero; 2) at least one of A and B or A, B, D and E is not selected from hydrogen or zero; 3) when R ⁵ is a six membered ring, then X is not a bivalent atom, an optionally substituted -alkoxy group or an optionally substituted -alkylthio group; 4) when G is N, then the corresponding A or B is not a halogen or a group directly bonded to G via a heteroatom; 5) when X is not an aryl group, then R ⁵ is not substituted with two or more aryl groups and pharmaceutically acceptable prodrugs and salts thereof. 23. The pharmaceutical composition of claim 22, wherein said R ⁵ is selected from the group consisting of pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, 1, 2, 4-thiadiazolyl, pyrazolyl, isoxazolyl , 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3, 4-thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl and 1,3-selenazolyl, which 396 all contain at least one substituent. 24. A pharmaceutical composition according to claim 22, characterized in characterized in that R ⁵ is 2-thiazolyl or 2-oxazolyl. 25. A pharmaceutical composition according to claim 22, vyznaču- Jucá is characterized in that R ⁵ is selected from the group consisting of: where A 1 is selected from the group consisting of hydrogen, -NR ⁴ 2, -CONR ⁴ 2, -CO ² R ³ , halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 perhaloalkyl C 1 -C 6 haloalkyl, aryl, -CH 2 OH, -CH 2 NR ⁴ 2, -CH ₂ CN, -CN, 397-C (S) NH _2, -OR ^3, -SR ^3, -N 3 group, -NHC (S) NR ⁴ 2, and -NHAc group; B and D are independently selected from-H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, -C ^(O) R, -C (O) SR ^3, a group -SO 2 R ^u, -S (O) R ^3, -CN, -NR ⁹ 2, -OR ^3, -SR ^3, perhaloalkyl, and halo, all except H, CN, perhaloalkyl, and halo are optionally substituted; E "is selected from H, Cl-Cd alkyl, C ₂ -C ₈ alkenyl, C ₂ -C alkynyl, C ^ -CE alicyclic, alkoxyalkyl, -C (O) OR ^3, a group -CONR ⁴ 2, -CN, -NR ⁹ 2, -OR ^3, -SR ^3, C-C6 perhaloalkyl, and halo, all except H, CN, perhaloalkyl, and halo are optionally substituted; each R ³ is selected from the group consisting of a C -C _alkyl group, -C aryl, C 3 -C 6 heteroaryl, C ₃ -C ₈ alicyclic group, a C ₂ -C? a heteroalicyclic group, a C ₇ -C 18 aralkyl group and a C ₄ -C 9 heteroaralkyl group; each R ⁴ and R ⁹ is independently selected from the group consisting of hydrogen and C 1 -C ₂ alkyl; X is selected from the group consisting of -heteroaryl, -alkylcarbonylamino, -alkylaminocarbonyl, and -alkoxycarbonyl; each R ¹¹ is selected from the group consisting of -NR ⁴ 2, -OH, -OR ³ , C 1 -C 6 alkyl, C 8 aryl, and C 3 -C 10 heteroaryl. 26. The pharmaceutical composition of claim 25, wherein the composition is selected from the group consisting of: 398, wherein X is selected from the group consisting of -he teroaryl and -alkoxycarbonyl. The pharmaceutical composition of claim 25, wherein said compound is a compound of Formula XII, XIII or XIV: (XL) 28. The pharmaceutical composition of claim 25, wherein: Ά is selected from the group consisting of -NH ₂ , -Cl, -Br and -CH ₃ ; each B is selected from the group consisting of hydrogen, -C (O) OR ³ , -C (O) SR ³ , C 1 -C ₅ alkyl, alicyclic, halogen, heteroaryl, and -SR ³ ; D 1 is selected from the group consisting of hydrogen, -C (O) OR ³ , lower alkyl, alicyclic, and halogen; and E is selected from the group consisting of hydrogen, -Br, and -Cl. 399 29. The pharmaceutical composition of claim 27, wherein: 1 fl R is selected from the group consisting of hydrogen, methyl and ethyl, each R ¹² and R ¹³ is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CH 2 CH 2 -CH 3, phenyl and benzyl, or R ¹² and R ¹³ are joined together via 2 to 5 carbon atoms to form a cycloalkyl group; n is 1 or 2; each R ¹⁴ is independently selected from -OR ¹⁷ , wherein R ¹⁷ is selected from the group consisting of methyl, ethyl, propyl, and benzyl; R ¹⁵ and R ¹⁶ are independently selected from the group consisting of lower alkyl and aralkyl or R ¹⁵ and R ¹⁶ are joined together via a chain of 2 to 6 atoms, optionally including 1 heteroatom selected from 0, N and S. 30. The pharmaceutical composition of claim 27, vyznaču- Jucá is characterized in that R ¹⁶ is - (CR ¹² R ¹³⁾ _n -C (0) -R ^14th 31. The pharmaceutical composition of claim 27, wherein: R is selected from the group consisting of hydrogen, methyl and ethyl; R ¹² and R ¹³ are independently selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl and benzyl or together R ¹² and R ¹³ are joined via 2 to 5 carbon atoms to form a cycloalkyl group; 400 R ¹⁴ is -OR ¹⁷ , R ¹⁷ is selected from the group consisting of methyl, ethyl, propyl, tert-butyl and benzyl; R ¹⁵ and R ¹⁶ are independently selected from the group consisting of lower alkyl and lower aralkyl, or together R ¹⁵ and R ¹⁶ are linked via a chain of 2 to 6 atoms, optionally including 1 heteroatom selected from O and N. The pharmaceutical composition of claim 22, wherein said FBPase inhibitor is a compound of the formula: · R ¹⁴ wherein X is a radical selected from the group consisting of furan-2,5-diyl, alkoxycarbonyl-, and alkylaminocarbonyl group. 33. The pharmaceutical composition of claim 32 wherein n is 1 R ¹² and methyl R ¹³ are independently selected from the group consisting of hydrogen, isobutyl and a group, benzyl isopropyl, or together R ¹² and R ¹³ are linked via 2-5 ^{l of} carbon when R and R ¹³ are not atoms to form a cycloalkyl group are the same, and H ₂ N-CR ¹² R ¹³ -C (O) ^-R14 is an ester, or thioester of a naturally occurring amino acid; R ¹⁴ is selected from -OR ¹⁷ and -SR ¹⁷ is selected R ¹⁷ from the group of methyl, ethyl, propyl, t-butyl, and benzyl 401 hunting group; and R ¹⁸ is selected from the group consisting of hydrogen, methyl and ethyl. 34. The pharmaceutical composition of claim 25, characterized in characterized in that R ⁵ is: A is selected from the group consisting of -NH ₂ , -CONH ₂ , halogen, -CH ₃ , -CF ₃ , -CH ₂ -halogen, -CN, -OCH ₃ , -SCH _3, and hydrogen ; B is selected from the group consisting of hydrogen, -C (O) R ¹¹ , -C (O) SR ³ , alkyl, aryl, alicyclic, halogen, -CN, -SR ³ , -OR ³ and -NR ⁹ ₂ , a X is selected from the group consisting of -heteroaryl, -alkoxycarbonyl, and -alkylaminocarbonyl, all optionally substituted. The pharmaceutical composition of claim 34, wherein the FBPase inhibitor is a compound of Formula IA and wherein: R ¹⁴ ---- ABOUT II P-NR ¹³ r ¹⁶ is selected from the group consisting of 402 wherein C * has the stereochemistry S; R ¹⁸ and R ¹⁵ are independently selected from hydrogen and methyl, R ¹² and R ¹³ are independently selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl and benzyl or together R ¹² and R ¹³ are joined via 2 to 5 carbon atoms to form a cycloalkyl group; n = 1, R ¹⁴ is -OR ¹⁷ , R ¹⁶ is - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ , a R ¹⁷ is selected from the group consisting of methyl, ethyl, propyl, phenyl and benzyl; 36th Pharmaceutical composition according to claim 34, characterized in that A is -NH ₂ , X is furan-2,5-diyl C. B is 37. Pharmaceutical composition according to claim 34, characterized in that A 1 is -NH ₂ , X is furan-2,5-diyl B is 38. The pharmaceutical composition of claim 37 403, wherein the FBPase inhibitor is a compound of formula IA and wherein EtOOC --- C --- HN-P --- i Γ ch ₃ ² The pharmaceutical composition of claim 37, wherein the FBPase inhibitor is a compound of Formula IA and wherein: OR ⁴² R ⁴ ® O R ¹³ NR ^{1 S} R ¹⁶ wherein C * has S stereochemistry 40. The pharmaceutical composition of claim 22, wherein said insulin secretagogue is a sulfonylurea antidiabetic agent. 41. The pharmaceutical composition of claim 40, wherein said sulfonylurea antidiabetic The 404 reagent is selected from the group consisting of glyburide, glisoxepide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, gliclazide, gliquidone, glyhexamide, fenbutamide, tolcyclamide and glimepiride. 42. The pharmaceutical composition of claim 22, wherein said insulin secretagogue is selected from the group consisting of mitiglinide, BTS-67582, repaglinide, nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitors and glucagon-like peptide-1 receptor (GLP) agonists. -1). G is selected from -O- and -S-; A ² , L ² , E ² and J ² are selected from the group consisting of -NR ⁴ ₂ , -NO ₂ , hydrogen, -OR ² , -SR ² , -C (O) NR ⁴ 2, halo, -COR ^11, -SO 2 R ³ group, guanidinyl, amidinyl, aryl, aralkyl group, alkyloxyalkyl group, SCN group, -NHSO ₂ R, -SO ₂ NR ⁴ ₂ , -CN, -S (O) R ³ , perhaloacyl, perhaloalkyl, perhaloalkoxy, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl and lower alicyclic, or L ² and E or E ² and J ² together form a null cyclic group; X ² is selected from the group consisting of -CR ² ₂ -, a group 405 -CF ₂ -, -CR ² 2 -O-, -CR ² 2 -S-, -C (O) -O-, -C (O) -S-, -C (S) - O- and -CR ² 2-NR ^{L 9} - and wherein the phosphorus attached atom is a carbon atom, with the proviso that X ² is not substituted by -COOR ² , -SO 3 H, or -PO ³ R ² ₂ ; R ² is selected from R ³ and hydrogen; R ³ is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; each R ⁴ is independently selected from hydrogen and alkyl or together R ⁴ and R ⁴ form a cyclic alkyl group; each R ⁹ is independently selected from the group consisting of hydrogen, alkyl, aralkyl and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group; R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ² ; R ¹⁹ is selected from the group consisting of lower alkyl, hydrogen and -COR ² , and pharmaceutically acceptable prodrugs and salts thereof. 44. The pharmaceutical composition of claim 43 wherein G &apos; is -S-. 45. The pharmaceutical composition of claim 43, wherein said insulin secretagogue is a sulfonylurea antidiabetic agent. 46. A method of treating a mammal having diabetes comprising administering to said mammal a pharmaceutically effective amount of component (a) comprising at least one insulin secretagogue and a pharmaceutically effective amount of component (b). 406 comprising at least one FBPase inhibitor. 47th process treatment mammals according to claim 46 v y z n a č u - j ú c i s and by that said secretagogue insulin is a sulphonated nylurea antidiabetic agent. 48th process treatment mammals according to claim 47 v y z n a č u - characterized in that the sulphonylurea antidiabetic agent is selected from the group consisting of glyburide, glisoxepide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, gliclazide, gliquidone, glyhexamide, fenbutamide, tolcyclamide and glimepiride. 49. A method of treating mammals according to claim 46, wherein said insulin secretagogue is selected from the group consisting of mitiglinide, BTS-67582, repaglinide, nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitors and glucagon-like peptide-1 receptor agonists ( GLP-1). 50. A method for treating mammals according to claim 46, wherein said FBPase inhibitor is a compound selected from Formula I and IA: R ¹ Y R ¹⁴ WHAT) Wherein the compounds of Formula I and IA are converted in vivo or in vitro to M-PO3 ² ', which inhibits FBPase, and wherein: Y is independently selected from -O- and -NR ⁶ , with the proviso that: when Y is -O-, R ¹ attached to -O- is independently selected from the group consisting of hydrogen, alkyl, optionally substituted aryl, optionally substituted alicyclic, wherein the cyclic group comprises carbonate or thiocarbonate, optionally substituted -arylalkyl, group -C (R ² ) 2 OC (O) NR ² 2, -NR ² -C (O) -R ³ , -C (R ² ) 2 -OC (O) R ³ , -C (R ² ) 2-OC (O) OR ³ , -C (R ² ) 2 OC (O) SR ³ , -alkyl-SC (O) R ³ , -alkyl-SS-alkylhydroxy and -alkyl-SSS-alkylhydroxy when Y is -NR ⁶ -, R ¹ attached to -NR ⁶ - is independently selected from hydrogen, - [C (R ² ) 2] q -COOR ³ , -C (R ⁴ ) 2 COOR ³ , - [C (R ² ) ₂ ] _q -C (O) SR and a -cycloalkylene-COOR ^{3 group} , wherein q is 1 or 2 when only one Y is -O-, wherein -O- is not part of a cyclic group containing the other Y, the other Y is -N (R ¹⁸⁾ - (CR ¹² R ¹³⁾ -C (0) R ^14, and when Y is independently selected from -O- and -NR ^6, R ¹ and R ¹ together are alkyl-SS-alkyl- and form a cyclic group, or R ¹ and R ¹ together form: where a) V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl, or V and Z are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group being fused to an aryl group at the β and γ position to Y attached to V; or 408 Z is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OC (S) OR ³ , -CHR ² OC (O) SR ³ , -CHR ² OCO ² R ³ , -OR ² , -SR ² , -CHR ² N 3, -CH ² aryl, -CH (aryl) OH, -CH (CH = CR ² 2) OH, -CH (CsCR ² ) OH, -R ² , -NR ² 2, -OCOR ³ , -OCO2R ³ , -SCOR ³ , -SCO2R ³ , -NHCOR ² , - NHCO ² R ³ , -CH ₂ NHaryl, - (CH ₂ ) _p -OR ^2, and - (CH ₂ ) _p -SR ² , wherein p is an integer of 2 or 3, or Z and W are joined together through an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, and .V must be an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group; or W and W 'are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or W and W 'are joined together via an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V must be an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group; b) V ² , W ² and W are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; Z ² is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OCO ₂ R ³ , 409 -CHR ² OC (S) OR ³ , -CHR ² OC (O) SR ³ , -CH (aryl) OH, -CH (CH = CR ² 2) OH, -CH (CsCR ² ) OH, -SR ² , -CH ₂ -NHaryl, -CH ₂ aryl; or V ² and Z ² are joined together via an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 ring atoms, optionally containing 1 heteroatom, and substituted with a hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy group attached to a carbon atom that is three atoms from group Y attached to phosphorus; c) Z 'is selected from the group consisting of -OH, -OC (O) R ³ , -OCO ₂ R ^3, and -OC (O) SR ³ ; D 'is hydrogen; D is selected from the group consisting of hydrogen, alkyl, -OR ² , -OH, and -OC (O) R ³ ; each W ³ is independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; with the proviso that: a) V, Z, W, W 'are not all hydrogen and V ^z , Z ² , W ² , W are not all hydrogen; R ² is selected from R ³ and hydrogen; R ³ is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; each R ⁴ is independently selected from the group consisting of hydrogen, alkylene, alkylenearyl and aryl, or together R ⁴ and R ⁴ are connected via 2 to 6 atoms, 410 optionally containing one heteroatom selected from O, N, and S; R ⁶ is selected from the group consisting of hydrogen, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl; n is an integer from 1 to 3; 1 fi R is independently selected from the group consisting of hydrogen, lower alkyl, aryl, aralkyl, or R ¹² and R ¹⁸ are joined together via 1 to 4 carbon atoms to form a cyclic group; each R ¹² and each R ¹³ are independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, lower aralkyl, all optionally substituted or R ¹² and R ¹³ are joined together via 2 to 6 carbon atoms, optionally containing 1 heteroatom selected from O, N and S to form a cyclic group; each R ¹⁴ is independently selected from the group consisting of -OR ¹⁷ , -N (R ¹⁷ ) 2, -NHR ¹⁷ , -SR ^17, and -NR ² R ²⁰ ; R ¹⁵ j ^E selected from-H, lower alkyl, lower aryl, and lower aralkyl, or R ¹⁵ and R ¹⁶ are connected via 2-6 atoms to form a cyclic group, wherein the cyclic group optionally includes one heteroatom selected from O, N and S; R ¹⁵ is selected from the group consisting of - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ , hydrogen, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ¹⁶ are joined together via 2 to 6 atoms to form a cyclic group, wherein the cyclic group optionally comprises one heteroatom selected from O, N and S; 411 each R ¹⁷ is independently selected from the group consisting of lower alkyl, lower aryl and lower aralkyl, or when R ¹⁴ is -N (R ¹⁷ ) ₂ , both R ¹⁷ are joined via 2 to 6 atoms to form a cyclic ring a group wherein the cyclic group optionally comprises one heteroatom selected from O, N, and S; R ²⁰ is selected from the group consisting of hydrogen, lower R ^3, and -C (O) -lower R ³ ; and pharmaceutically acceptable prodrugs and salts thereof. 51. A method for treating mammals according to claim 50, wherein M is: where: A ² is selected from the group consisting of -NR ³ 2, -NHSO ² R ³ , -OR ²⁵ , -SR ²⁵ , halogen, lower alkyl, -CON (R ⁴ ) 2, guanidine, amidine, hydrogen and a perhaloalkyl group; E ² is selected from the group consisting of hydrogen, halogen, lower alkylthio, lower perhaloalkyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, -CN, and -NR ⁷ ₂ ; X ³ is selected from the group consisting of -alkyl (hydroxy) -, -alkyl-, -alkynyl-, -aryl · -, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkythioalkyl-, -alkythio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, - 412 -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino-, all optionally substituted, provided that X ³ is not substituted by -COOR ² , -SO 3 H or -PO ³ R ² 2; Y ³ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C (O) R ³ , -S (O) 2 R ³ , -C (O) -R ^n, a group -CONHR ^3, -NR ² 2, and -OR ^3, all except H are optionally substituted; each R ⁴ is independently selected from the group consisting of hydrogen and alkyl or together R ⁴ and R ⁴ form a cyclic alkyl group; R ²⁵ is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic; R ⁷ is independently selected from the group consisting of hydrogen, lower alkyl, lower alicyclic, lower aralkyl, lower aryl and -C (O) R ¹⁰ ; R ³ is independently selected from the group consisting of hydrogen, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, -C (O) R ^{± O,} or together both R ³ form a bidendate alkyl group; R ¹⁰ is selected from the group consisting of hydrogen, lower alkyl, -NH ₂ , lower aryl and lower perhaloalkyl, R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ² ; and pharmaceutically acceptable prodrugs and salts thereof. 413 52. A method of treating mammals according to claim 51, wherein the insulin secretagogue is a sulfonylurea new antidiabetic agent. 53. A method for treating mammals according to claim 52, wherein the sulfonylurea antidiabetic agent is selected from the group consisting of glyburide, glisoxepide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, gliclazide, gliquidone, glyhexamide, fenbutamide, fenbutamide. 54. The method of treatment of mammals according to claim 51, wherein said insulin secretagogue is selected from the group consisting of mitiglinide, BTS-67582, repaglinide, nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitors and glucagon-like peptide-1 receptor aconists ( GLP-1). -NO 2 radical, hydrogen, -OR ^7, -SR ^7, -C (O) NR ⁴ 2 / halogen, -COR ^11, -SO 2 R ³ group, guanidino group, amidino group, a group -NHSO 2 R ²⁵ group, -SO ₂ NR ⁴ ₂ , -CN, sulfoxide, perhaloacyl, perha loalkyl, perhaloalkoxy, C 1 -C 5 alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl and lower alicyclic, or A and L together form a cyclic group; or 414 L and E form a cyclic group or together E and J form a cyclic group selected from the group consisting of aryl, cyclic alkyl and heterocyclic groups; J is selected from the group consisting of -NR ⁸ 2, -NO 2 radical, hydrogen, -OR ^7, -SR ^7, -C (O) NR ⁴ 2, halo, -CtOJR ^11, -CN, sulfonyl a sulfoxide group, a perhaloalkyl group, a hydroxyalkyl group, a perhaloalkoxy group, an alkyl group, a haloalkyl group, an aminoalkyl group, an alkenyl group, an alkynyl group, an alicyclic group, an aryl group and an aralkyl group, or together with Y form a cyclic group selected from an alkyl and heterocyclic group; X ³ is selected from the group consisting of -alkyl (hydroxy) -, -alkyl · -, -alkynyl, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkythioalkyl-, -alkythio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino-, all optionally substituted, provided that X ³ is not substituted with -COOR ² , -SO 3 H, or -po ³ R ² 2; Y ^{3 fe} selected from-H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C (O) ^R3, -S (O) 2 R ^3, -C (O) -R ^n, a group -CONHR ^3, -NR ² 2, and -OR ^3, all except H are optionally substituted; each R ⁴ is independently selected from the group consisting of hydrogen and alkyl or R ⁴ and R ⁴ together form a cyclic alkyl group; R ²⁵ is selected from the group consisting of lower alkyl 415 nu, lower aryl, lower aralkyl, and lower alicyclic; R ⁷ is independently selected from the group consisting of hydrogen, lower alkyl, lower alicyclic, lower aralkyl, lower aryl and -C (O) R ¹⁰ ; R ⁸ is independently selected from the group consisting of hydrogen, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, -C (O) R ¹⁰ , or together form a bidendate alkyl group; R ¹⁰ j ^E selected from-H, lower alkyl, -NH _2, lower aryl, and lower perhaloalkyl; R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ² , and pharmaceutically acceptable prodrugs and salts thereof. 56. The method of claim 55, wherein said insulin secretagogue is a sulfonylurea antidiabetic agent. 57. The method of claim 56, wherein the sulfonylurea antidiabetic agent is selected from the group consisting of glyburide, glisoxepide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, gliclazide, gliquidone, glyhexamide, fenbutide, fenbutamide, fenbutide, fenbutamide, fenbutamide, fenbutamide, fenbutamide. . 58. The method of claim 55, wherein said insulin secretagogue is selected from the group consisting of mitiglinide, BTS-67582, repaglinide, nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitors, and glucagon-like re416 agonists. peptide-1 (GLP-1). treatment according to claim 50, s selected groups from a selected group containing a selected groups -C = a N; provided that: t when B ⁵ is -NH-, Q ⁵ is -C = and D ⁵ is, L when B ⁵ is -CH =, Q ⁵ is -N- and D ⁵ is ^C , and l when B ⁰ is -N = , D ⁵ is ^N and Q ⁵ is -C =, A, E and L are selected from the group consisting of -NR ⁸ ₂ , -NO 2, hydrogen, -OR ', -SR ⁷ , -C (O) NR ⁴ 2, halogen, -COR ¹¹ , -S02R ^3, guanidino, an amidino group, a group -NHSO ₂ R ^{Z 5,} -SO 2 NR ⁴ 2 group, -CN group, a sulfoxide group, perhaloacylovú group, perhaloalkvlovú group, perhaloalkoxy, 0ι-0 ₅ alkyl, C ₂ -C ₅ alkenyl group, a C ₂ -C ₅ alkynyl, and lower alicyclic, or together a and L form a cyclic group, or L and E form a cyclic group, or together E and J form a cyclic 417 is selected from the group consisting of aryl, cyclic alkyl and heterocyclic; J is selected from the group consisting of -NR ⁸ 2, -NO 2 radical, hydrogen, -OR ^7, -SR ^7, -C (O) NR ⁴ 2, halo, -C ^(O) R group, . -CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or together with Y, form a radical; containing an aryl, cyclic alkyl and heterocyclic group; X ³ is selected from the group consisting of -alkyl (hydroxy) -, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkythioalkyl-, -alkythio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino-, all optionally substituted, with the proviso that X ³ is not substituted with -COOR ² , -SO 3 H, or -PO ³ R ² 2; Y ³ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C (O) R ³ , -S (O) 2 R- ³ t-C (O) -R ^n, a group -CONHR ^3, -NR ² 2, and -OR ^3, all except H are optionally substituted; each R ⁴ is independently selected from the group consisting of hydrogen and alkyl or R ⁴ and R ⁴ together form a cyclic alkyl group; R ²⁵ is selected from the group consisting of lower alkyl 418 nu, lower aryl, lower aralkyl, and lower alicyclic; R ⁷ is independently selected from the group consisting of hydrogen, lower alkyl, lower alicyclic, lower aralkyl, lower aryl and -C (O) R ¹⁰ ; R ⁸ is independently selected from the group consisting of hydrogen, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, and -C (O) R ¹⁰ ; or together form a bidendate alkyl group; R ¹⁰ is selected from the group consisting of hydrogen, lower alkyl, -NH ₂ , lower aryl and lower perhaloalkyl; R is selected from ^the group consisting of alkyl, aryl, -NR ² _2, and -OR ^2, and pharmaceutically acceptable prodrugs and salts thereof. 60. The method of claim 59. characterized in that said insulin secretagogue is a sulfonylurea antidiabetic agent. 61. The method of claim 60, wherein the sulfonylurea antidiabetic agent is selected from the group consisting of glyburide, glisoxepide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, gliclazide, gliquidone, glyhexamide, fenbutide, fenbutamide, fenbutamide, fenbutamide, fenbutamide, fenbutamide, fenbutamide, fenbutamide. . 62. The method of claim 59, wherein said insulin secretagogue is selected from the group consisting of mitiglinide, BTS-67582, repaglinide, nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitors, and glucagon-like re419 agonists. peptide-1 (GLP-1). according to claim is selected from: 50, wherein each G is no more independently selected from group C, N, O, S and Se and as one G is O, S or Se and no more than one G is N; every G 'is independently selected from C and N and wherein no more than two The G 'groups are N; A is selected from the group consisting of hydrogen, -NR ⁴ 2, -CONR ⁴ 2, -CO ₂ R ³ , halogen, -S (O) R ³ , -SO ² R ³ , alkyl, alkenyl, alkynyl a group, perhaloalkyl, haloalkyl, aryl, -CH ₂ OH, -CH ₂ NR ⁴ ₂ , -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ^3, a group -N 3, -NHC (S) NR ⁴ 2, -NHAc group, a is zero; each B and D are independently selected from-H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, -C ⁽⁰⁾ R, -C (O) SR ³ , -SO 2 R ⁿ , -S (O) R ³ , -CN, -NR ⁹ 2, -OR ³ , -SR ³ , perhaloalkyl, halogen, -NO _2, and zero, all except hydrogen , -CN, perhaloalkyl, -NO _2, and halogen are optionally substituted; E is selected from the group consisting of hydrogen, alkyl, 420 alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, -C (O) OR ^3, -CONR ⁴ 2, -CN, -NR ⁹ 2, -NO _{2 Z} group -OR ^3, -SR ³ , perhaloalkyl, halo, and zero, all except hydrogen, cyano, perhaloalkyl, and halo are optionally substituted; J is selected from hydrogen or zero; X is an optionally substituted linking group that connects R ⁵ with a phosphorus atom through 2 to 4 atoms containing 0 to 1 heteroatom selected from N, O and S, except that when X is urea or carbamate, then there are 2 heteroatoms between R ⁵ and the phosphorus atom, measured by the shortest route, and wherein the atom attached to the phosphorus is a carbon atom and wherein X is selected from the group consisting of -alkyl (hydroxy), -alkynyl, -heteroaryl-, -carbonylalkyl- a group, -1,1-dihaloalkyl group, -alkoxyalkyl group, -alkyloxy group, -alkythioalkyl group, -alkythio group, -alkylaminocarbonyl group, -alkylcarbonylamino group, -alkoxycarbonyl group, -carbonyloxyalkyl group, -alkoxycarbonylamino and -alkylaminocarbonylamino, all optionally substituted, with the proviso that X is not substituted with -COOR ² , -SO 3 H, or PO ³ R ² 2; R ² is selected from R ³ and hydrogen; R ³ is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; each R ⁴ is independently selected from the group consisting of hydrogen and alkyl or R ⁴ and R ⁴ together form a cyclic alkyl group; each R ⁹ is independently selected from the group consisting of hydrogen, alkyl, aralkyl and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group; 421 R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ² ; with the proviso that: 1) when G 'is N, then the corresponding A, B, D or E is zero; 2) at least one of A and B or A, B, D and E is not selected from hydrogen or zero; 3) when R ⁵ is a six-membered ring, then X is not a bivalent atom, optionally substituted -alkyloxy or optionally substituted -alkylthio; 4) when G is N, then the corresponding A or B is not a halogen or a group directly bonded to G via a heteroatom; 5) when X is not an -aryl- group, then R ⁵ is not substituted with two or more aryl groups and pharmaceutically acceptable prodrugs and salts thereof. 64. The method of claim 63, wherein said insulin secretagogue is a sulfonylurea antidiabetic agent. 65. The method of claim 64 wherein the sulfonylurea antidiabetic agent is selected from the group consisting of glyburide, glisoxepide, acetohexamide, chloropropamide, glibornuride, tolbutamide, toiazamide, glipizide, gliclazide, gliquidone, glyhexamide, fenbutide, fenbutamide, fenbutide, fenbutamide, fenbutamide, fenbutamide, fenbutamide, fenbutamide. . 66. The method of claim 63, wherein said insulin secretagogue is selected from: 422 groups containing the mitiglinide, BTS-67582, repaglinide, nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. 67. The method of claim 50, wherein M is: N G is selected from -O- and -S-; A ² , L ² , E ² and J ² are selected from the group consisting of -NR ⁴ 2, -NO 2, hydrogen, -OR ² , -SR ² , -C (O) NR ⁴ 2 <halogen, -COR ¹¹ , -SO ² R ³ , guanidinyl, amidinyl, aryl, aralkyl, alkoxyalkyl, -SCN, -NHSO ² R ⁹ , -SO 2 NR ' ^, 2, -CN, -S (O) R ³ , perhaloacyl, perhaloalkyl, perhaloalkoxy, C 1 -C 5 alkyl, C 2 -C ₅ alkenyl, C 2 -C 5 alkynyl and a lower alicyclic group or L ² and E ² or E ² and J ² together form a null cyclic group. X ² is selected from the group consisting of -CR ² 2 -, -CF 2 -, -CR ² O-, -CR ^{2 2} S -, -C (O) -O-, -C (O) - S-, -C (S) -O- and CR ² 2-NR ¹⁹ - and wherein the atom attached to phosphorus is a carbon atom, provided that X is not substituted with -COOR ² , -SO 3 H, or group -? O2R ' ₂ ' R ² is selected from R ³ and hydrogen; 423 R ³ is selected from the group consisting of alkyl, aryl, alicyclic and aralkyl; each R ⁴ is independently selected from hydrogen and alkyl or together R ⁴ and R ⁴ form a cyclic alkyl group; each R ⁹ is independently selected from the group consisting of hydrogen, alkyl, aralkyl and alicyclic, or together R ⁹ and R ⁹ together form a cyclic alkyl group; R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² 2, and -OR ² ; R ¹⁹ is selected from the group consisting of lower alkyl, hydrogen and -COR ² , and pharmaceutically acceptable prodrugs and salts thereof. 68. The method of claim 67, wherein said insulin secretagogue is a sulfonylurea antidiabetic agent. 69. The method of claim 68 wherein the sulfonylurea antidiabetic agent is selected from the group consisting of glyburide, glisoxepide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, zolazamide, glipizide, gliclazide, gliquidone, glyhexamide, fenbutamide, fenbutamide, fenbutamide, fenbutamide, fenbutamide, fenbutamide, fenbutamide. . 70. The method of claim 67, wherein said insulin secretagogue is selected from the group consisting of mitiglinide, BTS-67582, repaglinide, nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitors, and glucagon-like peptide-1 receptor agonists. (GLP-1). 71. The method of claim 46 424 wherein said combination is administered orally. 72nd The method of claim 46, wherein said disease is characterized by hyperglycaemia. 73rd process treatment according to claim 46, no u j ú c i s a by that said disease is obesity. 74. process healing by claim 46, no u j ú c i s a by that is stated administered to mammals from 100 mg to about 2000 mg of said FBPase inhibitor and from 3 mg to about 250 mg said sulfonylurea antidiabetic agent. 75. A pharmaceutical composition comprising a pharmaceutically effective amount of an insulin or insulin analog and a pharmaceutically effective amount of an FBPase inhibitor. 76. The pharmaceutical composition of claim 75, wherein said insulin or insulin analog is selected from the group consisting of insulin, insulin lispro, insulin. lin aspart and insulin gargline. 77. Pharmacy composition, characterized t ý m that contains pharmaceutical effective amount of biguanide and a pharmaceutically effective amount of an FBPase inhibitor. 78. The pharmaceutical composition of claim 77 wherein said biguanide is selected from the group consisting of metformin, phenformin and buformin. 79th A pharmaceutical composition characterized by 425 by containing a pharmaceutically effective amount of an α-glucosidase inhibitor and a pharmaceutically effective amount of an FBPase inhibitor. 80. The pharmaceutical composition of claim 79 wherein said α-glucosidase inhibitor is selected from the group consisting of acarbose, miglitol, and voglibose. 81. A pharmaceutical composition comprising a pharmaceutically effective amount of an FBPase inhibitor and a pharmaceutically effective amount of a liver glucose inhibitor selected from the group consisting of glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists, amylin agonists, and fatty acid oxidation inhibitors. 82. The pharmaceutical composition of claim 81 wherein said amylin agonist is pramlintide. 83. The pharmaceutical composition of claim 1 75, 77 or 79 An FBPase inhibitor is a compound selected from Formula Ia IA: R ¹⁴ · nr ¹⁵ r ¹⁶ IA wherein the compounds of Formula I and IA are converted in vivo or in vitro to M-PO ₃ ² ', which inhibits FBPase, and wherein: Y is independently selected from -O- and -NR °, with the proviso that: when Y is -O-, R ¹ attached to -O- is independently selected from 426 a hydrogen-containing group, an alkyl group, an optionally substituted aryl group, an optionally substituted alicyclic group, wherein the cyclic group comprises a carbonate or thiocarbonate group, an optionally substituted -arylalkyl group, a -C (R ² ) 2-OC (O) NR ² 2 group -NR ² -C (O) -R ³ , -C (R ² ) ² -OC (O) R ³ , -C (R ² ) 2 -OC (O) OR ³ , -C (R ²⁾ ) ₂ 0C (0) SR ^3, -alkyl-SC (O) R ^3, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkyl hydroxy group; when Y is -NR ⁶ -, R ¹ attached to NR ⁶ is independently selected from hydrogen, - [C (R ² ) 2] q -COOR ³ , -C (R ⁴ ) 2 COOR ³ , - [ C (R ² ) ₂ ] _q -C (O) SR and -cycloalkylene-COOR ³ wherein q is 1 or 2; when only one Y is -0-, -0- which is part of the ring with the other Y, the other Y is -N (R ¹⁸⁾ - (CR ¹² R ¹³⁾ -C (0) -R ^14; and when Y is independently selected from -0- and -NR ^6, R ¹ and R ¹ together are alkyl-SS-alkyl to form a cyclic group, or R ¹ and R ¹ together form: where a) V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl, or V and Z are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group being fused to ary A 427-position group in the β and γ position to Y attached to V; or Z is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OC (S) OR ³ , -CHR ² OC (0) SR ³ , -CHR ² OCO ² R ³ , -OR ² , -SR ² , -CHR ² N 3, -CH ² aryl, -CH (aryl) OH, -CH (CH = CR ² 2) OH, -CH (C = CR ² ) OH, -R ² , -NR ² 2, -OCOR ³ , -OCO ² R ³ , -SCOR ³ , -SCO2R ³ , -NHCOR ² , -NHCO ² R ³ , -CH ₂ NHaryl, - (CH ₂ ) _p -OR ^2, and - (CH ₂ ) _p -SR ² wherein p is an integer of 2 or 3; or Z and W are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, and V must be an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group; or W and W 'are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or W and W 'are joined together via an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V must be an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group; b) V ² , W ² and W are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; Z ² is selected from the group consisting of -CHR'OH, 428 -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OCO ² R ³ , -CHR ² OC (S) OR ³ , -CHR ² OC (0) SR ³ , -CH (aryl) OH, -CH (CH = CR ² ) OH, -CH (C = CR ² ) OH, -SR ² , -CH ₂ NHaryl, -CH ₂ aryl; or V ² and Z ² are joined together via an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 ring atoms, optionally containing 1 heteroatom, and substituted with a hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy group attached to a three-carbon carbon atom from group Y attached to phosphorus; c) Z 'is selected from the group consisting of -OH, -OC (O) R ³ , -OCO ₂ R ^3, and -OC (O) SR ³ ; D 'is hydrogen; D is selected from the group consisting of hydrogen, alkyl, -OR ² , -OH, and -OC (O) R ³ ; each W ³ is independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; with the proviso that: a) V, Z, W, W 'are not all hydrogen and V ² , Z ² , W ² , W are not all hydrogen; R ² is selected from R ³ and hydrogen; is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; each R ⁴ is independently selected from the group consisting of hydrogen and alkyl or together R ⁴ and R ⁴ form a cyclic alkyl group; 429 R ⁶ is selected from the group consisting of hydrogen, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl; n is an integer from 1 to 3; R ¹⁸ is independently selected from the group consisting of hydrogen, lower alkyl, aryl, aralkyl or R ¹² and R ¹⁸ are joined together via 1 to 4 carbon atoms to form a cyclic group; each R ¹² and each R ¹³ are independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, lower aralkyl, all of which may be optionally substituted, or R ¹² and R ¹³ are joined together via 2 to 6 carbon atoms, wherein a cyclic group is formed; each R ¹⁴ is independently selected from the group consisting of -OR ¹⁷ , -N (R ¹⁷ ) 2, -NHR ^17, and -SR ¹ '; R ¹⁵ is selected from the group consisting of hydrogen, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ¹⁶ are joined together via 2 to 6 atoms, optionally containing one heteroatom selected from 0, N and S; R ¹⁶ is selected from the group consisting of - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ , lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ¹⁶ are joined together via 2 to 6 atoms, optionally containing one heteroatom selected from O, N and S; each R ¹⁷ is independently selected from the group consisting of lower alkyl, lower aryl and lower aralkyl or R ¹⁷ and R ¹⁷ to N are connected to each other via 2 to 6 atoms, optionally containing one heteroatom selected from O, N and S; and pharmaceutically acceptable prodrugs and salts thereof. 430 84. The pharmaceutical composition of claim 83, wherein said composition comprises an insulin or insulin analog selected from the group consisting of insulin, insulin lispro, insulin aspart, and insulin gargline. 85. The pharmaceutical composition of claim 83 wherein said composition comprises a biguanide selected from the group consisting of metformin, phenformin, and buffmin. 86. The pharmaceutical composition of claim 83 wherein said composition comprises an α-glucosidase inhibitor selected from the group consisting of acarbose, miglitol, and voglibose. A pharmacist, said M is where Z 0 is selected from the group consisting of alkyl and halogen; U ⁶ and V 0 are independently selected from the group consisting of: hydrogen, hydroxy and acyloxy, or together, U ⁶ and V ^c form a lower cyclic ring containing at least one oxygen; W ⁶ is selected from the group consisting of amino and lower alkylamino; and pharmaceutically acceptable prodrugs and salts thereof. 431 88. The pharmaceutical composition of claim 83 wherein M is: where: A ² is selected from the group consisting of -NR%, -NHSO ² R ³ , -OR ²⁵ , -SR ²⁵ , halogen, lower alkyl, -CON (R ⁴ ) 2, guanidine, amidine, hydrogen and a perhaloalkyl group; E ² is selected from the group consisting of hydrogen, halogen, lower alkylthio, lower perhaloalkyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, -CN, and -NR ⁷ ₂ ; X ³ is selected from the group consisting of -alkyl (hydroxy) -, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkythioalkyl-, -alkythio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, - a -alkoxycarbonylamino- group and a -alkylaminocarbonylamino- group, all optionally substituted, provided that X ³ is not substituted with -COOR ² , -SO 3 H, or -PO ³ R ² 2; Y ³ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C (O) R ³ , -S (O) ₂ R ^3, -C (O) -R ^n, a group -CONHR ³ group, a -OR -NRS, all except H are optionally substituted; 432 each R ⁴ is independently selected from the group consisting of hydrogen and alkyl, or together R ⁴ and R ⁴ form a cyclic alkyl group; R ²⁵ is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic; R ⁷ is independently selected from the group consisting of hydrogen, lower alkyl, lower alicyclic, lower aralkyl, lower aryl and -C (O) R ¹⁰ ; R ⁸ is independently selected from the group consisting of hydrogen, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, -C (O) R ^10, or together R ⁸ together form a bidendate alkyl group; R ¹⁰ is selected from the group consisting of hydrogen, lower alkyl, -NH ₂ , lower aryl and lower perhaloalkyl, and R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and ^the group -0R; and pharmaceutically acceptable prodrugs and salts thereof. 89. The pharmaceutical composition of claim 83 wherein M is: A, E, and L are selected from the group consisting of -NR ³ _2, -N0 ₂ group, hydrogen, ^-0R? , -SR ⁷ , 433 -C (O) NR ⁴ 2 Z halo, -COR ^11, -SO 2 R ³ group, guanidino group, amidino group, a group -NHSO 2 R ^25, a group of -SCkNR ^ -CN, sulfoxide group, perhaloacylovú group, a perhaloalkyl, perhaloalkoxy , A C1-C5 alkyl group, a C2-C5 alkenyl group, a C2-C5 alkynyl group and a lower alicyclic group, or A and L together form a cyclic group or L and E form a cyclic group or together E and J form a cyclic group selected from the group consisting of an aryl, cyclic alkyl and heterocyclic group; J is selected from the group consisting of -NR%, -NO 2 radical, hydrogen, -OR ^7, -SR ^7, -C (O) NR ⁴ 2 Z halogen, -C ^(O) R, -CN , a sulfonyl group, a sulfoxide group, a perhaloalkyl group, a hydroxyalkyl group, a perhaloalkoxy group, an alkyl group, a haloalkyl group, an aminoalkyl group, an alkenyl group, an alkynyl group, an alicyclic group, an aryl group and an aralkyl group, or together with Y form a cyclic group , cyclic alkyl and heterocyclic; X ³ is selected from the group consisting of -alkyl (hydroxy) -, -alkyl · -, -alkynyl, -aryl · -, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl- , -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl -alkoxycarbonylamino- and -alkylaminocarbonylamino-, all optionally substituted, with the proviso that X ³ is not substituted with -COOR ² , -SO 3 H or -PO ³ R ² 2; Y ^{3 e} j selected from-H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C (O) ^R3, -S (O) ₂ R ³ / 434 -C (O) -R ¹¹ , -CONHR ³ , -NR ² _2, and -OR ³ , all except hydrogen are optionally substituted; R ⁴ is independently selected from the group consisting of hydrogen and alkyl or R ⁴ and R ⁴ together form a cyclic alkyl group; R ²⁵ is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic; R ⁷ is independently selected from the group consisting of hydrogen, lower alkyl, lower alicyclic, lower aralkyl, lower aryl and -C (O) R ¹⁰ ; alkyl R ⁸ is independently selected from hydrogen, lower, lower aralkyl, lower alicyclic and lower aryl -C (O) R ¹⁰ , or together form a bidendate alkyl group; R ¹⁰ is selected from the group consisting of hydrogen, -NH ₂ , lower aryl and lower lower perhaloalkyl; is selected from aryl, -NR ² ₂ R ^N-containing alkyl, and -OR ^2; and pharmaceutically acceptable prodrugs and salts thereof. 90. The pharmaceutical composition of claim 87 wherein M is: where A 435 B ⁵ is selected from the group -NH-, -N = and -CH =; D ⁵ is selected from the group Q ^{5 e} j selected from with the proviso that: contain what -C = a N; when B ⁵ is -NH-, Q ⁵ is -C = and D ⁵ is l_ when B ⁵ is -CH =, Q ⁵ is -N- and D ⁵ is ^c , a when B ⁵ is -N =, 1 D ⁵ is ^N and Q ⁵ is -C, A, E and L are selected from the group consisting of -NR ⁸ 2, -NO 2, hydrogen, -OR ⁷ , -SR ', -C (O) NR ⁴ 2f halogen, -COR ¹¹ , - SO 2 R ^3, guanidino, an amidino group, a group -NHSO 2 R ^25, a group -S02NR ⁴ 2z -CN, sulfoxide group, perhaloacylovú group, a perhaloalkyl, perhaloalkoxy, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C ₂ -C 5 alkynyl and lower alicyclic, or A and L together form a cyclic group, or L and E together form a cyclic group, or E and J together form a cyclic group selected from the group consisting of aryl, cyclic alkyl and heterocyclic groups; J is selected from a group NR ^d 2, -NO 2 radical, hydrogen, -OR ^7, -SR ⁷ group, -Ο (Ο) ΝΒ ⁴ 2, halo, -C (0) R ¹¹ group, -CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or together with Y, form a group selected from Y; containing an aryl, cyclic alkyl and heterocyclic group; 436 X ³ is selected from the group consisting of -alkyl (hydroxy) -, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkythio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino-, all optionally substituted, with the proviso that X ³ is not substituted by -COOR ² , -SO 3 H or -PO ³ R ² 2; Y ³ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C (O) R ³ , -S (O) 2 R ³ , -C (O) -R ^n, a group -CONHR ^3, -NR ² 2, and -OR ^3, all except H are optionally substituted; R ⁴ is independently selected from the group consisting of hydrogen and alkyl or R ⁴ and R ⁴ together form a cyclic alkyl group; R ²⁵ is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic; R ⁷ is independently selected from the group consisting of hydrogen, lower alkyl, lower alicyclic, lower aralkyl, lower aryl and -C (O) R ^{± O} ; R ⁸ is independently selected from the group consisting of hydrogen, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, -C (O) R ^1C ; or together form a bidendate alkyl group; R ¹⁰ is selected from the group consisting of hydrogen, lower alkyl A 437 group, an -NH ₂ group, a lower aryl group, and a lower perhaloalkyl group; R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ³ , and pharmaceutically acceptable prodrugs and salts thereof. 91. The pharmaceutical composition of claim 83, vyznaču- Jucá in that the M is -XR ^5, wherein R ³ is selected from: each G is independently selected from C, N, O, S and Se and wherein only one G is O, S or Se and at most one G is N; each G 'is independently selected from C and N and wherein no more than two G 'groups are N; A is -CONR ⁴ 2, -SO ₂ R ³ , an alkyl group selected from the group consisting of -CO ₂ R ³ , a group, a perhaloalkyl group, a -CH ₂ OH group, a group -C (S) NH ₂ , a group - NHC (S) NR ⁴ _2, -NHAc group H, -NR ⁴ _2, halo, -S (O) ^R3, alkenyl group, alkynyl group, a haloalkyl group, an aryl _--CH2 NR ^<2 , -CH ₂ CN, -CN, -OR ³ , -SR ³ , and zero; ?, -N group, each B and D are independently selected from-H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, -C ^(O) R, a - C (O) SR ³ , -SO ² R ¹¹ , -S (O) R ³ , -CN, -NR ⁹ ₂ , sku 438 -OR ³ , -SR ³ , perhaloalkyl, halogen, -NO _2, and zero, all except hydrogen, -CN, perhaloalkyl, -NO _2, and halogen are optionally substituted; E is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, -C (O) OR ³ , -CONR ⁴ 2, -CN, -NR ⁹ 2 , -NO ₂ , -OR ³ , -SR ³ , perhaloalkyl, halogen and zero, all except hydrogen, cyano, perhaloalkyl and halogen are optionally substituted; J is selected from hydrogen or zero; X is an optionally substituted linking group that connects R ⁵ to a phosphorus atom through 2 to 4 atoms containing 0 to 1 heteroatom selected from N, O and S, except that when X is urea or carbamate, then there are 2 heteroatoms between R ⁵ and the phosphorus atom, measured by the shortest route, and wherein the atom attached to phosphorus is a carbon atom and wherein X is selected from the group consisting of -alkyl (hydroxy) -, -alkynyl -, -heteroaryl-, -carbonylalkyl- a group, -1,1-dihaloalkyl, -alkoxyalkyl, -alkyloxy, -alkythioalkyl, -alkyloxy, -alkylaminocarbonyl, -alkylcarbonylamino, -alkoxycarbonyl, -carbonyloxyalkyl, - alkoxykarbcnylaminoskupinu and -alkylaminocarbonylamino- radical, all optionally substituted, with the proviso that X is not substituted with -COOR ^2, -SO 3 H group or a group of PC-.FC ?; R ² is selected from R ³ and hydrogen; R ^{3 e} j selected from the group consisting of alkyl of purchase, aryl, alicyclic, and aralkyl; each R ⁴ is independently selected from the group consisting of hydrogen and alkyl or R ⁴ and R ⁴ together form a cyclic alkyl 439 group; each R ⁹ is independently selected from the group consisting of hydrogen, alkyl, aralkyl and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group; ^The R d ^E is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ^2; with the proviso that: 1) when G 'is N, then the corresponding A, B, D or E is zero; 2) at least one of A and B or A, B, D and E is not selected from hydrogen or zero; 3) when R ⁵ is a six-membered ring, then X is not a bivalent atom, an optionally substituted -alkyloxy group or an optionally substituted -alkylthio group; 4) when G is N, then the corresponding A or B is not a halogen or a group directly bonded to G via a heteroatom; 5) when X is not an -aryl- group, then R ⁵ is not substituted with two or more aryl groups; and pharmaceutically acceptable prodrugs or salts thereof. 92. The pharmaceutical composition according to claim 91, characterized in that R ⁵ is selected from the group consisting of pyrrolyl, imidazolyl, oxazclylovú, thiazolyl, isothiazolyl, 1, 2, 4-riaciazoly- fishing, pyrazolyl, izoxazolvlovú group 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl with a group, 1,2,5-oxadiazolyl with a group, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pvridyl, pyrimidinyl, pyrazyl, pyridazyl, 1,3,5-triazinyl, 1,2,4-tri 440 an azinyl group and a 1,3-selenazolyl group, all containing at least one substituent. 93. The pharmaceutical composition of claim 92, characterized in characterized in that R ⁵ is selected from: where A is selected from the group consisting of hydrogen, -NR 1; -CONRS, -CO 2 R ³ , halogen, C 1 -C 3 alkyl, C 1 -C 3 alkyl; ^A C 6 alkenyl group, a C 1 -C 8 alkynyl group, a C 1 -C ₅ perhaloalkyl group, a C 1 -C ₆ haloalkyl group, an aryl group, a -CH ₂ OH group, a -CH ₂ NR ⁴ ₂ group, a -CH ₂ CN group, a group -CN, -C (S) NH _2, -OR ^3, -SR ^3, -N ·, -NHC (S) NR a group -NHAc%; 441 B and D 'are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, -CťOjR ¹¹ , -C (O) SR ³ , -SO2R skupinu ¹¹ , -S (O) R ³ , -CN, -NR ⁹ ₂ , -OR ³ , -SR ³ , perhaloalkyl, and halogen, all except hydrogen, CN, perhaloalkyl, and halogen are optionally substituted ; E is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C ₂ -C 6 alkenyl, C ₂ -C ₆ alkynyl, C 1 -C ₆ alicyclic, alkoxyalkyl, -C (O) OR ³ , -CONR ⁴ 2, -CN, -NR ⁹ 2, -OR ^3, -SR ^3, C1-C6 perhaloalkyl, and halo, all except H, CN, perhaloalkyl, and halo are optionally substituted; and each R ³ is selected from the group consisting of a C ₂ -C 6 alkyl group, a C 6 aryl group, a C 3 -C 6 heteroaryl group, a C ₃ -C ₈ alicyclic group, a C ₂ -C ₃ heteroalicyclic group, a C 7 -C 10 aralkyl group and a C ₄ -C ₈ C 9 heteroaralkyl; each R ⁴ and R ⁹ is independently selected from the group consisting of hydrogen and C 1 -C ₂ alkyl; X is selected from the group consisting of -heteroaryl, -alkylcarbonylamino, -alkylaminocarbonyl, and -alkoxycarbonyl; each R ¹¹ is selected from the group consisting of -NR ⁴ 2, -OH, -OR ³ , C 1 -C 6 alkyl, C 5 aryl, and C ₃ -C 5 heteroaryl. 94. The pharmaceutical composition of claim 93 wherein said FBPase inhibitor is a compound of formula IA wherein R ⁵ is: 442 A is selected from the group consisting of -NH ₂ , -CONH ₂ , halogen, -CH ₃ , -CF ₃ , -CH ₂ -halogen, -CN, -OCH ₃ , -SCH _3, and hydrogen; B is selected from-H, -C (O) ^RU, -C (0) ^SR3, alkyl, aryl, alicyclic, halo, -CN, -SR ^S, -OR ³ and -NR ⁹ ₂ , a X is selected from the group consisting of -heteroaryl-, -alkoxycarbonyl- and -alkylaminocarbonyl-, all optionally substituted, and wherein 0 R ¹² II I R ¹⁸ 0 I II 14 1 '1 R ¹⁴ --- C-- C— I II -N --- P ---- R ¹³ NR ¹³ R ¹⁸ is selected from the group consisting of CH, O i1 II ^ί Γ CH ₃ ² a p EtOOC-C * H R ¹⁸ and R ¹⁵ are each independently selected from hydrogen and methyl wherein C * has the stereochemistry S; 443 groups, each R ¹² and R ¹³ are independently selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl and benzyl, or R ¹² and R ¹³ are joined together via 2 to 5 carbon atoms to form a cycloalkyl group; n = 1, R ¹⁴ is -OR ¹⁷ , R ¹⁶ is - (CR ¹² R ⁿ⁾ "-C (0) -R ^14, and R ¹⁷ is selected from the group consisting of methyl, ethyl, propyl, phenyl and benzyl. 95. The pharmaceutical composition of claim 94, wherein said composition comprises an insulin or insulin analog selected from the group consisting of insulin, insulin lispro, insulin aspart, and insulin garglin. 96. The pharmaceutical composition of claim 94 wherein said composition comprises a biguanide selected from the group consisting of metformin, phenformin and buformin. 97. The pharmaceutical composition of claim 94, wherein said composition comprises an α-glucosidase inhibitor selected from the group consisting of acarbose, miglitol, and voglibose. 98. The pharmaceutical composition of claim 83 wherein M is: 444 where: G 1 is selected from -O- and -S-; A ² , L ² , E ² and J ² are selected from the group consisting of -NR ⁴ 2, -NO 2, hydrogen, -OR ² , -SR ² , -C (O) NR ⁴ 2, halogen, a group -COR ^11, -SO 2 R ³ group, guanidinyl, amidinyl, aryl, aralkyl, alkyloxyalkyl group, SCN group, -NHSO 2 R ^9, -SO 2 NR ⁴ 2 group, -CN, -S (O) R ³ , perhaloacyl, perhaloalkyl, perhaloalkoxy, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl and a lower alicyclic group or L ² and E ² together or 1 'and J ² together form a null cyclic group ; X ² is selected from the group consisting of -CR ² 2-, -CF 2 -, -CR ² O-, -CR ^{2 2} S-, -C [O] -O-, -C (O) - S-, -C (S) -O-, and CR ² 2-NR ¹⁹ - and wherein the atom attached to phosphorus is a carbon atom, with the proviso that X ^c is not substituted with -COOR ² , -SO 3 H or -PO ³ R ² 2; R ² is selected from R ³ and hydrogen; R ³ is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; each R ⁴ is independently selected from hydrogen and alkyl, or together R ⁴ and R ⁴ form a cyclic alkyl group; 445 each R ⁹ is independently selected from the group consisting of hydrogen, alkyl, aralkyl and alicyclic, or together R ⁹ and R ⁹ together form a cyclic alkyl group; R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ² ; R ¹⁹ is selected from the group consisting of lower alkyl, hydrogen and -COR ² , and pharmaceutically acceptable prodrugs and salts thereof. 99. A method of treating a mammal having diabetes comprising administering to said mammal a pharmaceutically effective amount of component (a) comprising at least one insulin, an insulin analog, a biguanide, a liver glucose inhibitor or an α-glucosidase inhibitor, and a pharmaceutically effective amount of the ingredient. (b) comprising at least one FBPase inhibitor. · 100. The method of claim 99, wherein said insulin or insulin analog is selected from the group consisting of insulin, insulin lispro, insulin aspart and insulin garglin. 101. The method of claim 99, wherein said biguanide is selected from the group consisting of metformin, phenformin and buformin. 102. The method of claim 99 wherein said hepatic glucose production inhibitor is selected from the group consisting of glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists, amylin agonists, and fatty acid oxidation inhibitors. 103. The method of claim 102 446, wherein said amylin agonist is pramlintide. 104. The method of claim 99, wherein said alpha-glucosidase inhibitor is selected from the group consisting of acarbose, miglitol, and voglibose. 105th process healing by Claim 99 - c i by doing that FBPase inhibitor is a compound of formula I and IA: 1 J R ¹⁸ 0 i II R ¹ Yi --- MR ¹⁴ --- «I II -C (0) --- (CR ¹² R ¹³ ) _n —N --- P- -M fR ¹ nr ¹⁵ r ¹⁸ I IA wherein the compounds of Formula I and IA are converted in vivo or in vitro to M-PO3 ² ', which inhibits FBPase, and wherein: Y is independently selected from -O- and -NR ⁶ , with the proviso that: when Y is -O-, R ¹ attached to -O- is independently selected from the group consisting of hydrogen, alkyl, optionally substituted aryl, optionally substituted alicyclic, wherein the cyclic group comprises carbonate or thiocarbonate, optionally substituted -arylalkyl, -C (R ² ) 2 OC (O) NR ² 2, -NR ² -C (O) -R ³ , -C (R ² ) ₂ -OC (O) R ³ , -C (R ² ) 2-O-C (O) OR ³ , -C (R ² ) OC (O) SR ³ , -alkyl-SC (O) R ³ , -alkyl-SS-alkylhydroxy and -alkyl-SSS-alkylhydroxy group; when Y is -NR ⁶ -, R ¹ attached to NR ⁶ is independently selected from the group consisting of hydrogen, - [C (R ² ) 2] q - COOR ³ , -C (R ⁴ ) 2 COOR ³ , - [ C (R ² ) ₂ ] q C (O) SR and a -cycloalkylene-COOR ³ group wherein q is 1 or 2; when only one Y is -O-, wherein -O- is not part of a cyclic group containing a second Y, then the other Y is a group 447 -N (R ¹⁸ ) - (CR ¹² R ¹³ ) -C (O) -R ¹⁴ ; and when Y is independently selected from -0- and -NR ^6, R ¹ and R ¹ together are alkyl-SS-alkyl to form a cyclic group, or ^R1 and R together are: where a) V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl, or V and Z are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group being fused to an aryl group at the β and γ position to Y attached to V; or Z is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OC (S) OR ³ , -CHR ² OC (0) SR ³ , -CHR ² OCO ² R ³ , -OR ² , -SR ² , -CHR ^Z N 3, -CH 2 aryl, -CH (aryl) OH, -CH (CH = CR ² 2) ) OH, -CH (ΟξΟΗ ² ) OH, -R ² , -NR ² ₂ , -OCOR ³ , -OCO2R ³ , -SCOR ³ , -SCO2R ³ , -NHCOR ² , - NHCO ² R ³ , -CH ₂ NHaryl, - (CH ₂ ) _p -OR ^2, and - (CH ₂ ) _p -SR ² , wherein p is an integer of 2 or 3; or Z and W are joined together via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, and V must be an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group 448 group; or W and W 'are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or W and W 'are joined together via an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V must be an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group; b) V ² , W ² and W are independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; Z ² is selected from the group consisting of -CHR ² OH, -CHR ² OC (O) R ³ , -CHR ² OC (S) R ³ , -CHR ² OCO ² R ³ , -CHR ² OC (S) OR ^3, -CHR ² 0C (0) SR ^3, -CH (aryl) OH, -CH (CH = CR ² 2) OH, -CH (CSCR ²⁾ OH, -SR ^2, is - CH ₂ NHaryl, -CH ₂ aryl; or V ² and Z ² are joined together via an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 ring atoms, optionally containing 1 heteroatom and substituted with hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom which is three atoms from a group Y attached to phosphorus; c) Z 'is selected from the group consisting of -OH, -OC (O) R ³ , -OCO ₂ R ^3, and -OC (O) SR ³ ; D 'is hydrogen; 449 D is selected from the group consisting of hydrogen, alkyl, -OIV, -OH, and -OC (O) R ³ ; each W ³ is independently selected from the group consisting of hydrogen, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; with the proviso that: a) V, Z, W, W 'are not all hydrogen and V ² , Z ² , W ² , W are not all hydrogen; R ² is selected from R ³ and hydrogen; R ³ is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; each R ⁴ is independently selected from the group consisting of hydrogen and alkyl, or together R ⁴ and R ⁴ form a cyclic alkyl group; R ⁶ is selected from the group consisting of hydrogen, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl; n is an integer from 1 to 3; R ¹⁸ is independently selected from-H, lower alkyl, aryl, aralkyl, or R ^{L R} and ^R18 are connected via 1-4 carbon atoms to form a cyclic group; each R ¹¹ and R ¹³ is independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, lower aralkyl, all of which may be optionally substituted, or R ¹² and R ¹³ are joined together via 2 to 6 carbon atoms to form a cyclic group; 450 each R ¹⁴ is independently selected from the group consisting of -OR ¹⁷ , -N (R ¹⁷ ) ₂ , -NHR ^17, and -SR ¹⁷ ; R ¹⁵ j ^E selected from-H, lower alkyl, lower aryl, and lower aralkyl, or R ¹⁵ and R ¹⁶ are connected via 2-6 atoms, optionally containing one heteroatom selected from O, N and S; R ¹⁶ is selected from the group consisting of - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ , a lower alkyl group, a lower aryl group and a lower aralkyl group, or R ¹⁵ and R ¹⁶ are linked together via 2 to 6 atoms optionally containing one heteroatom selected from O, N and S; each R ¹⁷ is independently selected from the group consisting of lower alkyl, lower aryl and lower aralkyl, or R ¹⁷ and R ¹⁷ to N are connected to each other via 2 to 6 atoms, optionally containing one heteroatom selected from O, N and S ; M includes: A Y ³ J where: A, E, and L are selected from the group NR ₂ ^B, a group _-NO2, hydrogen, -OR ^7, -SR ', -C (O) NR ⁴ 2, halo, -COR ^11, -SO ² R ³ , guanidine, amidine, -NHSO ² R ²⁵ , -SO ₂ NR ⁴ ₂ , -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C 1 -C ₅ alkyl, C ₂ -C 5 alkenyl , A C2-C5 alkynyl group and a lower alicyclic group, or A and L together form a cyclic group, or 451 L and E form a cyclic group or together E and J form a cyclic group selected from the group consisting of aryl, cyclic alkyl and heterocyclic groups; J is selected from the group consisting of -NR ⁸ 2, -N02 group, hydrogen, -OR ^7, -SR ^7, -C (O) NR ⁴ 2, halo, -C (0) R ¹¹ group, -CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or together with Y are selected from the group consisting of Y; containing an aryl, cyclic alkyl and heterocyclic group; X ³ is selected from the group consisting of -alkyl (hydroxy) -, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkythioalkyl-, -alkythio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl- , -alkoxycarbonylamino- and -alkylaminocarbonylamino-, all optionally substituted, provided that X ³ is not substituted with -COOR ² , -SO 3 H or -po ³ R ² 2; Y ³ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C (O) R ³ , -S (O) 2 R ³ , -C (O) -R ^n, a group -CONHR ^3, -NR ^ 2, and -OR ^3, all except H are optionally substituted; R ⁴ is independently selected from the group consisting of hydrogen and alkyl or R ⁴ and R ⁴ together form a cyclic alkyl group; 452 R ²⁵ is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic; R ⁷ is independently selected from the group consisting of hydrogen, lower alkyl, lower alicyclic, lower aralkyl, lower aryl and -C (O) R ¹⁰ ; R ⁸ is independently selected from the group consisting of hydrogen, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, -C (O) R ¹⁰ , or together form a bidendate alkyl group; R ¹⁰ is selected from the group consisting of hydrogen, lower alkyl, -NH ₂ , lower aryl and lower perhaloalkyl; R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ² , and M is -XR ⁵ , wherein R ⁵ is selected from: wherein: each G is independently selected from C, N, O, S and Se and wherein only one G is O, S or Se and at most one G is N; each G 'is independently selected from C and N and wherein no more than two G' groups are N; A is selected from-H, -NR ⁴ 2, -CONRS group, a group of -CO 2 R ^S, halogen, -S (O) R ^3, -SO 2 R ³ radical, an alkyl, alkenyl, alkynyl, 453 perhaloalkyl, haloalkyl, aryl, -CH ₂ OH, -CH ₂ NR ^I _2, -CH ₂ CN, -CN, -C (S) NH _2, -OR ³ group, -SR ³ , -N 3, -NHC (S) NR ⁴ 2, -NHAc, and zero; each B and D are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, -C (O) R ^L1 , -C (O) SR ³ , a group -SO 2 ^U, -S (O) R ^3, -CN, -NR ⁹ 2, -OR ^3, -SR ^3, perhaloalkyl, halo, -N0 ₂ and null, all except H , -CN, perhaloalkyl, -NO _2, and halogen are optionally substituted; E is selected from-H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, -C (O) OR ^J, -CONR ⁴ 2 Z -CN, -NR ⁹ 2, -NO ₂ , -OR ³ ) -SR ³ , perhaloalkyl, halogen and zero, all except hydrogen, cyano, perhaloalkyl and halogen are optionally substituted; J is selected from hydrogen or zero; X is an optionally substituted linking group that connects R ⁵ with a phosphorus atom via 2 to 4 atoms containing 0 to 1 heteroatom selected from N, O and S, except that when X is urea or carbamate, then there are 2 heteroatoms between R ⁵ and the phosphorus atom, measured by the shortest route, and wherein the atom attached to the phosphorus is a carbon atom and wherein X is selected from the group consisting of -alkyl (hydroxy), -alkynyl, -heteroaryl, -carbonylalkyl, 1,1-dihaloalkyl, -alkoxyalkyl, -alkyloxy, -alkythioalkyl, -alkyloxy, -alkylaminocarbonyl, -alkylcarbonylamino, -alkoxycarbonyl, -carbonyloxyalkyl, -alkoxycarbonylamino and an -alkylaminocarbonylamino group, all at 454 is substituted, with the proviso that X is not substituted with -COOR ² , -SO 3 H, or PO ³ R ² 2; R ^{2 e} j is selected from hydrogen and R ^3; R ³ is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; each R ⁴ is independently selected from the group consisting of hydrogen and alkyl or R ⁴ and R ⁴ together form a cyclic alkyl group; each R ⁹ is independently selected from the group consisting of hydrogen, alkyl, aralkyl and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group; ^E j R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ^2; with the proviso that: 1) when G 'is N, then the corresponding A, B, D or E is zero; 2) at least one of A and B or A, B, D and E is not selected from hydrogen or zero; 3) when R ⁵ is a six membered ring, then X is not a bivalent atom, an optionally substituted -alkyloxy group or an optionally substituted -alkylthio group; 4) when G is N, then the corresponding A or B is not a halogen or a group directly bonded to G via a heteroatom; 5) when X is not an -aryl- group, then R 0 is not subsubstituted with two or more aryl groups. 106. The pharmaceutical composition of claim 11, characterized in that M is -X ⁴ -R ⁵⁵ wherein R ⁵⁵ is selected from: 455 G ² G ³ is selected from the group C, O and G ⁴ are independently selected from wherein a) no more than one of G ² , G ² is O or G ³ and day of G ² , S, not more than G ⁴ is C and d) G ² , G ⁵ , G ⁵ a G ⁷ are independently more than two of G ⁵ , G ⁶ J ³ , ^{J5, J6,} and júcej hydrogen, a gene, a group, a group -C (0) R ^11, S ⁷ j; Vn-6 J® of C, N, G ³ and one: G ³ and G ⁴ of G ³ are not selected and G ⁷ are N; J ⁷ is independently -S (O) ₂ NR ⁴ _2, the G ⁴ is O and G is or S; (b) when N; (c) at least all C groups are C; and N, where not selected from the group consisting of -NR ⁴ 2, -CONR ⁴ 2, -CO 2 R ', halo -S (O) R ³ , -SO ² R ³ , alkyl alkenyl, alkynyl, alkylenaryl perhaloalkyl heteroaryl -OR ¹¹ , CN-CN, -SR ² , -N ₃ , -NR ²¹ COR ² ; X ⁴ is selected by the number of atoms a group, a group, a haloalkyl group, a -NO ₂ group, a group selected from the group consisting of: a group having from 2 to 3 4 atoms measured by an aryl group -alkyl is the group most attached to the aromatic ring carbon and the phosphorus atom and is selected from the group consisting of -furanyl-, -thienyl-, -pyridyl-, -oxazolyl-, -imidazolyl-, -phenyl-, -pyrimidinyl-, -pyrazinyl- and - alkynyl - all of which may be optionally 456 substituted; and ii) a linker group having 3 to 4 atoms measured by the least number of atoms connecting the aromatic ring carbon and the phosphorus atom and is selected from the group consisting of -alkylenecarbonylamino-, -alkyleneamininocarbonyl-, -alkyleneoxycarbonyl-, -alkyleneoxy- and -alkyleneoxyalkylene-, all may be optionally substituted; R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ² ; ^R20 is selected from-H, lower R ^S and -C (O) - (lower R ^3); R ²¹ is selected from the group consisting of hydrogen and lower R ³ ; with the proviso that: 1) when G ⁵ , G ⁶ or G ⁷ is N, then the corresponding J ⁴ , J ⁵ or J ⁶ is zero; 2) when X ⁴ is substituted furanyl, then at least one of J ³ , J ⁴ , J ⁵ and J ⁵ is not hydrogen or zero; 3) when X ⁴ is not substituted furanyl, then at least two of J ³ , J ⁴ , J ⁵ and J ⁶ of formula VII-5 or J ³ , J 1, J ⁵ , J ⁶ , J ⁷ in formula VII-6 is not hydrogen or zero; 4) when G ² , G ³ or G ⁴ is O or S, then the corresponding J ³ , J ⁴ or J ⁵ is zero; 5) when G ³ or G ⁴ is N, then the corresponding J ⁴ or J ⁵ is not halogen or a group directly bonded to G ³ or G ⁴ via a heteroatom; 6) if both Y groups are -NR ⁰ - and R ¹ and R ¹ are not joined to form a cyclic phosphoramidate, then at least one of R ¹ is - (CR ¹² R ¹³ ) _n ^- C (O) -R ¹⁴ ; 457 7) when X ⁴ is -alkylenecarbonylamino- or -alkyleneamininocarbonyl-, then G ⁵ , G ⁶ and G ⁷ are not all C; 8) when X ⁴ is -alkenoxyalkylene- and G ⁵ , G ⁶ and G ⁷ are all C, then neither J ⁴ nor J ⁶ can be substituted with an acylated amine; 9) when R ⁵⁵ is a substituted phenyl group, then J ⁴ , J ⁵ and J ⁶ are not purinyl, purinylalkylene, deaza-purinyl or deazapurinalkylene; 10) R ¹ may be selected from a lower alkyl group only when the second YR ¹ is -NR ¹⁸ - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ ; 11) when R ⁵⁵ is substituted phenyl and X ⁴ is 1,2-ethynyl, then J ⁴ or J ⁶ is not a heterocyclic group; 12) when X ⁴ is a 1,2-ethynyl group, then G ⁵ or G ⁷ cannot be N; and pharmaceutically acceptable prodrugs and salts thereof. 107 A pharmaceutical composition, wherein said a is as in claim 40 The FBPase inhibitor is 108. The method of claim 46 or 99, wherein said component (a) and said component (b) are administered over an hour. 458 109. The method of claim 108, wherein said component (a) and said component (b) are administered over a 10 minute period. 110. The method of claim 46 or 99, wherein one of said component (a) and said component (b) is administered first and the other of said component (a) and said component (b) is administered 1 to 12 hours later. 111. The method of claim 46 or 99, wherein said mammal is a brittle diabetic. 112. The method of claim 46 or 99, wherein said mammal has NIDDM. 113. The method of claim 46 or 99, wherein said mammal has IDDM. 114. The pharmaceutical composition of claim 9, wherein said glucagon-like peptide-1 (GLP-1) receptor agonist is NN-2211 or exendin.