RU2328308C2 - Combinated inhibitors of fbp-ase and antidiabetic agents for diabetes treatment - Google Patents

Abstract

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to pharmacological formulation used for prevention and treatment of diabetes, containing at least one agent stimulating insulin secretion and at least one inhibitor of FBP-ase, selected of composition formulations I

and IA

.

EFFECT: improved therapeutic efficiency.

142 cl, 2 dwg, 21 tbl, 15 ex

Description

Related Applications

This application confirms the advantage of the provisional application, serial number 60/216531, entitled "Combination of FBPase inhibitors and antidiabetic agents for diabetes", which was filed July 6, 2000 and which is entered into the description by reference in full, including the figures.

The technical field of the invention

Combination therapy is described comprising at least one FBPase inhibitor and at least one other antidiabetic agent.

BACKGROUND OF THE INVENTION

At present, diabetes mellitus (usually also called "diabetes") is one of the most common diseases in the world. Diabetes patients (i.e., diabetics) are divided into two classes, namely, patients with type I diabetes, or insulin-dependent diabetes mellitus (IDDM), and patients with type II diabetes, or non-insulin-dependent diabetes mellitus (NIDDM).

Patients with IDDM are usually treated with insulin or insulin analogs. However, a subpopulation of the aforementioned patients, called “labile diabetic patients”, is difficult to treat with said therapy.

NIDDM patients account for approximately 90% of all diabetes patients, and NIDDM patients have been found to comprise 12-14 million adults in the United States alone (6.6% of the population). The three main metabolic disorders associated with NIDDM are: (a) impaired insulin secretion by the pancreas, (b) insulin resistance in peripheral tissues such as muscle and adipose tissue, and (c) increased liver glucose production (i.e., hepatic glucose production). These disorders usually lead to both fasting hyperglycemia and an abnormally increased postprandial increase in plasma glucose levels.

Diabetes is associated with a range of chronic complications, including microvascular diseases such as retinopathy, nephropathy and neuropathy, and macrovascular diseases such as coronary heart disease. Numerous studies in animal models have identified a causal relationship between prolonged hyperglycemia and known complications of diabetes. The results of the Diabetes and Complications Control Study (DCCT) and the Stockholm Prospective Study for the first time clearly demonstrated this relationship in humans, finding that patients with IDDM who had more stringent glycemic control were significantly lower at the risk of developing and progressing known diabetes complications. It is also believed that tight glycemic control is beneficial for patients with NIDDM.

Existing therapy for the treatment of patients with NIDDM includes both the control of lifestyle-related risk factors and pharmaceutical intervention. The first line of therapy for NIDDM is a tightly controlled diet and exercise regimen, as the vast majority of NIDDM patients are overweight or obese (67%), and weight loss can improve insulin secretion and / or insulin sensitivity and thus lead to normoglycemia. However, normalization of blood glucose levels occurs in less than 30% of these patients due to poor adherence to therapy and poor response to therapy. Patients in whom hyperglycemia is not regulated by a single diet are usually treated with oral hypoglycemic agents and / or insulin.

The four main classes of commonly prescribed oral medications are insulin secretion enhancing agents (e.g. sulfonylureas: glyburide, glimeperide and glipizide), biguanides (e.g. metformin and fenoformin), insulin sensitizers (e.g. rosiglitazone and pioglitozidazone) (e.g. acarbose). The targets for enhancing insulin secretion are defects in the secretion of insulin by the pancreas, disorders that are usually observed in patients with diabetes. Classical representatives of this class, as well as newer agents such as meglitinides (e.g. nateglanide and repaglinide), stimulate the secretion of insulin from the pancreas by binding to the adenosine triphosphate (ATP) -dependent channels of the pancreatic beta cells. Other insulin secretion enhancers include the glucagon-like peptide (GLP-1), whose main site of action is also the beta cell. Substances that prolong the half-life of GLP-1, that is, dipeptidyl peptidase IV (DPP-IV) inhibitors, are also considered as agents that enhance insulin secretion.

Biguanides have been used for several decades. The mechanism of action of this class of compounds is not yet clear, but in recent years it has been established that the glucose-lowering effect of metformin is largely due to the inhibition of glucose production in the liver.

Insulin sensitizers are another class of oral medication. It turned out that peroxisome proliferator-activated receptors (PPAR-gamma) are the target for most of the recently introduced class of antidiabetic insulin sensitizers. It is described that said drugs increase insulin-mediated glucose uptake and inhibition of glucose production in the liver without directly stimulating insulin secretion.

Clinical data regarding treatment with sulfonylureas, biguanides, and insulin sensitizers in patients with NIDDM show that even at maximum therapeutic doses, fasting blood glucose and Alc hemoglobin levels do not decrease below levels associated with chronic diabetes complications.

The last of the classic oral agents is the class of alpha-glucosidase inhibitors. Alpha glucosidases are enzymes responsible for the breakdown of complex hydrocarbons in the gastrointestinal tract and, thus, for the absorption of simple carbohydrates. Alpha glucosidase inhibitors prevent the rapid breakdown of hydrocarbons and, therefore, slow their absorption. These inhibitors inhibit postprandial deviations of glucose from the usual level observed in patients with diabetes.

A number of experimental approaches target the overproduction of glucose by the liver. Means from the said class of inhibitors of glucose production in the liver include: (a) glycogen phosphorylase inhibitors that prevent the breakdown of glycogen stores in the liver, (b) glucose-6-phosphatase inhibitors that block the release of glucose resulting from gluconeogenesis and glycolysis, ( c) glucagon antagonists, which act by reducing the stimulatory effects of glucagon on glucose production in the liver, and (d) amylin agonists, which improve glycemic control in part by inhibiting glucagon secretion, and (e) inhibitors of fatty acid oxidation, which reduce the stimulating effect that fatty acid oxidation has on gluconeogenesis.

The results of a prospective study of diabetes in the UK showed that patients who were treated with the maximum therapy with insulin, sulfonylurea or metformin did not manage to maintain normal fasting blood glucose levels for a six-year study period. U.K. Prospective Diabetes Study 16. Diabetes, 44: 1249-158 (1995). A clinical study of the recently introduced class of insulin sensitizers was insufficient to assess whether the drugs mentioned are capable of long-term monitoring of blood glucose levels. However, in order for the insulin sensitizers to be effective, the functioning of the pancreas is necessary, and thus they are of limited value for the treatment of progressive diabetes. There remains a need for alternative therapy for NIDDM.

It is believed that the increased rate of glucose production by the liver, characteristic of NIDDM, is mainly due to the activation of gluconeogenesis. Magnusson et.al. J. Clin. Invest. 90: 1323-1327 (1992). Gluconeogenesis is highly regulated in a biosynthetic manner dependent on eleven enzymes through which precursors such as lactate, pyruvate, alanine and glycine are converted to glucose. Seven enzymes catalyze reversible reactions and are common to both gluconeogenesis and glycolysis. Four enzymes catalyze exclusively gluconeogenesis reactions, namely pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-6-bisphosphatase and glucose-6-phosphatase. The entire metabolic pathway is controlled by the specific activities of these enzymes, which catalyze the corresponding stages in the glycolytic pathway, and the availability of substrates. Dietary factors (e.g., carbohydrates, protein, and fat) and hormones (e.g., insulin, glucagon, glucocorticoids, and epinephrine) coordinate enzyme activity in the metabolic pathways of gluconeogenesis and glycolysis through gene expression and post-translational mechanisms.

Gruber reported that some nucleosides can reduce glucose in the blood of an animal by inhibiting FBPase. Said compounds exhibit activity first by phosphorylation to the corresponding monophosphate. Gruber et al. (US Patent No. 5658889, EP 0427799 B1) describes the use of inhibitors of the AMP FBPase site for the treatment of diabetes. WO 98/39342 (US patent No. 6054587), WO 98/39343 (US patent No. 6110903), WO 98/39344 and WO 00.14095 describe the use of FBPase inhibitors for the treatment of diabetes.

SUMMARY OF THE INVENTION

Due to the prevailing need for diabetes, other diabetic medicines are required. None of the links described in the description refers to the previous level in this field, and all entered into the description by reference in their entirety.

The present invention provides a combination therapy and composition for treating diabetes or other diseases or conditions requiring improved glycemic control and / or increased peripheral sensitivity to insulin and / or increased insulin secretion. Therapy includes the administration of at least one FBPase inhibitor and at least one antidiabetic agent either together or at different times so that the desired response is achieved. Although any suitable antidiabetic agent can be used in combination with an FBPase inhibitor, the antidiabetic agent used in this invention (a) is usually selected from one or more of the following: (a) insulin secretion enhancing agents (e.g., sulfonylurea derivatives, non-derivatives sulfonylureas, GLP-1 receptor agonists, DPP-IV inhibitors, or other known agents that enhance insulin secretion), (b) insulin or insulin analogs, (c) insulin sensitizers (e.g. rosiglitazone and pioglitazone), (d) biguanides (e.g. metformin and phenformin), (e) alpha glucosidase inhibitors (e.g. acarbose), (f) glycogen phosphorylase inhibitors, (g) glucose-6 phosphatase inhibitors, (h) glucagon antagonists, (i) amylin agonists; or (j) fatty acid oxidation inhibitors.

In certain aspects of the 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 in excess of the decrease observed with glucose lowering doses of the antidiabetic agent in the absence of an FBPase inhibitor . In addition, combination therapy can lead to increased insulin sensitivity and / or insulin secretion, exceeding the increase in these factors observed when using any agent separately, and also provides a beneficial effect on carbohydrate and / or lipid (e.g. fat), and / or protein metabolism.

In other aspects of the invention, when using combination therapy, they achieve such an effective effect as is obtained with one of the other methods of treatment, however, at significantly lower doses of the therapy in question. The described phenomenon can be especially favorable, for example, when possible harmful side effects are associated with the treatment. For example, in certain aspects of the invention, combinations of the invention are used to attenuate some of the potential adverse effects associated with treatment with an FBPase inhibitor. Similarly, combinations of the invention can attenuate some of the potential detrimental effects associated with other antidiabetic agents, such as hyperinsulinemia, hypoglycemia, weight gain, gastrointestinal upsets, liver disorders, and adverse cardiovascular disorders.

Compared to the response rates associated with therapies including antidiabetic agents without an FBPase inhibitor, the combinations of the invention improve the primary response rate. In addition, combinations of the invention can reduce, slow down or prevent the occurrence of secondary disorders.

The present invention also relates to methods and compositions for treating an animal suffering from diabetes by administering to an animal a composition comprising a pharmaceutically effective amount of at least one FBPase inhibitor and a pharmaceutically effective amount of at least one other antidiabetic agent. In some aspects, the compositions of the invention are used to treat, improve, or prevent one or more symptoms of diabetes. In addition to methods and compositions for treating animals with diabetes, the invention also includes methods and compositions for treating diseases or conditions characterized by insulin resistance, including obesity, arterial hypertension, impaired glucose tolerance, diabetes of pregnant women and polycystic ovary syndrome. In addition, individuals with Syndrome X, kidney disease, or pancreatitis are also effectively treated with certain types of combination therapy. Particularly preferred combinations are characterized by the aforementioned therapeutic effects, as well as high efficacy and low toxicity.

Definitions

In accordance with this invention and as used here, the following terms have the following meanings, unless clearly indicated otherwise.

The term "diabetes" includes NIDDM and IDDM.

The term “labile diabetic patients” refers to subjects with insulin-dependent diabetes mellitus associated with glycemic instability, characterized by frequent and sharp fluctuations between hypoglycemia and hyperglycemia.

Used in the description of the nomenclature of groups X, X ² , X ³ and X ⁴ in the formulas II, II-A, III, III-A, IV, IV-A, V-1, V-1-A, V-2, V -2-A, X, XA, VII-1, VII-1-A, VII-2, and VII-2-A begins with a group attached to phosphorus and ends with a group attached to a heteroaromatic or aromatic ring. For example, if X is alkylamino in formula V-1, the following structure is contemplated:

P (O) (YR ¹ ) _2- alk-NR- (heteroaromatic ring).

Similarly, groups 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 and other substituents of the heteroaromatic or aromatic ring are described in such a way that the term ends with a group attached to the heteroaromatic or aromatic ring. In general, substituents are called so that the term ends with a group at the point of accession.

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

“Carbocyclic aryl” groups mean groups in which the ring atoms of the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and polycyclic or fused compounds, such as optionally substituted naphthyl groups.

“Heterocyclic aryl” or “heteroaryl” groups mean groups containing 1-4 heteroatoms in the form of ring atoms in the aromatic ring, and the remaining atoms in the ring are carbon atoms. Suitable heteroatoms include, for example, oxygen, sulfur, nitrogen and selenium. Suitable heteroaryl groups include, for example, furanyl, thienyl, pyridyl, pyrrolyl, lower N-alkylpyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl and the like, optionally all substituted.

The term “annelation” or “annelated” refers to the formation of an additional cyclic fragment on an existing aryl or heteroaryl group. The newly formed ring may be carbocyclic or heterocyclic, saturated or unsaturated and contain 2-9 atoms, 0-3 of which may be heteroatoms selected from groups N, O and S. Annelation may introduce atoms from group X as part of the newly formed ring . For example, the phrase “L ² and E ² together form an annelinated cyclic group” with respect to formula XA includes:

The term “biaryl” represents aryl groups containing more than one aromatic ring, and includes both fused ring systems and aryl groups substituted with other aryl groups. Such groups may optionally be substituted. Suitable biaryl groups include, for example, naphthyl and biphenyl.

The term "alicyclic" means groups that combine the properties of aliphatic and cyclic groups. Such cyclic groups, without limitation, include aromatic, cycloalkyl, and bridged cycloalkyl groups. The cyclic group includes heterocycles. Cyclohexenylethyl and cyclohexylethyl are examples of suitable alicyclic groups. Such groups may optionally be substituted.

The term “optionally substituted” includes groups substituted by zero to four substituents independently selected from lower alkyl, lower aryl, lower aralkyl, lower alicyclic, heterocyclic alkyl, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkyloxy, heteroaryl, heteroaryloxy, , heteroaralkyloxy, azido, amino, guanidino, amidino, halogen, lower alkylthio, oxo, acylalkyl, carboxy esters, carboxyl, β-carboxamido, nitro, acyloxy, aminoalkyl, alkylaminoaryl, alkyl silt, alkylaminoalkyl, alkoxyaryl, arylamino, aralkylamino, phosphono, sulfonyl, -carboxamidoalkylaryl, -carboxamidoaryl, hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy-, aminocarboxaminoalkyl-, cyano, lower alkoxyalkylalkyl, lower alkoxyalkylalkyl.

The term “substituted” includes groups substituted with one to four substituents independently selected from lower alkyl, lower aryl, lower aralkyl, lower alicyclic, heterocyclic alkyl, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaryloxy, heteroaryloxy, heteroaryloxy, heteroaryloxy azido, amino, guanidino, amidino, halogen, lower alkylthio, oxo, acylalkyl, carboxy esters, carboxyl, -carboxamido, nitro, acyloxy, aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoal yl, alkoxyaryl, arylamino, aralkylamino, phosphono, sulfonyl, -kaboksamidoalkilarila, -karboksamidoarila, hydroxyalkyl, haloalkyl, alkilaminoalkilkarboksi-, aminokarboksaminodoalkila-, cyano, lower alkoxyalkyl, and lower perhaloalkyl arilalkiloksialkila. "Substituted aryl" and "substituted heteroaryl" preferably refer to aryl and heteroaryl groups substituted with 1-3 substituents. Preferably, said substituents are selected from lower alkyl, lower alkoxy, lower perhaloalkyl, halogen, hydroxy and amino. In the description of R ⁵ or R ⁵⁵ , the “substituted” group does not include annelation.

The term “aralkyl” refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl and the like, and may optionally be substituted. The term “aralkyl-” refers to the divalent group of aryl-alkylene-.

The term “alkylaryl-” refers to an -alk-aryl- group in which “alk” means an alkylene group. “Lower alkylaryl-” refers to those groups in which alkylene is lower alkylene.

Mentioned in the description in connection with organic radicals or compounds, the term "lower" defines those radicals or compounds that contain up to and including 10, preferably up to and including 6 and preferably from one to four carbon atoms. Such groups may be straight chain, branched chain or cyclic.

The terms “arylamino” (a) and “aralkylamino” (b) respectively refer to the group —NRR ′, in which respectively (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” refers to —C (O) R, where R is alkyl or aryl.

The term “carboxy” refers to —C (O) OH.

The term “carboxy esters” refers to —C (O) OR, where R is alkyl, aryl, aralkyl or alicyclic, optionally all substituted.

The term "oxo" refers to = O in the alkyl group.

The term “amino” refers to —NRR ′, where R and R ′ are independently selected from hydrogen, alkyl, aryl, aralkyl and alicyclic, with the exception of hydrogen, all are optionally substituted; and R and R ′ may form a cyclic ring system.

The terms "carbonylamino" and "-carbonylamino" refer to RCONR- and -CONR-, respectively, in which each R independently represents 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, in which "alk" means an alkylene group and R is H or lower alkyl.

The term “alkylaminocarbonyl-” refers to an alk-NR-C (O) - group in which “alk” is an alkylene group and R is H or lower alkyl.

The term “-oxyalkyl-” refers to the group —O-alk—, in which “alk” means an alkylene group.

The term “-oxyalkylamino” refers to —O-alk-NR-, in which “alk” is an alkylene group, and R is H or alkyl. Thus, "-oxyalkylamino" is synonymous with "-oxyalkyleneamino".

The term "-alkylcarboxyalkyl" refers to an -alk-C (O) -O-alk- group in which each "alk" independently means an alkylene group.

The term “alkyl” refers to saturated aliphatic groups containing a straight chain, branched chain and cyclic groups. Alkyl groups may optionally be substituted. Suitable alkyl groups include, for example, groups containing from about 1 to about 20 carbon atoms (for example, methyl, isopropyl and cyclopropyl).

The term “cyclic alkyl” or “cycloalkyl” refers to alkyl groups that are cyclic groups of 3-10 atoms, more preferably 3-6 atoms. Suitable cyclic groups include norbornyl and cyclopropyl. Such groups may be substituted.

The term “heterocycle” and “heterocyclic alkyl” refers to cyclic groups of 3-10 atoms, more preferably 3-6 atoms, containing at least one heteroatom, preferably 1-3 heteroatoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. Heterocyclic groups may be attached via a nitrogen or carbon atom in the ring. Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl and pyridyl.

The term “phosphono” refers to —PO ₃ R ₂ , where R is selected from —H, alkyl, aryl, aralkyl, and alicyclic.

The term “sulfonyl” or “sulfonyl” refers to —S (O) ₂ OR, wherein R is selected from H, alkyl, aryl, aralkyl, and an alicyclic group.

The term “alkenyl” refers to unsaturated groups that contain at least one carbon-carbon double bond and include straight chain, branched chain and cyclic groups. Alkenyl groups optionally may be substituted. Suitable alkenyl groups include allyl. “1-Alkenyl” refers to alkenyl groups in which the double bond is between the first and second carbon atoms. If a 1-alkenyl group is attached to another group, for example, this corresponds to a W-substituent attached to a cyclic phosphate (oramide) atom, it is attached to the first carbon.

The term “alkynyl” refers to unsaturated groups that contain at least one carbon-carbon triple bond and include straight chain, branched chain and cyclic groups. Alkynyl groups may optionally be substituted. Suitable alkynyl groups include ethynyl. “1-Alkynyl” refers to alkynyl groups in which a triple bond is located between the first and second carbon atom. If a 1-alkynyl group is attached to another group, for example, this corresponds to a W-substituent attached to a cyclic phosphate (oramide) atom, it is attached to the first carbon.

The term “alkylene” refers to a divalent straight chain, branched chain or cyclic saturated aliphatic group.

The term "-cycloalkylene-COOR ³ " refers to a divalent cyclic alkyl group or heterocyclic group containing 4-6 atoms in the ring, with 0-1 heteroatoms selected from O, N and S. The cyclic alkyl or heterocyclic group is substituted with -COOR ³ .

The term “acyloxy” refers to an —O — C (O) R ester group in which R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or alicyclic.

The term “aminoalkyl” refers to NR ₂ -alk-, in which “alk” means an alkylene group and R is selected from H, alkyl, aryl, aralkyl and alicyclic.

The term “-alkyl (hydroxy) -” refers to an alkyl chain having a —OH side chain. When the term is used to describe a group X, —OH is in the α position on the phosphorus atom.

The term “alkylaminoalkyl-” refers to an alkyl-NR-alk— group in which “alk” is alkylene and R is H or lower alkyl. “Lower alkylaminoalkyl-” refers to groups in which the alkyl and alkylene groups are lower alkyl and lower alkylene.

The term "arylaminoalkyl-" refers to an aryl-NR-alk- group in which "alk" means an alkylene group and R means H, alkyl, aryl, aralkyl and alicyclic. In "lower arylaminoalkyl-", the alkylene group corresponds to lower alkylene.

The term “alkylaminoaryl-” refers to an alkyl-NR-aryl- group in which “aryl” is a divalent group and R is H, alkyl, aralkyl or alicyclic. In “lower alkylamino aryl—”, the alkyl group is lower alkyl.

The term “alkyloxyaryl-” refers to an aryl group substituted with an alkyloxy group. In "lower alkyloxyaryl-", the alkyl group is lower alkyl.

The term “aryloxyalkyl” refers to an alkylene group substituted with an aryloxy group.

The term "aralkyloxyalkyl-" refers to an aryl-alk-O-alk- group in which "alk" means an alkylene group. “Lower aralkyloxyalkyl-” refers to those groups in which alkylene groups are lower alkylene.

The term "-alkoxy-" or "-alkyloxy-" refers to the group-alk-O-, in which "alk" means an alkylene group. The term "alkoxy-" refers to an alkyl-O- group.

The term "-alkoxyalkyl-" or "-alkyloxyalkyl-" refers to an -alk-O-alk- group in which each "alk" means an independently selected alkylene group. In "lower-alkoxyalkyl-", each alkylene is lower alkylene.

The terms "alkylthio" and "-alkylthio" refer to alkyl-S- and -alk-S- groups, respectively, in which "alk" means an alkylene group.

The term "-alkylthioalkyl-" refers to an -alk-S-alk- group in which each "alk" means an independently selected alkylene group. In "lower-alkylthioalkyl-", each alkylene 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” refers to -alk-O — C (O) —NR ¹ -, in which “alk” means alkylene, and R ^{1 is} selected from —H, alkyl, aryl, alicyclic and aralkyl.

The term "-alkilaminokarbonilamino-" refers to -alk-NR ¹ -C (O) -NR ¹ -, where "alk" is alkylene, and each R ^{1 is} independently selected from H, alkyl, aryl, aralkyl, and alicyclic.

The terms “amido” or “carboxamido” refer to NR ₂ —C (O) - and RC (O) —NR ¹ -, in which each R and R ^{1 is} selected from H, alkyl, aryl, aralkyl, and alicyclic. The term does not include urea, -NR-C (O) -NR-.

The terms "-carboxamidoalkylaryl" and "-carboxamidoaryl" refer to aryl-alk-NR ¹ -C (O) - and ap-NR ¹ -C (O) - respectively, in which "ar" means aryl, and "alk" means alkylene, each R ^{1 is} independently selected from H, alkyl, aryl, aralkyl and alicyclic.

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

The term “-alkylaminocarbonyl-” refers to the group-alk-NR-C (O) -, in which “alk” means an alkylene group, and R means H or lower alkyl.

The term “aminocarboxamidoalkyl-” refers to an NR ₂ -C (O) -N (R) -alk- group, in which R is an alkyl group or H, and “alk” is an alkylene group. “Lower aminocarboxamidoalkyl-” refers to those groups in which “alk” means 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.

The term “haloalkyl” refers to an alkyl group substituted with one halogen selected from the group: I, Cl, Br and F.

The term “cyano” refers to —C = N.

The term “nitro” refers to —NO ₂ .

The term “acylalkyl” refers to alkyl-C (O) -alk-, in which “alk” means alkylene.

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

Regarding the use of X, X ² , X ³ or X ⁴ , the term “-1,1-dihaloalkyl-” refers to the group X, X ² , X ³ and X ⁴ , in which halogens at position-1 mean α to the atom phosphorus.

The term “perhalogen” refers to groups in which each CH bond has been replaced by a C-halogen bond on an aliphatic or aryl group. Suitable perhaloalkyl groups include, for example, —CF ₃ and —CFCl ₂ .

The term “guanidino” refers to the —NR — C (NR) —NR ₂ and the —N = C (NR ₂ ) ₂ group, where each R group is independently selected from —H, alkyl, alkenyl, alkynyl, aryl, and alicyclic, with the exception of —H, all are optionally substituted.

The term “amidino” refers to —C (NR) —NR ₂ in which each R group is independently selected from —H, alkyl, alkenyl, alkynyl, aryl, and alicyclic, with the exception of —H, all are optionally substituted.

The term “2-thiazolyl-” or “2-oxazolyl-” or “2-selenozolyl” refers to the corresponding base and its compound with the group X, X ² , X ³ or X ⁴ at position-2 of the heterocycle.

The term "pharmaceutically acceptable salt" includes salts of compounds of formulas I, IA, II, II-A, III, III-A, IV, IV-A, V-1, VlA, V-2, V-2-A, VI, VI-A, VII-1, VII-lA, VII-2, VII-2-A, X or XA and their prodrugs obtained from a combination of a compound of this invention and an organic or inorganic acid or base. Suitable acids include, for example, hydrochloric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and maleic acid.

As used herein, the term “prodrug” refers to any compound that, when introduced into a biological system, forms a “drug” substance (biologically active compound) in one or more steps, including spontaneous chemical reaction (s), enzyme-catalyzed chemical reaction (s), or both. Standard prodrugs are formed using groups attached to functional groups, for example, HO-, HS-, HOOC-, R ₂ N-, associated with the FBPase inhibitor, which are cleaved in vivo. Prodrugs for the aforementioned group are well known in the art and are often used to increase oral bioavailability or other properties favorable to the composition, delivery or activity of a drug. Standard prodrugs include, but are not limited to, carboxylate esters in which the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and also hydroxyl, thiol, and amine esters in which the attached group is an acyl, alkoxycarbonyl, aminocarbonyl group, phosphate or sulfate. Standard phosphonic acid prodrugs are also included in the invention and can be represented by R ¹ in formulas I, IA, II, II-A, III, III-A, IV, IV-A, V-1, VlA, V-2, V- 2-A, VI, VI-A, VII-1, VII-lA, VII-2, VII-2-A, X and XA. The groups represented are illustrative and not exhaustive, and those skilled in the art can obtain other known varieties of prodrugs. Such prodrugs of the compounds of formula I, IA, II, II-A, III, III-A, IV, IV-A, V-1, VlA, V-2, V-2-A, VI, VI-A, VII- 1, VII-lA, VII-2, VII-2-A, X and XA are within the scope of this invention. Prodrugs must undergo some type of chemical transformation to form a compound that is biologically active. In some cases, the prodrug is usually less biologically active than the drug itself and serves to improve efficacy or safety by improving oral bioavailability, pharmacodynamic half-life, and so on.

Used in the description, the term "ester prodrug", but not limited to, includes the following groups and combinations of these groups:

[1] Acyloxyalkyl esters are well described in the literature (Farquhar et al., J. Pharm. Sci. 72, 324-25 (1983)) and are represented by Formula A.

Formula A

in which R, R 'and R "independently mean H, alkyl, aryl, alkylaryl or alicyclic; (see WO 90/08155; WO 90/10636).

[2] Other acyloxyalkyl esters are possible in which the alicyclic ring is formed as shown in Formula B. It is shown that the esters form phosphorus-containing nucleotides inside the cells by means of the proposed sequence of reactions starting from deesterification and the subsequent series of elimination reactions (for example, Freed et al., Biochem. Pharm. 38: 3193-3198 (1989)).

Formula B

in which R is —H, alkyl, aryl, alkylaryl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, cycloalkyl or alicyclic.

[3] Another class of said ethers known as alkyloxycarbonyloxymethyl esters represented by Formula A in which R is alkoxy, aryloxy, alkylthio, arylthio, alkylamino and arylamino; R 'and R "independently mean H, alkyl, aryl, alkylaryl, and alicyclic, has been studied in the field of β-lactam antibiotics (Tatsuo Nishimura et al., J. Antibiotics, 1987, 40 (1), 81-90; for reference see Ferres, H., Drugs of Today, 1983, 19, 499. Later Cathy, MS, et al. (Abstract from AAPS Western Regional Meeting, April, 1997) showed that the mentioned prodrugs of alkyloxycarbonyloxymethyl esters at (9- [ (R) -2-phosphonomethoxy) propyl] adenine (PMPA) is bioavailable up to 30% in dogs.

[4] Aryl esters have also been used as phosphonate prodrugs (eg, Erion, DeLambert et al., J. Med. Chem. 37: 498, 1994; Serafinowska et al., J. Med. Chem. 38: 1372, 1995). Phenyl, as well as complex mono- and polysubstituted phenyl esters formed the starting phosphinic acid in studies conducted on animals and humans (Formula C). Another approach is described in which Y stands for a carboxylic ester in the ortho position to phosphate. Khamnei and Torrence, J. Med. Chem .; 39: 4109-4115 (1996).

Formula C

in which Y is H, alkyl, aryl, alkylaryl, alkoxy, acyloxy, halogen, amino, alkoxycarbonyl, hydroxy, cyano or alicyclic.

[5] It is also described that benzyl esters form the starting phosphinic acid. In some cases, using substituents in the para position, hydrolysis can be enhanced. Analogs of benzyl with a 4-acyloxy or 4-alkyloxy group [formula D, X = H, OR, or O (CO) R, or O (CO) OR] can form a 4-hydroxy compound by the action of enzymes, for example, oxidases esterases and so on. Examples of said class of prodrugs are described by Mitchell et al., J. Chem. Soc. Perkin Trans. I 2345 (1992); Brook, et al., WO 91/19721.

Formula D

in which X and Y independently mean H, alkyl, aryl, alkylaryl, alkoxy, acyloxy, hydroxy, cyano, nitro, perhaloalkyl, halogen or alkyloxycarbonyl;

R 'and R "independently mean H, alkyl, aryl, alkylaryl, halogen and alicyclic.

[6] Thiose-containing phosphonate esters are described which are used to deliver FBPase inhibitors to hepatocytes. These esters contain a protected thioethyl moiety as shown in Formula E. One or more phosphonate oxygen can be esterified. Since the mechanism that leads to de-esterification requires the formation of thiolate, a number of thiol protecting groups are suitable. For example, disulfides are reduced in a reductase-mediated process (Puech et al., Antiviral Res., 22; 155-174 (1993)). Thioesters will also form free thiolates after esterase-mediated hydrolysis. Benzaria, et al., J. Med. Chem., 39; 4958 (1996). Cyclic analogs are also suitable and have been shown to release phosphonate in isolated rat hepatocytes. The cyclic disulfide shown below has not been previously described and is a new disulfide.

Formula E

in which Z is alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl or alkylthio.

Other examples of suitable prodrugs include the ester classes provided by Biller and Magnin (US Pat. No. 5,157,027); Serafinowska et al. (J. Med. Chem. 38, 1372 (1995)); Starrett et al. (J. Med. Chem. 37, 1857 (1994)); Martin et al., J. Pharm. Sci. 76, 180 (1987); Alexander et al., Collect. Czech Chem. Commun, 59, 1853 (1994)); and patent application EPO 0632048 A1. Some of the structures described are possibly substituted, including fused lactones attached at the omega position (formulas E-1 and E-2), and optionally substituted with 2-oxo-1,3-dioxolenes attached via methylene to phosphorus oxygen ( formula E-3), such as:

3-phthalidyl
E-1 2-oxo-tetrahydrofuran-5-yl
E-2 2-oxo-4,5-didehydro-1,3-dioxolanmethyl
E-3

wherein

R is —H, alkyl, cycloalkyl or alicyclic;

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

Prodrugs of formula E-3 are an example of an “optionally substituted alicycle in which the cyclic moiety contains carbonate or thiocarbonate.”

[7] Prolyl phosphonate esters can also be used to deliver FBPase inhibitors to hepatocytes. These esters may contain hydroxyl and derivatives of a hydroxyl group at the position of the propyl group, as shown in Formula F. Groups R and X may form a cyclic ring system, as shown in Formula F. One or more phosphonate oxygen can be esterified.

Formula F

in which R is alkyl, aryl or heteroaryl;

X is hydrogen, alkylcarbonyloxy or alkyloxycarbonyloxy;

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

[8] Phosphoramidate derivatives have been investigated as phosphate prodrugs (eg, McGuigan et al., J. Med. Chem., 1999, 42: 393 and cited in the description) and phosphonate prodrugs (Bischofberger, et al., US patent 5798340 and cited in the description), which are represented by formulas G and N.

Formula G Formula H

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

Another type of nucleotide prodrug is described as a combination of 3-acyl-2-thioethyl ester and phosphoramidate (Egron et al., Nucleosides & Nucleotides, 1999, 18, 981), as shown in Formula J.

Formula J

Other prodrugs, such as substituted ethyls, for example, bis (trichlorethyl) esters as described by McGuigan, et al., Bioorg, are reported in the literature. Med. Chem. Lett., 3: 1207-1210 (1993), and the phenyl and benzyl combined nucleotide esters described by Meier, C. Et al., Bioorg. Med. Chem. Lett., 7; 99-104 (1997).

Structure

has a symmetry plane passing through the double bond, phosphorous-oxygen, R ⁶ = R ^6, V = W, W '= H, a V or W and are both directed upwards, or both pointing down. The structure has a center of symmetry or an alternating axis of symmetry with the axis passing through the phosphorus-oxygen double bond, when R ⁶ = R ⁶ , V = W, W '= H, and V and W are substituted on opposite sides of the plane, one is directed downward, while the other is pointing up. The same is true for structures in which each —NR ^{6 is} substituted with —O—.

“Cis stereochemistry,” if used to describe stereochemistry for phosphorus in cyclic phosphoramidate, means a configuration if V or W are in the trans position to the phosphorus-oxygen double bond.

The terms “cyclic 1 ′, 3′-propane ester”, “cyclic 1,3-propane ester”, “cyclic 1 ′, 3′-propanyl ester” and “cyclic 1,3-propanyl ester” refer to to the following:

The phrase "V ² and Z ^{2 are} joined together by an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally including 1 heteroatom substituted by hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy, attached to a carbon atom, which is three atoms from of two groups of Y combined with phosphorus ”encompasses the following:

The above structure (on the left) has an additional 3 carbon atoms, which form a five-membered cyclic group. Such cyclic groups must contain the described substitution for oxidation.

The phrase “V and Z together join through an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, which condenses with an aryl group attached at the beta and gamma positions of Y attached to phosphorus” includes the following:

The phrase “V and W are joined together by an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted by one substituent selected from hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy and aryloxycarbonyloxy attached to one of the aforementioned additional carbon atoms, which is three atoms from Y adjacent to phosphorus, "contains the following:

The above structure has an acyloxy substituent, which is three carbon atoms from Y, and a possible substituent, —CH ₃ , on a new 6 membered ring. There must be at least one hydrogen in each of the following positions: carbon attached to Z; two carbons in the alpha position to the carbon labeled “3”; and carbon attached to the above "OS (O) CH ₃ ".

The phrase "W and W ′ together join through an additional 2-5 atoms to form a cyclic group possibly containing 0-2 heteroatoms, and V should mean aryl, substituted aryl, heteroaryl or substituted heteroaryl" includes the following:

The above structure contains V = aryl, and a spiro-fused cyclopropyl group for W and W ′. The term "cyclic phosph (oramide) at" refers to

in which Y independently means —O— or —NR ⁶ -. The carbon attached to V must have a CH bond. The carbon attached to Z must also have a CH bond.

The term "phosph (oramide) at" refers to phosphonates and phosphoramidates, which are compounds of the formula —PO (YR ¹ ) - (YR ¹ ), including the cyclic form in which Y independently means —O— or —NR ⁶ -.

The term “increase” refers to an increase or improvement in a specific property.

The term "increased oral bioavailability" refers to an increase of at least 50% in the absorption of a dose of a parent drug or prodrug (not from this invention) from the gastrointestinal tract. More preferably, the absorption is at least 100%. Typically, the definition of oral bioavailability refers to determinations of a prodrug, drug, or drug metabolite in blood, tissues, or urine after oral administration, compared with determinations after systemic administration.

The term “parent drug” refers to any compound that delivers the same biologically active compound. The parent dosage form is P (O) (OH) ₂ —X — M and standard prodrugs such as esters.

The term "drug metabolite" refers to any compound formed in vivo or in vitro from the parent drug, which may comprise a biologically active drug.

The term "pharmacodynamic half-life" refers to the time after administration of a drug or prodrug during which a decrease in half of a certain pharmacological response is observed. The pharmacodynamic half-life of existence increases if the half-life of existence preferably increases by at least 50%.

The term "pharmacokinetic half-life" refers to the time after administration of the drug or prodrug during which a decrease in half the concentration of the drug in the plasma or tissues is observed.

The term "glycemic control" refers to a decrease in postprandial and / or fasting blood glucose levels, a decrease in Ale hemoglobin concentration, a decrease in glycosuria, a decrease in glucose production in the liver, or a positive dynamics in glucose excretion from the whole organism or to any other standard parameters used to evaluate glucose homeostasis.

The term "therapeutic index" refers to the ratio of the dose of a drug or prodrug that causes a therapeutically favorable response, relative to the dose that causes an undesirable response, such as death, an increase in markers that are indicative of toxicity and / or pharmacological side effects.

The term "biologically active drug or agent" refers to a chemical substance that has a biological effect. Thus, active drugs or agents include compounds that, like P (O) (OH) 2-X-M, are biologically active.

The term “therapeutically effective amount” refers to an amount that has any beneficial effect in the treatment of a disease or condition.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a combination therapy and composition for treating diabetes or other diseases or conditions requiring improved glycemic control and / or increased peripheral sensitivity to insulin and / or increased insulin secretion. The therapy includes the administration of at least one FBPase inhibitor and at least one antidiabetic agent, either together or at different times so that the desired response is obtained. Although any suitable antidiabetic agent can be used in combination with an FBPase inhibitor, the antidiabetic agent (s) used in this invention are usually selected from one or more of the following substances: (a) insulin secretion enhancing agents (e.g. sulfonylurea derivatives, non-sulfonylureas, GLP-1 receptor agonists, DPP-IV inhibitors, or other known agents that enhance insulin secretion), (b) insulin or insulin analogs, (c) insulin sensitizers (e.g. rosiglitazone and pioglitazone), (d) b guanides (e.g. metformin and phenformin), (e) alpha-glucosidase inhibitors (e.g. acarbose), (f) glycogen phosphorylase inhibitors, (g) glucose-6-phosphatase inhibitors, (h) glucagon antagonists, (i) amylin agonists or (j) fatty acid oxidation inhibitors.

In certain aspects of the 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 in excess of the decrease observed with glucose lowering doses of the antidiabetic agent in the absence of an FBPase inhibitor. In addition, combination therapy can lead to an increase in insulin sensitivity and / or insulin secretion, exceeding the increase in these factors observed for any agent separately, and also provides a beneficial effect on carbohydrate and / or lipid (for example, fat) and / or protein metabolism.

In other aspects of the invention, when using combination therapy, the same beneficial effect is achieved that they are obtained with one of the other types of therapies separately, however, at significantly lower doses of the described therapy. The described phenomenon can be especially favorable, for example, when possible harmful side effects are associated with such treatment. For example, in certain aspects of the invention, combinations of the invention are used to attenuate some of the potential adverse effects associated with treatment with an FBPase inhibitor. Similarly, combinations of the invention can attenuate some of the potential detrimental effects associated with other antidiabetic agents, such as hyperinsulinemia, hypoglycemia, milk acidosis, weight gain, gastrointestinal upsets, liver disorders and adverse cardiovascular disorders.

Compared to response rates in therapies that include antidiabetic agents without an FBPase inhibitor, combinations of the invention improve the primary response rate. In addition, combinations of the invention can reduce, slow down or prevent the occurrence of secondary disorders.

The invention also relates to methods and compositions for treating an animal suffering from NIDDM or IDDM by administering to an animal a composition comprising a pharmaceutically effective amount of at least one FBPase inhibitor and a pharmaceutically effective amount of at least one other antidiabetic agent . In some aspects, the compositions of the invention are used to treat, improve, or prevent one or more symptoms of NIDDM or IDDM. In addition to methods and compositions for treating animals having NIDDM or IDDM, it is within the scope of interest of the invention to methods and compositions for treating diseases or conditions characterized by insulin resistance, including obesity, arterial hypertension, impaired glucose tolerance, pregnant diabetes and polycystic ovary syndrome. In addition, individuals with Syndrome X, kidney disease, or pancreatitis are also effectively treated with certain types of combination therapy. Individuals who are “labile diabetic patients” can also be treated with certain types of combination therapy of the present invention.

Particularly preferred combinations are characterized by the aforementioned therapeutic advantage, as well as high efficiency and low toxicity. The toxicity of the combination can be determined, for example, using standard pharmaceutical methods in cell cultures or in experimental animal models, for example, determination of LD ₅₀ and ED ₅₀ .

Combinations of the invention can be administered to a patient using any suitable method, including, for example: oral, rectal, nasal, local, vaginal, parenteral (including subcutaneous, intramuscular, intravenous and intradermal) and transdermal methods. The preferred method is oral.

Combination therapy involves administering drugs to the host, either separately or simultaneously. In one aspect, two substances are administered simultaneously, either in the same capsule or from separate capsules. In another aspect, two drugs are administered during a meal (i.e., a period of time ranging from immediately before feeding to right after feeding). In a further aspect, the antidiabetic agent is administered during a meal and the FBPase inhibitor is administered on an empty stomach, for example, before bedtime. In yet another aspect, two agents are administered within one hour, 30 minutes, 10 minutes, 5 minutes, or 1 minute one after another. In another aspect, one agent is first administered, and another agent is administered after 1-12 hours, usually 3-6, 6-9, or 9-12 hours, after administration of the first agent.

FBP-inhibitors

Combinations of the invention include at least one FBPase inhibitor. In most aspects, the combinations contain one FBPase inhibitor. The FBPase inhibitors used in the invention are compounds that can inhibit human FBPase activity (Examples AB), inhibit glucose production in hepatocytes (Examples CD), lower glucose levels in hungry animals (Examples EG), or lower glucose levels in blood tests in diabetic animal models (Examples V and W). Preferred FBPase inhibitors are compounds that inhibit enzyme activity as determined in in vitro inhibition studies (Examples A and B).

In some cases, in vivo metabolic activation of a compound may be required to form an FBPase inhibitor. Compounds of this class may be inactive in the study of enzyme inhibition (Example A), may or may not be active in hepatocytes (Examples C and D), but they are active in vivo, as evidenced by a decrease in glucose to normal in fasting rats (Examples E, F , G) and / or in animal models of diabetes (Examples K, VZ, AA-JJ).

Although the invention is not limited to the following structures, typically FBPase inhibitors have the following formulas:

Particularly preferred are compounds of formulas I and IA.

or their pharmaceutically acceptable prodrugs or salts in which, in vivo or in vitro, the compounds of formulas I and IA are converted to M-PO ₃ ^2- , which inhibits FBPase. In said preferred compounds:

Y is independently selected from —O— and NR ⁶ , provided that:

if Y is -O-, R ¹ attached to -O- is independently selected from -H, alkyl, optionally substituted aryl, optionally substituted alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -arylalkyl, -C (R ² ) ₂ OC (CO) 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-S — C (O) R ³ , -alkyl-SS-alkyl hydroxy, and -alkyl-SSS-alkyl hydroxy;

if Y is —NR ⁶ -, then R ¹ attached to —NR ⁶ - is independently selected from —H, - [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, where q is 1 or 2;

if only one Y is —O—, where —O— is not part of a cyclic group containing another Y, then the other Y is —N (R ¹⁸ ) - (CR ¹² R ¹³ ) —C (O) —R ¹⁴ ;

if Y is independently selected from —O— and —NR ⁶ , then R ¹ and R ² together mean alkyl-SS-alkyl and form a cyclic group, or R ¹ and R ² together form:

wherein

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 through an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is condensed with an aryl group at the beta and gamma positions of Y adjacent to V; or

Z is selected from the group —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, -OCOR ^3, OCO ₂ R, -SCOR ^3, -SCO ₂ R ^3, -NHCOR ^2, NHCO ₂ R ^3, -CH ₂ NH-aryl, - (CH _{2) p} —OR ² and - (CH ₂ ) _p —SR ² in which p is an integer of 2 or 3;

or

Z and W are joined together by an additional 3-5 atoms to form a cyclic group optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl; or W and W ′ are independently selected from the group of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or

W and W ′ are joined together through an additional 2-5 atoms to form a cyclic group optionally containing 0-2 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 of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;

Z ^{2 is} selected from the group —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) OR ³ , -CH (aryl) OH, -CH (CH = CR ² ₂ ) OH, -CH (C = CR ² ) OH, -SR ² , -CH ₂ NH-aryl, -CH ₂ aryl; or

V ² and Z ^{2 are} joined together through an additional 3-5 atoms to form a cyclic group containing 5-7 atoms in the ring, optionally containing 1 heteroatom, and substituted by hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom located at a distance of three atoms from Y connected to phosphorus;

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

D 'is —H;

D "is selected from the group —H, alkyl, —OR ² , —OH and —OC (O) R ³ ;

Each W ^{3 is} independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

provided that:

a) V, Z, W, W 'not all mean -H and V ² , Z ² , W ² , W "not all mean -H;

R ^{2 is} selected from R ³ and —H;

R ³ selected from alkyl, aryl, alicyclic and aralkyl;

each R ^{4 is} independently selected from the group of —H, alkylene, α-alkylene aryl and aryl, or R ⁴ and R ^{4 are} joined together through 2-6 atoms, optionally including one heteroatom selected from the group O, N and S;

R ^{6 is} selected from —H, 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 and aralkyl, or R ¹² and R ¹⁸ , together, are joined through 1-4 carbon atoms to form a cyclic group;

each R ¹² and each R ^{13 is} independently selected from H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R ¹² and R ¹³ together are joined through 2-6 carbon atoms, optionally including 1 heteroatom selected from the group O, N and S, with the formation of a cyclic group;

each R ^{14 is} independently selected from —OR ¹⁷ , —N (R ¹⁷ ) ₂ , —NHR ¹⁷ , —SR ^17, and —NR ² R ²⁰ ;

R ^{15 is} selected from —H, lower alkyl, lower aryl, and lower aralkyl, or R ¹⁵ and R ¹⁶ together are joined through 2-6 atoms to form a cyclic group, the cyclic group optionally including one heteroatom selected from group O , N and S;

R ¹⁶ is selected from - (CR ¹² R ¹³⁾ _n -C (O) -R ^14, -H, lower alkyl, lower aryl, and lower aralkyl, or R ¹⁵ and R ¹⁶ together are connected via 2-6 atoms with the formation of a cyclic group, and the cyclic group optionally includes one heteroatom selected from the group O, N and S;

each R ^{17 is} independently selected from lower alkyl, lower aryl and lower aralkyl, or, if R ¹⁴ is —N (R ¹⁷ ) ₂ , two R ¹⁷ together are joined through 2-6 atoms to form a cyclic group, with the cyclic group optionally includes one heteroatom selected from the group O, N and S;

R ^{20 is} selected from the group —H, lower R ^3, and —C (O) —lower — R ³ .

FBPase inhibitors in which M-PO ₃ ^2- has an IC ₅₀ for isolated human FBPase of less than or equal to 5 μM are preferred. Similarly, FBPase inhibitors having an IC ₅₀ <50 μM regarding glucose production in isolated rat hepatocytes are preferred. Particularly preferred are those compounds that bind the AMP site to FBPases.

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

Prodrugs of formula IA can have two isomeric forms near phosphorus. It is preferred if phosphorus is not chiral. It is also preferable if there is no chiral center on amino groups attached to phosphorus. Also preferred is if n is 1 and R ¹² is —H, then the carbon attached to R ¹² and R ¹³ has S stereochemistry.

In one aspect, compounds of formula I or formula IA are preferred in which M is —XR ⁵ , or a pharmaceutically acceptable prodrug or salt thereof, in which R ^{5 is} selected from:

in which:

each G is independently selected from C, N, O, S, and Se, and in which only one G is O, S, or Se, and, at best, one G is N;

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

A is selected from -H, -NR ^{April _2,} -CONR ^{April _2,} -CO ₂ R ^3, halo, -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 or absent;

each B and D is independently selected from —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, —C (O) R ¹¹ , —C (O) SR ³ , —SO ₂ R ¹¹ , —S (O ) R ³ , —CN, —NR ⁹ ₂ , —OR ³ , —SR ³ , or no perhaloalkyl, halogen, —NO ₂ , with the exception of —H, —CN, perhaloalkyl, —NO ₂ and halogen, are all optionally substituted ;

E is selected from -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, -C (O) OR ^3, -CONR ^{April _2,} -CN, -NR ^{September _2,} -NO _2, -OR ^3, -SR ³ , perhalogenated, halogen or absent, with the exception of -H, -CN, perhalogenated and halogen, all are optionally substituted;

 J is selected from —H or absent;

X is optionally substituted by a linking group that binds R ⁵ to the phosphorus atom through 2-4 atoms, including 0-1 heteroatoms selected from N, O and S, except that if X corresponds to urea or carbamate, then there are 2 heteroatoms defined 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 -alkyl (hydroxy) -, -alkinila-, -geteroarila-, -karbonilalkila- , -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthio-alkyl-, alkylthio, -alkylamino rbonyl-, -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 —H;

R ³ selected from alkyl, aryl, alicyclic and aralkyl;

each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group;

each R ^{9 is} independently selected from —H, alkyl, aralkyl, and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group;

R ^{11 is} selected from alkyl, aryl, —NR ₂ ^2, and —OR ² ;

and provided that

1) if G 'means N, then A, B, D or E is absent;

2) at least one of A and B or A, B, D and E cannot be selected from -H or absent;

3) if R ⁵ is a six-membered ring, then X is not a diatomic linker, optionally substituted with -alkyloxy or optionally substituted with -alkylthio;

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

5) if 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-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; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; 1,3,5-triazinyl; 1,2,4-triazinyl and 1,3-selenazolyl, all of which contain at least one substituent.

Preferably, R ⁵ does not mean 2-thiazolyl or 2-oxazolyl. If R ⁵ is 2-thiazolyl, 2-oxazolyl or 2-selenazolyl, and X is alkoxyalkyl, alkylthioalkyl, alkyloxy or alkylthio, then it is preferred that A does not correspond to —CONH ₂ and B does not mean -N. Similarly, if R ⁵ is 2-thiazolyl, 2-oxazolyl or 2-selenazolyl, then X does not mean -alkoxyalkyl, alkylthioalkyl, alkyloxy or alkylthio.

A is selected from —H, —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 ⁴ , -SR ⁴ , -N ₃ , -NHC (S) NR ⁴ ₂ , -NHAc or absent.

B and D are independently selected from —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, —C (O) R ¹¹ , —C (O) SR ³ , —SO ₂ R ¹¹ , —S (O) R ³ , —CN, —NR ² ₂ , —OR ³ , —SR ³ , or no perhaloalkyl, halogen, with the exception of —H, —CN, perhaloalkyl, halogen, are all optionally substituted.

E is selected from —H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, aryl, 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, halogen or absent, with the exception of —H, —CN, perhaloalkyl and halogen, are all optionally substituted.

Each R ^{4 is} independently selected from —H and C ₁ –C ₂ alkyl. More preferred are compounds of formula I or IA, in which M is —XR ⁵ , in which R ^{5 is} selected from:

wherein

A "is selected from -H, -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 - -pergalogenalkila C _6, C ₁ -C ₆ -haloalkyl, aryl, -CH ₂ OH, -CH ₂ NR ^{April _2,} -CH ₂ CN, -CN, -C (S) NH _2, -OR ^3, -SR ³ , -N ₃ , -NHC (S) NR ⁴ ₂ and -NHAc;

B "and D" are independently selected from -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, -C (O) R ^11, -C (O) SR ^3, -SO ₂ R ^11, -S ( O) R ³ , —CN, —NR ² ₂ , —OR ³ , —SR ³ , perhaloalkyl and halogen, with the exception of —H, —CN, perhaloalkyl and halogen, are all optionally substituted;

E "is selected from -H, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₄ -C ₆ -alitsikla, alkoxyalkyl, -C (O) OR ^3, - CONR ⁴ ₂ , —CN, —NR ⁹ ₂ , —OR ³ , —SR ³ , C ₁ -C ₆ -perhaloalkyl and halogen, with the exception of —H, —CN, perhaloalkyl and halogen, are all optionally substituted;

each R ^{3 is} independently selected from C ₁ -C ₆ alkyl, C ₆ aryl, C ₃ -C ₆ heteroaryl, C ₃ -C ₈ alicyclic, C ₂ -C ₇ heteroalicycle, C ₇ -C ₁₀ aralkyl and C ₄ -C ₉ heteroaryl;

each R ⁴ and R ^{9 is} independently selected from —H and C ₁ -C ₂ alkyl;

X is selected from -heteroaryl-, -alkylcarbonylamino, alkylaminocarbonyl- and -alkoxycarbonyl-;

each R ^{11 is} selected from NR ⁴ ₂ , —OH, —OR ³ , C ₁ -C ₆ alkyl, C ₆ aryl and C ₃ -C ₆ heteroaryl.

More preferred are those compounds in which X is heteroaryl or alkoxycarbonyl.

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

in which

A "is selected from —NH ₂ , —CONH ₂ , halogen, —CH ₃ , —CF ₃ , —CH ₂ halogen, —CN, —OCH ₃ , —SCH _3, and —H;

In “selected from —H, —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 —H, —C (O) R ¹¹ , —C (O) SR ³ , —NR ⁹ ₂ , alkyl, aryl, alicyclic, halogen, and SR ³ ;

E "is selected from —H, C ₁ -C ₆ 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, in which

selected from the group:

where C * has S-stereochemistry;

R ¹⁸ and R ¹⁵ are selected from H and methyl;

each R ¹² and R ^{13 is} independently selected from —H, methyl, isopropyl, isobutyl and benzyl, or R ¹² and R ^{13 are} joined through 2-5 carbon atoms to form a cycloalkyl group;

n is 1;

R ¹⁴ is —OR ¹⁷ ;

R ¹⁶ means - (CR ¹² R ¹³ ) _n —C (O) —R ¹⁴ ; and

R ^{17 is} selected from methyl, ethyl, propyl, phenyl and benzyl.

Also particularly preferred are those compounds in which R ^{5 is} selected from:

Also particularly preferred are those compounds in which R ^{5 is} selected from:

Also particularly preferred are those compounds in which R ^{5 is} selected from:

In one particularly preferred aspect, R ⁵ means

A "is selected from —NH ₂ , —CONH ₂ , halogen, —CH ₃ , —CF ₃ , —CH ₂ halogen, —CN, —OCH ₃ , —SCH _3, and —H;

In "selected from -H, -C (O) R ¹¹ , -C (O) SR ³ , alkyl, aryl, alicyclic, halogen, -CN, -SR ³ , -OR ³ and -NR ⁹ ₂ and

X is selected from -heteroaryl-, -alkoxycarbonyl- and -alkylaminocarbonyl-, all optionally substituted.

More preferred are those compounds in which X is selected from methyleneoxycarbonyl and furan-2,5-diyl, and their pharmaceutically acceptable salts and prodrugs. More preferred are those compounds in which A "is —NH ₂ , X is furan-2,5-diyl, and B" is —S (CH ₂ ) ₂ CH ₃ ; in which A "means —NH ₂ , X means furan-2,5-diyl and B" means —CH ₂ —CH (CH ₃ ) ₂ ; in which A "means —NH ₂ , X means furan-2,5-diyl, and B" means —COOEt; in which A "means -NH ₂ , X means furan-2,5-diyl and B" means -SMe; or in which 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 in which A "is —NH ₂ , X is furan-2,5-diyl and B” is —S (CH ₂ ) ₂ CH ₃ and in which

means

or

where C * has S-stereochemistry.

Also most preferred are those thiazoles in which A "is —NH ₂ , X is furan-2,5-diyl, B" is —CH ₂ —CH (CH ₃ ) ₂ . Particularly preferred are those compounds in which:

means

or

means

where C * has S-stereochemistry.

In another preferred aspect, R ⁵ means

X is selected from furan-2,5-diyl and methyleneoxycarbonyl; A “means —NH ₂ and their pharmaceutically acceptable salts and prodrugs. More preferred are those compounds in which X is furan-2,5-diyl and B” is —SCH ₂ CH ₂ CH ₃ .

In another preferred aspect, R ⁵ means

And "means -NH ₂ , E" and D "mean -H, B" selected from cyclopropyl and n-propyl, X selected from methyleneoxycarbonyl and furan-2,5-diyl, and their pharmaceutically acceptable salts and prodrugs.

In a further preferred aspect, R ⁵ means

And "means -NH ₂ , D" means -H, B "is selected from n-propyl and cyclopropyl, X is selected from furan-2,5-diyl and methyleneoxycarbonyl, and their pharmaceutically acceptable salts and prodrugs.

Preferred groups X include -heteroaryl-, -alkylcarbonylamino, -alkylaminocarbonyl- and -alkoxycarbonyl. More preferred are -heteroaryl- and -alkoxycarbonyl-.

Compounds of formula IA are preferred. Also preferred are compounds of formulas XII, XIII and XIV:

More preferred are compounds of formulas XII or XIV:

Preferred groups A ″ include —NH ₂ , —CONH ₂ , halogen, —CH ₃ , —CF ₃ , —CH ₂ halogen, —CN, —OCH ₃ , —SCH ₃ and —H. More preferred groups A ″ include - NH ₂ , —Cl, —Br, and —CH ₃ .

Preferred B ″ groups include —H, —C (O) R ¹¹ , —C (O) SR ³ , alkyl, aryl, alicyclic, halogen, —CN, —SR ³ , NR ⁹ _2, and —OR ^3. More preferred are —H, —C (O) OR ³ , —C (O) SR ³ , C ₁ -C ₆ alkyl, alicyclic, halogen, heteroaryl, and —SR ³ .

Preferred D ″ groups include —H, —C (O) R ¹¹ , —C (O) SR ³ , alkyl, aryl, alicyclic, halogen, NR ⁹ _2, and —SR ^3. More preferred are —H, —C (O ) OR ³ , lower alkyl, alicyclic and halogen.

Preferred E ″ groups include —H, C ₁ -C ₆ alkyl, lower alicyclic, halogen, —CN, —C (O) OR ³ , —SR ^3, and —CONR ^4. More preferred are —H, Br, and Cl.

Preferred R ¹⁸ groups include —H, methyl, and ethyl. More preferred are —H and methyl. Of particular respect is -H.

Preferred compounds include those in which each R ¹² and R ^{13 is} independently selected from —H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, CH ₂ CH ₂ SCH ₃ , phenyl and benzyl, or R ¹² and R ^{13 are} joined together through 2-5 carbon atoms to form a cycloalkyl group. More preferably, each R ¹² and R ^{13 is} independently selected from —H, methyl, isopropyl, isobutyl and benzyl, or R ¹² and R ^{13 are} joined together by 2-5 carbon atoms to form a cycloalkyl group. Also more preferred are those compounds in which each R ¹² and R ^{13 is} independently selected from —H, methyl, isopropyl, isobutyl and benzyl, or R ¹² and R ^{13 are} joined together via 4 carbon atoms to form a cyclopentyl group. Particularly preferred are those compounds in which R ¹² and R ^{13 are} both —H, both are methyl, or R ¹² is H, and R ^{13 is} selected from methyl, isopropyl and benzyl. Most preferred are those compounds in which n is 1, R ¹² is —H, then carbon is attached to R ¹² , and R ¹³ has S stereochemistry.

Preferably n is an integer of 1-2. More preferably, when n is 1.

Preferred compounds include those in which each R ^{14 is} independently selected from —OR ¹⁷ and —SR ¹⁷ ; and R ^{17 is} selected from optionally substituted methyl, ethyl, propyl, tert-butyl and benzyl. More preferred are compounds in which each R ^{14 is} independently selected from —OR ¹⁷ and R ^{17 is} selected from methyl, ethyl, propyl, and benzyl. Most preferred are those compounds wherein R ^{17 is} selected from ethyl and benzyl.

Preferred are compounds in which R ¹⁵ does not mean H. More preferred are compounds in which R ¹⁵ and R ^{16 are} independently selected from lower alkyl and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together through 2-6 atoms, optionally including 1 a heteroatom selected from O, N and S. Also preferred are compounds in which R ¹⁵ and R ^{16 are} independently selected from C ₁ -C ₆ alkyl, or R ¹⁵ and R ¹⁶ together are joined through 2-6 atoms, optionally including 1 heteroatom selected from O, N and S. In one aspect, particularly preferred which are compounds in which —NR ¹⁵ R ¹⁶ is a cyclic amine. Particularly preferred are those compounds in which —NR ¹⁵ R ^{16 is} selected from morpholinyl and pyrrolidinyl.

Preferred compounds are those wherein R ¹⁶ is - (CR ¹² R ¹³ ) _n —C (O) —R ¹⁴ . Particularly preferred are compounds of the formula:

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

More preferred are those compounds in which n is 1. Particularly preferred are those compounds in which, if R ¹² and R ¹³ are not the same, then H ₂ N-CR ¹² R ¹³ -C (O) -R ¹⁴ means complex natural amino acid ester or thioester; and R ^{14 is} selected from -OR ¹⁷ and -SR ¹⁷ .

More preferred are compounds in which n is 1 and in which R ^{18 is} selected from —H, methyl and ethyl;

R ¹² and R ^{13 are} independently selected from —H, methyl, isopropyl, isobutyl and benzyl or are joined together through a chain of 2-5 carbon atoms to form a cycloalkyl group;

R ¹⁴ means OR ¹⁷ ;

R ^{17 is} selected from methyl, ethyl, propyl, tert-butyl and benzyl;

R ¹⁵ and R ^{16 are} independently selected from lower alkyl and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together through a chain of 2-6 atoms, optionally including 1 heteroatom selected from O and N.

In one aspect, compounds of formula IA are preferred in which M is

wherein

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

A ² , L ² , E ² and J ² are selected from —NR ⁴ ₂ , —NO ₂ , —H, OR ² , SR ² , —C (O) NR ⁴ ₂ , halogen, —COR ¹¹ , —SO ₂ R ³ , guanidinyl, amidinyl, aryl, aralkyl, alkyloxyalkyl, -SCN, -NHSO ₂ R ³ , -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 ² or E ² and J ² together form an annelated cyclic group.

X ^{2 is} selected from —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 -, in which an atom attached to phosphorus means a carbon atom; with the proviso that X ^{2 is} not substituted with —COOR ² , —SO ₃ H or —PO ₃ P ² ₂ ;

R ^{2 is} selected from R ³ and —H;

R ³ selected from alkyl, aryl, alicyclic and aralkyl;

each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group;

each R ^{9 is} independently selected from —H, alkyl, aralkyl, and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group;

R ^{11 is} selected from alkyl, aryl, —NR ₂ ^2, and —OR ² ;

R ^{19 is} selected from lower alkyl, —H and —COR ² ; and

their pharmaceutically acceptable prodrugs and salts. More preferred are compounds in which G "is —S—. Most preferred are compounds in which A ² , L ² , E ² and J ^{2 are} independently selected from —H, —NR ⁴ ₂ , —SC = N, halogen, -OR ³ , hydroxy, alkyl- (OH), aryl, alkyloxycarbonyl, -SR ³ , lower perhaloalkyl and C ₁ -C ₅ -alkyl, or L ² and E ² together form an annelated cyclic group. More preferred A ² , L ² , E ² and J ^{2 are} independently selected from the group —H, —NR ⁴ ₂ , —SC = N, halogen, lower alkoxy, hydroxy, lower alkyl (hydroxy), lower aryl, and C ₁ -C ₅ alkyl, or L ² and E ² together form an elirovannuyu cyclic group.

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

The most preferred groups of L ² and E ^{2 are} independently selected from the group consisting of —H, —SC = N, lower alkoxy, C ₁ -C ₅ alkyl, lower alkyl (hydroxy), lower aryl and halogen, or L ² and E ² together form an annelated cyclic group containing an additional 4 carbon atoms.

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

Preferred X ² groups include —CF ₂ -, —CH ₂ -, —C (O) —O—, —CH ₂ —O—, —CH ₂ —S—, —CH ₂ —NH— 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—.

One preferred aspect includes compounds wherein A ^{2 is} selected from —H, —NH ₂ , —CH ₃ , —Cl, and —Br;

L ² means —H, lower alkyl, halogen, lower alkyloxy, hydroxy, α-alkenylene-OH, or together with E ² forms a cyclic group selected from the group consisting of aryl, cyclic alkyl, heteroaryls, heterocyclic alkyl;

E ^{2 is} selected from the groups consisting of H, lower alkyl, halogen, SCN, lower alkyloxycarbonyl, lower alkyloxy, or together with L ² forms a cyclic group selected from the group of aryl, cyclic alkyl, heteroaryl or heterocyclic alkyl;

J ^{2 is} selected from the group consisting of H, halogen and lower alkyl;

G "means -S-;

X ² is —CH ₂ —O—;

and their pharmaceutically acceptable salts and prodrugs.

More preferred are those compounds in which

R ^{18 is} selected from —H, methyl, and ethyl;

R ¹² and R ^{13 are} independently selected from —H, methyl, isopropyl, isobutyl and benzyl, or are joined together by 2-5 carbon atoms to form a cycloalkyl group;

R ¹⁴ is —OR ¹⁷ ;

R ¹⁷ 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 R ¹⁵ and R ^{16 are} joined together through 2-6 atoms, optionally including 1 heteroatom selected from O and N.

Also more preferred are compounds in which 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 —H. Particularly preferred are those compounds in which

selected from group

where C * has S-stereochemistry.

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

Preferred compounds include those compounds in which each R ¹² and R ^{13 is} independently selected from —H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, —CH ₂ CH ₂ SCH ₃ , phenyl and benzyl, or R ¹² and R ^{13 are} joined together through 2-5 carbon atoms to form a cycloalkyl group. More preferred is that each R ¹² and R ^{13 is} independently selected from —H, methyl, isopropyl, isobutyl and benzyl, or R ¹² and R ^{13 are} joined together through 2-5 carbon atoms to form a cycloalkyl group. Also more preferred are those compounds in which each R ¹² and R ^{13 is} independently selected from —H, methyl, isopropyl, isobutyl and benzyl, or R ¹² and R ^{13 are} joined together via 4 carbon atoms to form a cyclopentyl group. Particularly preferred are those compounds in which R ¹² and R ^{13 are} both —H, both are methyl, or R ¹² is H, and R ^{13 is} selected from methyl, isopropyl and benzyl. Most preferred are those compounds in which n is 1 and R ¹² is —H, then carbon is attached to R ¹² and R ¹³ has S stereochemistry.

Preferably n is an integer of 1-2. More preferred is if n is 1.

Preferred compounds include those in which each R ^{14 is} independently selected from —OR ¹⁷ and —SR ¹⁷ ; and R ^{17 is} selected from optionally substituted methyl, ethyl, propyl, tert-butyl and benzyl. More preferred are compounds in which each R ^{14 is} independently selected from —OR ¹⁷ and R ^{17 is} selected from methyl, ethyl, propyl, and benzyl. More preferred are those compounds wherein R ^{17 is} selected from ethyl and benzyl.

Preferred are compounds in which R ¹⁵ does not mean H. More preferred are compounds in which R ¹⁵ and R ^{16 are} independently selected from lower alkyl and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together through 2-6 atoms, optionally including 1 a heteroatom selected from O, N and S. Also preferred are compounds in which R ¹⁵ and R ^{16 are} independently selected from C ₁ -C ₆ alkyl, or R ¹⁵ and R ^{16 are} joined together through 2-6 atoms, optionally including 1 a heteroatom selected from O, N and S. In one aspect, I am particularly preferred Xia compounds wherein -NR ¹⁵ R ¹⁶ is a cyclic amine. Particularly preferred are those compounds in which —NR ¹⁵ R ^{16 is} selected from morpholinyl and pyrrolidinyl.

Compounds in which R ¹⁶ is - (CR ¹² R ¹³ ) _n —C (O) —R ¹⁴ are preferred.

More preferred are compounds in which n is 1 and in which R ^{18 is} selected from —H, methyl, and ethyl;

R ¹² and R ^{13 are} independently selected from —H, methyl, isopropyl, isobutyl and benzyl, or are joined together through 2-5 carbon atoms to form a cycloalkyl group;

R ¹⁴ means OR ¹⁷ ;

R ^{17 is} selected from methyl, ethyl, propyl, tert-butyl and benzyl;

R ¹⁵ and R ^{16 are} independently selected from lower alkyl and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together through a chain of 2-6 atoms, optionally including 1 heteroatom selected from O and N. Particularly preferred are compounds of the formula:

More preferred are those compounds in which n is 1. Especially preferred are those compounds in which, if R ¹² and R ¹³ are not the same, H ₂ N-CR ¹² R ¹³ -C (O) - R ¹⁴ is an ester or natural amino acid thioether; a R ^{14 is} selected from -OR ¹⁷ and -SR ¹⁷ .

In one aspect, compounds of formula IA or formula I are preferred in which M is

wherein

A, E and L are selected from —NR ⁸ ₂ , —NO ₂ , —H, OR ⁷ , SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —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, 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 including aryl, cyclic alkyl and heterocycle;

J is selected from —NR ⁸ ₂ , —NO ₂ , —H, OR ⁷ , SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —COR ¹¹ , —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl , haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or together with Y forms a cyclic group including aryl, cyclic alkyl and heterocyclic alkyl;

X ^{3 is} selected from -alkyl (hydroxy) -, alkyl-, -alkynyl-, aryl-, -carbonyl-, alkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, - alkylthio -, - alkylaminocarbonyl-, -alkylcarbonylamino, -alicyclo-, -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 P ² ₂ ;

Y ^{3 is} selected from —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C (O) R ³ ,

—S (O) ₂ R ³ , —C (O) —R ¹¹ , —CONHR ³ , —NR ² _2, and —OR ³ , with the exception of H, are all optionally substituted;

R ^{2 is} selected from R ³ and —H;

R ³ selected from alkyl, aryl, alicyclic and aralkyl;

each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group;

R ^{25 is} selected from lower alkyl, lower aryl, lower aralkyl and lower alicyclic;

R ^{7 is} independently selected from —H, 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 together they form a bidentate alkyl;

each R ^{9 is} independently selected from —H, alkyl, aralkyl, and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group;

R ^{10 is} selected from —H, lower alkyl, —NH ₂ , lower aryl, and lower perhaloalkyl;

R ^{11 is} selected from alkyl, aryl, —NR ² _2, and —OR ² ; and

their pharmaceutically acceptable prodrugs and salts.

In another aspect of the invention, compounds of formula I and formula IA are described above, with the proviso that

a) if X ³ is alkyl or alkene, then A is —N (R ⁸ ₂ );

b) X ³ does not mean alkylamine and alkylaminoalkyl substituted with phosphonic esters and acids;

c) A, L, E, J, and Y ³ together can form only 0-2 cyclic groups.

More preferred are those compounds in which X ³ does not mean -alkoxyalkyl-, -alkyloxy-, alkylthioalkyl- and -alkylthio. Particularly preferred are such compounds with the additional condition that if X ³ is aryl or alkylaryl, then the aryl or alkylaryl group mentioned is not bonded 1,4 via a six-membered aromatic ring.

Particularly preferred benzimidazole compounds include those in which A, L and E are independently selected from —H, —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 —H, halogen, lower alkyl, lower hydroxyalkyl, —NR ⁸ ₂ , lower R ⁸ ₂ N-alkyl, lower haloalkyl, lower perhaloalkyl, lower alkenyl, lower alkynyl, lower aryl, heterocycle, and alicyclic; and in which Y is selected from alicyclic and lower alkyl; in which X ^{3 is} selected from -heteroaryl-, -alkylcarbonylamino, alkylaminocarbonyl- and -alkoxycarbonyl-. Compounds in which

R ^{18 is} selected from —H, methyl, and ethyl;

R ¹² and R ^{13 are} independently selected from —H, methyl, isopropyl, isobutyl and benzyl, or are joined together by 2-5 carbon atoms to form a cycloalkyl group;

R ¹⁴ is —OR ¹⁷ ;

R ^{17 is} selected from 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 R ¹⁵ and R ^{16 are} joined together through a chain of 2-6 atoms, optionally including 1 heteroatom selected from O and N. Most preferred are such compounds, in which A is selected from —H, —NH ₂ , —F, and —CH ₃ ;

L is selected from —H, —F, —OCH ₃ , Cl, and —CH ₃ ;

E is selected from —H and —Cl;

J is selected from —H, halogen, C ₁ -C ₅ hydroxyalkyl, C ₁ -C ₅ haloalkyl, C ₁ -C ₅ -R ⁸ ₂ N-alkyl, C ₁ -C ₅ alicyclic, and C ₁ -C ₅ -alkyl;

X ^{3 is} selected from —CH ₂ OCH ₂ -, -methyleneoxycarbonyl- and -furan-2,5-diyl-;

Y is lower alkyl.

Also preferred are those benzimidazoles in which A is —NH ₂ , L is —F, E is —H, J is ethyl, Y is isobutyl, and X ³ is furan-2,5-diyl; or

wherein A is —NH ₂ , L is —F, E is —H, J is N, N-dimethylaminopropyl, Y is isobutyl, and X ³ is furan-2,5-diyl.

Particularly preferred are compounds in which

selected from

where C * has S-stereochemistry.

In one aspect, compounds of formula III are preferred:

wherein:

A, E and L are selected from —NR ⁸ ₂ , —NO ₂ , —H, OR ⁷ , SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —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, 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 form a cyclic group selected from the group consisting of aryl, cyclic alkyl and heterocycle;

J is selected from —NR ⁸ ₂ , —NO ₂ , —H, OR ⁷ , SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —COR ¹¹ , —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl , haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or together with Y ³ forms a cyclic group selected from the group consisting of aryl, cyclic alkyl and heterocyclic alkyl;

X ^{3 is} selected from -alkyl (hydroxy) -, alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclo-, -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 —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C (O) R ³ , —S (O) ₂ R ³ , —C (O) —R ¹¹ , - CONHR ³ , —NR ² ₂ and —OR ³ , with the exception of H, are all optionally substituted;

Y is independently selected from —O— and —NR ⁶ , provided that:

if Y is —O—, R ¹ attached to —O— is independently selected from —H, alkyl, optionally substituted aryl, optionally substituted alicyclic, in which the cyclic moiety contains carbonate or thiocarbonate, optionally substituted α-arylalkyl—, —C ( R ² ) ₂ CO (O) NR ² ₂ , -NR ² -C (O) -R ³ , -C (R ² ) ₂ -OC (O) R ³ , -C (R ² ) ₃ -OC (O ) OR ³ , —C (R ² ) ₂ —OC (O) SR ³ , -alkyl-SC (O) R ³ , -alkyl-SS-alkyl hydroxy, and -alkyl-SSS-alkyl hydroxy;

if Y is —NR ⁶ -, R ¹ attached to —NR ⁶ - is independently selected from —H, - [C (R ² ) ₂ ] _q —COOR ³ , —C (R ⁴ ) ₂ COOR ³ , - [ C (R ² ) ₂ ] _q —C (O) SR ³ and -cycloalkylene-COOR ³ , where q is 1 or 2;

if only one Y is —O—, where —O— is not part of a cyclic group containing another Y, then the other Y is —N (R ¹⁸ ) - (CR ¹² CR ¹³ ) —C (O) R ¹⁴ ; and

if Y is independently selected from —O— and —NR ⁶ - and forms a cyclic group, or R ¹ and R ¹ together form:

in which

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 through an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is condensed with an aryl group at the beta and gamma positions of Y adjacent to V; or

Z is selected from the group —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) SP 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 , -SCO ₂ R ³ , -NHCOR ² , NHCO ₂ R ³ , -CH ₂ NH-aryl, - (CH ₂ ) _p —OR ² and - (CH ₂ ) _p —SR ² in which p is an integer of 2 or 3;

or

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

W and W ′ are independently selected from the group —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or

W and W ′ are joined together via an additional 2-5 atoms to form a cyclic group optionally containing 0-2 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 —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

Z ^{2 is} selected from the group —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) OR ³ , —CH (aryl) OH,

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

V ² and Z ^{2 are} joined together through an additional 3-5 atoms to form a cyclic group containing 5-7 atoms in the ring, optionally containing 1 heteroatom, and substituted by hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom located at a distance of three atoms from Y connected to phosphorus;

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

D 'is —H;

D "is selected from the group —H, alkyl, —OR ² , —OH and —OC (O) R ³ ;

if W ^{3 is} independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

provided that:

a) V, Z, W, W ′ do not all mean -H and V ² , Z ² , W ² , W ′ ′ do not all mean -H;

R ^{2 is} selected from R ³ and —H;

R ³ selected from alkyl, aryl, alicyclic and aralkyl;

each R ^{4 is} independently selected from the group —H, alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group;

R ^{6 is} selected from —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl;

R ^{25 is} selected from lower alkyl, lower aryl and lower aralkyl and lower alicyclic;

R ^{7 is} independently selected from —H, 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 together they form a bidentate alkyl;

R ^{9 is} selected from alkyl, aralkyl, and alicyclic;

R ^{10 is} selected from —H, lower alkyl, —NH ₂ , lower aryl, and lower perhaloalkyl;

R ^{11 is} selected from alkyl, aryl, —NR ² ₂ and —OR ₂ ,

n is an integer from 1 to 3;

R ^{18 is} independently selected from H, lower alkyl, aryl and aralkyl, or R ¹² and R ^{18 are} joined together through 1-4 carbon atoms to form a cyclic group;

each R ¹² and each R ^{13 is} independently selected from H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R ¹² and R ^{13 are} joined together through 2-6 carbon atoms, optionally including 1 heteroatom selected from group O, N and S, with the formation of a cyclic group;

each R ^{14 is} independently selected from —OR ¹⁷ , —N (R ¹⁷ ) ₂ , —NHR ¹⁷ , —SR ^17, and —NR ² R ²⁰ ;

R ^{15 is} selected from —H, lower alkyl, lower aryl, and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together through 2-6 atoms to form a cyclic group, the cyclic group optionally including one heteroatom selected from the group O, N and S;

R ^{16 is} selected from - (CR ¹² R ¹³ ) nC (O) -R ¹⁴ , -H, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together through 2-6 atoms to form a cyclic group, wherein the cyclic group optionally includes one heteroatom selected from the group O, N and S;

each R ^{17 is} independently selected from lower alkyl, lower aryl and lower aralkyl, or, if R ¹⁴ is —N (R ¹⁷ ) ₂ , two R ^{17 are} joined together through 2-6 atoms to form a cyclic group, the cyclic group optionally including one heteroatom itself selected from the group O, N and S;

R ^{20 is} selected from the group —H, lower R ^3, and —C (O) —lower — R ³ ,

and their pharmaceutically acceptable prodrugs and salts.

Preferred groups A, E and L for formula III include —H, —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. Such a cyclic group may be aromatic, cyclic alkyl or heterocyclic alkyl and may optionally be substituted. Suitable aromatic groups include thiazole. Particularly preferred groups A, L and E are —NR ⁸ ₂ , —H, hydroxy, halogen, lower alkoxy, lower perhaloalkyl and lower alkyl.

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

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

Preferred J groups for formula III include —H, halogen, lower alkyl, lower hydroxyalkyl, —NR ⁸ ₂ , lower — R ⁸ ₂ N-alkyl, lower haloalkyl, lower perhaloalkyl, lower alkenyl, lower alkynyl, lower aryl, heterocycle and the alicyclic or together with Y ³ forms a cyclic group. Such a cyclic group may be aromatic, cyclic alkyl or heterocycle and may optionally be substituted. Particularly preferred J groups include —H, halogen and lower alkyl, lower hydroxyalkyl, —NR ⁸ ₂ , lower — R ⁸ ₂ N-alkyl, lower haloalkyl, lower alkenyl, alicyclic, and aryl. Particularly preferred are alicyclic and lower alkyl.

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

In another preferred aspect, if X ³ is aryl or alkylaryl, the groups described are not linked 1,4 via a 6 membered aromatic ring.

Preferred Y ³ groups for formula III include —H, alkyl, aralkyl, aryl, and alicyclic, with the exception of H, all are optionally substituted. Particularly preferred are lower alkyl and alicyclic.

Preferred R ⁴ and R ⁷ groups include —H and lower alkyl.

In one preferred aspect, the compounds of formula III, A, L, and E independently mean —H, 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 -alkylcarbonylamino; and each R ⁴ and R ⁷ independently means —H and lower alkyl. Particularly preferred are those compounds in which A, L and E are independently —H, lower alkyl, halogen and —NR ⁸ ₂ ; J is —H, halogen, haloalkyl, hydroxyalkyl, R ⁸ ₂ N-alkyl, lower alkyl, lower aryl, heterocycle and alicyclic, or together with Y ³ form a cyclic group; and X ³ is -heteroaryl-, -alkylaminocarbonyl-, -1,1-dihaloalkyl- and -alkoxyalkyl-. Particularly preferred are those compounds wherein A is —H, —NH ₂ , —F, and —CH ₃ , L is —H, —F, —OCH ₃ , —Cl, and —CH ₃ ; E is —H and —CH ₃ , J is —H, halogen, C ₁ -C ₅ hydroxyalkyl, C ₁ -C ₅ haloalkyl, C ₁ -C ₅ - R ⁸ ₂ N-alkyl, C ₁ -C ₅ -alkyl and C ₁ -C ₅ -alkyl, X ³ means —CH ₂ OCH ₂ - and -furan- 2,5-diyl and Y ³ means lower alkyl. Most preferred are the following such compounds and their salts and prodrugs and their salts:

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

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

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

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

6) A is —NH ₂ , L is —F, E is —H, 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 —H, 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 in which 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 those in which R ¹ is pivaloyloxymethyl or its HCl salt.

In another aspect, compounds of formula I or IA are preferred in which M is

wherein

Z ^{6 is} selected from alkyl and halogen,

U ⁶ and V ^{6 are} independently selected from hydrogen, hydroxy, acyloxy or, when taken together, form a lower cyclic ring containing at least one oxygen;

W ^{6 is} selected from amino and lower alkylamino;

and their pharmaceutically acceptable prodrugs and salts. In another aspect of the invention, compounds of formula VI are provided:

wherein:

Z ^{6 is} selected from alkyl and halogen,

U ⁶ and V ^{6 are} independently selected from hydrogen, hydroxy, acyloxy or, taken together, form a lower cyclic ring containing at least one oxygen;

W ^{6 is} selected from amino and lower alkylamino;

Y is independently selected from —O— and —NR ⁶ , provided that:

if Y is —O—, R attached to —O— is independently selected from —H, alkyl, optionally substituted aryl, optionally substituted alicyclic, in which the cyclic moiety contains carbonate or thiocarbonate optionally substituted by arylalkyl-, —C (R ² ) ₂ CO (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;

if Y is —NR ⁶ -, R ¹ attached to —NR ⁶ - is independently selected from —H, - [C (R ² ) ₂ ] _q —COOR ³ , —C (R ⁴ ) ₂ COOR ³ , - [ (C (R ₂ ) ₂ ] _q -C (O) SR ³ and -cycloalkylene-COOR ³ , where q is 1 or 2;

if only one Y is —O—, where —O— is not part of a cyclic group containing another Y, then the other Y is —N (R ¹⁸ ) - (CR ¹² R ¹³ ) —C (O) R ¹⁴ ; and

if 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:

in which

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 through an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is condensed with an aryl group at the beta and gamma positions of Y adjacent to V; or Z is selected from the group —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 CO 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 , -SCO ₂ R ³ , -NHCOR ² , NHCO ₂ R ³ , -CH ₂ NH-aryl, - (CH ₂ ) _p —OR ² and - (CH ₂ ) _p —SR ² in which p is an integer of 2 or 3;

or

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

W and W ′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

or

W and W ′ are joined together via an additional 2-5 atoms to form a cyclic group optionally containing 0-2 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 —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

Z ^{2 is} selected from the group —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) OR ³ , —CH (aryl) OH, —CH (CH = CR ² ₂ ) OH, —CH (C = CR ² ) OH, —SR ² , —CH ₂ NH-aryl, —CH ₂ aryl; or

V ² and Z ^{2 are} joined together through an additional 3-5 atoms to form a cyclic group containing 5-7 atoms in the ring, optionally containing 1 heteroatom, and substituted by hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom located at a distance of three atoms from Y connected to phosphorus;

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

D 'is —H;

D "is selected from the group —H, alkyl, —OR ² , —OH and —OC (O) R ³ ;

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

provided that:

a) V, Z, W, W ′ all do not mean -H and V ² , Z ² , W ² , W "all do not mean -H;

R ^{2 is} selected from R ³ and —H;

R ³ selected from alkyl, aryl, alicyclic and aralkyl;

each R ^{4 is} independently selected from the group consisting of —H, alkylene, α-alkylenearyl and aryl, or R ⁴ and R ^{4 are} joined together through 2-6 atoms, optionally including one heteroatom selected from the group O, N and S;

R ^{6 is} selected from —H, 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 and aralkyl, or R ¹² and R ^{18 are} joined together through 1-4 carbon atoms to form a cyclic group;

each R ¹² and R ^{13 is} independently selected from H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R ¹² and R ^{13 are} joined together via 2-6 carbon atoms, optionally including 1 heteroatom selected from the group O, N and S, with the formation of a cyclic group;

each R ^{14 is} independently selected from —OR ¹⁷ , —N (R ¹⁷ ) ₂ , —NHR ¹⁷ , —SR ^17, and —NR ² R ²⁰ ;

R ^{15 is} selected from —H, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together by 2-6 atoms to form a cyclic group, the cyclic group optionally including one heteroatom selected from the group O, N and S;

R ^{16 is} selected from - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ , -H, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together by 2-6 atoms to form a cyclic group wherein the cyclic group optionally includes one heteroatom selected from the group O, N and S;

each R ^{17 is} independently selected from lower alkyl, lower aryl, and lower aralkyl, or, if R ¹⁴ is —N (R ¹⁷ ) ₂ , two R ^{17 are} joined together by 2-6 atoms to form a cyclic group, the cyclic group optionally including one heteroatom itself selected from the group O, N and S;

R ^{20 is} selected from the group —H, lower R ^3, and —C (O) —lower — R ³ .

and their pharmaceutically acceptable prodrugs and salts.

In another aspect of the invention, there are provided compounds of formula I and formula IA, in which M means:

wherein:

And ^{2 is} selected from —NR ⁸ ₂ , —NHSO ₂ R ³ , —OR ²⁵ , —SR ²⁵ , halogen, lower alkyl, —CON (R ⁴ ) ₂ , guanidine, amidine, —H, and perhaloalkyl;

E ^{2 is} selected from —H, halogen, lower alkylthio, lower perhaloalkyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, —CN and —NR ⁷ ₂ ;

X ^{3 is} selected from -alkyl (hydroxy) -, alkyl-, -alkynyl-, aryl-,

-carbonyl-, alkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-,

-alkyloxy-, -alkylthioalkyl-, -alkylthio -, - alkylaminocarbonyl-,

-alkylcarbonylamino, -alicyclo-, -aralkyl-, -alkylaryl-,

-alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-and -alkylaminocarbonylamino, all optionally substituted, provided that X ^{3 is} not substituted -COOR ² , -SO ₃ H or -PO ₃ R ² ₂ ;

Y ^{3 is} selected from —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C (O) R ³ ,

—S (O) ₂ R ³ , —C (O) —R ¹¹ , —CONHR ³ , —NR ² _2, and —OR ³ , with the exception of H, are all optionally substituted;

each R ^{4 is} independently selected from —H and alkyl, or two R ⁴ together form a cyclic alkyl group;

R ^{25 is} selected from lower alkyl, lower aryl, lower aralkyl and lower alicyclic;

each R ^{7 is} independently selected from —H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and —C (O) R ¹⁰ ;

each R ^{8 is} independently selected from —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —C (O) R ¹⁰ , or together two R ⁸ form bidentate alkyl;

R ^{10 is} selected from —H, lower alkyl, —NH ₂ , lower aryl, and lower perhaloalkyl; and

R ^{11 is} selected from alkyl, aryl, —NR ² _2, and —OR ² .

In another aspect, compounds of formula II are preferred:

wherein

And ^{2 is} selected from —NR ⁸ ₂ , —NHSO ₂ R ³ , —OR ²⁵ , —SR ²⁵ , halogen, lower alkyl, —CON (R ⁴ ) ₂ , guanidine, amidine, —H, and perhaloalkyl;

E ^{2 is} selected from —H, halogen, lower alkylthio, lower perhaloalkyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, —CN and —NR ⁷ ₂ ;

X ^{3 is} selected from -alkyl (hydroxy) -, alkyl-, -alkynyl-, aryl-,

-carbonyl-, alkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-,

-alkyloxy-, -alkylthioalkyl-, -alkylthio -, - alkylaminocarbonyl-,

-alkylcarbonylamino, -alicyclo-, -aralkyl-, -alkylaryl-,

-alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-and -alkylaminocarbonylamino, all optionally substituted, provided that X ^{3 is} not substituted -COOR ² , -SO ₃ H or -PO ₃ R ² ₂ ;

Y ^{3 is} selected from —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C (O) R ³ , —S (O) ₂ R ³ , —C (O) —R ¹¹ , - CONHR ³ , —NR ² ₂ and —OR ³ , with the exception of H, are all optionally substituted;

Y is independently selected from —O— and —NR ⁶ , provided that:

if Y is —O—, R ¹ attached to —O— is independently selected from —H, alkyl, optionally substituted aryl, optionally substituted alicyclic, in which the cyclic moiety contains carbonate or thiocarbonate optionally substituted by arylalkyl-, —C ( R ² ) ₂ CO (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;

if Y is —NR ⁶ -, R ¹ attached to —NR ⁶ - is independently selected from —H, - [C (R ² ) ₂ ] _q —COOR ³ , —C (R ⁴ ) ₂ COOR ³ , - [ C (R ² ) ₂ ] _q —C (O) SR ³ and -cycloalkylene-COOR ³ , where q is 1 or 2;

if only one Y means —O—, where —O— is not part of a cyclic group containing another Y, then another Y means

-N (R ¹⁸ ) - (CR ¹² R ¹³ ) -C (O) R ¹⁴ ; and

if 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:

in which 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 by an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is condensed with an aryl group at the beta and gamma positions of Y adjacent to V; or

Z is selected from the group —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 , -SCO ₂ R ³ , -NHCOR ² , NHCO ₂ R ³ , -CH ₂ NH-aryl, - (CH ₂ ) _p —OR ² and - (CH ₂ ) _p —SR ² in which p is an integer of 2 or 3; or

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

W and W ′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

or

W and W ′ are joined together by an additional 2-5 atoms to form a cyclic group optionally containing 0-2 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

-H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

Z ^{2 is} selected from the group —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) OR ³ , —CH (aryl) OH,

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

V ² and Z ^{2 are} joined together by an additional 3-5 atoms to form a cyclic group containing 5-7 atoms in the ring, optionally containing 1 heteroatom, and substituted by hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyl-oxy attached to the carbon atom located on the distance of three atoms from Y, combined with phosphorus;

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

D 'is —H;

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

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

provided that:

a) V, Z, W, W ′ all do not mean -H and V ² , Z ² , W ² , W "all do not mean -H;

R ^{2 is} selected from R ³ and —H;

R ³ selected from alkyl, aryl, alicyclic and aralkyl;

each R ^{4 is} independently selected from the group consisting of —H, alkyl, or R ⁴ and R ^{4 are} joined together to form a cyclic alkyl group;

R ^{6 is} selected from —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl;

R ^{25 is} selected from lower alkyl, lower aryl, lower aralkyl and lower alicyclic;

R ^{7 is} independently selected from —H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and - (CO) R ¹⁰ ;

R ^{8 is} independently selected from —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, - (CO) R ¹⁰ , or two R ⁸ together form a bidentate alkyl;

R ^{9 is} selected from alkyl, aralkyl, and alicyclic;

R ^{10 is} selected from —H, lower alkyl, —NH ₂ , lower aryl, and lower perhaloalkyl; and

R ^{11 is} selected from alkyl, aryl, —NR ² _2, and —OR ² ;

n is an integer from 1 to 3;

R ^{18 is} independently selected from H, lower alkyl, aryl and aralkyl, or R ¹² and R ^{18 are} joined together through 1-4 carbon atoms to form a cyclic group;

each R ¹² and each R ^{13 is} independently selected from H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R ¹² and R ^{13 are} joined together by 2-6 carbon atoms, optionally including 1 heteroatom selected from group O, N and S, with the formation of a cyclic group;

each R ^{14 is} independently selected from —OR ¹⁷ , —N (R ¹⁷ ) ₂ , —NHR ¹⁷ , —SR ^17, and —NR ² R ²⁰ ;

R ^{15 is} selected from —H, lower alkyl, lower aryl, and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together by 2-6 atoms to form a cyclic group, the cyclic group optionally including one heteroatom selected from the group O, N and S;

R ^{16 is} selected from - (CR ¹² R ¹³ ) _n —C (O) —R ¹⁴ , —H, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together by 2-6 atoms to form a cyclic group wherein the cyclic group optionally includes one heteroatom selected from O, N and S;

each R ^{17 is} independently selected from lower alkyl, lower aryl, and lower aralkyl, or, if R ¹⁴ is —N (R ¹⁷ ) 2, two R ^{17 are} joined together by 2-6 atoms to form a cyclic group, the cyclic group optionally including one a heteroatom selected from O, N and S;

R ^{20 is} selected from the group consisting of —H, lower R ³ and —C (O) —lower R ³ ;

and their pharmaceutically acceptable prodrugs and salts.

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. Particularly preferred is —NR ⁸ ₂ . Most preferred is —NH ₂ .

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

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

Preferred Y ³ groups for formula II include aralkyl, alicyclic, alkyl and aryl, all optionally substituted. Particularly preferred is lower alkyl. Particularly preferred Y ³ groups include (2-naphthyl) methyl, cyclohexylethyl, phenylethyl, nonyl, cyclohexylpropyl, ethyl, cyclopropylmethyl, cyclobutylmethylphenyl, (2-methyl) propyl, neopentyl, cyclopropyl, cyclopentyl, (1-imidosolyl) propyl, 2-ethib , 1-hydroxy-2,2-dimethylpropyl, 1-chloro-2,2-dimethylpropyl, 2,2-dimethylbutyl, 2- (spiro-3 ', 3'-dimethylcyclohex-4-enyl) propyl and 1-methylneopentyl. Neopentyl and isobutyl are particularly preferred.

Preferred R ⁴ and R ⁷ groups include —H and lower alkyl. Particularly preferred are —H and methyl.

In another preferred aspect, A ² is —NR ⁸ ₂ or halogen, E ² is —H, 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 are} —H or lower alkyl. Particularly preferred are those compounds in which Y ³ is aralkyl, aryl, alicyclic or alkyl.

In yet another aspect, A ² is —NR ⁸ ₂ , E ² is —H, Cl, or methylthio, and X ³ is optionally substituted —furan-2,5-diyl or alkoxyalkyl. Particularly preferred are those compounds in which A ² is —NH ₂ , X ³ is furan-2,5-diyl or methoxymethyl, and Y ³ is lower alkyl. Most preferred are those compounds in which E ² is —H, X ³ is furan-2,5-diyl, and Y ³ is neopentyl; compounds in which E ² is —SCH ₃ , X ³ is furan-2,5-diyl, and Y ³ is isobutyl; and compounds in which E ² is —H, X ³ is furan-2,5-diyl, and Y ³ is 1- (3-chloro-2,2-dimethyl) propyl. Particularly preferred are those compounds in which R ¹ is —CH ₂ OC (O) —C (CH ₃ ) ₃ .

In a further aspect of the invention, compounds of formula I or formula IA are preferred in which M is

in which B ^{5 is} selected from —NH—, —N = and —CH =;

D ^{5 is} selected from

Q ^{5 is} selected from —C = and —N—;

provided that:

if B ⁵ means —NH—, then Q ⁵ means —C = and D ⁵ means

if B ⁵ means —CH =, then Q ⁵ means —N— and D ⁵ means

if B ⁵ means -N =, D ⁵ means

and Q ⁵ means —C =;

A, E and L are selected from —NR ⁸ ₂ , —NO ₂ , —H, OR ⁷ , SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —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, 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 heterocycle;

J is selected from —NR ⁸ ₂ , —NO ₂ , —H, OR ⁷ , SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —COR ¹¹ , —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl , haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or together with Y ³ forms a cyclic group selected from the group consisting of aryl, cyclic alkyl and heterocyclic alkyl;

X ^{3 is} selected from -alkyl (hydroxy) -, alkyl-, -alkynyl-, aryl-,

-carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-,

-alkyloxy-, -alkylthioalkyl-, -alkylthio -, - alkylaminocarbonyl-,

-alkylcarbonylamino-, -alicyclo-, -aralkyl-, - al-kylaryl-,

-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 P ² ₂ ;

Y ^{3 is} selected from —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C (O) R ³ , —S (O) ₂ R ³ , —C (O) —R ¹¹ , - CONHR ³ , —NR ² ₂ and —OR ³ , with the exception of H, are all optionally substituted;

R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group;

R ^{25 is} selected from lower alkyl, lower aryl, lower aralkyl and lower alicyclic;

R ^{7 is} independently selected and —H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and - (CO) R ¹⁰ ;

R ^{8 is} independently selected from —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, - (CO) R ¹⁰ , or two R ⁸ together form a bidentate alkyl;

R ^{10 is} selected from —H, lower alkyl, —NH ₂ , lower aryl, and

lower perhaloalkyl;

R ^{11 is} selected from alkyl, aryl, —NR ² _2, and —OR ² ;

or their pharmaceutically acceptable prodrugs or salts. Preferred are compounds of formula IV:

wherein:

^{5 is} selected from —NH—, —N = and —CH =;

D ^{5 is} selected from

Q ^{5 is} selected from —C = and —N—;

provided that:

if B ⁵ means —NH—, then Q ⁵ means —C = and D ⁵ means

if B ⁵ means —CH =, then Q ⁵ means —N— and D ⁵ means

и Q⁵ означает -С=;if B ⁵ means -N =, D ⁵ means

and Q ⁵ means —C =;

A, E and L are selected from —NR ⁸ ₂ , —NO ₂ , —H, OR ⁷ , SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —COR ¹¹ , —SO ₂ R ³ , 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 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 heterocycle;

J is selected from —NR ⁸ ₂ , —NO ₂ , —H, —OR ⁷ , —SR ⁷ , —C (O) NR ⁴ ₂ , halogen,

-COR ¹¹ , -CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or together with Y ³ forms a cyclic group selected from the group consisting of aryl cyclic alkyl and heterocyclic alkyl;

X ^{3 is} selected from -alkyl (hydroxy) -, alkyl-, -alkynyl-, aryl-,

-carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-,

-alkyloxy-, -alkylthioalkyl-, -alkylthio -, - alkylaminocarbonyl-,

-alkylcarbonylamino-alicyclo-. -aralkma-, -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 —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C (O) R ³ , —S (O) ₂ R ³ , —C (O) —R ¹¹ , - CONHR ³ , —NR ² ₂ and —OR ³ , with the exception of H, are all optionally substituted;

Y is independently selected from —O— and —NR ⁶ , provided that:

if Y is —O—, R ¹ attached to —O— is independently selected from —H, alkyl, optionally substituted aryl, optionally substituted alicyclic, in which the cyclic moiety contains carbonate or thiocarbonate, optionally substituted α-arylalkyl—, —C ( R ² ) ₂ CO (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-S-S-alkyl-hydroxy; and -alkyl-S-S-S-alkyl-hydroxy;

if Y is —NR ⁶ -, R ¹ attached to —NR ⁶ - is independently selected from —H, - [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 , where q is 1 or 2;

if only one Y means —O—, where —O— is not part of a cyclic group containing another Y, then another Y means

-N (R ¹⁸ ) - (CR ¹² R ¹³ ) -C (O) R ¹⁴ ; and

if 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 together form:

wherein

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 by an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is condensed with an aryl group at the beta and gamma positions of Y adjacent to V; or

Z is selected from the group —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 , -SCO ₂ R ³ , -NHCOR ² , NHCO ₂ R ³ , -CH ₂ NH-aryl, ~ ( CH ₂ ) _p —OR ² and - (CH ₂ ) _p —SR ² in which p is an integer of 2 or 3;

or

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

W and W ′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

or

W and W ′ are joined together by an additional 2-5 atoms to form a cyclic group optionally containing 0-2 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

-H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

Z ^{2 is} selected from the group —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) OR ³ , —CH (aryl) OH,

-CH (CH = CR ² ₂ ) OH, -CH (C = CR ² ) OH, -SR ² , -CH ₂ NH-apnn, -CH ₂ -aryl; or

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

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

D 'is —H;

D "is selected from the group —H, alkyl, —OR ² , —OH and —OC (O) R ³ ;

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

provided that:

a) V, Z, W, W ′ all do not mean -H and V ² , Z ² , W ² , W "all do not mean -H;

R ^{2 is} selected from R ³ and —H;

R ³ selected from alkyl, aryl, alicyclic and aralkyl;

each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group;

R ^{6 is} selected from —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl;

R ^{25 is} selected from lower alkyl, lower aryl, lower aralkyl and lower alicyclic;

R ^{7 is} independently selected from —H, lower alkyl, lower alicyclic, 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 together they form a bidentate alkyl;

R ^{9 is} selected from alkyl, aralkyl, and alicyclic;

R ^{10 is} selected from —H, lower alkyl, —NH ₂ , lower aryl, and lower perhaloalkyl;

R ^{11 is} selected from alkyl, aryl, —NR ² _2, and —OR ² ;

n is an integer from 1 to 3;

R ^{18 is} independently selected from H, lower alkyl, aryl and aralkyl, or R ¹² and R ^{18 are} joined together by 1-4 carbon atoms to form a cyclic group;

each R ¹² and R ^{13 is} independently selected from H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R ¹² and R ^{13 are} joined together by 2-6 carbon atoms, optionally including 1 heteroatom selected from the group O, N and S, with the formation of a cyclic group;

each R ^{14 is} independently selected from —OR ¹⁷ , —N (R ¹⁷ ) ₂ , —NHR ¹⁷ , —SR ^17, and —NR ² R ²⁰ ;

R ^{15 is} selected from —H, lower alkyl, lower aryl, and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together by 2-6 atoms to form a cyclic group, the cyclic group optionally including one heteroatom selected from the group O, N and S;

R ^{16 is} selected from - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ , -H, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together by 2-6 atoms to form a cyclic group wherein the cyclic group optionally includes one heteroatom selected from the group O, N and S;

each R ^{17 is} independently selected from lower alkyl, lower aryl, and lower aralkyl, or, if R ¹⁴ is —N (R ¹⁷ ) ₂ , two R ^{17 are} joined together by 2-6 atoms to form a cyclic group, the cyclic group optionally including one heteroatom itself selected from the group O, N and S;

R ^{20 is} selected from the group —H, lower R ^3, and —C (O) —lower — R ³ .

and their pharmaceutically acceptable prodrugs and salts.

Preferred groups A, E and L for formula IV include —H, —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. Such a cyclic group may be aromatic and cyclic alkyl and may optionally be substituted. Suitable aromatic groups include thiazole. Particularly preferred groups A, L and E are —NR ⁸ ₂ , —H, hydroxy, halogen, lower alkoxy, lower perhaloalkyl and lower alkyl.

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

Preferred groups L and E for formula IV include —H, lower alkoxy, lower alkyl and halogen.

Preferred J groups for formula IV include —H, halogen, lower alkyl, lower hydroxyalkyl, —NR ⁸ ₂ , lower — R ⁸ ₂ N-alkyl, lower haloalkyl, lower perhaloalkyl, lower alkenyl, lower alkynyl, lower aryl, heterocycle and an alicyclic, or together with Y ³ forms a cyclic group. Such a cyclic group may be aromatic and cyclic alkyl and may optionally be substituted. Particularly preferred J groups include —H, halogen and lower alkyl, lower hydroxyalkyl, —NR ⁸ ₂ , lower — R ⁸ ₂ N-alkyl, lower haloalkyl, lower alkenyl, alicyclic, and aryl.

Preferred X ³ groups for formula IV include -alkyl-,

-alkynyl-, -alkoxyalkyl-, -alkylthio-, -aryl-, alkylaminocarbonyl-, -alkylcarbonylamino, -1,1-dihaloalkyl-, -carbonylalkyl- and -alkyl (OH) -. Particularly preferred are -1,1-dihaloalkyl-, -alkylaminocarbonyl-, -alkoxyalkyl- and -heteroaryl-. Particularly preferred are compounds which are -heteroaryl-, -alkylaminocarbonyl- and alkoxyalkyl-. Most preferred are methylaminocarbonyl, methoxymethyl and furan-2,5-diyl.

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

Preferred Y ³ groups for formula IV include —H, alkyl, aryl, aralkyl, and the alicyclic, with the exception of H, are all optionally substituted. Particularly preferred Y ³ groups include lower alkyl and alicyclic.

Preferred R ⁴ and R ⁷ groups include —H and lower alkyl.

и Q⁵ означает -С=. В другом предпочтительном аспекте В⁵ означает -N=, D⁵ означает

и Q⁵ означает -С=.In one preferred aspect of formula IV, B ⁵ is NH, D ⁵ is

and Q ⁵ means —C =. In another preferred aspect, B ⁵ is —N =, D ⁵ is

and Q ⁵ means —C =.

In yet another preferred aspect of formula IV, A, L, and E independently mean —NR ⁸ ₂ , lower alkyl, lower perhaloalkyl, lower alkoxy, halogen, —OH or —H, X ³ means aryl—,

-alkoxyalkyl-, -alkyl-, -alkylthio- -1,1-dihaloalkyl-,

-carbonylalkyl-, -alkyl (hydroxy) -, -alkylaminocarbonyl- and

и Q⁵ означает -С=, или В⁵ означает

D⁵ означает, и Q⁵ означает -С=.-alkylcarbonylamino; and each R ⁴ and R ⁷ independently means —H or lower alkyl. Particularly preferred are those compounds in which A, L and E are independently —H, lower alkyl, halogen and —NR ⁸ ₂ ; J is —H, halogen, haloalkyl, hydroxyalkyl, R ⁸ ₂ N-alkyl, lower alkyl, lower aryl, heterocycle and alicyclic, or together with Y ³ form a cyclic group; and X ³ is -heteroaryl-, -alkylaminocarbonyl-, -1,1-dihaloalkyl- and -alkoxyalkyl-. Particularly preferred are those compounds wherein A is —H, —NH ₂ , —F, or —CH ₃ , L is —H, —F, —OCH ₃ , or —CH ₃ , E is —H or —CH ₃ , J means H, halogen, C ₁ -C ₅ hydroxyalkyl, C ₁ -C ₅ haloalkyl, C ₁ -C ₅ -R ⁸ ₂ N-alkyl, C ₁ -C ₅ -alkyl or C ₁ -C ₅ -alkyl , X ³ is —CH ₂ OCH ₂ - or —furan-2,5-diyl, and Y ³ is lower alkyl. Preferred are those compounds in which B ⁵ is NH, D ⁵ is

and Q ⁵ means —C =, or B ⁵ means

D ⁵ means, and Q ⁵ means -C =.

Most preferred are compounds in which:

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

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

Q⁵ означает -С=, и Y³ означает изобутил; и3) A means —H, L means —H, E means —Cl, J means —H, B ⁵ means —NH, D ⁵ means

Q ⁵ is —C =, and Y ³ is isobutyl; and

Q⁵ означает -С= и Y³ означает изобутил.4) A means —CH ₃ , L means —H, E means —H, J means —H, B ⁵ means —N =, D ⁵ means

Q ⁵ means —C = and Y ³ means isobutyl.

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

In another particularly preferred aspect, there are provided compounds in which A, L and E are —H, lower alkyl, halogen or —NR ⁸ ₂ , J is —H, halogen, lower alkyl, lower aryl, heterocycle or alicyclic, or together with Y ³ forms a cyclic group, and X ³ means -heteroaryl-, alkylaminocarbonyl- or -alkoxyalkyl-.

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

in which:

each G is independently selected from C, N, O, S and Se, and in which only one G is O, S or Se and, at best, one G is N;

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

And selected from —H, —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 or missing.

each B and D is independently selected from —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, —C (O) R ¹¹ , —C (O) SR ³ , —SO ₂ R ¹¹ , —S (O ) R ³ , —CN, —NR ² ₂ , —OR ³ , —SR ³ , or no perhaloalkyl, halogen, —NO ₂ , with the exception of —H, —CN, perhaloalkyl, —NO ₂ and halogen, are all optionally substituted.

E is selected from —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, —C (O) OR ³ , —CONR ⁴ ₂ , —CN, —NR ⁹ ₂ , —NO ₂ , —OR ³ , —SR ³ , perhalogenated, halogen or absent, with the exception of -H, -CN, perhalogenated and halogen, all are optionally substituted.

J is selected from —H or absent;

X is an optionally substituted linking group that binds R ⁵ to a phosphorus atom through 2-4 atoms including 0-1 heteroatoms selected from N, O and S, except that if X is urea or carbamate, then there are 2 heteroatoms located along the shortest path between R ⁵ and the phosphorus atom, and where the atom attached to the phosphorus is a carbon atom, and where X is selected from -alkyl (hydroxy) -, -alkynyl-, heteroaryl-, -carbonylalkyl-, -1, 1-dihaloalkyl-,

-alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-,

-alkylaminocarbonyl. -alkylcarbonylamino, -alkoxycarbonyl-,

-carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylamino-carbonylamino, 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 —H;

R ³ selected from alkyl, aryl, alicyclic and aralkyl;

each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group;

R ^{6 is} selected from —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl;

each R ^{9 is} independently selected from —H, alkyl, aralkyl, and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group;

R ^{11 is} selected from alkyl, aryl, —NR ² _2, and —OR ² ;

n is an integer from 1 to 3;

R ^{18 is} independently selected from H, lower alkyl, aryl and aralkyl, or R ¹² and R ^{18 are} joined together by 1-4 carbon atoms to form a cyclic group;

each R ¹² and each R ^{13 is} independently selected from H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R ¹² and R ^{13 are} joined together by 2-6 carbon atoms, optionally including 1 heteroatom selected from group O, N and S, with the formation of a cyclic group;

each R ^{14 is} independently selected from —OR ¹⁷ , —N (R ¹⁷ ) ₂ , —NHR ¹⁷ , —SR ^17, and —NR ² R ²⁰ ;

R ^{15 is} selected from —H, lower alkyl, lower aryl, and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together by 2-6 atoms to form a cyclic group, the cyclic group optionally including one heteroatom selected from the group O, N and S;

R ^{16 is} selected from - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ , -H, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together by 2-6 atoms to form a cyclic group wherein the cyclic group optionally includes one heteroatom selected from the group O, N and S;

each R ^{17 is} independently selected from lower alkyl, lower aryl, and lower aralkyl, or, if R ¹⁴ is —N (R ¹⁷ ) ₂ , two R ^{17 are} joined together by 2-6 atoms to form a cyclic group, the cyclic group optionally including one heteroatom itself selected from the group O, N and S;

R ^{20 is} selected from the group —H, lower R ^3, and —C (O) —lower — R ³ ,

and provided that:

1) if G 'means N, then, respectively, A, B, D or E is absent;

2) at least one of A and B or A, B, D and E cannot be selected from -H or absent;

3) if R ⁵ is a six-membered ring, then X is not a 2 atomic linker, optionally substituted with -alkyloxy or optionally substituted with -alkylthio;

4) if G means N, then respectively A or B do not mean halogen or a group directly connected to G through a heteroatom;

5) if X does not mean an aryl- group, then R ^{5 is} not substituted with two or more aryl groups;

Y is independently selected from —O— and —NR ⁶ , provided that:

if Y is —O—, R ¹ attached to —O— is independently selected from —H, alkyl, optionally substituted aryl, optionally substituted alicyclic, in which the cyclic moiety contains carbonate or thiocarbonate, optionally substituted α-arylalkyl—, —C ( R ² ) ₂ CO (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-alkyl hydroxy, and -alkyl-SSS-alkyl hydroxy;

if Y is —NR ⁶ -, R ¹ attached to —NR ⁶ - is independently selected from —H, - [C (R ² ) ₂ ] _q —COOR ³ , —C (R ⁴ ) ₂ COOR ³ , - [ C (R ² ) ₂ ] _q -C (O) SR ³ and -cycloalkylene-COOR ³ , where q is 1 or 2;

if only one Y is —O—, where —O— is not part of a cyclic group containing another Y, then the other Y is —N (R ¹⁸ ) - (CR ¹² R ¹³ ) —C (O) R ¹⁴ and

if 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 together form:

wherein

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 by an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is condensed with an aryl group at the beta and gamma positions of Y adjacent to V; or

Z is selected from the group —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 , -SCO ₂ R ³ , -NHCOR ² , NHCO ₂ R ³ , -CH ₂ NH-aryl, - (CH ₂ ) _p —OR ² and - (CH ₂ ) _p —SR ² in which p is an integer of 2 or 3;

or

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

W and W ′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

or

W and W ′ are joined together by an additional 2-5 atoms to form a cyclic group optionally containing 0-2 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

-H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

Z ^{2 is} selected from the group —CHR ² H, —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) OR ³ , —CH (aryl) OH,

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

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

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

D 'is —H;

D "is selected from the group —H, alkyl, —OR ² , —OH and —OC (O) R ³ ;

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

provided that:

a) V, Z, W, W ′ all do not mean -H and V ² , Z ² , W ² , W ^" all do not mean -H.

In one preferred aspect of formula V-1 and formula V-2, there are provided compounds in which

A "is selected from —NH ₂ , —CONH ₂ , halogen, —CH ₃ , —CF ₃ , —CH ₂ halogen, —CN, —OCH ₃ , SCH _3, and —H;

In "selected from —H, —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 —H, —C (O) R ¹¹ , —C (O) SR ³ , —NR ⁹ ₂ , alkyl, aryl, alicyclic, halogen, and —SR ³ ;

E "is selected from —H, C ₁ -C ₆ alkyl, lower alicyclic, halogen,

-CN, -C (O) OR ³ and -SR ³ ;

X is selected from -alkyl (hydroxy) -, -alkyl-, -alkynyl-,

-aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio, alkylaminocarbonyl-, -alkylcarbonylamino, -alicyclo-, aralkyl-, -alkylaryl-, - alkoxycarbonyl-, carbonyloxyalkyl-, -alkoxycarbonylamino and alkylaminocarbonylamino, all optionally substituted;

if both Y groups are —O— then R ^{1 is} independently selected from optionally substituted aryl, optionally substituted benzyl, —C (R ² ) ² OC (O) R ³ , —C (R ² ) ² OC (O) OR ³ and -H; or

if one Y is —O—, then R ¹ attached to —O— is an optionally substituted aryl; and the other Y is —NR ⁶ -, then R ¹ attached to —NR ⁶ - is selected from —C (R ⁴ ) ₂ COOR ³ and —C (R ² ) ₂ COOR ³ ; or

if Y is —O— or —NR ⁶ -, then R ¹ and R ¹ together form:

in which

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 by an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is condensed with an aryl group at the beta and gamma positions of Y adjacent to V; or

Z is selected from the group —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 , -SCO ₂ R ³ , -NHCOR ² , NHCO ₂ R ³ , -CH ₂ NH-aryl, - (CH ₂ ) _p —OR ² and - (CH ₂ ) _p —SR ² in which p is an integer of 2 or 3;

or

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

W and W ′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

or

W and W ′ are joined together by an additional 2-5 atoms to form a cyclic group optionally containing 0-2 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 —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

Z ^{2 is} selected from the group —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) OR ³ , —CH (aryl) OH,

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

V ² and Z ^{2 are} joined together by an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally containing 1 heteroatom, and substituted by hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom, which is three atoms from Y adjacent 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 —H;

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

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

provided that:

a) V, Z, W, W 'all do not mean -H and V ² , Z ² , W ² , W "all do not mean -H;

b) both groups Y do not mean —NR ⁶ -;

R ^{2 is} selected from R ³ and —H;

R ³ selected from alkyl, aryl, alicyclic and aralkyl;

R ^{6 is} selected from —H and lower alkyl.

In one preferred aspect, there are provided compounds of formula I in which M is —XR ⁵ and R ⁵ is

X is selected from methyleneoxycarbonyl and furan-2,5-diyl; at least one group Y is —O—; and their pharmaceutically acceptable salts and prodrugs. More preferred are those compounds in which, if Y is —O—, then R ¹ attached to —O— is independently selected from —H, optionally substituted phenyl, —CH ₂ OC (O) —tBu, —CH ₂ OC (O) Et and -CH ₂ OC (O) -iPr;

if Y is —NR ⁶ -, then R ¹ attached to —NR ⁶ - is independently selected from —C (R ² ) ₂ COOR ³ , —C (R ⁴ ) ₂ COOR ^3, or

if Y is —O— or —NR ⁶ - and at least one Y is —O— then R ¹ and R ¹ together are

in which V is selected from optionally substituted aryl and optionally substituted heteroaryl; and Z, W and W ′ are H; and

R ^{6 is} selected from —H and lower alkyl.

The following compounds and their salts are most preferred:

1) A "means -NH ₂ , X means furan-2,5-diyl and B" means -CH ₂ -CH (CH ₃ ) ₂ ;

2) A "means -NH ₂ , X means furan-2,5-diyl and B" means -COOEt;

3) A “means —NH ₂ , X — means furan-2,5-diyl, and B” means —SCH ₃ ;

4) A "means -NH ₂ , X means furan-2,5-diyl and B" means -SCH ₂ CH ₂ CH ₃ ;

5) A "means -NH ₂ , X means methyleneoxycarbonyl and B" means -CH (CH ₃ ) ₂ ;

6) A "means -NH ₂ , X means furan-2,5-diyl and B" means 4-morpholinyl.

In another preferred aspect, there are provided compounds of formula I in which M is —XR ⁵ and R ⁵ is

X is furan-2,5-diyl and methyleneoxycarbonyl, and A ″ is —NH ₂ ; at least one Y group is —O—; and their pharmaceutically acceptable salts and prodrugs.

Particularly preferred are those compounds in which, if Y is —O—, then R ^{1 is} independently selected from —H, optionally substituted phenyl, —CH ₂ OC (O) —tBu, —CH ₂ OC (O) Et and —CH ₂ OC (O) -iPr;

or if Y means —NR ⁶ -, then R ^{1 is} independently selected from

-C (R ² ) ₂ C (O) OR ³ ; -C (R ⁴ ) ₂ COOR ³ ;

or if Y is independently selected from —O— or —NR ⁶ -, then R ¹ and R ¹ together mean

wherein

V is selected from optionally substituted aryl and optionally substituted heteroaryl; and Z, W and W ′ are H. Also particularly preferred are those compounds in which B ″ is —SCH ₂ CH ₂ CH ₃ .

In another particularly preferred aspect are compounds of formula I, in which M is —XR ⁵ and R ⁵ is

And "means -NH ₂ , E" and D "mean -H, B" means n-propyl and cyclopropyl, X means furan-2,5-diyl and methyleneoxycarbonyl; at least one group Y is —O—;

and their pharmaceutically acceptable salts and prodrugs. Particularly preferred are those compounds wherein R ^{1 is} selected from —H, optionally substituted phenyl, —CH ₂ OC (O) -tBu, —CH ₂ OC (O) Et, and —CH ₂ OC (O) —iPr;

or if Y is —NR ⁶ -, then each R ^{1 is} independently selected from —C (R ² ) ₂ C (O) OR ³ , —C (R ⁴ ) ₂ COOR ³ ;

or if any Y is independently selected from —O— or —NR ⁶ - and at least one Y is —O— then R ¹ and R ¹ together are

wherein

V is selected from optionally substituted aryl and optionally substituted heteroaryl; and Z, W and W ′ mean N.

In a further particularly preferred aspect, there are provided compounds of formula I in which M is —XR ⁵ and R ⁵ is

A "means -NH ₂ , D" means -H, B "means n-propyl and cyclopropyl, X means furan-2,5-diyl and methyleneoxycarbonyl; at least one group Y means -O-; and their pharmaceutically acceptable salts and prodrugs. Particularly preferred are those compounds in which when Y is —O— then R ^{1 is} selected from —H, optionally substituted phenyl, —CH ₂ OC (O) —tBu, —CH ₂ OC (O) Et, and -CH ₂ OC (O) -iPr;

or if one Y is —O— and its corresponding R is phenyl, while the other Y is —NH— and its corresponding R ¹ is —CH (Me) C (O) OEt, or

if at least one group Y is —O— then R and R ¹ together are

wherein

V is selected from optionally substituted aryl and optionally substituted heteroaryl; and Z, W and W ′ mean N.

Preferred are compounds of formula X:

wherein:

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 , —H, 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 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 ² or E ² and J ² together form an annelated cyclic group;

X ^{3 is} selected from —CR ² ₂ , —CF ₂ , —CR ² 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 the 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 lower alkyl, —H and —COR ² ; and Y is independently selected from —O— and —NR ⁶ , provided that:

if Y is —O—, R ¹ attached to —O— is independently selected from —H, alkyl, optionally substituted aryl, optionally substituted alicyclic, in which the cyclic moiety contains carbonate or thiocarbonate, optionally substituted α-arylalkyl—, —C ( R ² ) ₂ CO (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;

if Y is —NR ⁶ -, then R ¹ attached to —NR ⁶ - is independently selected from —H, - [C (R ² ) ₂ ] _q —COOR ³ , —C (R ⁴ ) ₂ COOR ³ , [ C (R ² ) ₂ ] qC (O) SR ³ and -cycloalkylene-COOR ³ , where q is 1 or 2;

if only one Y is —O—, —O— which is not part of a cyclic group containing another Y, the other Y is —N (R ¹⁸ ) - (CR ¹² R ¹³ ) —C (O) R ¹⁴ ; and

if 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 together form:

in which

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 by an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is condensed with an aryl group at the beta and gamma positions of Y adjacent 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 , -SCO ₂ R ³ , -NHCOR ² , NHCO ₂ R ³ , -CH ₂ NH- aryl, - (CH ₂ ) _p -OR ² and - (CH ₂ ) _p -SR ² in which p is an integer of 2 or 3; or

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

W and W ′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

or

W and W ′ are joined together by an additional 2-5 atoms to form a cyclic group optionally containing 0-2 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

-H, 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 OCO2R ³ , —CHR ² OC (O) SR ³ , - CHR ² OC (S) OR ³ , -CH (aryl) OH, -CH (CH = CR ² ₂ ) OH, -CH (C = CR ² ) OH, -SR ² , -CH ₂ NH-aryl, -CH _2- aryl; or

V ² and Z ^{2 are} joined together by an additional 3-5 atoms to form a cyclic group containing 5-7 atoms in the ring, optionally containing 1 heteroatom, and substituted by hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom, which is three atoms from Y adjacent to phosphorus;

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

D 'is —H;

D "is selected from the group —H, alkyl, —OR ² , —OH and —OC (O) R ³ ;

each W ^{3 is} independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, 1-alkynyl;

provided that:

a) V, Z, W, W ′ all do not mean -H and V ² , Z ² , W ² , W '' do not all mean -H;

R ^{2 is} selected from R ³ and —H;

R ³ selected from alkyl, aryl, alicyclic and aralkyl;

each R ^{4 is} independently selected from the group consisting of —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group;

R ^{6 is} selected from —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl;

R ^{9 is} independently selected from —H, alkyl, aralkyl, and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group;

R ^{11 is} selected from alkyl, aryl, —NR ² _2, and —OR ² ;

n is an integer from 1 to 3;

R ^{18 is} independently selected from H, lower alkyl, aryl and aralkyl, or R ¹² and R ^{18 are} joined together by 1-4 carbon atoms to form a cyclic group;

each R ¹² and each R ^{13 is} independently selected from H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R ¹² and R ^{13 are} joined together by 2-6 carbon atoms, optionally including 1 heteroatom selected from group O, N and S, with the formation of a cyclic group;

each R ^{14 is} independently selected from —OR ¹⁷ , —N (R ¹⁷ ) ₂ , —NHR ¹⁷ , —SR ^17, and —NR ² R ²⁰ ;

R ^{15 is} selected from —H, lower alkyl, lower aryl, and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together by 2-6 atoms to form a cyclic group, the cyclic group optionally including one heteroatom selected from the group O, N and S;

R ^{16 is} selected from - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ , -H, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together by 2-6 atoms to form a cyclic group wherein the cyclic group optionally includes one heteroatom selected from the group O, N and S;

each R ^{17 is} independently selected from lower alkyl, lower aryl, and lower aralkyl, or, if R ¹⁴ is —N (R ¹⁷ ) ₂ , two R ^{17 are} joined together by 2-6 atoms to form a cyclic group, the cyclic group optionally including one heteroatom itself selected from the group O, N and S;

R ^{20 is} selected from the group of —H, lower R ^3, and —C (O) —lower — R ³ .

and their pharmaceutically acceptable prodrugs and salts.

In one aspect, compounds of formula X are preferred in which A ^{2 is} selected from —H, —NH ₂ , —CH ₃ , —Cl, and Br;

L ² is —H, lower alkyl, halogen, lower alkyloxy, hydroxy, α-alkenylene-OH, or together with E ² forms a cyclic group including aryl, cyclic alkyl, heteroaryls, heterocyclic alkyl;

E ^{2 is} selected from the group consisting of H, lower alkyl, halogen, lower alkyloxycarbonyl, lower alkyloxy, or together with L ² forms a cyclic group comprising aryl, cyclic alkyl, heteroaryl or heterocyclic alkyl;

J ^{2 is} selected from the group consisting of H, halogen and lower alkyl;

G "means -S-;

X ² is —CH ₂ —O—; and

at least one Y is —O—; and their pharmaceutically acceptable salts and prodrugs. Also particularly preferred are those compounds in which A ² is NH ₂ , G "is —S—, L ² is Et, E ² is SCN, and J ² is H. More preferred are those wherein one Y is —O - and its corresponding R ¹ means optionally substituted phenyl, while the other Y means —NH— and its corresponding R ¹ means —C (R ² ) ₂ —COOR. If R ¹ means —CHR ³ COOR ³ , then the corresponding —NR ⁶ - * CHR ³ COOR ³ preferably has L-stereochemistry.

Also preferred are those compounds in which 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 the compounds of formula I, II, III, IV, V-1, V-2, VI, VII-1, VII-2 or X, preferably, both groups Y are —O—; or one group Y is —O— and one Y is —NR ⁶ -. If only one group Y is —NR ⁶ -, preferably Y is closest to W and W is —O—. Most preferred are prodrugs in which both Y groups are —O—;

In another particularly preferred aspect, both Y groups are —O—, and R ¹ and R ¹ together are

and V is phenyl substituted with 1-3 halogens. Particularly preferred are 3-bromo-4-fluorophenyl, 3-chlorophenyl, 3-bromophenyl and 3,5-dichlorophenyl.

In another particularly preferred aspect, one Y is —O— and its corresponding R ¹ is phenyl or phenyl substituted with 1-2 substituents selected from —MHC (O) CH ₃ , —F, —Cl, —Br, —C ( O) OCH ₂ CH ₃ and —CH ₃ ; while the other Y is —NR ⁶ - and its corresponding R ¹ is —C (R ² ) COOR ³ ; each R ^{2 is} independently selected from —H, —CH ₃ and —CH ₂ CH ₃ . More preferred R ⁶ is —H, and R ¹ attached to —NH— is —CH (Me) CO ₂ Et.

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

in which R ^{55 is} selected from the group:

in which:

G ² selected from the group of C, O and S:

G ³ and G ^{4 are} independently selected from the group consisting of C, N, O, and S;

in which a) not more than one of G ² , G ³ and G ⁴ means O or S; b) if G ² means O or S, then not more than one of G ³ and G ⁴ means N; c) at least one of G ² , G ³ and G ⁴ means C; d) G ² , G ³ and G ⁴ all do not mean C;

G ⁵ , G ⁶ and G ^{7 are} independently selected from the group of C and N, and no more than two of G ⁵ , G ⁶ and G ⁷ mean N:

J ³ , J ⁴ , J ⁵ , J ⁶ and J ^{7 are} independently selected from the group consisting of —H, —NR ⁴ ₂ , —CONR ⁴ ₂ , —CO ₂ R ³ , halogen, —S (O) ₂ NR ² ₂ , -S (O) R ³ , -SO ₂ R ³ , alkyl, alkenyl, alkynyl, alkylene aryl, perhaloalkyl, haloalkyl, aryl, heteroaryl, alkylene-OH, -C (O) R ¹¹ , -OR ¹¹ , -alkylene -NR ⁴ ₂ , -alkylene-CN, -CN, -C (S) NR ⁴ ₂ , -OR ² , -SR ² , -n ₃ , -NO ₂ , -NHC (S) NR ⁴ ₂ and -NR ²¹ COR ² ;

X ^{4 is} selected from the group consisting of:

i) a linking group containing 2-4 atoms, determined by the smallest number of atoms connecting the carbon of the aromatic ring and the phosphorus atom, which is selected from the group consisting of furanyl, thienyl, pyridyl, oxazolyl, imidazolyl -, -phenyl-, -pyrimidinyl-, -pyrazinyl- and -alkynyl-, all of which may optionally be substituted; and

ii) a linking group containing 3-4 atoms, determined by the smallest number of atoms connecting the carbon of the aromatic ring and the phosphorus atom, which 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 optionally be substituted;

Y is independently selected from the group consisting of —O— and —NR ⁶ ;

if Y is —O—, R ¹ attached to —O— is independently selected from the group of —H, alkyl, optionally substituted aryl, optionally substituted alicyclic, in which the cyclic moiety contains carbonate or thiocarbonate, optionally substituted α-arylalkylene—, - C (R ² ) ₂ CO (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-S-C (O) R ³ , -alkyl-SS-alkyl hydroxy and -alkyl-SSS-alkyl hydroxy;

if Y is —NR ⁶ -, R ¹ attached to —NR ⁶ - is independently selected from —H, - [C (R ² ) ₂ ] _q —COOR ³ , —C (R ⁴ ) ₂ COOR ³ , - [ C (R ² ) ₂ ] _q —C (O) SR ³ and α-cycloalkylene-COOR ³ , where q is 1 or 2;

if only one Y is —O—, where —O— is not part of a cyclic group containing another Y, then the other Y is —N (R ¹⁸ ) - (CR ¹² R ¹³ ) —C (O) R ¹⁴ ; and

if 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 together form:

in which

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 by an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is condensed with an aryl group at the beta and gamma positions of Y adjacent 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 , -SCO ₂ R ³ , -NHCOR ² , NHC ₂ R ³ , -CH ₂ NH-aryl, - (CH ₂ ) _p -OR ² and - (CH ₂ ) _p -SR ² in which p is an integer of 2 or 3; or

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

W and W ′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

or

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

b) V ² , W ² and W ″ are independently selected from the group consisting of —H, 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 (O) SR ³ , —CHR ² OC (S) OR ³ ,

—CH (aryl) OH, —CH (CH = CR ² ₂ ) OH, —CH (C = CR ² ) OH, —SR ² , —CH ² NH-aryl, —CH ₂ aryl; or

V ² and Z ^{2 are} joined together by an additional 3-5 atoms to form a cyclic group containing 5-7 atoms in the ring, optionally including 1 heteroatom, and substituted by hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom located at a distance of three atoms from Y connected to phosphorus;

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

D 'is —H;

D "is selected from the group —H, alkyl, —OR ² , —OH and —OC (O) R ³ ;

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

provided that:

a) V, Z, W, W 'all do not mean -H and V ² , Z ² , W ² , W "all do not mean -H;

R ^{2 is} selected from the group of R ³ and —H;

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

each R ^{4 is} independently selected from the group consisting of —H, alkyl, α-alkylenearyl and aryl, or R ⁴ and R ^{4 are} joined together by 2-6 atoms, optionally including one heteroatom selected from the group of O, N and S;

R ^{6 is} selected from the group of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl;

R ⁷ means lower R ³ ;

each R ^{9 is} independently selected from the group of —H, alkyl, aralkyl, and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group;

R ^{11 is} selected from the group of alkyl, aryl, —NR ² ₂ and —OR ² ; and

each R ¹² and R ^{13 is} independently selected from the group of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R ¹² and R ^{13 are} joined together by 2-6 carbon atoms, optionally including 1 heteroatom selected from group O , N and S, with the formation of a cyclic group;

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

R ^{15 is} selected from the group of —H, lower alkyl, lower aryl and lower aralkyl, or is joined together with R ¹⁶ by 2-6 atoms, optionally including 1 heteroatom selected from the group O, N and S;

R ^{16 is} selected from the group of - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ , -H, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together by 2-6 atoms, optional including 1 heteroatom selected from the group O, N and S;

each R ^{17 is} independently selected from the group of lower alkyl, lower aryl and lower aralkyl, or R ¹⁷ and R ^{17 are} joined together on N by 2-6 atoms, optionally including 1 heteroatom selected from the group O, N and S;

R ^{18 is} independently selected from H, lower alkyl, aryl and aralkyl, or R ¹² and R ^{18 are} joined together by 1-4 carbon atoms to form a cyclic group;

R ^{19 is} selected from the group of —H and lower acyl;

R ^{20 is} selected from the group of —H, lower R ^3, and —C (O) - (lower — R ³ ).

R ^{21 is} selected from the group of —H and lower R ³ ;

n is an integer from 1 to 3;

provided that:

1) if G ⁵ , G ⁶ or G ⁷ means N, then the corresponding J ⁴ , J ⁵ or J ^{6 is} absent;

2) if G ² , G ³ or G ⁴ means O or S, then J ³ , J ⁴ or J ^{5 is} absent;

3) if G ³ or G ⁴ means N, then the corresponding J ⁴ or J ⁵ does not mean halogen or a group directly bonded to G ³ or G ⁴ via a heteroatom;

4) if two Y groups mean —NR ⁶ , and R ¹ and R ¹ do not combine to form a cyclic phosphoramidate, then at least one R ¹ means - (CR ¹² R ¹³ ) _n —C (O) —R ¹⁴ ;

5) R ¹ can be selected from lower alkyl only if the other YR ¹ is —NR ¹⁸ —C (R ¹² R ¹³ ) _n —C (O) R ¹⁴ ;

and their pharmaceutically acceptable prodrugs and salts.

Suitable groups X ⁴ include

i) a linking group containing 2-4 atoms, determined by the smallest number of atoms connecting the carbon of the aromatic ring and the phosphorus atom, which is selected from the group consisting of

-furanyl-, -thienyl-, -pyridyl-, -oxazolyl-, -imidazolyl-,

-pyrimidinyl-, -pyrazinyl- and -alkynyl-, all of which may optionally be substituted; and

ii) a linking group containing 3-4 atoms, determined by the smallest number of atoms connecting the carbon of the aromatic ring and the phosphorus atom, which 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 optionally be substituted /

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

in which R ^{55 is} selected from the group of:

in which:

G ² selected from the group C, O and S;

G ³ and G ^{4 are} independently selected from the group consisting of C, N, O, and S;

in which a) not more than one of G ² , G ³ and G ⁴ means O or S; b) if G ² means O or S, then not more than one of G ³ and G ⁴ means N; c) at least one of G ² , G ³ and G ⁴ means C; d) G ² , G ³ and G ⁴ all do not mean C;

G ⁵ , G ⁶ and G ^{7 are} independently selected from the group of C and N, and no more than two of G ⁵ , G ⁶ and G ⁷ mean N:

J ³ , J ⁴ , J ⁵ , J ⁶ and J ^{7 are} independently selected from the group consisting of —H, —NR ⁴ ₂ , —CONR ⁴ ₂ , —CO ₂ R ³ , halogen, —S (O) ₂ NR ² ₂ , -S (O) R ³ , -SO ₂ R ³ , alkyl, alkenyl, alkynyl, alkylene aryl, perhaloalkyl, haloalkyl, aryl, heteroaryl, alkylene-OH,

-C (O) R ¹¹ , -OR ¹¹ , -alkylene-NR ⁴ ₂ , -alkylene-CN, -CN, -C (S) NR ⁴ ₂ , -OR ² ,

-SR ² , -N ₃ , -NO ₂ , -NHC (S) NR ⁴ ₂ and -NR ²¹ COR ² ;

X ^{4 is} selected from the group consisting of:

i) a linking group containing 2-4 atoms, identified by the smallest number of atoms connecting the carbon of the aromatic ring and the phosphorus atom, which is selected from the group consisting of

-furanyl-, -thienyl-, -pyridyl-, -oxazolyl-, -imidazolyl-,

-phenyl-, -pyrimidinyl-, -pyrazinyl- and -alkynyl-, all of which may optionally be substituted; and

ii) a linking group containing 3-4 atoms, identified by the smallest number of atoms connecting the carbon of the aromatic ring and the phosphorus atom, which is selected from the group consisting of

-alkylcarbonylamino, -alkylaminocarbonyl-, -alkoxycarbonyl-,

-alkoxy- and -alkoxyalkyl-, all of which may optionally be substituted;

Y is independently selected from the group consisting of —O— and —NR ⁶ ;

if Y is —O—, then R ¹ attached to —O— is independently selected from the group of —H, alkyl, optionally substituted aryl, optionally substituted alicyclic, in which the cyclic moiety contains carbonate or thiocarbonate, optionally substituted α-arylalkylene—, -C (R ² ) ₂ CO (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;

if one Y is —NR ⁶ - and R ¹ attached to it is — (CR ¹² R ¹³ ) nC (O) —R ¹⁴ , then the other YR ^{1 is} selected from the group of —NR ¹⁵ R ¹⁶ , —OR ^7, and NR ¹⁸ (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ ;

if only one Y is —O—, where —O— is not part of a cyclic group containing another Y, then the other Y is —N (R ¹⁸ ) - (CR ¹² R ¹³ ) —C (O) R ¹⁴ ; and

if 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 together form:

in which

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 OS (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 , -SCO ₂ R ³ , -NHCOR ² , NHCO ₂ R ³ , -CH ₂ NH-aryl, - (CH ₂ ) _p -OR ² and - (CH ₂ ) _p -SR ² in which p is an integer of 2 or 3; or

V and Z are joined together by an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is condensed with an aryl group at the beta and gamma positions of Y adjacent to V; or

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

W and W ′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

or

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

b) V ² , W ² and W ″ are independently selected from the group consisting of —H, 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 (O) SR ³ , -CHR ² OC (S) OR ³ ,

-CH (aryl) OH, -CR (CH = CR ² ₂ ) OR, -CH (C = CR ² ) OH, -SR ² , -CH ₂ NH-aryl, -CH ₂ -aryl; or

V ² and Z ^{2 are} joined together by an additional 3-5 atoms to form a cyclic group containing 5-7 atoms in the ring, optionally including 1 heteroatom, and substituted by hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom located at a distance of three atoms from Y connected 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 —H;

D "is selected from the group of —H, alkyl, —OR ² , —OH and —OC (O) R ³ ;

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

provided that:

a) V, Z, W, W ′ all do not mean -H and V ² , Z ² , W ² , W "all do not mean -H;

R ^{2 is} selected from the group of R ³ and —H;

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

each R ^{4 is} independently selected from the group consisting of —H, alkyl, α-alkylenearyl and aryl, or R ⁴ and R ^{4 are} joined together by 2-6 atoms, optionally including one heteroatom selected from the group of O, N and S;

R ^{6 is} selected from the group of —H, lower alkyl, acyloxyalkyl, aryl, aralkyl, alkoxycarbonyloxyalkyl and lower acyl; or combines together with R ¹² through 1-4 carbon atoms to form a cyclic group;

R ⁷ means lower R ³ ;

each R ^{9 is} independently selected from the group of —H, alkyl, aralkyl, and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group;

R ^{11 is} selected from the group of alkyl, aryl, —NR ² ₂ and —OR ² ; and

each R ¹² and R ^{13 is} independently selected from the group of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R ¹² and R ^{13 are} joined together by 2-6 carbon atoms, optionally including 1 heteroatom selected from group O , N and S, with the formation of a cyclic group; each R ^{14 is} independently selected from the group 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 —H, lower alkyl, lower aryl and lower aralkyl, or is joined together with R ¹⁶ by 2-6 atoms, optionally including 1 heteroatom selected from the group O, N and S;

R ^{16 is} selected from the group of - (CR ¹² R ¹³ ) _n —C (O) —R ¹⁴ , —H, lower alkyl, lower aryl, lower aralkyl, or is joined together with R ¹⁵ by 2-6 atoms, optionally including 1 a heteroatom selected from the group O, N and S;

each R ^{17 is} independently selected from the group of lower alkyl, lower aryl and lower aralkyl, or R ¹⁷ and R ^{17 are} joined together on N by 2-6 atoms, optionally including 1 heteroatom selected from the group O, N and S;

R ^{18 is} independently selected from H, lower alkyl, aryl and aralkyl, or R ¹² and R ^{18 are} joined together by 1-4 carbon atoms to form a cyclic group;

R ^{19 is} selected from the group of —H and lower acyl;

R ^{20 is} selected from the group of —H, lower R ^3, and —C (O) - (lower — R ³ ).

R ^{21 is} selected from the group of —H and lower R ³ ;

n is an integer from 1 to 3;

provided that:

1) if G ⁵ , G ⁶ or G ⁷ means N, then the corresponding J ⁴ , J ⁵ or J ^{6 is} absent;

2) if X ⁴ is substituted furanyl, then at least one of J ³ , J ⁴ , J ⁵ and J ⁶ cannot mean —H or be absent;

3) if X ⁴ means substituted furanyl, then at least one of J ³ , J ⁴ , J ⁵ and J ⁶ in formula VI 1-5 or J ³ , J ⁴ , J ⁵ , J ⁶ , J ⁷ in formula VII-6 cannot mean -H or absent;

4) if G ² , G ³ or G ⁴ means O or S, then the corresponding J ³ , J ⁴ or J ^{5 is} absent;

5) if G ³ or G ⁴ means N, then the corresponding J ⁴ or J ⁵ does not mean halogen or a group directly linked to G ³ or G ⁴ via a heteroatom;

6) if two Y groups mean —NR ⁶ -, and R ¹ and R ¹ do not combine to form a cyclic phosphoramidate, then at least one R ¹ means - (CR ¹² R ¹³ ) _n —C (O) —R ¹⁴ ;

7) if X ⁴ means -alkylcarbonylamino- or -alkylaminocarbonyl-, then G ⁵ , G ⁶ or G ⁷ all do not mean C;

8) if X ⁴ means -alkoxyalkyl-, and G ⁵ , G ⁶ or G ⁷ all mean C, then neither J ⁴ nor J ⁶ can be substituted by an acylated amine;

9) if R ⁵⁵ means substituted phenyl, then J ⁴ , J ⁵ and J ⁶ do not mean purinyl, purinylalkylene, deazapurinyl or deazapurinylalkylene;

10) R ¹ can be lower alkyl only if the other YR ¹ is —NR ¹⁸ —C (R ¹² R ¹³ ) _n —C (O) —R ¹⁴ ;

11) if R ⁵⁵ means substituted phenyl and X ⁴ means 1,2-ethynyl, then J ⁴ or J ⁶ does not mean a heterocyclic group;

12) if X ⁴ is 1,2-ethynyl, then G ⁵ or G ⁷ cannot be N;

and their pharmaceutically acceptable prodrugs and salts.

In one aspect of the invention, compounds of formula VII-1 are contemplated.

In another aspect of the invention, compounds of formula VII-2 are contemplated.

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

In a further aspect of the invention, compounds of formula VII-2-A are contemplated.

In one aspect of the present invention, compounds of formulas VII-1 or VII-2 are contemplated with the further reservations that if X ⁴ is alkoxyalkyl and R ⁵⁵ is substituted thienyl, substituted furanyl or substituted phenyl, then J ⁴ , J ⁵ or J ^{6 is} not means halogen or alkenyl.

In another aspect of the present invention, compounds of formulas VII-1 or VII-2 are contemplated with the further reservations that if X ⁴ is -alkoxyalkyl-, then R ^{55 is} not substituted thienyl, substituted furanyl, or substituted phenyl.

In yet another aspect of the present invention, compounds of formulas VII-1 or VII-2 are contemplated, with further reservations that if X ⁴ is alkoxyalkyl and G ⁵ , G ⁶ and G ^{7 are} all C, then neither J ³ nor J ⁷ means a group attached via a nitrogen atom.

In a further aspect, compounds of formulas VII-1 or VII-2 are contemplated with the further reservations that if X ⁴ is -alkoxyalkyl- or -alkoxycarbonyl-, then R ^{55 is} not substituted phenyl.

In yet another aspect of the invention, there are provided compounds of formulas VII-1 or VII-2 in which, if Y is —O—, then R ¹ attached to —O— is independently selected from the group of —H, optionally substituted aryl, optionally substituted alicyclic, where the cyclic fragment contains a carbonate or thiocarbonate, optionally substituted with arylalkylene-, -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 and -alkyl-SS-alkyl hydroxy;

if Y is —NR ⁶ -, then R ¹ attached to —NR ⁶ - is independently selected from the group of —H and - (CR ¹² R ¹³ ) _n —C (O) R ¹⁴ ;

or if any Y is independently selected from —O— and —NR ⁶ -, then R ¹ and R ¹ together mean

in which

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 by an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is condensed with an aryl group at the beta and gamma positions of Y adjacent 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) R 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 , -SCO ₂ R ³ , -NHCOR ² , NHCO ₂ R ³ , -CH ₂ NH- aryl, - (CH ₂ ) _p -OR ² and - (CH ₂ ) _p -SR ² in which p is an integer of 2 or 3; or

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

W and W ′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

or

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

b) V ² , W ² and W ″ are independently selected from the group consisting of —H, 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 (O) SR ³ , -CHR ² OC (S) OR ³ , -CH (aryl) OH, -CH (CH = CR ² ₂ ) OH, -CH (C = CR ² ) OH, -SR ² , -CH ₂ NH-aryl, -CH ₂ -aryl; or

V ² and Z ^{2 are} joined together by an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally including 1 heteroatom, and substituted by hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom located at a distance of three atoms from Y combined with 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 —H;

D "is selected from the group of —H, alkyl, —OR ² , —OH and —OC (O) R ³ ;

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

provided that:

a) V, Z, W, W 'all do not mean -H and V ² , Z ² , W ² , W "all do not mean -H; and

b) both groups Y do not mean —NR ⁶ -;

R ^{2 is} selected from the group of R ³ and —H;

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

R ^{6 is} selected from the group consisting of —H and lower alkyl.

In a further aspect of the invention, there are provided compounds in which, if 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 ) ₂ OC (O) R ³ , -C (R ² ) ₂ -OC (O) OR ³ and -H; or

if Y is —NR ⁶ -, then R ¹ attached to the named group —NR ⁶ - is selected from the group of —C (R ⁴ ) ₂ —C (O) OR ³ and —C (R ² ) ₂ C (O ) OR ³ ;

or another Y group is —O—, and then R ¹ attached to the named —O— is selected from the group consisting of optionally substituted aryl, —C (R ² ) ₂ OC (O) R ³ and —C (R ² ) ₂ OC (O) OR ³ . Such a group includes compounds in which both groups Y are —O— and R ¹ is H.

In another aspect of the invention, compounds are provided in which at least one Y is —O—, and R ¹ and R ¹ together are

in which

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 by an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is condensed with an aryl group at the beta and gamma positions of Y adjacent 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 , -SCO ₂ R ³ , -NHCOR ² , NHCO ₂ R ³ , -CH ₂ NH- aryl, - (CH ₂ ) _p -OR ² and - (CH ₂ ) _p -SR ² in which p is an integer of 2 or 3; or

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

W and W ′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

or

W and W ′ are joined together by an additional 2-5 atoms to form a cyclic group optionally containing 0-2 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 —H, 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 (O) SR ³ , -CHR ² OC (S) OR ³ , -CH (aryl) OH, -CH (CR = CR ² ₂ ) OH, -CH (C = CR ² ) OH, -SR ² , -CH ₂ NH-aryl, -CH ₂ -

aryl; or

V ² and Z ^{2 are} joined together by an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally including 1 heteroatom, and substituted by hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom located at a distance of three atoms from Y combined with 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 —H;

D "is selected from the group of —H, alkyl, —OR ² , —OH and —OC (O) R ³ ;

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

provided that:

a) V, Z, W, W 'all do not mean -H and V ² , Z ² , W ² , W "all do not mean -H;

b) two groups Y do not mean —NR ⁶ -;

R ^{2 is} selected from the group of R ³ and —H;

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

R ^{6 is} selected from the group consisting of —H and lower alkyl.

In a further aspect of the invention, such compounds are provided wherein one Y is —O— and R ¹ is an optionally substituted aryl; and the other Y means —NR ⁶ -, where R ¹ attached to the named —NR ⁶ - is selected from the group of

-C (R ⁴ ) ₂ C (O) OR ³ and -C (R ² ) ₂ C (O) OR ³ .

In another aspect, there are provided compounds in which R ¹ attached to the named —O— is selected from the group of phenyl and phenyl substituted with 1-2 substituents selected from the group consisting of —NHC (O) CH ₃ , —F, -Cl, -Br, -C (O) OCH ₂ CH ₃ and -CH ₃ ; and in which R ¹ attached to —NR ⁶ - means —C (R ² ) ₂ C (O) OR ³ ; each R ^{2 is} independently selected from the group of —CH, —CH ₂ CH ₃ and —H. Such a group includes compounds in which substituents of the named substituted 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 yet another aspect of the invention, there are provided compounds of formula VII in which J ³ , J ⁴ , J ⁵ , J ⁶ and J ^{7 are} independently selected from the group consisting of —H, —NR ⁴ ₂ , —CONR ₂ , —CO ₂ R ³ , halogen, —SO ₂ NR ⁴ ₂ , lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, lower haloalkyl, lower aryl, lower alkylene — OH, —OR ¹¹ , —CR ² NR ₂ , —CN, —C (S ) NR ⁴ ₂ , -OR ² , -SR ² , -N ₃ , -NO ₂ , -NHC (S) NR ⁴ ₂ , -NR ² COOR ² , -CR ₂ CN;

X ^{4 is} selected from the group consisting of:

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 linking group containing 3 atoms, identified by the smallest number of atoms, connecting the carbon of the aromatic ring and the phosphorus atom, which is selected from the group consisting of alkylcarbonylamino, -alkylaminocarbonyl-, -alkoxycarbonyl- and -alkoxyalkyl-;

if two Y groups are —O— then R ^{1 is} independently selected from the group of optionally substituted aryl, optionally substituted benzyl, —C (R ² ) ₂ OC (O) OR ³ , —C (R ² ) ₂ OC (O) OR ³ and —H; or

if one Y is —O—, then R ¹ attached to —O— is an optionally substituted aryl; and the other Y means —NR ⁶ -, then R ¹ attached to —NR ⁶ - is selected from the group of —C (R ⁴ ) ₂ C (O) R ³ and —C (R ² ) ₂ C (O) OR ^S : or

if Y is —O— or —NR ⁶ -, then R ¹ and R ¹ together mean

in which

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 by additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group in the beta and gamma positions of Y adjacent 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 OR (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 , -SCO ₂ R ³ , -NHCOR ² , NHCO ₂ R ³ , -CH ₂ NH- aryl, - (CH ₂ ) _p -OR ² and - (CH ₂ ) _p -SR ² in which p is an integer of 2 or 3; or

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

W and W ′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

or

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

b) V ² , W ² and W ″ are independently selected from the group consisting of —H, 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 (O) SR ³ , —CHR ² OC (S) OR ³ ,

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

V ² and Z ^{2 are} joined together by an additional 3-5 atoms to form a cyclic group containing 5-7 atoms in the ring, optionally including 1 heteroatom, and substituted by hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom located at a distance of three atoms from Y connected 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 —H;

D "is selected from the group of —H, alkyl, —OR ² , —OH and —OC (O) R ³ ;

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

provided that:

a) V, Z, W, W 'all do not mean -H and V ² , Z ² , W ² , W "all do not mean -H;

b) two groups Y do not mean —NR ⁶ -;

R ^{2 is} selected from the group of R ³ and —H;

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

R ^{6 is} selected from the group consisting of —H and lower alkyl.

In a further aspect, R ^{55 is} substituted with phenyl; X ⁴ means 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 NHR ⁷ , —CN, —H, halogen, —NR ⁴ ₂ , - (CH ₂ ) aryl , - (CH ₂ ) NH-aryl and -NO ₂ ; at least one group Y is —O—;

and their pharmaceutically acceptable salts and prodrugs.

In another aspect of the invention, such compounds are provided in which, if Y is —O—, then R ¹ attached to —O— is independently selected from the group consisting of optionally substituted phenyl, —CH ₂ OC (O) —tBu, - CH ₂ OC (O) OEt and -CH ₂ OS (O) OiPr;

if 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 , —C (R ⁴ ) ₂ ^- C ( O) OR ³ , or

if Y is —O— or —NR ⁶ -, and at least one Y is —O— then R ¹ and R ¹ together are

wherein

V is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; and Z, W and W ′ are H; and

R ^{6 is} selected from the group of —H and lower alkyl.

In one aspect of the invention, compounds are provided in which both Y groups are —O— and R ¹ is —H. In another aspect, compounds are provided in which both Y groups are —O— and R ¹ is —CH ₂ OC (O) OEt. In yet another aspect, compounds are provided in which two Y groups are —O—, and R ¹ and R ¹ together are

and V is phenyl substituted with 1-3 halogens. Such a group includes compounds in which V is selected from the group consisting of 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 3-chlorophenyl, 2-bromophenyl and 3-bromophenyl.

In one aspect of the invention, such compounds are provided wherein n is 1 and the carbon attached to R ¹² and R ¹³ has S stereochemistry.

In a further aspect of the invention, there are provided compounds in which R ¹⁵ does not mean N.

In yet another aspect of the invention, compounds of Formulas VII-1 or VII-2 are provided wherein -NR ¹⁵ R ¹⁶ is a cyclic amine. Such a group includes compounds in which —NR ¹⁵ R ^{16 is} selected from the group consisting of morpholinyl and pyrrolidinyl.

In a further aspect of the invention, R ¹⁶ groups include - (CR ¹² R ¹³ ) _n —C (O) R ¹⁴ .

In another aspect, are compounds of formula

Such a group includes compounds in which n is 1. In one aspect of the invention, there are contemplated compounds in which if R ¹² and R ¹³ are not the same, then R ¹⁴ —C (O) —CR ¹² R ¹ —NH ₂ is an ester or a thioether of a natural amino acid; and R ^{14 is} selected from the group of —OR ¹⁷ and —SR ¹⁷ .

In a further aspect of the invention, there are provided compounds in which 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. If R ¹ is —CHR ³ COOR ³ , then the corresponding —NR ⁶ - * CHR ³ COOR ³ usually has L-stereochemistry.

Relative to the foregoing, applicants contemplate any combination of the Markush groups as set forth above and the Markush subgroups with respect to any of the options presented in the following Tables A-Q.

Table B
Markush subgroup table for option R ¹ Subgroups of Markush R ⁴ one -H, lower alkyl and lower aryl 2 -H, C ₁ -C ₄ alkyl 3 N four substituted phenyl 5 4-hydroxyphenyl 6 R ⁴ and R ^{4 are} joined together through 2-5 atoms, optionally including one heteroatom selected from the group of O, N and S 7 R ⁴ and R ^{4 are} joined together by 2-5 atoms, optionally including one O

Table C
Markush subgroup table for option R ¹² Subgroups of Markush R ¹² one -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CH ₂ CH ₃ -SCH ₃ , phenyl and benzyl 2 -H, methyl, isopropyl, isobutyl and benzyl 3 -H, methyl, isopropyl and benzyl four -methyl 5 -H 6 R ¹² and R ¹³ join together through 2-5 carbon atoms to form a cycloalkyl group 7 R ¹² and R ^{13 are} joined together through 4 carbon atoms to form a cyclopentyl group 8 not like R ¹³ , and R ¹⁴ —C (O) —CR ¹² R ¹³ —NH ₂ means an ester or thioester of a natural amino acid, and R ^{14 is} selected from the group of OR ¹⁷ and SR ¹⁷

Table D
Markush subgroup table for option R ¹³ Subgroups of Markush R ¹³ one -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CH ₂ CH ₂ -SCH ₃ , phenyl and benzyl 2 -H, methyl, isopropyl, isobutyl and benzyl 3 -H, methyl, isopropyl and benzyl four methyl, isopropyl and benzyl 5 -methyl 6 -H 7 R ¹² and R ¹³ join together through 2-5 carbon atoms to form a cycloalkyl group 8 R ¹² and R ^{13 are} joined together by 4 carbon atoms to form a cyclopentyl group 9 not like R ¹² , and R ¹² —C (O) —CR ¹² R ¹³ —NH ₂ means an ester or thioester of a natural amino acid, and R ^{14 is} selected from the group of OR ¹⁷ and SR ¹⁷

Table E
Markush subgroup table for option R ¹⁵ Subgroups of Markush R ¹⁵ one lower alkyl and lower aralkyl 2 C ₁ -C ₆ -alkyl 3 methyl, ethyl and propyl four R ¹⁵ and R ^{16 are} joined together through 2-6 atoms, optionally including 1 heteroatom selected from the group of O, N and S 5 R ¹⁵ and R ^{16 are} joined together by 2-6 atoms, optionally including 1 heteroatom selected from the group of O and N

Table F
Markush subgroup table for option R ¹⁶ Subgroups of Markush R ¹⁶ one lower alkyl and lower aralkyl 2 C ₁ -C ₆ -alkyl 3 C ₁ -C ₃ -alkyl four R ¹⁵ and R ^{16 are} joined together by 2-6 atoms, optionally including 1 heteroatom selected from the group of O, N and S 5 R ¹⁵ and R ^{16 are} joined together by 2-6 atoms, optionally including 1 heteroatom selected from the group of O and N 6 lower alkyl

Table g
Markush subgroup table for options X ⁴ Subgroups of Markush X ⁴ one 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, methyleneoxymethylene and methylene-aminocarbonyl four 2,5-furanyl 5 1,2-ethynyl 6 -alkylenecarbonylamino, alkyleneaminocarbonyl-, -alkyleneoxycarbonyl- and alkyleneoxyalkylene 7 -methylenecarbonylamino, methyleneaminocarbonyl-, -methyleneoxycarbonyl and -methyleneoxymethylene 8 alkyleneoxyalkylene 9 alkyleneoxycarbonyl 10 alkyleneoxyalkylene and alkyleneoxycarbonyl

Table H
Markush subgroup table for options V Subgroups of Markush V one -H, 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 four aryl and substituted aryl 5 heteroaryl and substituted heteroaryl 6 optionally substituted monocyclic heteroaryl containing at least a 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 in the trans position 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, 3,5-difluorophenyl and 3-bromophenyl eleven 4-pyridyl 12 -H 13 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 of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy and aryloxycarbonyloxy attached to one of these carbon atoms attached to carbon atom, which is three atoms from Y, adjacent to phosphorus fourteen V and W are joined together via an additional 3 carbon atoms to form a cyclic substituted group containing 6 carbon atoms and a monosubstituted substituent selected from the group of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy and aryloxycarbonyloxy attached to one of these carbon atoms, which is three atoms from Y adjacent to phosphorus fifteen V and W together form a cyclic group selected from the group of —CH ₂ CH (OH) —CH ₂ -, —CH ₂ CHO (OCOR ³ ) —CH ₂ - and —CH ₂ CH- (OCO ₂ R ³ ) —CH ₂ - 16 V and Z are joined together via additional 3-5 atoms, optionally including 1 heteroatom, to form a cyclic group that is fused to the aryl group at the beta and gamma positions of Y 17 V and Z are joined together via an additional 3-5 atoms, optionally including 1 heteroatom, to form a cyclic group that is fused to the aryl group at the beta and gamma positions of Y, and the aryl group is optionally substituted with a monocyclic aryl group and the bond between Z and the aryl group is selected from the group of —O, —CH ₂ CH ₂ , —OCH ₂ and —CH ₂ O eighteen the same aryl, substituted aryl, heteroaryl or substituted heteroaryl, like W, and V, is in cis to W 19 optionally substituted aryl and optionally substituted heteroaryl

Table I
Markush subgroup table for options V ² Subgroups of Markush V ² one -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl 2 H, alkyl, alicyclic, aralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl 3 aryl, substituted aryl, heteroaryl and substituted heteroaryl four aryl and substituted aryl 5 heteroaryl 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 of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy and aryloxycarbonyloxy attached to one of these additional atoms carbon, which is three atoms from Y, adjacent to phosphorus eleven V ² and W ^{2 are} joined together via an additional 3 carbon atoms to form a cyclic substituted group containing 6 carbon atoms and a monosubstituted substituent selected from the group consisting of hydroxyl, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy and aryloxycarbonyloxy attached to one of these additional carbon atoms , which is three atoms from Y adjacent 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 ³ ) —CH ₂ - and —CH ₂ CH- (OCO ₂ R ³ ) -CH ₂ - 13 V ² and W ^{2 are} joined together through an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally containing 1 heteroatom, and substituted by hydroxy, acyloxy, alkoxy, carbonyloxy or aryloxycarbonyloxy attached to a carbon atom, which is three an atom from Y adjacent to phosphorus fourteen -H

Table j
Markush subgroup table for options W Subgroups of Markush N one -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl 2 -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl 3 —H, —R ³ , aryl, substituted aryl, heteroaryl and substituted heteroaryl four aryl, substituted aryl, heteroaryl and substituted heteroaryl 5 same as w ' 6 -H 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, alkylthio-carbonyloxy and aryloxycarbonyloxy attached to one of the above additional carbon atoms attached to a carbon atom, which is three atoms from Y adjacent to phosphorus 8 V and W are joined together via an additional 3 carbon atoms to form a cyclic substituted group containing 6 carbon atoms and a monosubstituted substituent selected from the group consisting of hydroxyl, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy and aryloxycarbonyloxy attached to one of these carbon atoms, attached to the carbon atom, which is three atoms from Y adjacent to phosphorus 9 V and W together 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 ₂ - 10 V and W together form a cyclic group selected from the group consisting of —CH ₂ —CH (OE) —CH ₂ -, —CH ₂ CH— (OCOR ³ ) CH ₂ - and —CH ₂ CH— (OCO ₂ R ³ ) -CH ₂ - eleven W and W ′ are joined together via an additional 2-5 atoms to form a cyclic group optionally containing 0-2 heteroatoms, and V is aryl, substituted aryl, heteroaryl or substituted heteroaryl 12 the same aryl, substituted aryl, heteroaryl or substituted heteroaryl like V, and W is in cis to V

Table K
Markush subgroup table for options W Subgroups of Markush W one -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl 2 -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 3 —H, —R ³ , aryl, substituted aryl, heteroaryl and substituted heteroaryl four same as w 5 -H 6 W and W ′ are joined together via an additional 2-5 atoms to form a cyclic group optionally containing 0-2 heteroatoms, and V is aryl, substituted aryl, heteroaryl or substituted heteroaryl

Table L
Markush subgroup table for option W ² Subgroups of Markush W ² one -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl 2 -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 3 —H, —R ³ , aryl, substituted aryl, heteroaryl and substituted heteroaryl four aryl, substituted aryl, heteroaryl and substituted heteroaryl 5 same as W " 6 -H 7 V ² and W ^{2 are} joined together by 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, alkylthio-carbonyloxy and aryloxycarbonyloxy attached to one of these additional carbon atoms attached to carbon atom, which is three atoms from Y, adjacent to phosphorus 8 V ² and W ^{2 are} joined together by an additional 3 carbon atoms to form a cyclic substituted group containing 6 carbon atoms and a monosubstituted substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy and aryloxycarbonyloxy attached to one of these additional atoms carbon, which is three atoms from Y, adjacent to phosphorus 9 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 ³ ) CH ₂ - and —CH ₂ CH- (OCO ₂ R ³ ) CH ₂ - 10 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 ³ ) CH ₂ - and —CH ₂ CH— (OCO ₂ R ³ ) CH ₂ -

Table M
Markush subgroup table for option Y Subgroups of Markush Y one two Y groups mean -O- 2 two Y groups mean -NR ⁶ - 3 Y is —O— adjacent to the groups W, W, W "and W ² four Y is —O— adjacent to group V or group V ² 5 one Y means —NR ⁶ -, and one Y means —O— 6 one Y is —NR ⁶ - and the other YR ¹ is —NR ¹⁵ R ¹⁶ , —OR ⁷ 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 ¹⁶ , and R ^{15 is} not H 8 one Y is —NR ⁶ -, and the other YR ¹ is —NR ¹⁵ R ¹⁶ , and R ¹⁶ is - (CR ¹² R ¹³ ) ₂ —C (O) —R ¹⁴ 9 the two Y groups are the same —NR ⁶ — so that the phosphonate fragment of the prodrug has a plane of symmetry through the phosphorus-oxygen double bond 10 one Y is —NR ⁶ - and the other YR ¹ is —NR ¹⁵ R ¹⁶ , where —NR ¹⁵ R ¹⁶ is a cyclic amine eleven one Y is —NR ⁶ - and the other YR ¹ is —NR ¹⁵ R ¹⁶ , where —NR ¹⁵ R ^{16 is} selected from the group consisting of morpholinyl and pyrrolidinyl 12 one Y means —NR ⁶ - and the other YR ¹ means —NR ¹⁵ R ¹⁶ , where —NR ¹⁵ R ¹⁶ means - (CR ¹² R ¹³ ) _n —C (O) R ¹⁴ Table n
Markush subgroup table for option Z Subgroups of Markush Z one —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 , —H, —OC (O) R ³ , —OCO ₂ R ³ and —NHC (O) R ² , four -CHR ² OH, -CHR ² OC (O) R ³ and -CHR ² O-CO ₂ R ³ 5 -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 , -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 , -SCO ₂ R ³ , -NHCOR ² , -NHCO ₂ R ³ , -CH ₂ NH-aryl, - (CH ₂ ) _p OR ² and - (CH ₂ ) _p SR ² 6 -OR ² , -SR ² , -CHR 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 NH-aryl, - (CH ₂ ) _p 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 —H, OR ² and —NHC (O) R ² , 9 -H 10 V and Z are joined together by 3-5 atoms, optionally including 1 heteroatom, to form a cyclic group that is fused to the aryl group at the beta and gamma positions of Y eleven Z and W are joined together by 3-5 atoms to form a cyclic group optionally containing one heteroatom, and V is aryl, substituted aryl, heteroaryl or substituted heteroaryl

Table o
Markush subgroup table for option Z ' Subgroups of Markush Z ' one -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 , -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 , —H, —OC (O) R ³ , —OCO ₂ R ³ , and —NHC (O) R ² , four -CHR ² OY, -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) SR ³ 6 -OH, -OC (O) R ³ and -OCO ₂ R ³ 7 -OR ² , -SR ² , -CHR 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 NH aryl, - (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 , —NHC (O) R ² , —NHCO ₂ R ³ , - (CH ₂ ) _p —OR ¹⁹ and - (CH ₂ ) _p SR ¹⁹ 9 -H, OR ² and -NHC (O) R ² 10 -H

Table P
Markush subgroup table for option Z ² Subgroups of Markush Z ² one -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 NH-aryl, - (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 , —H, —OC (O) R ³ , —OCO ₂ R ³ , and —NHC (O) R ² , four —CHR ² OH, —CHR ² OC (O) R ³ , and —CHR ² O — CO ₂ R ³ 5 -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) OR ³ , -CH (aryl) OH, CH (CH = CR ² ₂ ) OH, CH (C = CR ² ) OH, -SR ² , CH ₂ NH-aryl, -CH ₂ -aryl 6 -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) OR ³ , -CH ₂ -aryl 7 -OR ² , -SR ² , -CHR 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 NH-aryl, - (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 , —NHC (O) R ² , —NHCO ₂ R ³ , - (CH ₂ ) _p —OR ¹⁹ and - (CH ₂ ) _p -SR ¹⁹ 9 —H, OR ² and —NHC (O) R ² , 10 -H eleven V ² and Z ^{2 are} joined together by 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally including 1 heteroatom, and substituted by hydroxy, acyloxy, carbonyloxy or aryloxycarbonyloxy attached to a carbon atom, which is three atoms from Y adjacent to phosphorus

Table Q
Table of Markush subgroups according to variability Markush Group A Markush group B Markush group C Markush group D Markush group E n 1 and 2 one 2 1 and carbon, pro-compound. to R ¹² and R ¹³ , has S-stereochemistry R 2 3 R ² -H, lower alkyl, lower aryl, lower alicyclic and lower aralkyl ethyl, methyl and H -No aryl -H R ³ Lower alkyl, lower aryl, lower alicyclic and lower aralkyl Lower alkyl, lower aryl ethyl and methyl Markush Group A Markush group B Markush group C Markush group D Markush group E Rbb Substituted phenyl, substituted pyrrolyl, substituted oxazolyl, substituted thiazolyl, substituted isothiazolyl, substituted pyrazolyl, substituted isoxazolyl, substituted pyridinyl, substituted thienyl, substituted furanyl, substituted pyrimidinyl and substituted pyridazinyl Substituted pyrrolyl, substituted oxazolyl, substituted thiazolyl, substituted isothiazolyl substituted pyrazolyl, substituted isoxazolyl substituted pyridinide, substituted thienyl, substituted furanyl, substituted pyrimidinyl substituted pyradazinyl Substituted pyrrolyl, substituted oxazolyl, substituted thiazolyl, substituted isothiazolyl substituted pyrazolyl, substituted isoxazolyl substituted pyridinyl, substituted pyrimidinyl and substituted pyridazinyl Substituted thienyl, substituted furanyl, and substituted phenyl Substituted phenyl R ⁶ -H, lower alkyl, acyloxyalkyl alkoxy-carbonyl-hydroxyalkyl and lower acyl -H, lower alkyl and acyloxyalkyl -H and C ₁ -C ₆ alkyl -H, methyl and ethyl -H and methyl Markush Group A Markush group B Markush group C Markush group D Markush group E R ⁷ Lower alkyl, lower aryl, and lower alicyclic lower alkyl and lower aryl lower aryl Substituted phenyl Phenyl, phenyl substituted with 4-NHC (O) -CH ₃ , -Cl, -Br, 2-C (O) O-
CH ₂ CH ₃ or —CH ₃ R ¹¹ Alkyl and aryl lower alkyl C ₁ -C ₄ -alkyl Methyl R ¹⁴ OR ¹⁷ , SR ¹⁷ and NR ² R ²⁰ OR ¹⁷ and SR OR ¹⁷ R ¹⁷ Lower alkyl, lower aryl, lower aralkyl, alicyclic, or R ¹⁷ and R ^{17 are} joined together through 2-6 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 -H, lower alkyl, aryl and aralkyl; R ¹² and R ^{18 are} joined together through 1-4 atoms -H and lower alkyl -H, methyl and ethyl carbon to form a cyclic group R ¹⁹ -H and acetyl -H R ²⁰ -H, C ₁ -C ₄ -alkyl, C ₄ -C ₆ aryl, C ₂ -C ₇ - alicyclic and C ₅ -C ₇ - aralkyl -H and C ₁ -C ₄ -alkyl D " -H, alkyl, OH, and -OC (O) R ³ -H G ² C and O FROM O Markush Group A Markush group B Markush group C Markush group D Markush group E G ³ C and S FROM S G ⁴ C and N FROM N J ³ -H, -NR ⁴ ₂ , -C (O) NR ⁴ ₂ , -CO ₂ R ³ , halogen, -S (O) ₂ NR ⁴ ₂ , lower alkyl, lower alicyclic, lower alkenyl, lower alkynyl, lower perhalogen- alkyl, lower haloalkyl lower aryl, lower alkylaryl, lower alkylene — OH, —OR ¹¹ , —CR ² ₂ NR ⁴ ₂ , —CN,
-C (S) NRS, -OR ² , -SR ² , -N3, -NO ₂ , -NHC (S) NR ⁴ ₂ , -NR ²¹ C (O) R ² , And -CR ² ₂ CN —H, —NO ₂ , lower alkyl, lower alkylaryl, lower aoxy, lower perhalogen-alkyl, halogen, —CH ₂ NHR ⁴ , —C (O) NR ⁴ ₂ , —S (O) ₂ NHR ⁴ , —OH, -NH ₂ , and -NHC (O) R ² —OCH ₃ , —CN, —H, halogen, —NH ₂ and —NO ₂ -OSN ₃ -H, -OR ³ , -NO ₂ , halogen, - (CH ₂ ) ₂ - aryl,
- (CH ₂ ) ₂ - NH-aryl, -S (O) ₂ - NHR ⁷ , -CN, -NR ⁴ ₂ Markush Group A Markush group B Markush group C Markush Group D Markuig Group E J ⁴ -H, -NR ⁴ ₂ , -C (O) NR ⁴ ₂ , -CO ₂ R ³ , halogen, -S (O) ₂ NR ⁴ ₂ , lower alkyl, lower alicyclic, lower alkenyl, lower alkynyl, lower perhalogen- alkyl, lower halogen-alkyl, lower aryl, lower arylalkyl, lower alkylene-OH, -OR ¹¹ ,
-CR ² ₂ NR ⁴ ₂ , -CN, -C (S) NR ⁴ ₂ , -OR ² , -SR ² , -N ₃ , -NO ₂ , -NHC (S) NR ⁴ ₂ , -NR ²¹ C ( O) R ² , and -CR ² ₂ CN -H, -NO ₂ ,
lower
alkyl lower alkylaryl, lower alkoxy, lower perhalogen-alkyl, halogen, —CH ₂ NHR ⁴ ,
—C (O) NR ⁴ ₂ —S (O) ₂ NHR ⁴ , —OH, —NH ₂ , and —NHC (O) R ² , —OCH ₃ , —CN, —H, halogen, —NH ₂ and —NO ₂ not halogen or alkenyl -H, -OR ³ , -NO ₂ , halogen,
- (CH ₂ ) ₂ -aryl,
- (CH ₂ ) ₂ -
NH-aryl,
-S (O) ₂ -
NHR ⁷ , -CN, -NR ⁴ ₂ Markush Group A Markush group B Markush group C Markush group D Markush group E J ⁵ -H, -NR ⁴ ₂ , -C (O) NR ⁴ ₂ , -CO ₂ R ³ , halogen, -S (O) ₂ NR ⁴ ₂ , lower alkyl lower alkenyl, lower alkynyl, lower perhalogen-alkyl, lower halogen -alkyl, lower aryl, lower alkylaryl, lower alkylene-OH, -OR ¹¹ , -CR ² ₂ NR ⁴ ₂ , -CN, -C (S) NR ⁴ ₂ , -OR ² , -SR ² , -N ₃ , -NO ₂ , -NHC (S) NR ⁴ ₂ , -NR ²¹ C (O) R ² , and -CR ² ₂ CN —H, —NO ₂ , lower alkyl, lower alkylaryl, lower alkoxy, lower perhalogen-alkyl, halogen, —CH ₂ NHR ⁴ ,
—C (O) NR ⁴ ₂ , —S (O) ₂ NHR ⁴ , —OH, —NH ₂ , and —NHC (O) R ² —OCH ₃ , —CN, —H, halogen, —NH ₂ and —NO ₂ not halogen or alkenyl -H, -OR ³ , -NO ₂ , halogen,
- (CH ₂ ) ₂ -aryl,
- (CH ₂ ) ₂ -
NH aryl,
-S (O) ₂ -
NHR ⁷ , -CN, -NR ⁴ ₂ , Markush Group A Markush group B Markush group C Markush group D Markush group E J ⁶ -H, NR ⁴ ₂ , -C (O) NR ⁴ ₂ , -CO ₂ R ³ , halogen,
-S (O) ₂ NR ⁴ ₂ ,
lower alkyl, lower alenyl, lower alkenyl, lower alkynyl, lower perhalogen-alkyl, lower halogen-alkyl, lower aryl, lower alkylaryl, lower alkylene-OH, -OR ¹¹ , -CR ² ₂ NR ⁴ ₂ , -CN, -C (S) NR ⁴ ₂ -OR ² , -SR ² , -Na, -NO ₂ , -NHC (S) NR ⁴ ₂ , -NR ²¹ C (O) R ² , and -CR ² ₂ CN —H, —NO ₂ , lower alkyl, lower alkylaryl, lower alkoxy, lower perhalogen-alkyl, halogen, —CH ₂ NHR ⁴ , —C (O) NR ⁴ ₂ , —S (O) ₂ NHR ⁴ , —OH, -NH ₂ and -NHC (O) R ² —OCH ₃ , —CN, —H, halogen, —NO ₂ and —CH ₂ NHR ⁴ not halogen or alkenyl -H, -OR ³ , -NO ₂ , halogen,
- (CH ₂ ) ₂ -aryl,
- (CH ₂ ) ₂ -NH-aryl, -S (O) ₂ -NHR ⁷ , -CN, -NR ⁴ ₂ Markush Group A Markush group B Markush group C Markush group D Markush group E J ⁷ -H, -NR ⁴ ₂ , -C (O) NR ⁴ ₂ , -CO ₂ R ³ , halogen, -S (O) ₂ NR ⁴ ₂ , lower alkyl, lower alkenyl, lower alkenyl, lower alkynyl, lower perhalogen- alkyl, lower halo-alkyl, lower aryl, lower alkylaryl, lower alkylene-OH, -OR ¹¹ , -CR ² ₂ NR ⁴ ₂ , -CN, -C (S) NR ⁴ ₂ , -OR ² , -SR ² , -N ₃ , -NO ₂ , -NHC (S) NR ⁴ ₂ , -NR ²¹ C (O) R ² , and -CR ² ₂ CN -H, -NO ₂ , lower alkyl, lower aryl, lower alkylaryl, lower alkoxy, lower perhalogen-alkyl, halogen, -CH ₂ NHR ⁴ ,
—C (O) NR ⁴ ₂ , —S (O) NHR ⁴ , —OH, —NH ₂ , and —NHC (O) R ² —OCH ₃ , —CN, —H, halogen and lower alkyl Markush Group A Markush group B Markush group C Markush group D Markush group E W ³ -H, alkyl -H W " -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl —H, —R ³ , aryl, substituted aryl, heteroaryl and substituted heteroaryl -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl same as W ² -H G ⁵ FROM N G ⁶ FROM N G ⁷ FROM N

Generally preferred substituents V, Z, W, W ', V, Z, W, W', V ² , Z ² , W ² , W ", Z ', D', D" and W ^{3 of} formulas I, II, III , IV, V-1, V-2, VI, VII-1, VII-2 or X are selected so that they exhibit one or more of the following properties:

(1) enhancing the oxidation reaction, since it is possible that this reaction is a speed-determining stage and, therefore, must compete with the elimination of the drug;

(2) increasing stability in an aqueous solution and in the presence of other enzymes other than p450;

(3) an increase in cell permeability, for example, substituents are uncharged or high molecular weight, since both properties can limit oral bioavailability, as well as cell permeability;

(4) enhancing the β-elimination reaction after the initial oxidation by forming open ring products, which has one or more of the following properties:

a) loss of recyclability;

b) exposure to limited covalent hydration;

c) enhancing β-elimination by promoting proton cleavage;

d) the ability to inhibit addition reactions in which stable adducts are formed, for example, the interaction of thiols with an initially hydroxylated product or nucleophilic addition to a carbonyl formed after ring opening; and

e) limiting the metabolism of reaction intermediates (e.g., open ring ketones);

(5) lead to the formation of 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 that limit the attachment of Michael (Michael), reactions, for example,

a) electron-donating groups Z, which reduce the polarization of the double bond;

b) W groups that sterically block nucleophilic addition to β-carbon;

c) Z groups that eliminate the double bond after the elimination reaction or through retautomerization (enol-> keto) or hydrolysis (e.g. enamine);

d) V groups that contain groups joining α, β-unsaturated ketones to form a ring;

e) groups Z, which form a stable ring by attaching Michael (Michael) to a double bond;

and

f) groups that enhance the neutralization of by-products due to one or more of the following properties:

(i) restriction in the liver; and

(ii) carrying out neutralization-sensitive reactions (for example, ketone reduction); and

(6) the ability to form a pharmacologically active product.

In another aspect of the invention, if Y is independently selected from

-O- and -NR ⁶ - provided that:

if Y is —O—, R ¹ attached to —O— is independently selected from —H, alkyl, optionally substituted aryl, optionally substituted alicyclic, in which the cyclic moiety contains carbonate or thiocarbonate, optionally substituted α-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 -OC (O ) OR ³ , -C (R ² ) ₂ -OC (O) SR ³ , -alkyl-S-C (O) R ³ , -alkyl-SS-alkyl hydroxy and -alkyl-SSS-alkyl hydroxy;

if Y is —NR ⁶ -, R ¹ attached to —NR ⁶ - is independently selected from —H, - [C (R ² ) ₂ ] _q —COOR ³ , —C (R ⁴ ) ₂ COOR ³ , - [ C (R ² ) ₂ ] _q —C (O) SR ³ , and -cycloalkylene-COOR ³ , where q is 1 or 2; and

if only one Y is —O—, where —O— is not part of a cyclic group containing another Y, then the other Y is —N (R ¹⁸ ) - (CR ¹² R ¹³ ) —C (O) R ¹⁴ ; and

=== if Y is independently selected from —O— and —NR ⁶ -, then R ¹ and R ¹ together form:

in which

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 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 , -SCO ₂ 2R ³ , -NHCOR ² , -NHCO ₂ R ³ ,

—CH ₂ NH aryl, - (CH ₂ ) _p —OR ² and - (CH ² ) _p —SR ² , where p is an integer of 2 or 3; or

V and Z are joined together by 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma positions of Y adjacent to V; or

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

W and W ′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

or

W and W ′ are joined together by an additional 2-5 atoms to form a cyclic group optionally containing 0-2 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

-H, 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 (O) SR ³ , —CHR ² OC (S) OR ³ ,

—CH (aryl) OH, —CH (CH = CR ² ₂ ) OH, —CH (C = CR ² ) OH, —SR ² , —CH ₂ NH-aryl, —CH ₂ aryl; or

V ² and Z ^{2 are} joined together by an additional 3-5 atoms to form a cyclic group containing 5-7 atoms in the ring, optionally including 1 heteroatom, and substituted by hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyl-oxy attached to the carbon atom located on the distance of three atoms from Y, combined with 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 —H;

D "is selected from the group of —H, alkyl, —OR ² , —OH and —OC (O) R ³ ;

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

provided that:

a) V, Z, W, W 'all do not mean -H and V ² , Z ² , W ² , W "all do not mean -H;

b) two groups Y do not mean —NR ⁶ -;

R ^{2 is} selected from the group of R ³ and —H;

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

R ^{6 is} selected from the group consisting of —H and lower alkyl.

More preferred are those compounds in which both Y groups are —O—, then R ^{1 is} independently selected from optionally substituted aryl, optionally substituted benzyl, —C (R ² ) ₂ OC (O) R ³ , —C (R ² ) ₂ OS (O) OR ³ and —H; and

if Y is —NR ⁶ -, then R ¹ attached to the named group —NR ⁶ - is selected from —C (R ⁴ ) ₂ —COOR ³ and —C (R ² ) ₂ COOR ³ ; and the other Y means —O—, then R ¹ attached to the named group —O— is selected from optionally substituted aryl, —C (R ² ) ₂ OC (O) R ³ and —C (R ² ) ₂ OC (O ) OR ^З.

In yet another aspect, if one Y is —O— and its corresponding R ¹ is phenyl, then the other Y is —NR ⁶ and its corresponding R ¹ is —CH ₂ CO ₂ Et.

In another preferred aspect, if one Y is —O— and its corresponding R ¹ is phenyl, then the other Y is

—NH— and its corresponding R ¹ is —C (Me) ₂ CO ₂ Et.

In another preferred aspect, if one Y is —O— and its corresponding R ¹ is 4-NHC (O) CH ₃ phenyl, then the other Y is —NH— and its corresponding R ¹ is —CH ₂ COOEt.

In a further preferred aspect, if one Y is

—O— and its corresponding R ¹ is 2-CO ₂ Et-phenyl, then the other Y is —NH— and its corresponding R ¹ is —CH ₂ CO ₂ Et.

In another preferred aspect, if one Y is —O— and its corresponding R ¹ is 2-CH ₃ -phenyl, then the other Y is —NH— and its corresponding R ¹ is —CH ₂ CO ₂ Et.

In yet another aspect, compounds in which two Y groups are —O— and R ¹ is aryl or —C (R ² ) ₂ -aryl are preferred.

Also preferred are compounds in which both Y groups are —O— and at least one R ^{1 is} selected from C (R ² ) ₂ OC (O) R ³ and —C (R ² ) ₂ OC (O) OR ^H.

In a further aspect, compounds in which both Y groups are —O— and at least one R ¹ is —alkyl-SS-alkylhydroxy, —alkyl-S — C (O) R ³ and —alkyl-SSS— are preferred alkyl hydroxy, or R ¹ and R ¹ together mean -alkyl-SS-alkyl- to form a cyclic group.

In one aspect, compounds in which both Y groups are —O— and R ^{1 are} H. are particularly preferred.

In another aspect, compounds are particularly preferred wherein both Y groups are —O— and R ¹ is —CH ₂ OC (O) OEt.

More preferred are compounds in which at least one Y is —O— and R ¹ and R ¹ together form:

in which

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 OCOR 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 , -SCO ₂ R ³ , -NHCOR ² , -NHCO ₂ R ³ ,

—CH ₂ NHaryl, - (CH ₂ ) _p —OR ² and - (CH ² ) _p —SR ² , where p is an integer of 2 or 3; or

V and Z are joined together by 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is condensed with an aryl group at the beta and gamma positions of Y attached to V;

or

Z and W are joined together by additional 3-5 atoms to form a cyclic group optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl or substituted β-heteroaryl; or

W and W ′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;

or

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

b) V ² , W ² and W ″ are independently selected from the group consisting of —H, 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 (O) SR ³ , —CHR ² OC (S) OR ³ ,

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

V ² and Z ^{2 are} joined together by an additional 3-5 atoms to form a cyclic group containing 5-7 atoms in the ring, optionally including 1 heteroatom, and substituted by hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom located at a distance of three atoms from Y connected 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 —H;

D "is selected from the group of —H, alkyl, —OR ² , —OH and —OC (O) R ³ ;

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

provided that:

a) V, Z, W, W 'all do not mean -H and V ² , Z ² , W ² , W "all do not mean -H;

b) two groups Y do not mean —NR ⁶ -;

R ^{2 is} selected from the group of R ³ and —H;

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

R ^{6 is} selected from the group consisting of —H and lower alkyl.

In another aspect, more preferred are those compounds wherein one Y is —O—, and R ¹ is optionally substituted aryl; and the other Y means —NR ⁶ -, where R ¹ on the named —NR ⁶ - is selected from —C (R ⁴ ) ₂ COOR ³ and —C (R ² ) ₂ OC (O) R ³ . Particularly preferred are those compounds in which R ¹ attached to —O— is phenyl, and R ¹ on —NH— is —CH (Me) CO ₂ Et, a —NH * CH (Me) CO ₂ Et has L -configurations.

Particularly preferred are compounds in which R ¹ attached to —O— is selected from phenyl and phenyl substituted with 1-2 substituents selected from —NHAc, —F, —Cl, —Br, —COOEt and CH ₃ ; and R ¹ attached to —NR ⁶ - means —C (R ² ) ₂ COOR ³ , in which R ² and R ^{3 are} independently —H, —CH ₃ and —Et. As for such compounds, if R ¹ attached to —O— is phenyl substituted with —NHAc or —COOEt, then it is preferable that any —NHAc is at position 4 and any —COOEt is at position 2. More preferred are such compounds in which the substituents on substituted phenyl are 4-NHC (O) CH ₃ , —Cl, —Br, 2 — C (O) OCH ₃ CH or —CH ₃ .

In one aspect of the invention, prodrugs of formula 6-i are preferred:

in which V is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl, 1-alkenyl and 1-alkynyl. More preferred groups V of formula 6-i are aryl, substituted aryl, heteroaryl and substituted heteroaryl. Preferably, Y is —O—. Particularly preferred aryl and substituted aryl groups include phenyl and substituted phenyl. Particularly preferred heteroaryl groups include monocyclic substituted and unsubstituted heteroaryl groups. Particularly preferred are 4-pyridyl and 3-bromopyridyl.

More preferred groups V of formula 6-i are aryl, substituted aryl, heteroaryl and substituted heteroaryl. Preferably, Y is —O—. Particularly preferred aryl and substituted aryl groups include phenyl and phenyl substituted with 1-3 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 monocyclic heteroaryl and monocyclic substituted heteroaryl containing at least one nitrogen atom. Most preferred is if such heteroaryl and substituted heteroaryl are 4-pyridyl and 3-bromopyridyl, respectively.

It is also preferred that V and Z are joined together by 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, which condenses with the aryl group at the beta and gamma positions of Y attached to phosphorus. In such compounds, said aryl group preferably means an optionally substituted monocyclic aryl group, and the bond between the Z and gamma positions of the aryl group is selected from O, CH ₂ , CH ₂ CH ₂ , OCH _2, or CH ₂ O.

In another aspect, it is preferred that 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 one substituent selected from hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy and aryloxycarbonyloxy attached to one of these carbon atoms, located at a distance of three atoms from 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 ₃ -, —CH ₂ CH (OCOR ³ ) —CH ₂ - and —CH ₂ CH (OCO ₂ ) R ³ ) -CH ₂ -.

Another preferred group V is 1-alkene. It is known that oxidation by p450 enzymes occurs at benzyl and allylic carbons.

In one aspect, a preferred group V is —H if Z is selected from —CHR ² OH, —CHR ² OCOR ^3, and —CHR ² OCO ₂ R.

In another aspect, if V is aryl, substituted aryl, heteroaryl or substituted heteroaryl, preferred Z groups include —OR ² , —SR ² , —CHP ² N ₃ , —R ² , —NR ² ₂ , —OCOR ² , -OCO ₂ R ³ , -SCOR ³ , -SCO ₂ R ³ , -NHCOR ² , -NHCO ₂ R ³ , -CH ₂ NH-aryl, - (CH ₂ ) _p OR ² and - (CH ₂ ) _p -SR ² . More preferred Z groups include —OR ² , —R ² , —OCOR ² , —OCO ₂ R ³ , —CH ₃ , —NHCOR ² , —NHCO ₂ R, - (CH ₂ ) _p OR ² and - (CH ₂ ) _p -SR ² . Most preferred Z groups include —OR ² , —H, —OCOR ² , —OCO ₂ R ^3, and —NHCOR ² .

Preferred W and W ′ groups include H, R ³ , aryl, substituted aryl, heteroaryl and substituted heteroaryl. Preferably, W and W ′ are the same groups. More preferably, if W and W ′ are N.

In one aspect, the compounds of formulas I and IA preferably have a group Z, which means H, alkyl, alicyclic, hydroxy, alkoxy,

or NHCOR. Preferred are those groups in which Z reduces the tendency of the by-product, vinyl aryl ketone, to undergo a Michael addition reaction. Preferred groups are those that supply electrons to the vinyl group, which is known to be strategic to reduce the tendency of α, β-unsaturated carbonyl compounds to undergo a Michael addition reaction. For example, the methyl group in a similar position on the acrylamide residue does not lead to mutagenic activity, while the unsubstituted vinyl analogue is highly mutagenic. Other groups serve a similar function, for example Z = OR, NHAc, and so on. Other groups can also prevent Michael joining, especially groups that result in the removal of the double bond as a whole such as Z = OH, —OC (O) R, —OCO ₂ R and NH ₂ , which will rapidly undergo retautomerization after the elimination reaction. Some groups W and W 'are also suitable in this role, since group (s) inhibits the reaction of addition to β-carbon or destabilization of the product. Another preferred group Z is a group that contains a nucleophilic group capable of attaching to the α, β-unsaturated double bond after the elimination reaction, i.e. (CH ₂ ) _p SH or (CH ₂ ) _p OH, in which p is 2 or 3. Another preferred group is a group attached to V, which is capable of attaching to the α, β-unsaturated double bond after the elimination reaction:

In another aspect, prodrugs of formula 7-i are preferred:

wherein Z is selected from —CHR ² OH, —CHR ² OCOR ³ , —CHR ² OC (S) R ³ , —CHR ² OCO ₂ R ³ ,

-CHR ² OC (O) SR ³ ; and -CHR ² OC (S) OR ³ . Preferably, Y is —O—. More preferred groups include —CHR ² OH, —CHR ² OC (O) R ^3, and —CHR ² OCO ₂ R ³ .

In another aspect, prodrugs of formula 8-i are preferred:

in which Z 'is selected from —OH, —OC (O) R ³ , —OCO ₂ R ^3, and —OC (O) SR ³ ;

D ⁴ and D ^{3 are} independently selected from —H, alkyl, OR ² , —OH and —OC (O) R ³ ; with the proviso that at least one of D ⁴ and D ³ means —H. Preferably, Y is —O—.

In one preferred aspect, W ′ and Z are —H, W and V are both the same aryl, substituted aryl, heteroaryl or substituted heteroaryl such that the phosphonate fragment of the prodrug:

has a plane of symmetry. Preferably, Y is —O—.

In another preferred aspect, W and W ′ are H, V is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, and Z is selected from —H, OR ² and —NHCOR ² . More preferred are those compounds in which Z is —H.

The oxidation of p450 may be sensitive to stereochemistry, which may be either a phosphorus or carbon-bearing aromatic group. The prodrugs of this invention have two isomeric forms relative to phosphorus. Stereochemistry is preferred, which makes oxidation and elimination possible. Preferred is cis stereochemistry for phosphorus.

In preferred compounds of formula 8-i, a Z 'group is used, which is capable of undergoing an oxidative reaction, resulting in an unstable intermediate which, via elimination reactions, is degraded to the corresponding R ⁵ -X-PO ₃ ^2- , R ⁵ -XP (O) (NHR ⁶ ) ₂ or R ⁵ —XP (O) (O ^- ) (NHR ⁶ ). Particularly preferred Z 'groups are OH. Preferred D ⁴ and D ³ groups are hydrogen, alkyl, and —OR ² , —OC (O) R ³ , but at least one of D ⁴ and D ³ must be H.

The following prodrugs of formulas I, II, III, IV, V-1, V-2, VI, VII-1, VII-2 and X are preferred:

Acyloxyalkyl esters;

Alkoxycarbonyloxyalkyl esters;

Aryl esters;

Benzyl and substituted benzyl esters;

Esters containing difulfides;

Complex substituted (1,3-dioxolen-2-one) methyl esters;

Complex 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-omega-substituted lactone esters and all mixed esters derived from possible combinations of the above esters.

More preferred are the following:

Bis-pivaloylmethyl esters;

Bis-isobutyryloxymethyl esters;

Cyclic- [2-hydroxymethylpropane-1,3-diyl] diesters;

Cyclic- [2-acetoxymethylpropane-1,3-diyl] diesters;

Complex cyclic- [2-methyloxycarbonyloxymethylpropane-

1,3-diyl] diesters;

Cyclic- [1-phenylpropane-1,3-diyl] diesters;

Cyclic- [1- (2-pyridyl) propan-1,3-diyl] diesters;

Cyclic- [1- (3-pyridyl) propan-1,3-diyl] diesters;

Cyclic- [1- (4-pyridyl) propan-1,3-diyl] diesters;

Complex cyclic- [5-hydroxycyclohexane - 1,3-diyl]

diesters and hydroxy-protected form;

Bis-benzoylthiomethyl esters;

Bis-benzoylthioethyl 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 (4-methoxyphenyl) esters;

Bis (2-methoxyphenyl) esters;

Bis (2-ethoxyphenyl) esters;

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-thiazolophenyl) esters;

Bis (3-N, N-dimethylaminophenyl) esters;

Bis (1,2,3,4-tetrahydronaphthalen-2-yl) esters;

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;

Complex (3,4-dithihexane-1,6-diyl) esters;

Complex bis- (5-methyl-1,3-dioxolen-2-one-4-yl) methyl

ethers;

Complex bis- (5-ethyl-1,3-dioxolen-2-one-4-yl) methyl

ethers;

Complex bis- (5-tert-butyl-1,3-dioxolen-2-one-4-yl) methyl

ethers;

Bis-3- (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) hydroxycarbonyloxymethyl] esters;

Bis (N-phenyl-N-methylcarbonyloxymethyl) esters;

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)] carbamoyl methyl esters;

Bis (2-aminoethyl) esters;

Bis (2-methyl-5-thiazolomethyl) esters;

Bis (bis-2-hydroxyethylcarbamoylmethyl) 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) (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-4-NHAc) (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);

0-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] -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-4-NHAc) (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).

Most preferred are the following:

Bis-pivaloylmethyl esters;

Bis-isobutyroloxymethyl esters;

Cyclic (2-hydroxymethylpropane-1,3-diyl) esters;

Cyclic (2-acetoxymethylpropan-1,3-diyl) esters;

Cyclic (2-methyloxycarbonyloxymethylpropane-1,3-diyl) esters;

Cyclic (2-cyclohexylcarbonyloxymethylpropane-1,3-diyl) esters;

Cyclic- [phenylpropane-1,3-diyl) diesters;

Cyclic- [1- (2-pyridyl) propan-1,3-diyl) diesters;

Cyclic- [1- (3-pyridyl) propan-1,3-diyl) diesters;

Cyclic- [1- (4-pyridyl) propan-1,3-diyl] diesters;

Cyclic- [5-hydroxycyclohexane-1,3-diyl] diesters and hydroxy-protected form;

Bis-benzoylthiomethyl esters;

Bis-benzoylthioethyl esters;

Bis-benzyloxymethyl 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-methoxybenzyl) esters;

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 -. (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) hydroxycarbonyloxymethyl] esters;

Bis (6-hydroxy-3,4-dithia) hexyl esters;

Cyclic (3,4-dithihexane-1,6-diyl) esters;

Bis (2-bromoethyl) esters;

Bis (2-aminoethyl) esters;

Bis (2-N, N-diaminoethyl) esters;

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-4-NHAc) - (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] -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).

In the above prodrugs, an asterisk (*) on carbon refers to the L configuration.

O-phenyl- [N- (ethoxycarbonyl-1-methyl] -phosphoramidates (-P (O) (OPh) - (NH-CH ₂ CO ₂ Et);

O-phenyl- [N- (methoxycarbonyl-1-methyl] -phosphoramidates (-P (O) (OPh) - (NH-CH ₂ CO ₂ Me);

O- (3-chlorophenyl) - [N- (ethoxycarbonyl-1-methyl] -phosphoramidates (-P (O) (OPh-3-Cl) - (NH-CH ₂ CO ₂ Et);

O- (2-chlorophenyl) - [N- (ethoxycarbonyl-1-methyl] -phosphoramidates (-P (O) (OPh-2-Cl) - (NH-CH ₂ CO ₂ Et);

O- (4-chlorophenyl) - [N- (ethoxycarbonyl-1-methyl] -phosphoramidates (-P (O) (OPh-4-Cl) - (NH-CH ₂ CO ₂ Et);

O- (4-acetamidophenyl) - [N- (ethoxycarbonyl-1-methyl] -phosphoramidates (-P (O) (OPh-4-NHAc) - (NH-CH ₂ CO ₂ Et);

O- (2-ethoxycarbonylphenyl) - [N- (ethoxycarbonyl-1-methyl] -phosphoramidates (-P (O) (OPh-2-CO ₂ Et) - (NH-CH ₂ CO ₂ Et).

The compounds shown in Table 1 are preferred compounds of formula IA in which M is R ⁵ —X— as defined in the following formulas: formula i, formula ii and formula iii, in which Q ¹ and Q ² correspond to NR ¹⁵ R ¹⁶ and N (R ¹⁸ ) - (CR ¹² R ¹³ ) _n —C (O) —R ^{14 of} formula IA.

In the above formulas i, ii and iii, R ⁵ may be substituted with A or B. Preferred compounds of the formulas i, ii and iii are listed in Table 1 by the designated numbers for R ⁵ , A, B, Q ¹ and Q ² in the above formulas i, ii and iii, in accordance with the following order: Q ¹ , Q ² , R ⁵ , B, A. For each fragment of the structure are determined by the number presented in the following tables for R ⁵ , A, B, Q ¹ and Q ² .

Option R ^{5 is} divided into two groups, each represented in four different structures.

The compounds are shown in table 1 of formulas i, ii and iii, in which R ⁵ fragments are defined by the following numbers:

Fragments of option A are represented by the following numbers:

one 2 3 four A = NH ₂ N Me Cl

Fragments of option B are represented by the following numbers:

one 2 3 four 5 6 7 8 B = -SCH ₃ -iBu -cPr -S-nPr -SEt -iPr -nPr -CH ₂ cPr

Options Q ¹ and Q ^{2 are} divided into three groups, each represented by eight different substituents.

Fragments Q ¹ and Q ^{2 are} represented by the following numbers:

Group 1:

Q ¹ and Q ²

1.-NH-CH ₂ -C (O) R ¹⁴

2.-NH-CH (CH ₃ ) -C (O) R ¹⁴

3. -NH-C (CH ₃ ) ₂ -C (O) R ¹⁴

4. -NH-C (CH ₃ ) ₂ CH ₂ -C (O) R ¹⁴

5. -NH-CH (CH (CH ₃ ) ₂ )) - C (O) R ¹⁴

6.-NH-CH (CH ₂ (CH (CH ₃ ) ₂ ))) -C (O) R ¹⁴

7. -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

1.-NH-CH ₂ CH ₂ -C (O) R ¹⁴

2.-NH-CH (CH ₂ CH ₂ COR ¹⁴ ) -C (O) R ¹⁴

3. -NH-CH (CH ₂ COR ¹⁴ ) -C (O) R ¹⁴

4.-NH-CH (CH ₂ CONH ₂ ) -C (O) R ¹⁴

5.-NH-CH (COR ¹⁴ ) CH ₂ -C (O) R ¹⁴

6.-NH-CH (CH ₂ OR ¹⁷ ) -C (O) R ¹⁴

7. -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

1. -NH-CH (CH ₂ -C ₆ H ₅ OH) -C (O) R ¹⁴

2.-NH-C (cyclopropyl) -C (O) R ¹⁴

3.-NH-C (cyclopentyl) -C (O) R ¹⁴

4.-NH-C (cyclohexyl) -C (O) R ¹⁴

5.-NH-CH (CH ₂ Ph) -C (O) R ¹⁴

6.-N (CH ₃ ) -CH ₂ -C (O) R ¹⁴

8. -NR ¹⁸ R ¹⁹

in which R ^{14 is} selected from the groups consisting of OMe, OEt, OBn, O-tBu, O-nPr, -N (Me) ₂ , morpholine, SMe, SEt; R ¹⁷ means methyl, ethyl, benzyl and propyl; R ¹⁸ means H, Me, Et, Bn, Pr and Ph and R ¹⁹ means Me, Et, Bn, Pr and Ph; R ¹⁸ and R ^{19 are} morpholinyl and pyrrolidinyl.

Thus, if 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 structure below for formula i :

and if R ¹⁴ means ethoxy, the structure will be

Alternatively, if Q ¹ and Q ² are selected from group 3 Q ¹ and group 3 Q ² , and R ^{5 is} selected from group 2 R ⁵ , then compound 3.3.1.2.1 shown in table 1 corresponds to the structure below for the formula i:

The numbers indicated in table 1 also refer to the preferred compounds of benzothiazole and benzoxazole of formula X. These preferred compounds are represented by formulas iv and v:

Preferred compounds of formula iv and formula v are presented in table 1 by the assigned numbers defined for A, B, D, Q ¹ and Q ² in the above formulas iv and v in accordance with the following order: Q ¹ .Q ² .ABD For each fragment the structures identified by numbers are presented in the following tables for A, B, D, Q ¹ and Q ² .

Options Q ¹ and Q ^{2 are} divided into three groups, each represented by eight different substituents. Fragments Q ¹ and Q ^{2 are} identified by the following numbers:

Group 1:

Q ¹ and Q ²

1.-NH-CH ₂ -C (O) R ¹⁴

2.-NH-CH (CH ₃ ) -C (O) R ¹⁴

3. -NH-C (CH ₃ ) ₂ -C (O) R ¹⁴

4. -NH-C (CH ₃ ) ₂ CH ₂ -C (O) R ¹⁴

5.-NH-CH (CH (CH ₃ ) ₂ )) - C (O) R ¹⁴

6.-NH-CH (CH ₂ (CH (CH ₃ ) ₂ ))) -C (O) R ¹⁴

7. -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

1.-NH-CH ₂ CH ₂ -C (O) R ¹⁴

2.-NH-CH (CH ₂ CH ₂ COR ¹⁴ ) -C (O) R ¹⁴

3. -NH-CH (CH ₂ COR ¹⁴ ) -C (O) R ¹⁴

4.-NH-CH (CH ₂ CONH ₂ ) -C (O) R ¹⁴

5.-NH-CH (COR ¹⁴ ) CH ₂ -C (O) R ¹⁴

6.-NH-CH (CH ₂ OR ¹⁷ ) -C (O) R ¹⁴

7. -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

1. -NH-CH (CH ₂ -C ₆ H ₅ OH) -C (O) R ¹⁴

2. -NH-C (cyclopropyl) -C (O) R ¹⁴

3. -NH-C (cyclopentyl) -C (O) R ¹⁴

4.-NH-C (cyclohexyl) -C (O) R ¹⁴

5.-NH-CH (CH ₂ Ph) -C (O) R ¹⁴

6.-N (CH ₃ ) -CH ₂ -C (O) R ¹⁴

7.

8. -NR ¹⁸ R ¹⁹

Option B is divided into three groups, each represented by eight different substituents. Fragments B are identified by the following numbers.

Group 1: one 2 3 four 5 6 7 8 B = n Me Et nPr Br iPr Cl cpr

Group 2: one 2 3 four 5 6 7 8 B = CN F OMe Oet SMe Set 2-furanyl C (0) -OEt

Group 3 for option B can only be combined with group 3 for option D. Option D is divided into three groups, each represented by four different substituents.

Group 1: one 2 3 four D = N Me Et SCN

Group 2: one 2 3 four D = SMe Set CH ₂ OMe OMe

Group 3: one 2 3 four D = absent absent absent absent

The compounds shown in table 1, formulas iv and v, in which fragments a are defined by the following numbers:

one 2 3 four A = NH ₂ N Me Cl

where R ^{14 is} selected from the groups consisting of OMe, OEt, OBn, O-tBu, O-nPr, OPh, -N (Me) ₂ , morpholine, SMe, SEt; R ¹⁷ means methyl, ethyl, benzyl and propyl; R ¹⁸ means H, Me, Et, Bn, Pr and Ph and R ¹⁹ means Me, Et, Bn, Pr and Ph; R ¹⁸ and R ^{19 are} morpholinyl and pyrrolidinyl.

Thus, the connection 2.2.1.7.4. from group 1 for B, D, Q ¹ and Q ² corresponds to the structure below for formula iv:

and if R ¹⁴ means ethoxy, the structure should be

Similarly, in group 3 for option B, compound 2.2.1.7.4 corresponds to the structure below for formula iv:

and if R ¹⁴ means ethoxy, the structure should be

Examples of compounds of formula VII, without limitation, include pharmaceutically acceptable salts and prodrugs of the compounds shown in Tables viia and viib as follows:

Insulin secretion enhancers

In one aspect, the use of at least one FBPase inhibitor and at least one insulin secretion enhancing agent is considered preferred. Drugs that enhance insulin secretion are aimed at one of the three main disorders associated with diabetes, namely pancreatic beta cell dysfunction. Drugs that enhance insulin secretion are compounds that stimulate the release of insulin by the pancreatic beta cells and, as a result, improve glycemic control, as evidenced by improved glucose tolerance and / or lowering fasting blood glucose levels and / or lowering levels hemoglobin Ale. The described effects can lead to positive dynamics in the elimination of glucose from the whole body, a decrease in glucose production in the liver, an increase in insulin-mediated gluconeogenesis, a decrease in lipolysis and / or other manifestations of an improved insulin secretory response. In some cases, insulin secretion enhancers used in the present invention can also lower circulating triglycerides and / or free fatty acids, can increase HDL cholesterol levels, can lower total cholesterol, can lower fasting insulin and C-peptide levels may decrease appetite and / or slow down gastric emptying.

Examples of insulin secretion enhancing agents are those compounds that bind ATP-dependent potassium channels on pancreatic beta cells, thereby causing channel closure and insulin secretion. Said compounds include, for example, sulfonylurea agents and non-sulfonylurea agents.

Sulfonylurea Agents

Sulfonylurea agents have been widely used in clinical practice since the mid-1960s. Although sulfonylurea agents are the primary treatment for patients with NIDDM, four factors limit their overall success.

First, most diabetes patients do not respond adequately to therapy with sulfonylurea agents (that is, therapy leads to primary disorders in approximately 20-25% of patients), or in some diabetes patients treated with sulfonylurea agents, resistance to the therapeutic effect appears (i.e. treatment leads to secondary disorders in approximately 5-10% of patients each year). It is believed that the secondary disturbance is the result of overstimulation of the pancreas by sulfonylurea agents, accompanied by the toxic effects of high blood glucose levels and high levels of lipids on the beta cell.

Second, sulfonylurea-based agent therapy is associated with a high risk of severe hypoglycemic conditions. It is well known that severe hypoglycemic conditions pose a significant risk to affected individuals.

Third, chronic hyperinsulinemia is associated with an increase in cardiovascular disease. However, the relationship has not yet been specifically proven.

Lastly, the use of sulfonylurea agents is associated with weight gain. Weight gain is undesirable, as it can lead to a deterioration in peripheral sensitivity and, consequently, accelerate the progression of the disease.

The mechanism of action of sulfonylurea agents includes the binding of a specific domain of the adenoine triphosphate (ATP) -dependent potassium channel of the beta cell, the so-called "sulfonylurea receptor" or SUR1. As a result of this binding, sulfonylurea inhibits the outflow of potassium ions.

The second key domain of the potassium channel, encoded by a separate protein subunit, is a fragment that forms ionic pores, Kir6.x. For an example see Groop LC Diabetes Care 6: 737-754 (1992); Luna B et al. Diabetes 26: 895-915 (1999); Babenk AR, Aguilar-Bryan L, Bryan J Annu. Rev. Physiol 60; 667-87 (1998); and Aguilar-Bryan L. et al. Science 268: 423-6 (1995).

SUR1 binding leads to depolarization of the cell membrane and influx of calcium ions. Calcium forms a complex with calmodulin, which, in this case, acts as a secondary messenger, which stimulates exocytosis of insulin-containing granules, thus releasing insulin into the circulation. Two key metabolic effects of insulin are to enhance glucose transport in tissues such as muscles, and suppress liver glucose production, the overall result of which is to improve glycemic control.

Examples of sulfonylurea agents include compounds such as glyburide, glimeperide and glipizide. Sulfonylurea agents are known and described, for example, in US Pat. Nos. 2,968,158; 3,097,242; 3,454,635; 3,501,495; 3,654,357; 3,668,215; 3,696,966; and 3708486.

Particularly preferred sulfonylurea derivatives are compounds of formula XV:

wherein:

A is selected from hydrogen, halogen, alkyl, alkanoyl, aryl, aralkyl, heteroaryl and cycloalkyl; and B is selected from alkyl, cycloalkyl and heterocyclic alkyl.

The following sulfonylurea-based agents are particularly preferred: glyburide, glisoxepide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, glyclazide, glychidone, glyhexamide, fenbutamide, tolcyclamide and glimepiride.

Derivatives of non-sulfonylureas

The fast-acting derivatives of non-sulfonylureas nateglinide and repaglinide from the benzoic and phenylpropionic series respectively stimulate the secretion of insulin from the pancreas through a mechanism similar to the mechanism of action of sulfonylureas. Panten U. et al. Biochem. Pharmacol 38: 1217-1229 (1989); Grell W. et al. J. Med. Chem. 41: 5219-5246 (1998);

Priscilla A. et al. Diabetes 49 (suppl.) 449 P (2000). However, the effect of repaglinide is mediated by binding to the binding site on the sulfonylurea receptor, which is different from the glyburide binding site. Fuhlendorff et al. Diabetes 47: 345-351 (1998). Another class of non-sulfonylurea derivatives that mediates insulin secretion by closing potassium channels are imidazolines (e.g., midaglizole, BTS-67582, isaglidol, deriglidol, idazoxane, efaroxane and fluparoxane). Rustenbeck I. et al. Ann. NY Acad. Sci. 881: 229-240 (1999); Mourtada M. et al. Br J. Pharmacol. 127: 1279-1287 (1999); Le Brigand L. et al. Br J. Pharmacol 128: 1021-1026 (1999). It is known that these compounds bind a pore-forming channel fragment (Kir6.x), and not a sulfonylurea binding site (SUR1).

Examples of non-sulfonylurea derivatives include compounds such as benzoic acid derivatives (e.g. mitiglinide and repaglinide), phenylpropionic acid derivatives (e.g. nateglinide) and imidazoline derivatives (e.g. BTS-67582 (Knoll Pharmaceuticals, Co.), midaglizole, isaglidol, degiglidol, idazoxane, efaroxane and fluparoxane). Most of these non-sulfonylurea derivatives 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 01/26639; US patent 5631224 and US patent 5741926. Particularly preferred non-sulfonylurea-based agents include mitiglinide, BTS-67582, repaglinide and nateglinide.

GLP-1 receptor agonists

Another class of insulin serum enhancing agents is represented by GLP-1 receptor agonists, which include GLP-1 and GLP-1 fragments, including their analogs and functional derivatives, as well as peptidomimetics. These compounds act by binding to a receptor on the surface of the beta cell of the pancreas and, consequently, increasing glucose-stimulated secretion of insulin through a cAMP-dependent mechanism. The mentioned class of insulin secretion enhancing agents is described, for example, in US 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; 5908830; 5,958,909; 5,977,071; 5981488 and publications RTS No. WO 87/06941 and WO 99/25728. Examples of the described types of insulin secretion enhancing agents include NN-2211 (Scios Inc./Novo Nordisk A / S), exendin and exedin agonists.

DPP-IV Inhibitors

The third class of insulin secretion enhancing agents is comprised of agents that prolong the plasma half-life of GLP-1. These drugs include dipeptidyl peptidase (DPP) -IV inhibitors (e.g., NVP-DPP728, p32 / 98 (Probiodrug) and valine pyrrolidide) that prevent DPP-IV-mediated inactivation of GLP-1 and therefore prolong their biological effects. Mentioned compounds are described, for example, in the following patents and publications: German patent No. DE 29909208; DE 2 9909210 and DE 2 9909211; U.S. Patent No. 6011155; 6,107,317; 6,110,949 and 6,124,305 and in RTS publications No. WO 97/40832; WO 98/19998; WO 99/61431; WO 99/67279 and WO 00/34241.

Other insulin secretion enhancing agents include glucagon-like peptide receptor agonists (GLP-1), such as GLP-1, fragments and analogs thereof, and functional derivatives of GLP-1 and its fragments. GLP-1 is an incretin that is produced by post-translational cleavage of proglucagon in L cells of the lower gastrointestinal tract in response to food intake. The main site of action of the described insulin secretion enhancing agents are pancreatic beta cells, where, after binding to the GLP-1 receptor, they increase glucose-stimulated insulin secretion via a cAMP-mediated mechanism. Nauck M.A. et al. Diabetes Care 21: 1925-31 (1998). The duration of action of GLP-1 is short, due to its rapid metabolism through DPP-IV.

It is described that GLP-1 analogs are characterized by high resistance to metabolism and, correspondingly, an increased half-life in vivo. For an example, see Sturis J. et al. Diabetes 40 (suppl.) 943-P (2000). GLP-1 analogs are also known having high binding affinity for the GLP-1 receptor. See, for example, Xiao Q et al. Diabetes 46 (Suppl. 1) 941-P (2000). Examples of GLP-1 agonists include NN-2211 (Scios Inc./Novo Nordisk A / S) and exendin.

The third class of insulin secretion enhancing agents includes those compounds that increase the pharmacodynamic half-life of GLP-1. It was shown that, for example, DPP-IV inhibitors (for example, NVP-DPP728) increase plasma levels of GLP-1 and, therefore, prolong its stimulating effect on insulin secretion. See, for example, Hoist J.J., Deacon C.F. 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 secretion enhancing agents are the compounds described in the following publications and patents:

1. Sulfonylureas: US Patents Nos. 2968158; 3,097,242; 3,454,635; 3,501,495; 3,654,357; 3,668,215; 3669966 and 3708486.

2. Non-sulfonylureas: US Patents Nos. 5631224 and 5741926; PCT Publication No. WO 91/03247; WO 93/00337; WO 96/34870; WO 97/31019; WO 98/07681; WO 98/27078; WO 98/56378; WO 00/71117 and WO 01/26639.

3. GLP-1 receptor agonists: US Patent Nos. 5118666; 5,120,712; 5,512,549; 5,545,618; 5,574,008; 5,614,492; 5,631,224; 5,705,483; 5,766,620; 5908830; 5,958,909; 5977071 and 5981488 and PCT Publication Nos. WO 87/06941 and WO 99/25728.

4. Inhibitors of DPP-IV: German Patent Publications No. DE 2990208; DE 2990210 and DE 2990211; U.S. Patent Nos. 6011155; 6,107,317; 6,110,949; and 6,124,305; and PCT Publication No. WO 97/40832; WO 98/19998; WO 99/61431; WO 99/67278; WO 99/67279 and WO00 / 34241.

Since a large number of insulin secretion enhancing agents are provided in such descriptions, without limitation, any compound that enhances insulin secretion can be used in the present invention.

The insulin secretion enhancing agents used in the present invention, which are known to generally be active in research, are used to characterize compounds that act as insulin secretion enhancing agents. Without limitation, studies include the identification of the following characteristic activities: (a) insulin secretion from pancreatic islets or beta cell lines (Example H), (b) rat insulin secretion (Example L), (c) rat glucose reduction on an empty stomach (Example I), (d) intravenous or oral glucose tolerance in rats on an empty stomach (Examples J and K), (e) inhibition of ATP-dependent potassium channels in pancreatic beta cells (Example M), (f) receptor binding sulfonylureas (Example N), (d) GLP-1 receptor binding and (h) inhibiting DPP-IV (Example O). Other studies include those described by Bergsten P. et al. J. Biol. Chem. 269: 1041-45 (1994); Flodin M. et al. J. Biol. Chem. 270: 7882-89 (1995); Dickinson L. et al. Eur. J. Pharmacol. 339: 69-76 (1997); Ladriere L et al. Eur. J. 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 CF, Hughes TE, Hoist JJ Diabetes 47: 764-9 (1998). Particularly preferred insulin secretion enhancing agents are glyburide, glipizide and glimepiride, mitiglinide, BTS-67582, repaglinide and nateglinide.

It is believed that, based on their mechanism of action, insulin secretion enhancing agents will be effective in the early stages of NIDDM, during which all or partial insulin secretory capacity of the pancreas is preserved. The effectiveness of sulfonylureas, for example, is significantly reduced at the progressive stage of NIDDM, which is associated with seriously impaired beta-cell function and, consequently, reduced insulin secretion. Groop L.C. Diabetes Care. 15: 737-54 (1992). The dependence of drugs on the functioning of beta cells is reflected in the high frequency of their primary and secondary complications (approximately 20-25% and 5-10% per year, respectively). Gerich J.E. N. Engi. J. Med. 321: 1231-45 (1989).

Basically, treatment with agents that enhance insulin secretion reduces the existing failure to restore euglycemia or normalize Ale (HbAlc) hemoglobin levels in patients. It was shown that the second generation of sulfonylurea-based agents reduces Ale hemoglobin by an average of 0.8-1.7% and lowers fasting blood glucose levels by 50-70 mg / dl. See for example. Dills D.J. et al. Horm. Metab. Res. 28: 426-9 (1996); Mooradian A.D. et al. Diabetes Care 19: 883-4 (1996); Siminson DC et al. Diabetes Care 20: 597-606 (1997). However, in patients with progressive NIDDM, an average decrease of> 140 mg / dl and> 3% is usually necessary to restore these parameters to normal levels.

Unlike agents that enhance insulin secretion, FBPase inhibitors are effective both in the early stages and in the stages of diabetes progression. In animal studies, FBPase inhibitors significantly reduced blood glucose levels in db / db hyperinsulinemic mice (early diabetes model (Example V), as well as in progressive diabetes model: rat with streptozotocin-induced diabetes with insulinopenia). The latter model was also widely used as a model of type I diabetes, suggesting that the possible use of FBPase inhibitors in this case is appropriate. In ZDF rats, FBPase inhibitors were effective both in the early stages of diabetes (period 8–9 weeks. Example W) and also in the progression stage of diabetes (period 16 weeks).

Based on the pharmacological profile of the above insulin secretion enhancing agents and FBPase inhibitors, therapy in which the insulin secretion enhancing agents were combined with FBPase inhibitors was effective in a large patient population. In the early stages of diabetes patients, FBPase inhibitors and insulin secretion enhancing agents were both completely effective. Despite the well-characterized action of insulin on hepatic glucose production, combined treatment with insulin secretion enhancing agents and FBPase inhibitors not only provided improved glycemic control in the early stages of diabetes (Example X), but also reduced the frequency of secondary disorders commonly seen with monotherapy insulin secretion enhancing agents (Example Y). In advanced diabetes, insulin secretion enhancing agents have a high incidence of primary disorders and are only partially effective, while FBPase inhibitors maintain reliable efficacy. In advanced diabetes, the benefit of the combination is a significant reduction in the number of therapy insensitive and an extremely increased degree of glycemic control. While the initial response to combination therapy in patients with advanced diabetes can be largely due to treatment with an FBPase inhibitor, lowering blood glucose significantly improves pancreatic function and allows the insulin secretion enhancing agent to become more effective over time and thus provide a long-lasting improved response to an agent that enhances insulin secretion, and increase glycemic control.

Another important advantage of the combination: an insulin secretion enhancing agent, an FBPase inhibitor, is an unexpectedly beneficial effect on the metabolism of carbohydrates and / or lipids and / or proteins.

Another advantage of combination therapy is that FBPase inhibitors can attenuate side effects associated with treatment with agents that enhance insulin secretion, and vice versa. Hyperinsulinemia, which leads to undesirable side effects, stimulating weight gain, exacerbation of insulin resistance and predisposition of patients to hypoglycemic conditions, is a key result of therapy with agents that enhance insulin secretion. Hyperinsulinemia may also be associated with an increased risk of macrovascular disease. Remedies that enhance insulin secretion can also excessively stimulate the pancreas and, therefore, contribute to the degeneration of beta cells and, thus, secondary disorders. Similarly, FBPase inhibitors can exhibit undesirable side effects in humans. FBPase inhibitors, for example, can cause a temporary increase in blood lactate levels. As described in Example X, combination therapy with an FBPase inhibitor and an insulin secretion enhancing agent (glyburide) resulted in an unexpected attenuation of the increase in blood lactate caused by monotherapy with an FBPase inhibitor.

Insulin / Insulin Analogs

In another aspect, the use of an FBPase inhibitor and an insulin or insulin analogue is considered preferred. Insulin is a polypeptide hormone (molecular weight ~ 6000), which is secreted into the circulation by the beta cells of the pancreas in response to metabolic energetic substances such as amino acids, sugars containing three carbon, such as glyceraldehyde, and mainly glucose. The key physiological role of insulin is to regulate glucose hemeostasis. Insulin, once secreted, binds to specific receptors located on cell surfaces, and through a complex cascade of signaling regulates various processes, including the utilization of glucose by tissues such as muscle and fat, and the inhibition of glucose production by the liver (“glucose production by the liver” or HGO ) It is believed that insulin inhibits HGO mainly by reducing excess excretion through the metabolic pathway of de novo glucose production, or gluconeogenesis. The effect on gluconeogenesis is mediated by numerous mechanisms, including: (a) decreased supply of important precursors, such as glycerin, lactate and amino acids, (b) increased levels of fructose-6-bisphosphate, an inhibitor of fructose-1,6-bisphosphatase in the liver, and (c ) a decrease in the expression of 3 important enzymes of gluneogenesis, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase and glucose-6-phosphatase. Diabetes Mellitus, eds. LeRoith D, Taylor SI, Olefsky GM, Lippincott-Raven Publishers, Philadelphia (1996).

Typically, insulin is the basis of IDDM therapy. In addition, insulin has been proven to be one of the best treatments for NIDDM. Its use has been evaluated in several extensive, prospective, randomized trials. For example, it has been shown that insulin treatment is effective as monotherapy in the early stages of diabetes (UKPDS study), as well as in progressive diabetes (VACSDM study). UK Prospective Diabetes Study group. Diabetes 44: 1249 (1995); Colwell JA, Ann. Intern. Med. 124: 131 (1996). A UKPDS study showed that early intervention through insulin is associated with a reduction in microvascular complications and a serious tendency towards a reduction in macrovascular complications. However, regular and intensive insulin therapy was not able to maintain glycemic control during the six-year study period due to a progressive increase in insulin resistance. In the VACSDM study, in which patients were registered whose therapy with sulfonylurea derivatives was unsuccessful, one third of the patients did not achieve glycemic control and the remaining ones generally required massive and multiple doses of insulin to control blood glucose. Insulin treatment causes a significant increase in weight, which is associated with increased insulin resistance, arterial hypertension and dyslipidemia, all of which are risk factors for cardiovascular disease.

Traditionally, insulin was obtained by purification from the pancreas of a bull and a pig. Later, advances in recombinant technology have made it possible to obtain human insulin in vitro. It is now common practice in the United States to prescribe recombinant human insulin to all patients, which is stimulating insulin therapy. A wide variety of purified insulin and insulin analogues are prescribed. There are compositions that are divided into drugs of short, medium duration and long action, as well as a number of mixtures of these compositions. The insulin preparations used in this invention include: humulin N, humulin N NPH, humulin N NPH syringe pen, novolin N - human insulin ampoule, novolin N in the pen syringe cartridges, novolin N - pre-filled syringe representing the delivery system insulin, humulin R regular, humulin R, humulin R regular in cartridges, novolin R - human insulin in ampoules, novolin R in syringe cartridges, novolin R - a pre-filled syringe representing the insulin delivery system, Velosulin BR - human insulin in ampoules , NovoPen, Humulin 50/50, Humulin 70/30, Humulin 70/30 in cartridges, Humulin 70/30 Pen, Novolin 70/30 - human insulin in ampoules, Novolin 70/30 in cartridges for syringe pens, Novolin 70 / 30 is a pre-filled syringe representing the insulin delivery system, humulin L, humulin U, novolin L - human insulin in ampoules, yletin II, NPH (Pork: nopK), purified isofran-insulin Pork NPH, yletin II regular (Pork), purified insulin tape pork. Other insulin preparations used in this invention are described in US Pat. Nos. 5,149,716, WO 92/00321 and WO 99/65941. The invention is not limited to the described special compositions; any insulin or insulin analogue may be used by injection, inhalation, transdermally, orally, by means of an implanted pump or any other suitable methods. Used in this invention, insulin analogues, without limitation, include the following: insulin lispro, insulin aspart, insulin glargine. Some of the newer analogues / compositions include inhalation insulins (e.g., AERx, spyros, aerodose) and oral insulins (e.g., oralin, macrulin, M2). The listed analogues are described in the following publications / patents:

Heller SR, Amiel SA, Mansell P Diabetes Care 22: 1607-1611 (1999); Raskin P, Guthrie RA, Leiter L, Riis A, Jovanovic L. Diabetes Care 23: 583-588 (2000);

Heinemann L, Linkeschova R, Rave K et al. Diabetes Care 23: 644-649 (2000);

EP-00622376; US 5681811 and US 5438040.

Preferred insulia have linked a soluble, recombinant insulin receptor with a dissociation constant between 0.03 nM and 300 nM in the study described by Kristensen C, Wiberg FC, Schaffer L, Andersen AS, J. Biol. Chem. 273: 1778-1786 (1998). More preferred is a dissociation constant between 0.3 nM and 30 nM.

The FBPase inhibitors of the invention have also been found to be effective in patients who have been implanted with an “artificial pancreas” (that is, for example, a pancreas with recombinant human pancreatic beta cells or other cells capable of producing insulin in response to elevated glucose levels). The methods used to identify and characterize insulin or insulin analogs with insulin-like activity are well known and include, for example, binding of an insulin receptor, activation of an insulin receptor tyrosine kinase, phosphorylation of insulin receptor substrates, and interaction of these substrates with molecules that reduce signal transmission.

Despite the known inhibitory effect of insulin on gluconeogenesis, the combination of an FBPase inhibitor and insulin or an insulin analogue unexpectedly led to significantly higher glycemic control than using any substance on its own. This has been demonstrated in the main type of obese NIDDM patients in db / db mice, as well as in a series of thin NIDDM patients, the Goto-Kakizaki rat (Examples Z, AA, BB, CC). In addition, glycemic control was achieved with a combination of drugs using reduced doses of insulin. Thus, this invention provides a safer, more effective treatment for diabetes.

Another advantage of combination therapy is that FBPase inhibitors can attenuate side effects associated with insulin therapy or insulin analogues and vice versa. An important outcome of insulin therapy or an insulin analogue is hyperinsulinemia, which leads to an undesirable side effect that causes weight gain. It is known that weight gain exacerbates insulin resistance, leading to a worsening of hyperinsulinemia, and is the cause of arterial hypertension and dyslipidemia. Hyperinsulinemia 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 unexpected observation that the simultaneous use of an FBPase inhibitor led to a significant reduction in the dose of insulin, while the glycemic control remained the same as in the insulin monotherapy group. Such a mild insulin action is appropriate to reduce the risk of the side effects described above associated with insulin therapy.

Another important advantage of the combined treatment of an FBPase / insulin inhibitor was an unexpectedly beneficial effect on the metabolism of carbohydrates and / or lipids and / or proteins.

Biguanides

Biguanides are a series of compounds that include metformin, phenformin, and buformin. Compound compounds have the general formula: (R ¹ R ¹ ) NC (NH) NHC (NH) NH ₂ . Where R ¹ and R ² include H, alkyl, aryl, aralkyl or the like, including their salts and standard prodrugs. Metformin has been marketed in the US for the treatment of NIDDM since 1995. The mechanism of action of this class of compounds is not clear, but it is believed that their main mode of action is to inhibit glucose production in the liver. Inzucchi SE, Maggs DG, Spollett GR et al. N. Engi. J. Med. 338: 867-872 (1998). All compounds of the class of biguanides, which are characterized by the described rapidly manifested activity, were used in this invention. Preferred biguanides inhibited gluconeogenesis from lactate in rat hepatocytes in the presence of insulin with an IC ₅₀ of 10 nM to 100 μM in the study described by Wollen N, Bailey CJ, Biochem. Pharmacol 37: 4353-4358 (1998). More preferred compounds have an ICao between 1 μM and 30 μM. Preferred biguanides also inhibit glucagon-stimulated glucose production from lactate in rat hepatocytes. Yu B, Pugazhenthi S, Khandlewal RL, Biochera. Pharmacol 48: 949-954 (1994). Preferred compounds are characterized by IC ₅₀ from 0.1 to 5000 μm. Most preferred have an IC _{50 of} from 0.1 to 500 mKM.

In another aspect, the use of an FBPase inhibitor and a biguanide is considered 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 is the result of increased peripheral insulin sensitivity and decreased postprandial carbohydrate absorption. Currently, it is believed that metformin acts mainly by reducing the endogenous formation of glucose. Inzucchi SE, Maggs DG, Spollett GR et al. N. Engl. J. Med. 338: 867-872 (1998). There is important evidence that the effect of metformin on endogenous glucose production is a result of inhibition of gluconeogenesis. Studies on isolated perfused liver and animal hepatocytes have shown that metformin, through a mechanism that is synergistic with insulin, reduces gluconeogenesis from a number of substrates, including lactate, pyruvate, alanine, glutamine and glycerin. Wiernsperger NF and Bailey CJ Drugs 58 (suppl. 1): 31-39 (1999). A recent study of type 2 diabetes patients also indicates 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 the described inhibitory effect is carried out is not clear, and it has been suggested that it involves decreased hepatic uptake of gluconeogenesis precursors and / or stimulation of pyruvate kinase and, therefore, inhibits glycolysis.

Metformin was one of the treatments considered in a UK UK diabetes prospective study (UKPDS), which examined whether intensive glycemic control of type 2 diabetes patients reduces the incidence of clinical complications. The data from this extensive multicenter study were reported in 1998 and showed that although metformin initially provided adequate glycemic control, there was a gradual loss of effectiveness during the 6-year treatment period; only 41% of patients were adequately controlled by the end of the study. The results of intensive treatment with insulin and sulfonylurea derivatives were equally disappointing. This study highlighted the need for new anti-diabetic treatments. U.K. Prospective Diabetes Study Group Diabetes 44: 1249-1258 (1995).

In the United States, metformin (a salt of hydrochloric acid) is currently prescribed as an oral tablet (Glucophage, Bristol-Myers Squibb). Metformin is the preferred biguanide. Other biguanides used in this invention include phenformin and buformin. Other metformin compositions used in the present invention, without limitation, include those described in the patents / publications listed below:

US patent No. 3174901 describes phosphate, sulfate, bromohydrate, salicylate, maleate, benzoate, succinate, ethanesulfonate, fumarate and metformin glycolate;

US patent No. 4835184 describes the metformin salt of p-chlorophenoxyacetic acid;

US patent No. 6031004 describes the metformin salt of fumaric acid;

US patent No. 4028402 describes the metformin salt of dichloroacetic acid;

French patent No. 2320735 and 2037002 describes the metformin salt of pamic acid;

French patent No. 2264539 and Japanese patent No. 66008075 describe the metformin salt of orotic acid;

French Patent No. 2275199 describes (4-chlorophenoxy) isobutyrate of metformin;

US patent No. 4080472 describes metformin clofibrate;

US patent No. 3957853 describes metformin acetylsalicylate;

French patent No. 2220256 describes theophylline-7-acetate metformin;

German patents Nos. 2357864 and 1967138 describe the metformin salt of nicotinic acid;

U.S. Patent No. 3,903,141 describes metformin adamantoate;

Japan Patent No. 69008566 describes a metformin salt of zinc-chlorophyllinic acid;

Japanese Patent No. 64008237 describes metformin salts of hydroxy acids, including salts of hydroxyaliphatic dicarboxylic acids, such as mesovic acid, tartaric acid, mesopaque acids, and oxidized maleates;

Japan Patent No. 63014942 describes a metformin salt of tannic acid;

Japanese Patents Nos. 87005905 and 61022071 describe the metformin salt of 3-methyl-pyrazole-5-carboxylic acid (or another 5-membered heterocyclic carboxylic acid);

Romanian Patent No. 82052 describes the metformin salts of sulfamido aryloxyalkylcarboxylic acid;

Soviet patent No. 992512 describes a metformin salt of trimethoxybenzoic acid;

WO 99/29314 A1;

WO 99/47128 A1;

WO 98/10786 A2;

EP-00976395;

WO 99/55320;

WO 96/08243.

Although metformin was thought to have a glucose-lowering effect in patients with type 2 diabetes, combined treatment with an FBPase inhibitor and metformin unexpectedly led to significantly more effective glycemic control than administration of any agent alone (Example DD).

Another important advantage of the combined treatment of an FBPase-metformin inhibitor is its surprisingly effective effect on the metabolism of carbohydrates and / or lipids and / or proteins.

Another advantage of combination therapy was that FBPase inhibitors can attenuate side effects associated with metformin therapy, and vice versa. One of the main metabolic complications that can occur with metformin treatment is milk acidosis. The incidence of this side effect is approximately 0.03 cases / 1000 patients per year. In a well-lit study, the UGDP study, it was found that a structurally related biguanide, phenformin, is associated with an increased risk of cardiovascular complications. FBPase inhibitors can also cause unwanted side effects in humans.

Alpha Glucosidase Inhibitors

In another aspect, the use of an FBPase inhibitor and an alpha glucosidase inhibitor is considered preferred. Alpha glucosidases are a family of enzymes responsible for the breakdown of carbohydrates in the gastrointestinal tract. Elbein AD FASEB J. 5: 3055 (1991). Inhibition of alpha glucosidase has been found to reduce the high postprandial glucose uptake characteristic of NIDDM, and thus improves glucose tolerance. Reaven GM, Lardinois CK, Greenfield MS et al Diabetes Care 13: 32-36 (1990). Under normal circumstances, a complex carbohydrate is broken down in the proximal small intestine, and small complex carbohydrates reach the distal intestine. Treatment with alpha glucosidase inhibitors prevents the breakdown of complex carbohydrates in the proximal intestine and thus slows down the absorption of carbohydrates until the complex carbohydrates are cleaved by glucosidases in the distal intestine (ileum). The indicated slowdown in the breakdown of carbohydrates leads to a dulling of the postprandial peaks of glucose in the blood and insulin after eating and the alignment of the daily profiles of glucose and insulin. Hillebrand, I, Boehme K, Frank G et al. Res. Exp. Med. 175: 81 (1979).

Most preferred of the alpha glucosidase inhibitors is acarbose (Bayer), a pseudotetasaccharide of microbial origin, which is approved for clinical use worldwide. The most preferred alpha glucosidase inhibitors are acarbose, miglitol and voglibose. Other preferred alpha glucosidase inhibitors include: miglitol, voglibose, emiglate, MDL-25637, camiglibose and MDL-73945.

Preferred alpha-glucosidase inhibitors inhibit sucrose-alpha-glucosidase and maltose-alpha-glucosidase with an IC _{50 of} from 1 nM to 10 μM (Example P). Most preferred have an IC ₅₀ between 1 nM and 1 μM.

Additional preferred alpha glucosidase inhibitors used in this 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-427694-A;

EP-406211-A;

EP-409812-A;

US 5017563;

US 5025098;

US 4013510;

US 5,028,614;

US 5097023;

US 5157116;

US 5504078;

US 5,840,705;

US 5,844,102;

JP 08040998 A2;

JP 08289783 A2;

JP 09048735 A2;

JP 11236337 A2;

JP 11286449 A2;

JP 11029472 A2;

JP 10045588 A2;

JP 09104624 A2.

Since the above descriptions represent a large number of alpha-glucosidase inhibitors, any alpha-glucosidase inhibitor can be used in this invention, without limitation. The methods used to identify and characterize alpha glucosidase inhibitors are well known and described.

Combined treatment with an FBPase inhibitor and an alpha glucosidase inhibitor unexpectedly led to significantly improved postprandial glycemic control compared with the use of any substance separately in a group of thin patients with NIDDM, in Goto-Kakizaki rats (Example EE). The results indicate that absorption of carbohydrates from the gut and gluconeogenesis are two important components of postprandial blood glucose levels.

Another advantage of combination therapy is an unexpected beneficial effect on the metabolism of carbohydrates and / or lipids and / or proteins.

A further advantage of combination therapy is that FBPase inhibitors can attenuate side effects associated with alpha glucosidase treatment, and vice versa. Alpha glucosidase inhibitors are known to cause side effects in the human gastrointestinal tract and cause an increase in serum transaminases. Similarly, FBPase inhibitors can cause side effects in humans.

Inhibitors of glucose production in the liver

In another aspect, it is preferable to use an FBPase inhibitor and an inhibitor of glucose production in the liver (for example, a glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon antagonists, amylin agonists or a fatty acid oxidation inhibitor). The formation of glucose in the liver occurs through two metabolic pathways: gluconeogenesis (glucose synthesis de novo) and glycogenolysis (breakdown of glycogen stores). Although overproduction of glucose through gluconeogenesis is the main cause of hyperglycemia associated with NIDDM, nevertheless glycogenolysis is an essential component of HGO and, therefore, an important target for the treatment of hyperglycemia. The step limiting the rate of glycogen breakdown is catalyzed by alpha-glycogen phosphorylase, a well-studied enzyme that is regulated by numerous covalent, substrate and allosteric effectors. Newgard CB, Hwang PK, Fletterick RJ Crit. Rev. Biochem. Mol. Biol. 24, 69-99 (1989). Glycogen phosphorylase catalyzes the breakdown of glycogen to glucose-1-phosphate. Two additional enzymatic steps are required for the release of glucose into the circulation: glucose-6-phosphate isomerase and glucose-6-phosphatase.

Two types of glycogen phosphorylase inhibitors are described: glucose analogues that bind near the active center of the enzyme, and caffeine and other heteroaromatic analogues that bind the regulatory site, 1-site. Indole-2-carboxamides have been described as acting as human liver glycogen phosphorylase inhibitors and lowering blood glucose after oral administration to diabetic ob / ob mice. Hoover DJ, Lefkowitz-Snow S, Burgess-Henry JL et al. J. Med. Chem. 41: 2934-2938 (1998). It is also described that piperidine and pyrrolidine inhibitors reduce both basal and glucagon-stimulated glucose production by rat hepatocytes (WO 97/09040).

The IC ₅₀ for preferred glycogen phosphorylase inhibitors ranged from 1 nM to 10 μM when testing recombinant human glycogen phosphorylase (Example Q). Most preferred had an IC ₅₀ between 1 nM and 1 μM.

Preferred glycogen phosphorylase inhibitors used in the present invention include CP-91149, CP-316819 and CP-368296. These 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, Neluraja K, Ross K et al. Biochemistry 30: 10101-10116 (1991);

Waston KA, Mitchell EP, Johnson LN et al. Biochemistry 3: 5745-5758 (1994);

Bichaed CJF, Mitchell EP, Wormald MR et al. Tetrahedron Lett. 36: 2145-2148 (1995);

Krulle TM, Watson KA, Gregorious M et al. Tetrahedron Lett. 36,8291-8294 (1995);

Kasvinsky PJ, Madsen NB, Sygusch J J. Biol. Chem. 253: 3343-3351 (1978);

Ercan-Fang and Nuttall FQ J. Phamacol. Exp. Ther 280: 1312-1318 (1997);

Kasvinsky PJ, Fletterick RJ, Madsen NB, Can. J. Biochem. 59: 387-395 (1981);

Waagpetersen HS, Westergaard N, Schousboe A Neurochem. Int. 36: 435-440 (2000);

Oikonomakos NG, Tsitsanou 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 5998463;

US-05998563;

EP 00978279;

EP 00832066;

EP 00832065;

EP-1088824;

EP-00978279.

Since a large number of glycogen phosphorylase inhibitors are represented in such descriptions, any glycogen phosphorylase inhibitor can be used in this invention, without limitation. The methods used to identify and characterize glycogen phosphorylase inhibitors are well known and described.

Although glycogen phosphorylase inhibitors have a glucose-lowering effect by inhibiting glucose production in the liver, combined treatment with an FBPase inhibitor and a glycogen phosphorylase inhibitor unexpectedly led to significantly higher glycemic control than when administered separately, either (Example FF).

Another important advantage of combination therapy is the FBPase inhibitor-glycogen phosphorylase inhibitor, which has an unexpectedly beneficial effect on the metabolism of carbohydrates and / or lipids and / or proteins.

Another benefit of combination therapy is that an FBPase inhibitor can attenuate side effects associated with treatment with a glycogen phosphorylase inhibitor, 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 gluconeogenesis in the liver and glycogenolysis, inhibition of this enzyme directly reduces the production of glucose in the liver. Glucose-6-phosphatase is associated with a multienzyme complex in the endoplasmic reticulum of cells. The enzyme complex consists of specific translocase in the membrane of the endoplasmic reticulum, phosphatase is located on the luminal side of the membrane and phosphate translocase. Burchell A and Waddell ID Biochim. Biophys. Acta 1092: 129-137 (1990). The activity of the described multienzyme complex increased in all studied conditions, which in animals led to an increase in blood glucose (for example, treatment with streptozotocin). In addition, clinical studies have also shown that the increased glucose production observed with NIDDM is associated with increased glucose-6-phosphatase activity. Clore JN, Stillman J, Sugerman H Diabetes 49 (6): 969-74 (2000).

The IC _{50 of} preferred glucose-6-phosphatase inhibitors is from 0.1 nM to 10 μM (Example R). More preferred have an IC ₅₀ between 0.1 nM and 300 nM.

Preferred glucose-6-phosphatase inhibitors used in the present invention include compounds that inhibit dephosphorylation of glucose-6-phosphate through interaction with glucose-6-phosphatase itself or other essential components of the glucose-6-phosphatase multienzyme complex (i.e., translocase or phosphatase). The methods used to identify and characterize glucose-6-phosphatase inhibitors are well known and described. Hoecht reported that derivatives of chlorogenic and benzoic acids inhibit glucose-6-phosphatase, Novo Nordisk described active derivatives of tetrahydroteinol pyridine, and Pfizer described selective derivatives of chlorogenic acid. Examples of said compounds include S-0034 and S-4048. Representative glucose-6-phosphatase inhibitors are described in the following publications and patents:

Arion WJ, Canfield WK, Ramos FC et al. Arch. Biochem. Biophys. 15: 279-285 (1998);

Herling 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;

EP9 3114261.6;

US 5567725

EP 816329;

EP 0682024 A1

WO 98/40385.

Since such descriptions represent a large number of glucose-6-phosphatase inhibitors, any glucose-6-phosphatase inhibitor is used in the present invention, without limitation.

Although glucose-6-phosphatase inhibitors have a glucose-lowering effect by inhibiting liver glucose production, the combined treatment with an FBPase inhibitor and a glucose-6-phosphatase inhibitor unexpectedly led to significantly higher glycemic control than the use of any agent alone (YGG Example).

Another important advantage of the combination treatment: an FBPase inhibitor / glucose-6-phosphatase inhibitor is that it has an unexpected effective effect on the metabolism of carbohydrates and / or lipids and / or proteins.

Another advantage of combination therapy is that an FBPase inhibitor can attenuate the side effects associated with glucose-6-phosphatase inhibitor therapy, and vice versa.

Glucagon is a polypeptide hormone formed by post-translational processing of pro-glucagon in pancreatic alpha cells. The main physiological role of glucagon, in accordance with insulin, is to provide acute and long-term maintenance of blood glucose levels. Low plasma glucose triggers the secretion of glucagon, which then stimulates the production of glucose in the liver by increasing both the rate of glycogenolysis and gluconeogenesis. The described effects are mediated by the binding of glucagon to a specific receptor that is positively associated with adenylcyclase via the Gs protein. There is important evidence that indicates that excessive glucagon levels contribute to the development of NIDDM hyperglycemia, both on an empty stomach and after a meal. It was also shown that the removal of circulating glucagon using selective antibodies leads to the normalization of glucose in the blood. Such observations provided a reasonable basis for the use of glucagon antagonists for the treatment of NIDDM. Scheen AJ 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. Science 215: 1115-1116 (1982). Baron AD, Schaeffer L, Shragg P, Kolterman OG, Diabetes 36: 274-283 (1987).

In addition to antibodies to the glucagon receptor, there are two classes of antagonists: antagonists, derivatives of peptides, and non-peptide compounds. Examples of glucagon antagonists of peptide origin are described, for example, in the following US patents Nos. No. 4879273; 5,143,902; 5,480,867; 5,665,705; 5408037 and 5510459.

Examples of non-peptide antagonists are described, for example, in the following publications and patents:

Collins JL, Dambek PJ, Goldstein SW, Faraci WS, Bioorg.Med.Chem.Lett. 2: 915-918 (1992);

Guillon J. Dallemange 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 99/01423;

US 5508304;

US 5677334.

Since a large number of glucagon antagonists are presented in such descriptions, in this invention, without limitation, any glucagon antagonists can be used. Examples of known glucagon antagonists include ALT-3000 (Alteon, Inc.), BAY-27-9955 (Bayer, AG), CP-99711, skyrin, and NNC-92-1687. The methods used to identify and characterize glucagon antagonists are also well known (for example, see Example S) and are described.

Glucagon antagonists inhibit binding to hamster baby kidney cells transfected with the human glucagon receptor (Example S). Preferred antagonists have an IC ₅₀ between 0.1 nM and 100 μM. More preferred compounds inhibit binding to an IC ₅₀ between 0.1 nM and 1 μM.

Although glucagon antagonists act mainly by inhibiting glucose production in the liver, combined treatment with an FBP-az inhibitor and a glucagon antagonist unexpectedly results in significantly higher glycemic control than using any agent alone.

A further important advantage of the combined treatment of an FBPase inhibitor / glucagon antagonist is its surprisingly effective effect on the metabolism of carbohydrates and / or lipids and / or proteins.

Another advantage of combination therapy is that FBPase inhibitors can attenuate side effects associated with glucagon antagonist therapy, and vice versa.

As described above, glucagon is an important regulator of glucose production in the liver. Basal glucagon levels are higher with NIDDM than in control subjects, despite concomitant hyperglycemia and hyperinsulinemia, two factors that are known to inhibit insulin 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 concentrations and blood glucose levels was detected with NIDDM. In addition, it has been shown that glucagon may be responsible for maintaining up to 60% of the elevated levels of glucose production in the liver observed in NIDDM patients. Baron AD, Schaeffer L, Shragg P, Kolterman OG, Diabetes 36: 274-283 (1987). The secretion of glucagon from pancreatic alpha cells is inhibited by insulin from beta cells.

Amylin / Amylin Agonists

Amylin is a 37 amino acid peptide hormone that is co-packaged and secreted by the pancreatic beta cells in conjunction with insulin in response to a nutritional stimulus. The effects of amylin include limiting the absorption of food products, controlling the motor function of the stomach and suppressing postprandial secretion of glucagon, which can reduce postprandial glucose production in the liver. It turned out that amylin secretion slows down and decreases at the last stage of NIDDM. The use of amylin agonists, including amylin itself, for the treatment of diabetes is described in US Pat. No. 5,175,145. Pramlintide, a synthetic analogue of human amylin, has been shown to improve metabolic control in patients with NIDDM receiving insulin. RG Thompson, L Pearson, SL Schoenfeld, OG Kolterman, Diabetes Care 21: 987-993 (1998). A significant decrease in two serum glycemic control indicators, fructosamine and Ale hemoglobin, was observed during a multicenter clinical trial. The methods used to identify and characterize amylin agonists are well known and described, for example, in WO 92/11863 and in US patent No. 5264372.

Amylin agonists inhibit the binding of 1251-labeled amylin in membrane preparations isolated from the core accumulation region of the rat basal forebrain (Example T). Preferred agonists inhibit at Ki values between 0.001 nM and 1 μM. More preferred compounds inhibit binding at Ki values between 0.001 nM and 10 nM. Alternative studies in which agonists have been active include a study of rat sole muscle described by Leighton B and Cooper GJS, Nature 335: 632-635 (1988). In the aforementioned study, the stimulation of glycogen synthesis by insulin was determined in the absence and in the presence of amylin or amylin agonists. The EC ₅₀ values of the preferred agonists are from 0.1 nM to 1 μM. Most preferred agonists have an EC _{50 of} from 0.1 nM to 100 nM.

Amylin is a partner hormone for insulin, secreted simultaneously in response to a nutritional stimulus. Amylin has been shown to be a potent inhibitor of glucagon secretion. Gedulin BR, Rink TJ, Young AA, Metabolism 46: 67-70 (1997). Amylin and amylin agonists are believed to reduce hepatic glucose production and are thus useful in treating hyperglycemia, which is characteristic of diabetes. Clinical evaluation has shown that pramlintide, an amylin agonist, improves glycemic control in NIDDM patients. RG Thompson, L Pearson, SL Schoenfeld, OG Kolterman, Diabetes Care 21: 987-993 (1998). Amylin agonist peptide pharmaceutical compositions comprising pramlintide are claimed in WO 99/34822. In the present invention, not limited to pramlintide, any amylin agonist can be used.

Although it was believed that amylin agonists inhibit the production of glucose in the liver, combined treatment with an FBPase inhibitor and an amylin agonist unexpectedly led to significantly higher glycemic control than the use of any single agent (Example HH).

Another important advantage of combination therapy: an FBPase inhibitor / amylin agonist, is an unexpected positive effect on the metabolism of carbohydrates and / or lipids and / or proteins.

Another advantage of combination therapy is that FBPase inhibitors can attenuate side effects associated with treatment with an amylin agonist, and vice versa.

Fatty Acid Oxidation Inhibitors

Under normal conditions, lower levels of free fatty acids (FFA) after a meal transmit a signal to the liver to reduce glucose production in the liver. In patients with NIDDM, FFA levels increase, and, as you know, their oxidation activates gluconeogenesis and, consequently, increase glucose production in the liver. Reberin K, Steil GM, Getty L, Bergman RN, Diabetes 44: 1038-1045 (1995); Foley JE Diabetes Care 15: 773-784 (1992). Thus, one approach to reducing blood glucose levels in NIDDM patients is to reduce the excess oxidation of fatty acids, an enzymatic process by which fatty acids are metabolized in the mitochondrial matrix with a decrease in the yield of equivalents and acetylCoA. The step that limits the rate of oxidation of long-chain fatty acids is the transport of FFA into mitochondria via carnitine palmitoyl transferase I (CPT I). Inhibition of CPT I has been shown to decrease liver glucose production and blood glucose levels in NIDDM patients. Ratheiser K, Schneeweiss B, Waldhausl W et al. Metabolism 40: 1185-90 (1991).

The CPT I inhibitors used in this invention include 2-tetradecyl-glycidic acid (methyl palmoxyrate), etomoxir, clomoxir, ST1326 and SDZ-CPI-975. The listed and other inhibitors are described in the following publications:

Tutwiler GF, Kirsch T, Bridi G, Washington F, Diabetes 27: 856 (1978);

Tutwiler GF, Dellevigne P. J. Biol. Chem. 254: 2935 (1979);

Koundakjian PP, Turnbull DM, Bone AJ Biochem. Pharmacol 33: 465 (1984);

Deems RO, Anderson RC, Foley JE, Am. J. Physiol. 274: R524-528 (1998).

The present invention is not limited to the inhibitors described above, and any CPT I inhibitor or other compounds that inhibit fatty acid oxidation can be used in the invention. The methods used to identify and characterize fatty acid oxidation inhibitors are well known and described.

Preferred fatty acid oxidation inhibitors showed an IC ₅₀ of 10 nM to 300 μM in a study of palmitate oxidation in rat hepatocytes (Example U). More preferred have an IC ₅₀ between 10 nM and 30 μM.

Although fatty acid oxidation inhibitors are known to inhibit liver glucose production, the combined treatment with an FBPase inhibitor and a fatty acid oxidation inhibitor unexpectedly led to significantly higher glycemic control than using any agent alone (Example JJ).

Another important benefit of the combination treatment: an FBPase inhibitor / fatty acid oxidation inhibitor is an unexpected beneficial effect on the metabolism of carbohydrates and / or lipids and / or proteins.

A further advantage of combination therapy is that FBPase inhibitors can attenuate side effects associated with treatment with a fatty acid oxidation inhibitor, and vice versa. It is known that treatment with an inhibitor of fatty acid oxidation is associated, for example, with cardiac hypertrophy. Bressler R, Gay R, Copenland G et al. Life Sci 44: 1897-1906 (1989).

FBPase inhibitors reduce blood glucose both on an empty stomach (Examples E-G), and in the case of free nutrition (Example W), and in the postprandial state (Example X). This provides a wide opportunity for therapy in combination with insulin secretion enhancing agents, insulin, biguanides, alpha-glucosidase inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists, amylin agonists or fatty acid oxidation inhibitors. The combination, for example, can be entered during food intake and provide increased glycemic control by any one means. Another possible regimen may be the administration of an agent that enhances the secretion of insulin, insulin, biguanide, a glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon antagonist, amylin agonist or fatty acid oxidation inhibitor in the daytime, and administration of an FBPase inhibitor separately in the evening. Many other dosing regimens are possible. Whereas a combination of FBPase inhibitors and an agent that enhances the secretion of insulin, insulin, biguanide, an alpha glucosidase inhibitor, a glycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, a glucagon antagonist, an amylin agonist or a fatty acid oxidation inhibitor are mainly considered for treatment, NIDDM and it is associated with renal, neural, retinal, micro- and macrovascular and metabolic complications, it is also possible to treat other diseases that respond to improved glycemic second control and / or increased sensitivity to insulin. Patients with impaired glucose tolerance (IGT) have minimal hyperglycemia, but can become hyperglycemic after taking large glucose loads. IGT is a predictive indicator of future diabetes, and in recent years, patients with this condition have been the subject of diabetes prevention research. The combined treatment of the described patients, especially during meals, restores the normal glucose response and reduces the risk of developing diabetes. Another separate group of subjects at high risk for developing NIDDM are women who suffer from polycystic ovary syndrome (POCS). Combined treatment is also beneficial for these patients, as they are usually insulin resistant and may suffer IGT. Combination therapy is also used to treat renal dysfunction and hypertension, especially in obesity, in insulin-resistant patients with IGT. Other uses for combination therapy include pregnant diabetes, poorly controlled IDDM, obesity, and dyslipidemia.

Songs

In accordance with this invention, new antidiabetic combinations are provided which comprise an FBPase inhibitor in combination with another agent that can be administered orally or by injection.

The FBPase inhibitor of the invention should be used with sulfonylurea and non-sulfonylurea derivatives that enhance insulin secretion in a weight ratio in the range of about 1000: 1 to 50: 1, preferably about 250: 1 to 75: 1.

The FBPase inhibitor of the invention should be used with metformin in a weight ratio in the range of from about 10: 1 to 0.01: 1, preferably from 3: 1 to 0.1: 1.

The FBPase inhibitor of the invention should be used with an alpha glucosidase inhibitor in a weight ratio in the range of about 300: 1 to 2: 1, preferably 200: 1 to 25: 1.

The FBPase inhibitor of the invention should be used with a glycogen phosphorylase inhibitor in a weight ratio in the range of about 100: 1 to 0.01: 1, preferably 10: 1 to 0.1: 1.

The FBPase inhibitor of the invention should be used with a glucose-6-phosphatase inhibitor in a weight ratio in the range of about 1000: 1 to 0.01: 1, preferably 100: 1 to 0.1: 1.

The FBPase inhibitor of the invention should be used with a glucagon antagonist in a weight ratio in the range of about 1000: 1 to 0.01: 1, preferably 100: 1 to 0.1: 1.

The FBPase inhibitor of the invention should be used with an amylin agonist in a weight ratio in the range of about 1000: 1 to 0.01: 1, preferably 100: 1 to 0.1: 1.

The FBPase inhibitor of the invention should be used with a fatty acid oxidation inhibitor in a weight ratio in the range of about 1000: 1 to 0.1: 1, preferably 100: 1 to 0.1: 1.

In addition, according to the present invention, there is provided a method of treating diabetes and related diseases in which a therapeutically effective amount of an FBPase inhibitor is administered to a patient, possibly in combination with another antidiabetic agent, if such treatment is necessary.

At present, sulfonylurea derivatives such as glyburide, glimepride, glypiride, glipizide, chlorpropamide and glycazide, and alpha-glucosidase inhibitors acarbose or miglitol, and biguanides such as metformin, should be used in the compositions in the amount and dosage indicated in the tabletop manual for doctors.

In the present invention, GLP-1 or analogues of GLP-1 can be administered with oral buccal compositions, by nasal administration or parenterally, as described in US 5346701, US 5614492 and US 5631224.

Currently, insulin can be used in the compositions in the amount and dosage that are indicated in the doctor's handbook.

Currently, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists, amylin agonists or fatty acid oxidation inhibitors are administered in a daily dose of 0.5 mg to 2500 mg, preferably from 10 mg to 1000 mg.

Inhibitors may be administered in the form of a daily dose or an appropriate part of the daily dose (for example, twice a day or three times a day).

The FBPase inhibitors of the invention can be administered alone or in combination with another antidiabetic agent in a conventional systemic dosage form, such as a tablet, capsule, elixir or injectable composition. The aforementioned dosage forms should also include the necessary physiologically suitable carrier, excipient, lubricant, buffer, antibacterial substance, a bulking agent (such as mannitol), antioxidants (ascorbic acid or sodium bisulfite) and the like. Oral dosage forms are preferred, although parenteral forms are also quite satisfactory.

The administered dose should be carefully selected in accordance with the age, weight and condition of the patient, as well as the route of administration, dosage form and regimen of the medication and the desired result. In general, dosage forms of an FBPase inhibitor can be administered in a daily dose of 5-2500 mg. Preferably, a dosage of from about 100 mg to 1000 mg should be used. Inhibitors should be administered in the form of a daily dose or an appropriate part of the daily dose (for example, twice a day or three times a day). The administration of an FBPase inhibitor can be performed at a time close to the moment when another antidiabetic agent is administered, or at different times.

The combination of the FBPase inhibitor of the invention and another antidiabetic agent may be prepared separately or, when possible, in one composition using conventional methods for preparing the compositions.

Various compositions of the invention may possibly include one or more fillers or fillers in an amount within the range of from about 0 to 90% by weight and preferably from 1 to 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.

In addition to or instead of fillers, one or more binders may be present in an amount in the range of from about 0 to 35% and preferably from 0.5 to 30% by weight of the composition. Examples of binders that are suitable for use in the invention include polyvinylpyrrolidone (with a molecular weight ranging from about 5000 to 80,000 and preferably about 40,000), lactose, starches, such as corn starch, modified corn starch, gum arabic and the like, and finely powdered wax binders (less than 500 microns), such as carnauba wax, paraffin, spermaceti, polyethylene or microcrystalline wax.

When the composition is to be in tablet form, it comprises one or more tablet disintegrants in an amount in the range of about 0.5 to 10% and preferably about 2 to 8% by weight of the composition, such as croscarmellose sodium, povidone, crospovidone, sodium glycolate starch, corn starch or microcrystalline cellulose, as well as one or more tablet lubricants in an amount within the range of from about 0.2 to 8% and preferably from 0.5 to 2% by weight of the composition, such as magnesium stearate, stearin hydrochloric acid, palmitic acid, calcium stearate, talc, carnauba wax and the like. Other common ingredients that may possibly be present include preservatives, stabilizing agents, anti-adhesive materials, or silica flowing conditioners or glidants such as Syloid silicon dioxide, as well as FD&C dyes.

The tablets of the invention may also include a coating layer, which may comprise from about 0 to 15% by weight of the tablet composition. The coating layer that is applied over the core of the tablet may contain any conventional coating preparations and should include one or more film forming substances or binders such as a hydrophilic polymer like hydroxypropyl methylcellulose and a hydrophobic polymer like ethyl cellulose, cellulose acetate, polyvinyl copolymers maleic anhydride alcohol, p-pinene polymers, wood gum glycerin esters, and the like, and one or more plasticizers, such as triethyl citrate, diethyl phthal t, propylene glycol, glycerin, butyl phthalate, castor oil and the like. Both the central mass of the tablets and the coating materials may contain aluminum inks to provide color.

The film-forming substances are applied from a solvent system containing one or more solvents including water, alcohols, such as methyl alcohol, ethyl alcohol or isopropyl alcohol, ketones, such as acetone or ethyl methyl ketone, chlorinated hydrocarbons, such as methylene chloride, dichloroethane and 1,1-trichloroethane.

When a colorant is used, the paint should be applied together with a mixture of a film forming agent, a plasticizer and a solvent.

A preferred tablet composition of the invention comprises from about 90 to 97.5% by weight of an FBPase inhibitor, from about 2 to 8% by weight of Providen, and from 0.5 to 2% by weight of magnesium stearate.

The pharmaceutical composition of the invention can be prepared as follows. A mixture of the drug and part (less than 50%) of the available excipient (such as lactose) with or without dye are mixed together and passed through a # 12 sieve to a # 40 mesh. Add and mix filler-binder, if present (such as microcrystalline cellulose), a disintegrant (such as providone). A lubricant (such as magnesium stearate) is added with stirring until a homogeneous mixture is obtained. Then, the resulting mixture can be compressed into tablets up to 2 grams by weight. If desired, tablets of the invention may be prepared by wet granulation methods as described in US Pat. No. 5,030,447, which is incorporated herein by reference.

EXAMPLES - SYNTHESIS SCHEMES

Compounds of formula VI were prepared according to the methods described in the literature, with modifications and additions that are well understood by those skilled in the art. Generally, said compounds are synthesized according to the method of Srivastava, J. Med. Chem. (1976). Other methodologies are described by 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 formulas II-IV were prepared according to the methods described in PCT Publication Nos. WO 98/39344, WO 98/39343 and WO 98/39342.

Section 1

The synthesis of compounds of formula I

The synthesis of compounds contemplated by this invention typically includes some or all of the following main steps:

(1) obtaining a phosphonate prodrug; (2) deprotection of the phosphonate ester; (3) heterocycle midification; (4) binding of the heterocycle to the phosphonate component; (5) the creation of a heterocycle; (6) closing the ring to construct a heterocycle with an existing phosphonate moiety; and (7) preparing the intermediates used. The above steps are illustrated in the following scheme for compounds of formula 2, in which R ⁵ means a 5-membered heteroaromatic ring. Compounds of formula 2 in which R ⁵ is a 6 membered heteroaromatic ring or other heteroaromatic rings were prepared in a similar manner.

(la) Obtaining a phosphonate prodrug

Prodrugs can be administered at various stages of the synthesis. Most often, these prodrugs are obtained from phosphonic acids of formula 2, since they are labile. It is advisable to introduce the prodrugs at an earlier stage, provided that they can withstand the reaction conditions of subsequent stages.

Compounds of formula 2 can be alkylated with electrophiles (such as alkyl halides, alkyl sulfonates, etc.) under the conditions of a nucleophilic substitution reaction to produce phosphonate esters. For example, compounds of formula I in which R ¹ is an acyloxyalkyl group can be synthesized by direct alkylation of compounds of formula 2 with an appropriate acyloxyalkyl halide (e.g., Cl, Br, I; Elhaddadi, et al. Phosphorus Sulfur, 1990, 54 (1-4) : 143; Hoffmann, Synthesis, 1988, 62) in the presence of a base (e.g., N, N'-dicyclohexyl-4-morpholinocarboxamidine, Hunigs base and so on) in suitable solvents such as 1,1-dimethylformamide (" DMF ") (Starrett, et al, J. Med. Che. 1994, 1857). The carboxylate compound of these acyloxyalkyl halides includes, but is not limited to, acetate, propionate, isobutyrate, pivalate, benzoate, and other carboxylates. Accordingly, further modification is apparent after the formation of the aforementioned acyloxyalkylphosphonate esters, such as reduction of a nitro group. For example, compounds of formula 3 in which A is a NO ₂ group can be converted to compounds of formula 3 in which A is an H ₂ N group under appropriate reduction conditions (Dickson, et al, J. Med. Chem. 1996, 39: 661; lyer, et al. Tetrahedron Lett., 1989, 30: 7141; Srivastva, et al, Bioorg. Chem., 1984, 12: 118). The described methods can be extended to the synthesis of other types of prodrugs, such as compounds of formula I, in which R ¹ means 3-phthalidyl, 2-oxo-4,5-didehydro-1,3-dioxolanmethyl, or the group 2-oxotetrahydrofuran-5-yl (Biller et al., US 5157027; 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. Chech. Chem. Commun. 1994, 59: 1853; EPO 0632048A1). N, N-dimethylformamide-dialkyl acetals can also be used for the alkylation of phosphonic acids (Alexander P., et al., Collect. Czech. Chem. Commun. 1994, 59, 1853).

Alternatively, the described phosphonate prodrugs can also be synthesized by reactions of the corresponding dichlorophosphonates with alcohol (Alexander P., et al., Collect. Czech. Chem. Commun. 1994, 59, 1853). For example, reactions of dichlorophosphonate with substituted phonols and aralkyl alcohols in the presence of a base (e.g. pyridine, triethylamine, etc.) give compounds of formula V in which R ¹ is an aryl group (Khamnei et al., J. Med. Chem. 1996, 39 : 4109; Serafinowska et ai., J. Med. Chem., 1995, 38: 1372; De Lombaert et al., J. Med. Chem., 1994, 37: 498) or the arylalkyl group (Mitchell et al., J Chem. Soc. Perkin Trans. 1, 1992, 38: 2345). Disulfide-containing prodrugs (Puech et al. Antiviral Res., 1993, 22: 155) can also be prepared from dichlorophosphonate and 2-hydroxyethyl disulfide under standard conditions.

Such reactive dichlorophosphonates can be formed 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 phosphorus pentachloride: Quast et al., Synthesis, 1974, 490). Alternatively, dichlorophosphonate can also be obtained from disilylphosphonate esters (Bhongle et al., Synth. Commun., 1987, 17: 1071) or dialkylphosphonate esters (Still et al .. Tetrahedron Lett., 1983, 24: 4405; Patois et al., Bull. Soc. Chom. Fr., 1993, 130: 485).

In addition, these prodrugs can be prepared using Mitsunobu reactions (Mitsunobu, Synthesis, 1981, 1; Campbell, J. Org. Chem., 1992, 52: 6331) and other binding reactions (for example, 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. Tetrahedron Lett., 1988, 29: 1189, and salts of benzothiazolyloxytris- (dimethylamino) phosphonium: Campagne et al. Tetrahedron Lett., 1993, 34: 6743). Compounds of formula I in which R ¹ is a cyclic carbonate, lactone or phthalidyl group can also be synthesized by direct alkylation of free phosphonic acid with the corresponding halides in the presence of a suitable base (e.g. NaH or diisopropylethylamine, Biller et al., US 5 157027; 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.

R ¹ can also be introduced at an early stage of the synthesis, provided that it is compatible with subsequent reaction stages. For example, compounds of formula I in which R ¹ is an aryl group can be prepared by metallation of a 2-furanyl heterocycle (for example, using LDA) followed by capture of the anion with diaryl chlorophosphate.

It is believed that the compounds of Formula V can be mixed phosphonate esters (e.g., phenyl and benzyl esters, or phenyl and acyloxyalkyl esters) including chemically coupled mixed esters, such as phenyl and benzyl combined prodrugs, as described by Meier, et al. , Bioorg. Med. Chem. Lett. 1997, 7:99.

(lb) Preparation of bisamidate phosphonate

General synthesis of bis-phosphoramidate prodrugs:

In general, bis-phosphoramidates of formula I in which both —NR ¹⁵ R ¹⁶ and —N (R ¹⁸ ) - (CR ¹² R ¹³ ) _n —C (O) —R ^{14 are} derived from the same amino acid residues may be obtained from activated phosphonates, for example dichlorophosphonate, by binding to an ester of an amino acid, for example glycineethyl ester, with or without base, for example, N-methylimidazole. Reactive dichloridates can be prepared as described above in the general prodrug section.

Alternatively, said bis-phosphoroamidates can be prepared by reacting the corresponding phosphonic acid with an amino acid ester, for example 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., J. Am. Chem. Zoe. 1972, 94, 8528.

The synthesis of mixed bis-phosphoroamidates of formula IA in which —NR ¹⁵ R ¹⁶ and —N (R ¹⁸ ) - (CR ¹² R ¹³ ) _n —C (O) -R ¹⁴ mean different amino acid esters or a combination of an amino acid ester and a substituted amine can be carried out by direct conversion through dichloridate, as described above (sequential addition), followed by separation of the desired product by column chromatography or HPLC. Alternatively, said mixed bis-phosphoroamidates can be prepared from the corresponding phosphonate monoester such as phenyl ether or benzyl ether to give the mixed phosphonoester amide via a chloride, followed by hydrolysis of the ester under conditions under which the amide bond is stable. The resulting mono-amide can be converted with mixed bis-amide by condensation with a second amino ester or substituted amine via a chloride, as described above. The synthesis of such a complex monoester can be carried out using the described method (EP 481214).

Substituted cyclic propylphosphonate esters can be synthesized by reaction of the corresponding dichlorophosphonate with substituted 1,3-propanediol. Some of the methods used to prepare substituted 1,3-propanediol are discussed below.

Synthesis of 1,3-propanediol

Various synthesis methods can be used to produce numerous types of 1,3-propanediols: (i) 1-substituted, (ii) 2-substituted, (iii) 1,2- or 1,3-annelated 1,3-propanediols. Substituents on a prodrug fragment of compounds of formula I (i.e., substituents on a 1,3-propanediol fragment) can be introduced or modified either during the synthesis of the mentioned diols or after binding of the obtained diols to compounds of formula 2.

(i) 1-Substituted 1,3-propanediols

The 1,3-propanediols used in the synthesis of the compounds of this invention can be prepared using various synthesis methods. The addition of aryl in the Grignard reaction to 1-hydroxy-propan-3-alu gives 1-aryl-substituted 1,3-propanediols (path 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). Conversions of aryl halides to 1-substituted 1,3-propanediols can also be carried out using Heck reactions (e.g., binding to 1,3-diox-4-ene), followed by reduction and subsequent hydrolysis reactions (Sakamoto et al. , Tetrahedron Lett., 1992, 33, 6845). Various aromatic aldehydes can also be converted to 1-substituted-1,3-propanediols using alkenyl in the Grignard addition reaction followed by hydroboration reactions (path b). The addition of metallated tert-butyl acetate to aromatic aldehydes followed by reduction of the ester (path e) is also used to synthesize 1,3-propanediols (Turner., J. Org. Chem., 1990, 55, 4744). In another method, epoxidation of cinnamyl alcohols using known methods (e.g., Sharpless epoxidation and other asymmetric epoxidation reactions) followed by a reduction reaction (e.g., using Red-Al) gives various 1,3-propanediols (pathway c). Alternatively, enantiometrically pure 1,3-propanediols can be prepared using chiral borohydride reduction reactions of hydroxyethylaryl ketone derivatives (Ramachandran et al., Tetrahedron Lett, 1997, 38: 761). Propan-3-ols with a 1-heteroaryl substituent (e.g. pyridyl, quinolinyl, or isoquinolinyl) can be oxygenated to produce 1-substituted 1,3-propanediols using N-oxide formation reactions followed by rearrangement reaction in acetic anhydride (path d) (Yamamoto et al., Tetrahedron, 1981, 37, 1871).

(ii) 2-substituted 1,3-propanediols

Various 2-substituted 1,3-propanediols used to synthesize compounds of formula I can be prepared from 2- (hydroxymethyl) -1,3-propanediols using known chemical approaches (Larock, Comprehensive Organic Transformations, VCH, New York, 1989) . For example, the reduction of trialkoxycarbonylmethane under known conditions gives a triol as a result of complete reduction (path a) or bis (hydroxymethyl) acetic acid by selective hydrolysis of one of the ester groups followed by reduction of the remaining two other ester groups. It is also known that nitrotriols form triols by reductive elimination (pathway b) (Latour et al., Synthesis, 1987, 8, 742). In addition, 2- (hydroxymethyl) -1,3-propanediol can be converted to a mono-acylated derivative (e.g. acetyl, methoxycarbonyl) using an acyl chloride or alkyl chloroformate (e.g. acetyl chloride or methyl chloroformate) (path d) using known chemical approaches (Greene et al., Protective Groups In Organic Synthesis; Wiley, New York, 1990). Manipulations with another functional group can also be used to produce 1,3-propanediols, such as the oxidation of one of the hydroxymethyl groups in 2- (hydroxymethyl) -1,3-propanediol to an aldehyde, followed by Grignard-aryl addition reactions (path c). Aldehydes can also be converted to alkyl amines via reductive amination reactions (pathway e).

(iii) Annelation of 1,3-propanediols

Compounds of formula I in which V and Z or V and W are joined via four carbons to form a ring can be prepared from 1,3-cyclohexanediol. For example, cis, cis-1,3,5-cyclohexanetriol can be modified as described for 2-substituted 1,3-propanediols. It is believed that the above modifications can be carried out either before or after the formation of the cyclic phosphonate ester of 1,3-propanediol. Various 1,3-cyclohexanediols can also be obtained using Diels-Alder reactions (Diels-Alder) (for example, using pyrone as a diene: Posner et al., Tetrahedron Lett., 1991, 32: 5295). Derivatives of 1,3-cyclohexanediol are also obtained by other cycloaddition reactions. For example, cycloaddition of nitrile oxide to an olefin, followed by conversion of the resulting cycloadduct to a 2-ketoethanol derivative, which can be converted to 1,3-cyclohexanediol using known chemical approaches (Curran et al., J. Am. Chem. Soc., 1985, 107, 6023). Alternatively, 1,3-cyclohexanediol precursors can be prepared from quinic acid (Rao, et al .. Tetrahedron Lett., 1991, 32, 547).

2) Deprotection of the phosphonate ester

Compounds of formula I in which R ¹ is H can be prepared from phosphonate esters using known conditions for the cleavage of phosphate and phosphonate esters. Silyl halides are usually used to cleave various phosphonate esters, and subsequent gentle hydrolysis of the resulting silylphosphonate esters gives the desired phosphonic acids. If necessary, acid scavengers (e.g. 1,1,1,3,3,3-hexamethyldisilazane, 2,6-lutidine, etc.) can be used to synthesize acid labile compounds. Such 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 can be cleaved under highly acidic conditions (e.g., HBr or HCl: Moffatt, et al., US Pat. No. 3,524,846, 1970). The cleavage of these esters can also be carried out with dichlorophosphonates obtained by treating the esters with halogenating agents (e.g., phosphorus pentachloride, thionyl chloride, BB ₃ : Pelchowicz et al, J. Chem. Soc., 1961, 238) followed by aqueous hydrolysis to obtain phosphonic acids. Aryl and benzyl phosphonate esters can be cleaved under hydrogenolysis (Lejczak, et al., Synthesis, 1982, 412; Elliott, et al., J. Med. Chem., 1985, 28: 1208; Baddiley, et al., Nature , 1953, 171: 76) or metal reduction conditions (Shafer, et al., J. Am. Chem. Soc., 1977, 99: 5118). Electrochemical conditions (Shono, et al., J. Org. Chem., 1979, 44: 4508) and pyrolysis conditions (Gupta, et al., Synth. Commun., 1980, 10: 229) were also used to break down complex phosphonate compounds.

(3) Modification of an Existing Heterocycle

The synthesis of heterocycles enclosed in the described compounds has been well studied and described in numerous reviews (see section 4). Although it is convenient to have the required substituents present in these heterocycles before the synthesis of compounds of formula 4, in some cases the required substituents are incompatible with subsequent reactions, and therefore, later it becomes necessary to modify the existing heterocycle in the synthesis scheme using generally accepted chemical approaches (Larock, Comprehensive organic transformations, VCH, New York, 1989; Trost, Comprehensive organic synthesis; Pergamon press. New York, 1991). For example, compounds of formula I in which A, A "or B means a halogen or cyano group can be obtained from the corresponding amine group by conversion to a diazonium group and reaction with various copper (I) salts (e.g. CuI, CuBr, CuCl, CuCN ). Halogens can also be introduced by direct halogenation of various heterocycles. For example, 5-unprotected-2-aminothiazoles can be converted to 2-amino-5-halo-thiazoles using various reagents (eg NIS, NBS, NCS). Heteroaryl halides are also used intermediates, and often their quickly converted to other substituents (such as A, A ", B, B", C ", D, D", E, E ") using transition metal-catalyzed coupling reactions such as the Suzuki, Heck ( Heck) and Stille (Farina et al., Organic Reactions, Vol. 50; Wiley, New York, 1997; Mitchell, Synthesis, 1992, 808; Suzuki, Pure App. Chem., 1991, 63, 419; Heck , Palladium Reagent in Organic Synthesis; Academic Press San Diego, 1985). Compounds of formula I in which A is a carbamoyl group can be prepared from their respective alkyl carboxylate esters via aminolysis with various amines, and conventional modifications of the functional groups of alkyl carboxylate esters are carried out to synthesize compounds of formula I in which A is a —CH ₂ OH group or the group -CH ₂ -halogen. Substitution reactions of haloheterocycles (for example, 2-bromothiazole, 5-bromothiazole) with different nucleophiles (for example, HSMe, HOMe and so on) are another way to introduce substituents such as A, A ", B and B". For example, substitution of 2-chlorothiazole with methanethiol gives the corresponding 2-methylthiothiazole.

It is believed that, if necessary, the alkylation of nitrogen atoms in heterocycles (e.g., imidazoles, 1,2,4-thiazoles and 1,2,3,4-tetrazoles) can be quickly carried out using, for example, standard alkylation reactions (with an alkyl halide) , aralkyl halide, alkyl sulfonate or aralkyl sulfonate) or Mitsunobu reactions (with alcohol).

(4) Binding of a heterocycle to a phosphonate component

At the same time, the resulting compounds described in this invention are conveniently prepared by a convergent synthesis method involving the binding of a heterocycle to a phosphonate diester component.

Binding reactions catalyzed by a transition metal, such as Still or Suzuki reactions, are particularly suitable for the synthesis of compounds of formula I. Binding reactions between heteroaryl halide or triflate (e.g. 2-bromopyridine) and M-PO ₃ R ', where M represents a group 2- ( 5-tributylstannyl) furanyl or 2- (5-boronyl) furanyl under palladium-catalyzed reaction conditions (Farina et al., Organic Reactions, Vol. 50: Wiley, New York, 1997; Mitchell, Synthesis, 1992, 808; Suzuki , Pure App. Chem., 1991, 63, 419) provide compounds of formula I in which X is a furan-2,5-diyl group. It is believed that the nature of the binding of the partners of these reactions may also be reversible (for example, the binding of trialkylstannyl or boronyl heterocycles to halogen-X-P (O) (O-alkyl) ₂ ). It is also described that other binding reactions between tin valent organic compounds and alkenyl halides or alkenyl triflate can be used to prepare compounds of formula I in which X is an alkenyl group. The Heck reaction can be used to prepare compounds of formula I in which X is an alkynyl group (Heck, Palladium Reagents in Organic Synthesis; Academic Press: San Diego, 1985). The reactions mentioned are especially convenient for the synthesis of various heteroaromatic groups, such as R ⁵ for compounds of the formula I, provided that numerous halogenated heterocycles are available, and the reactions mentioned are especially suitable for parallel synthesis (e.g., combined synthesis on a solid phase (Bunin, B.A., The Combinatorial Index .; Academic press: San Diego, 1998) or in solution phase (Flynn, DL et al., Curr. Op. Drug. Disc. Dev., 1998, 1, 1367) to form large combinatorial libraries. For example, ethyl 5-iodo-2-furanylphosphonate can be bound to a Wang resin under suitable binding reaction conditions. The resin bound to the 5-iodo-2- [5- (O-ethyl-O-Wang resin) phosphono] furan can then be subjected to the reactions of Suzuki and Still, catalyzed by a transition metal (as described above), with borane-organic compounds and organic tin compounds in a parallel manner to obtain a library of compounds of formula 3, in which X is furan-2,5-diyl.

Substitution reactions are used to bind the heterocycle to the phosphonate diester component. For example, cyanuric chloride may be substituted with dialkylmercaptoalkylphosphonates or dialkylaminoalkylphosphonates to give compounds of formula 2 in which R ⁵ is 1,3,5-triazine, X is an alkylthio or alkylamino group. Alkylation reactions are also used to bind the heterocycle to the phosphonate diester component. For example, a heteroaromatic thiol (e.g., 1,3,4-thiadiazole-2-thiol) can be alkylated with a dialkyl methylphosphonate derivative (e.g., ICH ₂ P (O) (OEt) ₂ , TsOCH ₂ P (O) (OEt) ₂ , TfOCH ₂ P (O) (OEt) ₂ ) to obtain compounds of formula I in which X is an alkylthio group. In another aspect, alkylation reactions 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 ) to obtain compounds of formula I in which X is an alkoxycarbonyl group, while alkylation reactions of a heteroaromatic tricarboxylic acid (e.g., thiazole-4-thiocarboxylic 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₎ lead to compounds of formula I, wherein X meaning t alkylthiocarbonyl group. Substitution of haloalkyl heterocycles (e.g. 4-haloalkylthiazole) with nucleophiles containing a phosphonate group (diethylhydroxymethylphosphonate) is used to prepare compounds of formula I in which X represents an alkoxyalkyl or alkylthioalkyl group. For example, compounds of formula I in which X represents a group —CH ₂ OCH ₂ - can be prepared from 2-chloromethylpyridine or 4-chloromethylthiazole using dialkylhydroxymethylphosphonates and a suitable base (e.g. sodium hydride). It turns out that the nature of nucleophiles and electrophiles can be reversed for substitution reactions, that is, halogenated alkyl and / or sulfonylalkylphosphonate esters can be substituted with heterocycles containing nucleophile (e.g. 2-hydroxyalkylpyridine, 2-mercaptoalkylpyridine or 4-hydroxyalkylazole.

Known amide bond formation reactions (e.g., the acyl halide method, the mixed anhydride method, the carbodiimide method) can also be used to couple the heteroaromatic carboxylic acid with a phosphonate diester component, which leads to compounds of formula 4, where X is an alkylaminocarbonyl or alkoxycarbonyl group. For example, the binding of a triazole-4-carboxylic acid to a dialkyl aminoalkylphosphonate or dialkyl hydroxyalkylphosphonate provides compounds of formula 4 in which R ⁵ is thiazole and X is an alkylaminocarbonyl or alkoxycarbonyl group. Alternatively, the nature of the binding partners can be changed to give compounds of formula 4 in which X is an alkylcarbonylamino group. For example, 2-aminothiazoles can be attached to (RO) ₂ P (O) -alkyl-CO ₂ H (e.g. diethylphosphonoacetic acid) under these reaction conditions to give compounds of formula 4 in which R ⁵ is thiazole and X is a group alkylcarbonylamino. The described reactions are also used for the parallel synthesis of compound libraries through combinatorial chemistry in the solid phase or in the solution phase. For example, HOSN ₂ P (O) (OEt) (O-resin), H ₂ NCH ₂ P (O) (OEt) (O-resin) and HOOCCH ₂ P (O) (OEt) (O-resin) (obtained using known methods) can be attached to various heterocycles using the reactions described above to obtain a library of compounds of formula 3 in which X is —C (O) OCH ₂ -, or —C (O) NHCH ₂ -, or —NHC ( O) CH ₂ -.

Rearrangement reactions can also be used to prepare the compounds of this invention. For example, Curtius rearrangement of thiazole-4-carboxylic acid in the presence of dialkyl hydroxyalkyl phosphonate or dialkyl aminoalkyl phosphonate results in compounds of formula 4 wherein X is an alkylaminocarbonylamino or alkoxycarbonylamino group. The described reactions can also be selected for the combinatorial synthesis of various libraries of compounds of the formula 3. For example, using Curtius rearrangement reactions between heterocyclic carboxylic acid and HOSN ₂ P (O) (OEt) (O-resin) or H ₂ NCH ₂ P ( O) (OEt) (O-resin), a library of compounds of formula I can be prepared in which X is a-NHC (O) OCH ₂ - or a-NHC (O) NHCH ₂ -.

For compounds of formula V in which X is an alkyl group, a phosphonate group can be introduced using other general phosphonate formation methods, such as the Michaelis-Arbuzov reaction (Bhattacharya et al., Chem. Rev., 1981, 81, 415), reaction Michaelis-Becker (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).

The phosphonate component can also be introduced via lithiation reactions. For example, lithiation of 2-ethynylpyridine using a suitable base followed by capture of the thus formed anion with dialkyl chlorophosphonate leads to compounds of formula 3 in which R ⁵ is pyridyl, X is a 1- (2-phosphono) ethynyl group.

(5) Construction of a heterocycle

Although existing heterocycles are used to synthesize compounds of formula V, heterocycles leading to the compounds of this invention can also be created if necessary, and in some cases they may be preferred for the preparation of certain compounds. The design of heterocycles using a variety of reaction conditions is well described in the literature (Joule et al., Heterocyclic Chemistry; Chapman hall, London, 1995; Boger, Weinber, Hetero Diels-Alder Methodology In Organic Synthesis; Academic press, San Diego, 1987; Padwa , 1,3-Dipolar Cycloaddition Chemistry; Wieley, New York, 1984; Katritzky 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 the methods that have been used to obtain the compounds of this invention are given as examples in the following discussion.

(i) Design of a thiazole ring system

The thiazoles used for this invention can be rapidly prepared using a variety of well-described ring formation reactions (Metzger, Thiazole and its derivatives, part 1 and part 2; Wiley & Sons, New York, 1979). The cyclization reactions of thioamides (e.g., thioacetamide, thiourea) and alpha-halogenocarbonyl compounds (such as alpha-halogen ketones, alpha-halogen-aldehydes) are particularly suitable for the construction of a thiazole ring system. For example, cyclization reactions between thiourea and 5-diethylphosphono-2 - [(- 2-bromo-1-oxo) alkyl] furans are used to synthesize compounds of formula 2 in which R ⁵ is thiazole, A is an amino group and X is a furan-group 2,5-diyl; the cyclization reaction between thiourea and bromopyruvate alkyl ester gives 2-amine-4-alkoxycarbonylthiazole, which is used to prepare compounds of formula 2 in which R ⁵ is thiazole and X is an alkylaminocarbonyl, alkoxycarbonyl, 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 alpha-halocarbonyl compounds are rapidly prepared using conventional reactions (Larock, Comprehensive organic transformations, VCH, New York, 1989). For example, amides can be converted to thioamides using Lawesson's reagent or P2S5, and ketones can be halogenated using various halogenating reagents (for example, NBS, CuBr ₂ ).

(ii) Design of the Oxazole Ring System

Oxazoles used for this invention can be obtained using various methods described in the literature (Turchi, Oxazoles; Wiley & Sons, New York, 1986). Reactions between isocyanides (e.g., tosylmethylisocyanide) and carbonyl compounds (e.g., aldehydes or acyl chlorides) can be used to create oxazole ring systems (van Leusen et al. Tetrahedron Lett., 1972, 2369). Alternatively, cyclization reactions of amides (eg, urea, carboxamides) and alpha-halogenocarbonyl compounds are typically used to create an oxazole ring system. For example, the reactions of urea and 5-diethylphosphono-2 - [(- 2-bromo-1-oxo) alkyl] furans are used to synthesize compounds of formula 2 in which R ⁵ is oxazole, A is an amino group and X is an furan-2 group, 5-diyl. The reactions between amines and imidates are also used to obtain the oxazole ring system (Meyers et al., J. Org. Chem., 1986, 51 (26), 5111).

(iii) Construction of the pyridine ring system

Pyridines used to synthesize compounds of formula I can be prepared using various known synthetic methods (Klingsberg, Pyridine and Its Derivatives; Interscience Publishers, New York, 1960-1984). The 1,5-dicarbonyl compounds or their equivalents can be reacted with ammonia or compounds that can form ammonia to produce 1,4-dihydropyridines, which are easily dehydrogenated to pyridines. When unsaturated 1,5-dicarbonyl compounds or their equivalents (for example, pyrulium ions) are used to react with ammonia, pyridines can be directly prepared.

Compounds of 1,5-dicarbonyl or their equivalents can be obtained using conventional chemical methods. For example, 1,5-ketones are obtained through a variety of methods, such as Michael addition of enolate to enone (or the predecessor of Mannich base (Gill et al., J. Am. Chem. Soc., 1952, 74, 4923) ), ozonolysis of the cyclopentene precursor or reaction of silylenol ethers with 3-methoxyallyl alcohols (Duhamel et al. Tetrahedron, 1986, 42, 4777). If one of the carbonyl carbon is oxidized in an acidic environment, then this type of reaction leads to the formation of 2-pyridones, which can quickly turn into 2-halogen-pyridines (Isler et al., Helv. Chim. Acta, 1955, 38, 1033) or 2-aminopyridines (Vorbruggen et al., Chem. Ber., 1984, 117, 1523). Alternatively, pyridines can be prepared from aldehyde, a 1,3-dicarbonyl compound and ammonia by classical Hantzsch synthesis (Bossart et al, Angew. Chem. Int. Ed. Engl., 1981, 20, 762). Reactions of 1,3-dicarbonyl compounds (or their equivalents) with 3-aminoenones or 3-aminonitriles were also used to obtain pyridines (e.g., Guareschi synthesis, Mariella, Org. Synth., Coll. Vol. IV, 1963, 210). Compounds of 1,3-dicarbonyl can be obtained by oxidation reactions with the corresponding 1,3-diols or with the products of the aldol reaction (Mukaiyama, Org. Reactions, 1982, 28, 203). The cycloaddition reactions were also used for the synthesis of pyridines, for example, the cycloaddition reaction between oxazoles and alkenes (Naito et al., Chem. Pharm. Bull., 1965, 13, 869) and the Diels-Alder reaction 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 used to synthesize compounds of formula V-2 can be readily prepared (Brown, The pyrimidines; Wiley, New York, 1994). One method for synthesizing pyrimidine involves linking a 1,3-dicarbonyl component (or its equivalent) with an N-C-N fragment. The choice of the NCN component is urea (Sherman et al., Org. Synth., Coil. Vol. IV, 1963, 247), amidine (Kenner et al., J. Chem. Soc., 1943, 125) or guanidine (Burgess , J. Org. Chem., 1956, 21, 97; VanAllan, Org. Synth., Coil. Vol. IV, 1963, 245) - determines the substitution in C-2 in pyrimidine products. The described method is especially suitable for the synthesis of compounds of formula V-2 with various groups A. In another way, pyrimidines can be obtained by cycloaddition reactions, such as aza-Diels-Alder reactions, between 1,3,5-triazine and enamine or inamine ( Boger et al., J. Org. Chem., 1992, 57, 4331 and references cited in the description).

(v) Design of the imidazole ring system

Imidazoles used to synthesize compounds of formula V-1 are prepared easily using a variety of different synthesis methodologies. Various cyclization reactions are commonly used to synthesize imidazoles, such as those between amidines and alpha-halogen ketones (Mallick et al., J. Am. Chem. Soc., 1984, 106 (23), 7252) or alpha-hydroxyketones (Shi et al., Synthetic Comm., 1993, 23 (18), 2623), reactions between urea and alpha-halogen ketones and reactions between aldehydes and 1,2-dicarbonyl compounds in the presence of amines.

(vi) Construction of the isoxazole ring system

The isoxazoles used to synthesize compounds of formula V-1 are synthesized quickly using various approaches (such as cycloaddition reactions between nitrile oxides and alkynes or active methylene compounds, oxime of 1,3-dicarbonyl compounds or alpha, beta acetylene carbonyl compounds or alpha compounds -, beta-dihalogenocarbonyl and so on) can be used to synthesize the isoxazole ring system (Grunanger et al., Isoxazoles; Wiley & Sons, New York, 1991). For example, the reactions between alkynes and 5-diethylphosphono-2-chloroximidofuran in the presence of a base (e.g. triethylamine, Hunig base, pyridine) are used to synthesize compounds of formula 2, wherein R ⁵ is isoxazole and X is furan-2,5 group Diila.

(vii) Design of the pyrazole ring system

Pyrazoles used to synthesize compounds of formula V-1 are prepared easily using a variety of methods (Wiley, Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles, and Condensed Rings; Interscience Publishers, New York, 1967), such as reactions between hydrazines and compounds 1 , 3-dicarbonyl or equivalents of 1,3-dicarbonyl (for example, one of the carbonyl groups disguised as enamine, or ketal, or acetal), and the addition of hydrazines to acrylonitriles with subsequent cyclization reactions (Dorn et al., Org. Synth., 1973 , Coil. Vol. V, 39). The reaction of 2- (2-alkyl-3-N, N-dimethylamino) acryloyl-5-diethylphosphonofurans with hydrazines is used to synthesize compounds of formula I in which R ⁵ is pyrazole, X is a furan-2,5-diyl group, and B "means an alkyl group.

(viii) Construction of the 1,2,4-triazole ring system

The 1,2,4-triazoles used to synthesize compounds of formula V-1 are prepared readily using various methodologies (Montgomery, 1,2,4-Triazoles; Wiley, New York, 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 to synthesize 1,2,4-triazoles.

(6) Ring closure for constructing a heterocycle with phosphonate

Compounds of formula 4 can also be prepared using a ring closure reaction to create a heterocycle from starting materials that contain a phosphonate component. For example, cyclization reactions between thiourea and 5-diethylphosphono-2 - [(- 2-bromo-1-oxo) alkyl] furans are used to synthesize compounds of formula 2 in which R ⁵ is thiazole, A is an amino group, and X is a furan group -2,5-diyl. The oxazoles of the present invention can also be prepared using a ring closure reaction. In this case, the reactions of urea and 5-diethylphosphono-2 - [(- 2-bromo-1-oxo) alkyl] furans are used to synthesize compounds of formula I in which R ⁵ is oxazole, A is an amino group, and X is a furan- 2,5-diyl. The reactions between 5-diethylphosphono-2-furaldehyde, alkylamine, 1,2-diketone and ammonium acetate are used to synthesize compounds of formula 2 in which R ⁵ is imidazole and X is the furan-2,5-diyl group. The described types of ring closure reactions can also be used for the synthesis of pyridines or pyrimidines used in this invention. For example, the 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-diethylphosphono) furanyl] -2- pyridones (Jain et al., Tetrahedron Lett., 1995, 36, 3307). Subsequent conversion of the obtained 2-pyridones to the corresponding 2-halo-pyridines (see references cited in Section 3 for modifications of heterocycles) lead to compounds of formula I in which R ⁵ means pyridine, A means a halogen group, X means a furan-2,5 group -diyl, and B represents an alkyl group. Reactions of 5-diethylphosphono-2- [3-dimethylamino-2-alkyl) acryloyl] furans and amidines in the presence of a base give 5-alkyl-6- [2- (5-diethylphosphono) furanyl] pyrimidines, which lead to compounds of formula 2, wherein R ⁵ is pyrimidine, X is a 2,5-diyl group, and B is an alkyl group.

(7) Obtaining various precursors used for cyclization reactions

Intermediates necessary for the synthesis of compounds of this invention are usually prepared using either a method available in the literature or a modification of an existing method. The description provides the syntheses of certain intermediates used for the synthesis of compounds of this invention.

In particular, various arylphosphonate dialkyl esters are used to synthesize compounds of formula I. For example, compounds of formula 3 in which X is a furan-2,5-diyl group can be prepared from a variety of furanyl precursors. It is believed that the synthesis of other precursors may follow some or all of the above reaction steps, and some modifications of the described reactions may be required for various precursors. Compounds of 5-dialkylphosphono-2-furancarbonyl (e.g. 5-diethylphosphono-2-furaldehyde, 5-diethylphosphono-2-acetylfuran) are well suited for the synthesis of compounds of formula I in which X is a furan-2,5-diyl group. These intermediates are prepared from furan or furan derivatives using conventional chemical methods such as lithiation reactions, protecting carbonyl groups and deprotecting carbonyl groups. For example, lithiation of furan using known methods (Gschwend Org. React. 1979, 26: 1), followed by addition of phosphorylating agents (e.g. ClPO ₃ R ₂ ), gives 2-dialkylphosphonofurans (e.g. 2-diethylphosphonofuran). The above method can also be used with 2-substituted furan (for example, 2-furonic acid) to obtain 5-dialkylphosphono-2-substituted furan (for example, 5-diethylphosphono-2-furonic acid). It is believed that other arylphosphonate esters can also be prepared using this approach or a modification of this approach. Alternatively, other methods, such as transition metal-catalyzed reactions of aryl halides or trifluoromethanesulfonic acids (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), used to produce arylphosphonates. Arylphosphonate esters can also be obtained from arylphosphates under anionic rearrangement conditions (Melvin, Tetrahedron Lett., 1981, 22: 3375; Casteel et al., Synthesis, 1991, 691). Salts of N-alkoxyaryl with alkali metal dialkylphosphonate derivatives represent another general synthesis of heteroaryl-2-phosphonate esters (Redmore J. Org. Chem., 1970, 35: 4114).

The second lithiation step can be used to introduce a second group onto an arylphosphonate dialkyl ester such as an aldehyde group, a trialkylstannyl or halogen group, although other known methods for forming the described functional groups (e.g., aldehydes) can also be considered (e.g., the Vilsmeier-Haack reaction or the Rymer-Timan reaction for the synthesis of aldehydes). In the second lithiation step, the lithiated aromatic ring is treated with reagents that either directly form the desired functional group (for example, for aldehyde using DMF, HCO ₂ R, etc.), or with reagents that lead to the formation of a group that subsequently transforms into the desired functional group, using well-known chemical approaches (for example, 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 anion thus formed by an electrophile (e.g. tributyltin chloride or iodine) leads to the formation of 5-functionalized-2-dialkylphosphonofuran ( for example, 5-tributylstannyl-2-diethylphosphonofuran or 5-iodo-2-diethylphosphonofuran). It is also believed that the sequence of the described reactions can be changed, that is, an aldehyde moiety can be introduced first, followed by a phosphorylation reaction. The order of the reactions will depend on the reaction conditions and protecting groups. Prior to phosphorylation, it is believed that it may be appropriate to protect some of the above functional groups using a number of well-known methods (for example, protecting aldehydes in the form of acetals, amines; protecting ketones in the form of ketals). Then, after phosphorylation, the protective groups are unmasked. (Protective groups in Organic Synthesis, Greene, TW, 1991, Wiley, New York). For example, protecting 2-furaldehyde in the form of 1,3-propanediol acetal followed by a lithiation step (using, for example, LDA) and capturing the anion with dialkyl chlorophosphate (e.g. diethyl chlorophosphate) and then removing the protection of activated acetal under normal deprotection conditions leads to the formation of 5-dialkylphosphono -2-furaldehyde (e.g. 5-diethylphosphono-2-furaldehyde). Another example is the preparation of 5-keto-2-dialkylphosphonofurans, which includes the following steps: acylation of furan under the Friedel-Crafts reaction, which gives 2-ketofuran, subsequent ketone protection in the form of ketals (e.g., 1,3-propanediol cyclic ketal ), followed by the lithiation step described above and gives 5-dialkylphosphono-2-furanketone with a ketone protected as a cyclic ketal of 1,3-propanediol, and, finally, deprotection in the form of a ketal under, for example, acidic conditions, gives 2-keto-5-dialkylphosphonofur s (e.g., 2-acetyl-5-dietilfosfonofuran). Alternatively, 2-ketofurans can be synthesized by a palladium-catalyzed reaction between 2-trialkylstannylfurans (e.g. 2-tributylstannylfuran) and acyl chloride (e.g. acetyl chloride, isobutyl chloride). It is advisable to have a phosphonate moiety present in 2-trialkylstannylfuranes (e.g. 2-tributylstannyl ~ 5-diethylphosphonofuran). 2-Keto-5-dialkylphosphonofurans can also be prepared from 5-dialkylphosphono-2-furonic acid (e.g. 5-diethylphosphono-2-furonic acid) by converting the acid to the corresponding acyl chloride and subsequent addition of the Grignard reagent.

Some of the intermediates described above can also be used to synthesize other useful intermediates. For example, 2-keto-5-dialkylphosphonofuran can be further converted to the 1,3-dicarbonyl derivative, which is used to prepare pyrazoles, pyridines or pyrimidines. The reaction of 2-keto-5-dialkylphosphonofuran (e.g. 2-acetyl-5-diethylphosphonofuran) with dialkyl acetal dialkylformamide (e.g. dimethyl acetal dimethylformamide) gives the 1,3-dicarbonyl equivalent as 2- (3-dialkylamino-2-alkyl ~ acroyl-5-dialkylphosphonofuran (e.g. 2- (3-dimethylaminoacryloyl) -5-diethylphosphonofuran).

It is believed that the above methods for the synthesis of furan derivatives, either directly or with some modifications, can be used to synthesize various other useful intermediates, such as arylphosphonate esters (e.g., thienylphosphonate esters, phenylphosphonate esters or pyridylphosphonate esters).

It is believed that, if necessary, the corresponding synthesis methods described above can be used for parallel synthesis. on a solid phase or in solution to ensure rapid SAR- (structure-activity dependence) studies of the FBPase inhibitors of this invention, provided that the improvement of the methods for such reactions is successful.

Section 2

The synthesis of compounds of formula X

The synthesis of the compounds contemplated by this invention typically includes some or all of the following general steps: (1) preparing a phosphonate prodrug; (2) deprotection of the phosphonate ester; (3) constructing a heterocycle; (4) administration of a phosphonate component; (5) synthesis of aniline derivative. Step (1) and step (2) are discussed in section 1, and a discussion of step (3), step (4), and step (5) is presented below. Basically, the above methods are also suitable for compounds of formula X.

(3) Construction of a heterocycle

(i) Benzothiazole ring system

Compounds of formula 3 in which G ″ = S, that is, benzothiazoles, can be prepared using various synthetic methods described in the literature. Two of these methods are presented as examples, which are discussed below. One method is a modification of the commercially available benzothiazole derivatives, to obtain the corresponding functional groups on the benzothiazole ring.Another method is to annel various anilines (for example, compounds of formula 4) to create a thiazole fragment of the benothiazole ring. For example, compounds of formula 3 wherein G "= S, A = NH _2, L ^2, E ^2, J ² = H, X ² = CH ₂ O, a R '= Et, may be prepared from commercially supplied 4- methoxy-2-aminothiazole using two stages of sequential reactions: the conversion of 4-methoxy-2-aminobenzothiazole to 4-hydroxy-2-amino-benzothiazole with reagents such as BBr ₃ (Node, M., et al., J. Org. Chem. 45, 2243-2246, 1980) or AlCl ₃ in the presence of a thiol (e.g., EtSH) (McOmie, JW, et al. Org. Synth., Collect. Vol. 412, 1973) and subsequent alkylation of the phenol group with diethylphosphonomethyl trifluoromethyl sulfonate (Phillion, DP; et al. Tetrahedron Lett. 27, 1477-1484, 1986) in the presence of a suitable base (e.g. NaH) in polar apotonic solvents (e.g. DMF), to provide the desired connection.

Several methods can be used to convert various anilines to benzothiazoles (Sprague, JM; Land, AH Heterocycle Compd. 5, 506-13, 1957). For example, 2-aminobenzothiazoles (formula 3 in which A = NHz) can be obtained by annelating compounds of formula 4 in which W ² = H using various conventional methods. One method involves treating a suitably substituted aniline with a mixture of KSCN and CuSO ₄ in methanol to obtain substituted 2-aminobenzothiazole (Ismail, IA; Sharp, DE; Chedekel, MR, J. Org. Chem. 45, 2243-2246, 1980). Alternatively, 2-aminobenzthiazole can also be obtained by treating Br ₂ in the presence of KSCN in acetic acid (Patil, DG; Chedekel, MR, J. Org. Chem. 49, 997-1000, 1984). The above reaction can also be carried out in two successive stages. For example, treatment of substituted phenylthioureas with Br ₂ in CHCl ₃ gives substituted 2-aminobenzothiazoles (Patil, DG; Chedekel, MR, J. Org. Chem. 49, 997-1000, 1984). 2-Aminobenzothiazoles can also be obtained by condensation of orthioiodanilines with thiourea in the presence of a Ni (NiCl ₂ (PPh ₃ ) ₂ ) catalyst (Takagi, K. Chem. Lett. 265-266, 1986).

Benzothiazoles can be electrophilically aromatic substituted to obtain 6-substituted benzothiazoles (Sprague, JM; Land, AH Heterocycle. Compd. 5, 606-13, 1957). For example, bromination of a compound of formula 3 in which G ″ = S, A = NH ₂ , L ² , E ² , J ² = H, X ² = CH ₂ O R ′ = Et, bromine in polar solvents such as AcOH, gives a compound of formula 3 in which E ² = Br.

In addition, compounds of formula 3 in which A is halogen, H, alkoxy, alkylthio or alkyl can be prepared from the corresponding amino compound (Larock, Comprehensive organic transformations, VCH, New Yore, 1989; Trost, Comprehensive organic synthesis; Pergamon press. New York, 1991).

(ii) Benzoxazoles

Compounds of formula 3 in which G ″ = O, that is, benzoxazoles, can be prepared by annelating ortho-aminophenols with a suitable reagent (e.g., cyanogen halide (A = NH ₂ ; Alt, K.O .; et al., J. Hetrocyclic 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 a phosphonate component

Compounds of formula 4 (in which X ² = CH ₂ O and R ′ = alkyl) can be prepared by various methods (for example, using alkylation or nucleophilic substitution reactions). Typically, compounds of formula 5 in which M ′ = OH are treated with a suitable base (e.g., NaH) in a polar apotonic solvent (e.g., DMF, DMSO) and the resulting phenoxide anion can be alkylated with a suitable electrophile, preferably with a phosphonate compound (e.g., diethyl iodomethylphosphonate, diethyl trifluoromethyl sulfonomethylphosphonate, diethyl p-methyltoluene sulfonomethylphosphonate). An alkylation method may also be used to convert the precursor compounds into compounds of formula 5 in which a phenol moiety is present, and may be alkylated with a phosphonate-containing component. Alternatively, compounds of formula 4 can also be prepared by nucleophilic substitution of the starting compounds to compounds of formula 5 (in which the halogen group, preferably fluorine or chlorine, is ortho to the nitro group). For example, a compound of formula 4 (in which X ² = CH ₂ O and R ′ = Et) can be obtained from a 2-chloro-1-nitrobenzene derivative by treating NaOCH ₂ P (O) (OEt) ₂ in DMF. Similarly, compounds of formula 4 can be prepared in which X ₂ = -alkyl-S— or -alkyl-N—.

(5) Synthesis of aniline derivative

Numerous methods have been described for the synthesis of aniline derivatives, the methods described can be used to synthesize suitable intermediates that can lead to compounds of formula X. For example, various alkenyl or aryl groups can be introduced into the benzene ring by transition metal catalyzed reactions (Kasibhatia, SR, et al WO 98/39343 and in cited references); anilines can be obtained from their respective nitro derivatives as a result of reduction reactions (for example, hydrogenation reactions in the presence of 10% Pd / C, or reduction reactions using SnCl ₂ in HCl (Patil, DG; Chedekel, MRJ Org. Chem. 49, 997 -1000, 1984)).

Section 3

The synthesis of compounds of formula VII

The synthesis of the compounds contemplated by this invention typically includes some or all of the following main steps, which are shown in the diagram below: (a) linking the phosphonate moiety (1a or 1b) to the aryl or heteroaryl moiety of the ring (2a or 2b, respectively); (b) if necessary, modification of the bound molecule; (c) deprotecting the phosphonate diester (3) to obtain phosphonic acid (4), and (d) obtaining a phosphonate prodrug.

(a) Binding of a phosphonate moiety (1) to an aryl moiety (2).

If necessary, it is advisable to obtain the compounds described in this invention by means of a convergent synthesis method, which involves binding a phosphonate component to an aryl or heteroaryl ring fragment.

Catalytic transition metal binding reactions, such as Still and Suzuki reactions, are especially useful for the synthesis of compounds of formula VII (Farina et al. Organic Reactions, Vol. 50; Wiley, New York, 1997; Suzuki in Metal Cataluzed Cross-Coupling Reactions; Wiley VCH, 1998, pp. 49-97). Binding reactions between compound 1 (in which B preferably means Bu ₃ Sn) and compound 2 (in which A means, for example, iodine, bromine or trifluoromethyl sulfonate) under conditions of a palladium-catalyzed reaction give compounds of formula 3 in which X ⁴ means, for example, 2,5-furanyl). The same type of binding between compound 1 (where B preferably means an iodine group) and compound 2 (where A = B (OH) ₂ or Bu ₃ Sn) can also be used to obtain compounds of formula 3 in which X ⁴ means, for example 2,5-furanyl.

Reagents 2, which are aryl and heteroaryl compounds, are either commercially available or synthesized quickly using known methods. Binding agents 1 are also prepared using well known chemical approaches. For example, if X ⁴ is 2,5-furanyl, a binding agent 1 is prepared starting from furan by a process involving the use of organic lithium compounds. Lithiation of furan using known methods (e.g. n-BuLi / TMEDA, Gschwend Org. React. 1979, 26: 1) followed by addition of phosphorylating agents (e.g. ClPO ₃ R ₂ ) gives 2-dialkylphosphonofurans (e.g. 2-diethylphosphonofuran) . The synthesis of the resulting blocks of 2,5-disubstituted furan can be completed by lithiation of 2-dialkylphosphonofuran (e.g. 2-diethylphosphonofuran) with a suitable base (e.g. LDA) followed by capture of the formed anion with an electrophile (e.g. tributyltin chloride, triisopropyl borate or iodine) to give 2 5-group activated dialkylphosphonofuran (e.g. 5-tributylstannyl-2-diethylphosphonofuran, 2-diethylphosphonofuran-5-boronic acid or 5-iodo-2-diethylphosphonofuran, respectively).

It is believed that the methods described above for synthesizing furan derivatives, either directly or with some modifications, can be used to synthesize various other intermediates used, such as arylphosphonate esters (e.g. thienylphosphonate esters, phenylphosphonate esters or pyridylphosphonate esters).

Known amide bond formation reactions can be used to couple the resulting phosphonate diester block 1 with an aryl or heteroaryl ring intermediate 2, resulting in compounds of formula VII in which X ⁴ is an alkylaminocarbonyl or alkylcarbonylamino group. For example, the binding of an arylcarboxylic acid preferably with diethylaminomethylphosphonate can lead to a compound of formula VII in which the ring moiety introduced from intermediate 2 is aryl and the moiety X ⁴ is —CH ₂ NHC (O) -. Similarly, the substitution of diethyl-alkylaminoalkylphosphonates according to the described method can lead to the formation of compounds with a moiety X ⁴ represented by -R'C (R ") N (R) C (O) -. Alternatively, for example, the binding of arylamine, preferably diethylphosphonoacetic acid, can result in a compound of formula VII in which the ring moiety introduced from intermediate 2 is aryl and the moiety X ⁴ is —CH ₂ C (O) NH—. Compounds with moiety X ⁴ , —R′C (R ″) C (O) NR-, can be obtained by continuing the described method.

Known ester linkage reactions can be used to prepare a compound of formula VII in which X ⁴ is alkylcarboxy or alkoxycarbonyl (for example, —CH ₂ C (O) O — or —CH ₂ OC (O) -. For example, if a fragment of compound 2 means hydroxy-substituted aryl (for example, a phenol derivative), it can be acylated with diethylphosphonoacetyl chloride in the presence of an inhibiting amine, such as triethylamine, to give compounds in which X ⁴ is —CH ₂ C (O) O—. Additionally, aryl— acyl halides (e.g., aryl-acyl chlorides) may bind to dialkyl (hydroxyalkyl) phosphonates (e.g. diethyl (hydroxy) methylphosphonate) to form compounds in which X ⁴ is -alkoxycarbonyl- (e.g. -CH ₂ OC (O) -).

Known ether linkage reactions can be used to prepare compounds of formula VII where X ⁴ is an alkylene-O or alkylene-O-alkylene group. For example, the phenol sodium salt can be alkylated with diethyl (iodomethyl) phosphonate or preferably diethylphosphonomethyl triflate to give compounds of formula VII in which X ⁴ is alkylene-O. Similarly, alkylation of the sodium salt of an arylmethyl alcohol with diethyl (iodomethyl) phosphonate or preferably diethylphosphonomethyl triflate can lead to the formation of compounds of formula VII in which X ⁴ is alkylene-O-alkylene-. Alternatively, treating diethyl hydroxymethylphosphonate with sodium hydride and reacting the resulting sodium salt with a haloalkylaryl compound can lead to the formation of compounds of formula VII in which X ⁴ is alkylene-O-alkylene-.

For compounds of formula VII in which X ⁴ is an alkyl group, the phosphonate group can be introduced using other general phosphonate formation methods, such as the Michaelis-Arbuzov reaction (Bhattacharya et al., Chem. Rev., 1981, 81: 415), reaction Michaelis-Becker (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 possible, and sometimes appropriate, compounds of formula 3 can also be prepared from an aryl compound (2b) by introducing a phosphonate moiety, such as a dialkylphosphono group (e.g., diethylphosphono group). For example, compounds of formula VII in which X ⁴ is 1,2-ethynyl can be prepared by lithiation of the final arylalkine followed by reaction of the anion with a phosphorylating agent (e.g. ClPO ₃ R ₂ ) to form an arylalkynylphosphonate. The required arylalkines are rapidly obtained using conventional chemical approaches. For example, arylalkines can be produced by reactions of aryl halides (e.g., iodides, bromides) or triflates and trimethylsilylacetylene using Sonogashira reactions (Sonogashira in Comprehensive Organic Synthesis, Pergamon Press, New York, 1991, vol. 3, pp 521-549 ), followed by deprotection of the trimethylsilyl group, which gives the final arylalkines.

(b) Modification of the bound molecule.

The bound molecule 3 can be modified using a number of methods. Aryl halides (J ³ -J ⁷ , each possibly Br, I or O-triflate, for example) are suitable intermediates and are often quickly converted to other substituents such as groups of aryls, olefins, alkyls, alkynyls, arylamines and aryloxy, transition metal-catalyzed binding reactions such as Still, Suzuki, Heck, Sonogashira, and other reactions (Farina et al. Organic Reactions, Vol. 50;

Wiley, New York, 1997; Mitchell, Synthesis, 1992, 808; Suzuki in Metal Catalyzed Cross-Couling 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 in which J ³ -J ^{7 may} each mean a carboxamido group, and may be prepared from their corresponding alkyl carboxylate esters by aminolysis using various amines, or by reacting carboxylic acids with amines under standard reaction conditions an amide bond (e.g., amide bond formation mediated by DIC / HOBt).

Compounds of formula VII in which J ³ -J ^{7 may} each be a carboxylate ester group 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 as a result of transition metal catalyzed carbonylation reactions.

Compounds of formula VII in which J ³ -J ^{7 may} each mean an alkylaminoalkyl or arylaminoalkyl group can be prepared from their corresponding aldehydes by standard hydroamination reactions (e.g. aryl or alkylamine, TMOF, AcOH, DMSO, NaBH ₄ ).

(c) Deprotection of the phosphonate or phosphoramidate ester.

Compounds of formula 4 can be prepared from phosphonate esters using known conditions for the cleavage of phosphate and phosphonate esters, as described in Section 1.

(d) Obtaining a phosphonate or phosphoramidate prodrug

Prodrug substitutions can be administered at various stages of the synthesis. Most often, a prodrug is made from phosphonic acid of formula 4 due to the instability of some of the prodrugs. It turns out to be useful that the prodrug can be administered at an earlier stage, provided that it can withstand the reaction conditions of subsequent stages.

Bis phosphoramidates, compounds of formula VII in which both Y 'is nitrogen and R ¹ ' are identical groups derived from amino acids, can be obtained from compounds of formula 4 by linking a suitable activated phosphonate (e.g. dichlorophosphonate) to an amino acid ester (e.g. alanylethyl ester) in the presence or absence 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 an amino acid ester (e.g. glycine ethyl ester) in the presence of triphenylphosphine and 2,2'-dipyridyl disulfide in pyridine, as described in WO 95/07920 or Mukaiyama, T. et al., J. Am. Chem. Soc., 1972, 94, 8528.

Mixed bis-phosphoramidates, compounds of formula VII in which both Y ′ are nitrogen and R ¹ ′ are different groups with one R ¹ derived from amino acids and another R ¹ derived from either amino acids or other groups (e.g. alkyl, aryl, arylalkylamines) can be formed according to the methods described above, but with the subsequent addition of various amines (for example, glycine ethyl ester and alanine ethyl ether) to correspondingly activated phosphonates (e.g. dichlorophosphonate). It is contemplated that mixed bisphosphonates should be separated from other products (for example, compounds of formula VII in which both Y 'are nitrogen and R ¹ ' are identical groups) using suitable purification methods such as column chromatography, MPLC or methods crystallization. Alternatively, mixed bis-phosphoramidates can be prepared as follows: the coupling of the corresponding phosphonate monoester (e.g. phenyl esters or benzyl esters) with an amine (e.g. alanine ethyl ether or morpholine) is carried out by the chlorination process described above, followed by removal of the phosphonate ester ( e.g. phenyl ethers or benzyl ethers) under conditions under which the phosphoramidate bond is stable (e.g. suitable hydrogenation conditions) and the resulting mono-phospho ramidate can be coupled to a second amine (e.g. glycine ethyl ether) to produce mixed bis-phosphoramidate by the chlorination process described above. Phosphonic acid monoesters can be prepared using conventional methods (for example, hydrolysis of phosphonate diesters or by the methods described in EP 481214).

Monophosphoramidate monoesters, compounds of formula VII in which one Y is O and the other Y is N, can also be prepared using the sequential coupling methods described above. For example, a dichloridate formed from compounds of formula 4 can be treated with 0.7-1 equivalents of an alcohol (e.g. phenol, benzyl alcohol, 2,2,2-trifluoroethanol), preferably in the presence of a suitable base (e.g., Hunig base, triethylamine ) After completion of the above reaction, 2-10 equivalents of an amine (for example, alanethyl ether) are added to the reaction mixture to obtain a compound of formula VII in which one Y is O and the other Y is N. Alternatively, selective hydrolysis (for example using lithium hydroxide) phosphonate diester (e.g. diphenylphosphonate) can also lead to the formation of phosphonate monoester (e.g. phosphonate monophenyl ether) and the phosphonate monoester can bind to an amine (e.g., alanine-type e firm) through the chlorination process described above to form mixed bis-phosphoramidates.

Compounds of formula 4 can be alkylated with electrophiles (such as alkyl halides, alkyl sulfonates, etc.) under the conditions of a nucleophilic substitution reaction to give phosphonate esters. For example, compounds of formula VII, wherein R ¹ is acyloxyalkyl group can be synthesized through direct alkylation of compounds of Formula 4 corresponding atsiloksialkilgalogenidami (e.g., Cl, Br, I;. Elhaddadi, et al, Phosphorus Sulfur, 1990, 54 (1-4) : 143; Hoffmann, Synthesis, 1988, 62) in the presence of a suitable base (e.g., N, N'-dicyclohexyl-4-morpholinecarboxamidine, Hunig bases, etc.) (Starrett, et al., J. Med. Chem., 1994 , 1857). The carboxylate component of these acyloxyalkyl halides may include acetate, propionate, 2-methylpropionate, pivalate, benzoate and other carboxylates, not limited to. If appropriate, further modifications are determined after the formation of acyloxyalkylphosphonate esters, such as nitro reduction. For example, compounds of Form 5 in which J ³ -J ^{7 may} each mean a nitro group may be converted to compounds of Formula 5 in which J ³ -J ⁷ each may be an amino group under suitable reduction conditions (Dickson , et al., J. Med. Chem., 1996, 39: 661; lyer et al., Tetrahedron Lett., 1989, 30: 7141; Srivastva, et al., Bioorg., 1984, 12: 118). Compounds of formula VII in which R ¹ is a cyclic carbonate, lactone or a phthalidyl group can also 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. Patent. US 5157027; 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 may also be used to alkylate compounds of formula 4 (for example, using M, I-dimethylformamide-dialkyl acetals as alkylating reagents: Alexander P., et al., Collect. Czech. Chem. Commun, 1994, 59: 1853).

Alternatively, the phosphonate prodrugs of interest can also be synthesized by reacting the corresponding dichlorophosphonates with alcohol (Alexander P., et al. Collect. Czech. Chem. Commun, 1994, 59: 1853). For example, reactions of dichlorophosphonate with substituted phonols, arylalkyl alcohols in the presence of a suitable base (e.g. pyridine, triethylamine and so on) give compounds of formula VII in which 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, the described methods can be extended to the synthesis of other types of prodrugs, such as compounds of formula VII, where R ¹ means a group of 3-phthalidyl, 2-oxo-4,5-didehydro-1,3-dioxolanmethyl or 2-oxotetrahydrofuran-5- silt.

The dichlorophosphonate or monochlorophosphonate derivative of the compounds of formula 4 can be formed from the corresponding phosphonic acids using a chlorinating agent (for example, thionyl chloride: Starrett et al., J. Med. Chem., 1994, 1857, oxalyl chloride: Stowell et al., Tetrahedron Lett., 1990, 31: 3261, and phosphorus pentachloride: Quast et al. Synthesis, 1974, 490). Alternatively, dichlorophosphonate can also be formed from its corresponding disilylphosphonate esters (Bhongle et al., Synth. Conunun., 1987, 17: 1071) or dialkylphosphonate esters (Still et al. Tetrahedron Lett., 1983, 24: 4405; Patois et al., Bull. Soc. Chim. Fr., 1993, 130: 485).

In addition, if possible, some of these prodrugs can be obtained through Mitsunobu reactions (Mitsunobu, Synthesis, 1981, 1; Campbell, J. Org. Chem., 1992, 52: 6331) and other binding reactions (for example, when using carbodiimides: (Alexander P., et al., Collect. Czech. Chem. Commun., 1994, 59: 1853; Casara et al., Bioorg. Med. Chem. Lett., 1992, 2: 145; Ohashi et al .. Tetrahedron Lett ., 1988, 29: 1189, and salts benzotiazoliloksitris (dimethylamino) phosphonium:.. Campagne et al Tetrahedron Lett , 1993., 34: 6743) In some cases it is advisable R ¹ administered at an early stage of the synthesis provided that it is compatible with the subsequent reaction steps, e.g. tions formula VII, wherein R ¹ represents an aryl group, can be prepared by the metallation-2-furanyl substituted heterocycle (e.g. using LDA) followed by trapping the anion diarilhlorfosfatom.

It is believed that the compounds of formula VII may be mixed phosphonate esters (e.g., phenyl and benzyl esters or phenyl and acyloxyalkyl esters) including chemically combined mixed esters such as phenyl and benzyl combined prodrugs described by Meier, et al. , Bioorg. Med. Chem. Lett., 1997, 7:99.

Complex substituted cyclic propylphosphonate or phosphoramidate esters can be synthesized by reacting the corresponding dichlorophosphonate with substituted 1,3-propanediol, 1,3-hydroxypropylamine or 1,3-propanediamine. Some of the methods used to produce substituted 1,3-propanediol, for example, are discussed below.

Synthesis of 1,3-propanediol, 1,3-hydroxypropylamine and 1,3-propanediamine

Various synthesis methods can be used to produce numerous types of 1,3-propanediols: (i) 1-substituted, (ii) 2-substituted, (iii) 1,2- or 1,3-annelated 1,3-propanediols, (iv ) 1,3-hydroxypropylamine and 1,3-propanediamine. The general approach used to obtain these fragments was discussed above.

Synthesis of chiral substituted 1,3-hydroxyamines and 1,3-diamines

Enantiomerically pure 3-aryl-3-hydroxypropan-1-amines are synthesized by the enantioselective catalytic reaction of CBS 3-chloropropiophenone followed by substitution of the halogen group to obtain secondary or primary amines as required (Corey, et al., Tetrahedron Lett., 1989 , 30, 5207). The chiral 3-aryl-3-aminopropan-1-ol type of the prodrug moiety can be obtained by 1,3-dipolar addition of a chiral pure olefin and a substituted arylaldehyde nitron followed by reduction of the resulting isoxazolidine (Koizumi, et al., J. Org. Chem. ., 1982, 47, 4005). The chiral induction at 1,3-polar additions with the formation of substituted isoxazolidines is also achieved using chiral phosphine-palladium complexes obtained by the enantioselective formation of 8-amino alcohol (Hori, et al., J. Org. Chem., 1999, 64, 5017). Alternatively, optically pure 1-aryl substituted amino alcohols are prepared by selectively opening the ring of the corresponding chiral epoxy alcohols with the desired amines (Canas et al., Tetrahedron Lett., 1991, 32, 6931).

Some methods for diastereoselective synthesis of 1,3-substituted amino alcohols are known. For example, treatment of (E) -N-cinnamyl trichloroacetamide with hypochlorous acid leads to trans-dihydrooxazine, which is rapidly hydrolyzed to erythro-β-chloro-α-hydroxy-δ-phenylpropanamine with high diastereoselectivity (Commercon et al., Tetrahedron Lett., 1990, 31, 3871). The diastereoselective formation of 1,3-aminoalcohols is also achieved by hydroamination of optically pure 3-hydroxyketones (Haddad et al .. Tetrahedron Lett., 1997, 338, 5981). In an alternative approach, 3-aminoketones are converted to high stereo selectivity 1,3-disubstituted amino alcohols by selective hydride reduction (Barluenga et al., J. Org. Chem., 1992, 57, 1219).

All of the above methods can also be used to obtain the corresponding VZ, VW or V ² -Z ² annihilated chiral aminoalcohols. In addition, such optically pure amino alcohols are also a source for the preparation of optically pure diamines using the methods described in the previous section.

Section 4

The cleavage mechanism of the prodrug of cyclic 1,3-propanyl ethers

Cyclic 1,3-propanyl ester prodrugs are readily cleaved in the presence of rat and human liver microsomes by freshly isolated rat hepatocytes and cytochrome P450 inhibitors. It is believed that the cytochrome CYP3A4 isoenzyme is responsible for the oxidation caused by inhibition of ketoconosole drug formation. It turned out that inhibitors of family 1 of cytochrome P450 and / or family 2 do not inhibit the cleavage of the prodrug. In addition, although it was found that the specific prodrugs mentioned are cleaved by CYP3A4, other prodrugs in the group may be substrates for other P450s.

Although the effects of the cyclic 1,3-propanyl esters of the invention are generally not limited to the above mechanisms, each ester contains a group or atom sensitive to microsomal oxidation (e.g. alcohol, a benzyl methine proton), which in turn forms an intermediate, which is cleaved to the starting compound in an aqueous solution through ** - elimination of phosphonate or phosphoramidate diacid.

Class (1) prodrugs are readily oxidized by P450, since they have Z ′ = hydroxyl or hydroxyl equivalent with an adjacent (double) acidic proton. D 'means hydrogen, which allows ultimate elimination to form phenol.

Typically, class (2) contains V, which is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl. This class of prodrugs readily undergoes P450 oxidation at the proton of benzyl methine (a proton on carbon to which V is attached). In the case of 1-alkenyl and 1-alkynyl, the allyl proton behaves similarly. Hydrogen must be doubled with V to undergo the described oxidation mechanism. Since Z, W and W 'are not in the oxidation site in this class of prodrugs, a wide variety of substituents is possible. In one aspect, Z may be a donor group that can reduce the mutagenicity or toxicity of aryl vinyl ketone, which is a by-product of the oxidation of this class of prodrugs. Thus, in this aspect, Z is —OR ² , —SR ² or —NR ² ₂ .

In the class of prodrugs under consideration, V and W can be in the cis position relative to each other or trans relative to each other.

The mechanism of class (2) is usually characterized as an oxidizing mechanism for cyclic 1,3-propanyl ethers in which V and Z are joined together by an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, this cyclic group condenses with the group aryl in beta and gamma position Y adjacent to V.

Class (3) includes compounds in which Z ^{2 is} selected from the group consisting of —CHR ² OH, —CHR ² OC (O) R ³ , —CHR ² OS (S) R ³ , —CHR ² OC (S) OR ³ , -CHR ² OC (O) SR ³ , -CHR ² OCO ₂ R ³ , -SR ² , -CHR ² N ₃ , -CH ₂ -aryl, -CH (aryl) OH, -CH (CH = CR ² ₂ ) OH, -CH (C * CR ² ) OH and -CH ₂ NHaryl.

Class (3) prodrugs are readily oxidized by P450, since Z ² contains hydroxyl or a hydroxyl equivalent (e.g., —CHR ² OC (O) R ³ , —CHR ² N ₃ ) with an adjacent (double) acidic proton. Z ² groups can also easily undergo P450 oxidation, since they contain a benzyl methine proton or equivalent (for example, CH ₂ aryl, —CH (CH = CR ² ₂ ) OH). When Z ² is —SR ² , it is believed that it is oxidized to sulfoxide or sulfone, which will increase the beta elimination step. When Z ² is -CH ₂ NH-aryl carbon adjacent to nitrogen is oxidized to form gemiaminalya which is hydrolyzed to the aldehyde (-C (O) H), as shown above for class (3). Since V ² , W ² and W "are not in the oxidation site in the class of prodrugs in question, a wide variety of V ² , W ² and W" substituents are possible.

The mechanism of action of class (3) described above is usually characterized as an oxidizing mechanism for cyclic 1,3-propanyl ethers in which V ² and Z ^{2 are} joined together by additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally including 1 heteroatom substituted with hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to carbon, representing three atoms from two Y groups attached to phosphorus. Prodrugs of the class in question undergo P450 oxidation and are oxidized by a mechanism similar to the mechanism described above for class (3). A wide variety of groups W and W are suitable.

Cleavage can be carried out by the following mechanism. Further proof of the described mechanism was obtained by analyzing the splitting of by-products. The characterized Prodrugs of class (1) in which Y is —O— form phenol, while the considered Prodrugs of class (2) in which Y is —O— form phenyl vinyl ketone.

Cyclic phosphoramidates in which Y is nitrogen, rather than an oxygen-containing moiety, can serve as a prodrug, since intermediate phosphoramidates can form intermediate phosphonates or phosphoramidates using the same mechanism. Then phosphoramidate (-P (O) (NH ₂ ) O-) is converted to phosphonate (-PO ² ₃ -)

EXAMPLES

Unless otherwise indicated, all chemicals and reagents mentioned in the description, including these Examples, are mainly supplied by Aldrich Chemical Company; Milwaukee, WI.

Section 1

Example 1

Obtaining 5-diethylphosphono-2-furaldehyde (1).

Stage A. A solution of 2-furaldehyde diethyl acetal (1 mmol) in THF (tetrahydrofuran) was treated with nBULi (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.

Stage 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 described aldehyde can be obtained from furan, as described below.

Stage C. A solution of furan (1 mmol) in diethyl ether was treated with TMEDA (N, N, N'N'-tetramethylethylenediamine) (1 mmol) and nBuLi (2 mmol) at -78 ° C for 0.5 hour. Diethyl chlorophosphate (1.2 mmol) was added to the reaction mixture and stirred for another hour. Extraction and distillation gave diethyl 2-furanphosphonate as a clear oil.

Stage D. A solution of diethyl 2-furanphosphonate (1 mmol) in THF was treated with LDA (1.12 mmol, N, N, N-diisopropylamide lithium) at -78 ° C for 20 minutes. Methyl formate (1.5 mmol) was added and the reaction mixture was stirred for 1 hour. Extraction and chromatography gave compound 1 as a clear yellow oil. Preferably, this aldehyde can be prepared from 2-furaldehyde as described below.

Stage E. A solution of 2-furaldehyde (1 mmol) and N, N'-dimethylethylenediamine (1 mmol) in toluene was refluxed, while the resulting water was collected using a Dean-Stark trap. After 2 hours, the solvent was removed and the residue was distilled to obtain furan-2- (N, N '-dimethylimidazolidine) as a clear, colorless oil. Boiling point 59-61 ° C (3 mm Hg).

Stage 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 mixture was stirred at 0 ° C for 1.5 hours, and then cooled to -55 ° C and treated with a solution of 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 obtain 5-diethylphosphonofuran-2- (N, N'-dimethylimidazolidine) as a brown oil.

Stage G. A solution of 5-diethylphosphonofuran-2- (N, N'-dimethylimidazolidine) (1 mmol) in water was treated with concentrated sulfuric acid to 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

Stage A. A solution of furan (1.3 mmol) in toluene was treated with 4-methyl pentanoic acid (1 mmol), trifluoroacetic anhydride (1.2 mmol) and boron trifluoroideterate (0.1 mmol) at 56 ° C for 3.5 hours. The cooled reaction mixture was quenched with aqueous sodium bicarbonate (1.9 mmol), filtered through a pad of celite. Extraction, evaporation and distillation gave 2 - [(4-methyl-1-oxo) phenyl] furan as a brown oil (boiling point 65-77 ° C, 0.1 mm Hg).

Stage B. A solution of 2 - [(4-methyl-1-oxo) phenyl] furan (1 mmol) in benzene was treated with ethylene glycol (2.1 mmol) and p-toluenesulfonic acid (0.05 mmol) under reflux in for 60 hours, while the resulting water was removed using a Dean-Stark trap. Triethylorthoformate (0.6 mmol) was added and the resulting mixture was heated under 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 reaction mixture was stirred at -5-0 ° C for 1 hour. The resulting reaction mixture was cooled to −45 ° C. and transferred through a cannula into a solution of diethyl chlorophosphate in THF at −45 ° C. The reaction mixture was gradually heated to ambient temperature over 1.25 hours. Extraction and evaporation gave 2- [2- (5-diethylphosphono) furanyl] -2 - [(3-methyl) butyl] -1,3-dioxolane as a dark oil.

Stage 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) at 60 ° C for 18 hours. Extraction and distillation gave 5-diethylphosphono-2 - [(4-methyl-1-oxo) pentyl] furan (2.1) as a light orange oil (boiling point 152-156 ° C, 0.1 mm Hg).

The following compounds were obtained according to the described method:

(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, the compounds shown can be prepared using the following methods:

Stage E. A solution of 2 - [(4-methyl-1-oxo) pentyl] furan (1 mmol), obtained as in stage 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-dimethyl hydrazone was subjected to the methods of step C to obtain 2 - [(4-methyl-1-oxo) pentyl] -5-diethylphosphonofuran N, N-dimethylhydrazone in the form of a brown liquid, which was treated with copper (II) chloride (1.1 equivalent) in an ethanol-water mixture at 25 ° C for 6 hours. Extraction and distillation gave compound 2.1 as a pale orange oil.

Some of the 5-diethylphosphono-2 - [(1-oxo) alkyl] furans were prepared using the following methods:

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-diethidophosphono) furanyl) -1,3-dithian as a pale yellow oil.

A solution of 2- (2- (5-diethidophosphono) furanyl) -1,3-dithian (1 mmol) in THF was cooled to -78 ° C and treated with nBuLi (1.2 mmol). After 1 hour at -78 ° C, the reaction mixture was treated with cyclopropanemethyl bromide and the resulting reaction mixture was stirred at -78 ° C for another hour. Extraction and chromatography gave 2- (2- (5-diethylphosphono) furanyl) -2-cyclopropane-methyl-1,3-dithian as an oil.

A solution of 2- (2- (5-diethylphosphono) furanyl) -2-cyclopropanmethyl-1,3-dithian (1 mmol) in an acetonitrile-water mixture was treated with [bis (trifluoroacetoxy) iodine] benzene (2 mmol) at 25 ° C in within 24 hours. Extraction and chromatography gave 5-diethylphosphono-2- (2-cyclopropylacetyl) furan as a pale orange oil.

The following compounds were obtained according to the described method:

(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

Stage A. A solution of compound 2.1 (1 mmol) in ethanol was treated with copper (II) bromide (2.2 mmol) at the boil under reflux for 3 hours. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. 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.

Stage 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 under reflux for 2 hours. The cooled reaction mixture was evaporated to dryness and the resulting yellow foam was suspended in saturated sodium bicarbonate and water (pH = 8). The resulting yellow solid was collected by filtration to obtain 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 collected by filtration to obtain 2-amino-5-isobutyl-4- [2- (5-phosphono) furanyl] triazole (3.1) as an off-white solid. Melting point> 250 ° C. Analytical calculation 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.

In accordance with the methods described above or, in some cases, with small modifications of the methods described, using conventional chemical approaches, the following compounds were obtained:

(3.2) 2-Methyl-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole. Analytical calculation for C ₁₂ H ₁₆ NO ₄ PS + HBr + 0.1 CH ₂ Cl 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. Analytical calculation 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. Melting point 235-236 ° C. Analytical calculation for C ₈ H ₈ NO ₄ PS + 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. Analytical calculation 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.

(3.6) 2-Isobutyl-4- [2- (5-phosphono) furanyl] thiazole. Melting point 194-197 ° C. Analytical calculation 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. Melting point 164-166 ° C. Analytical calculation for C ₁₁ 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.

Melting point 189-191 ° C. Analytical calculation 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. Analytical calculation for C ₁₆ H ₂₃ N ₂ O ₄ PS + 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. Analytical calculation 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. Analytical calculation for C ₁₆ H ₁₇ N ₂ O ₄ 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-Acetamino-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole. Melting point 179-181 ° C. Analytical calculation for C ₁₃ H ₁₇ N ₂ O ₅ PS + 0.25 H ₂ O: 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. Analytical calculation 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. Melting point 202-205 ° C. Analytical calculation 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. Melting point 179-181 ° C. Analytical calculation for C ₁₂ H ₁₈ N ₃ O ₄ PS + 1.25 HBr: C: 33.33; H: 4.49; N, 9.72. Found: C: 33.46; H: 4.81; N: 9.72.

(3.16) 2-amino-5-methyl-4- [2- (5-phosphono) furanyl] thiazole.

Melting point 200-220 ° C. Analytical calculation 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. Melting point 195 ° C (decomposition). Analytical calculation for C ₉ H ₁₀ NO 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. Analytical calculation 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.

Melting point 163-165 ° C. Analytical calculation for C ₁₀ H ₁₀ NO ₆ PS + 0.5 H ₂ O: 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- (5-phosphono) furanyl] thiazole. Analytical calculation 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. Melting point> 250 ° C. Analytical calculation for C ₉ H ₁₁ 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. Melting point 204-206 ° C. Analytical calculation 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-phosphono) furanyl] thiazole. Melting point 177-182 ° C. Analytical calculation for C ₁₂ H ₁₆ N ₃ O ₄ PS + 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] thiazole.

Melting point 235-237 ° C. Analytical calculation 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. Melting point 248-250 ° C. Analytical calculation for C ₁₀ H ₁₁ N ₂ O 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.

Melting point 181-184 ° C. Analytical calculation for C ₈ H ₉ N ₂ O ₄ PS ₂ +0.4 H ₂ O: C: 32.08; H: 3.30; N: 9.35. Found: C: 32.09; H: 3.31; N: 9.15.

(3.27) 2-amino-5-cyclopropyl-4- [2- (5-phosphono) furanyl] thiazole. Analytical calculation 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; N: 7.34.

(3.28) 2-amino-5-methanesulfinyl-4- [2- (5-phosphono) furanyl] thiazole. Melting point> 250 ° C. Analytical calculation for C ₈ H ₉ N ₂ O ₅ 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. Analytical calculation for C ₁₅ H ₁₃ N ₂ O 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. Analytical calculation 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. Analytical calculation for G ₁₀ H ₁₁ N ₂ O ₄ PSBr + 0.73 HBr + 0.15 MeOH + 0.5 N 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. Analytical calculation for C ₁₀ H ₁₆ N ₃ O 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. Melting point 227 ° C (decomposition). Analytical calculation for C ₉ H ₉ N ₂ O ₆ PS + 0.1 H ₂ O + 0.2 HBr: C: 33.35; 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. Melting point 245 ° C (decomposition). Analytical calculation for C ₁₀ H ₁₁ N ₂ O ₅ PS ₂ : C: 35.93; H: 3.32; N: 8.38. Found: C: 35.98; H: 3.13; N: 8.17.

(3.35) 2-amino-5-propyloxycarbonyl-4- [2- (5-phosphono) -furanyl] thiazole. Melting point 245 ° C (decomposition). Analytical calculation 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. Analytical calculation for C ₁₄ H ₁₃ N ₂ O ₄ PS + H ₂ O: C: 47.46; H: 4.27; N: 7.91. Found: 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. Analytical calculation of C ₁₂ H ₂₀ 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. Analytical calculation for C ₁₀ H ₁₂ N ₃ O ₅ PS + 1.3 HBr + 1.0 H ₂ O +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. Analytical calculation for C ₈ H ₇ N ₂ O ₆ PS + 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. Melting point 240 ° C (decomposition). Analytical calculation for C ₁₁ H ₁₃ N ₂ O 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. Analytical calculation for G 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: 86; N: 3.69.

(3.42) 2-Methyl-5-cyclopropyl-4- [2- (5-phosphono) furanyl] thiazole. Analytical calculation for C ₁₁ H 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. Analytical calculation for C ₁₁ H ₁₂ NO 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. Analytical calculation 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. Analytical calculation for C ₁₂ H ₁₈ Br ₂ N ₃ O ₅ PS + 0.25 HBr: C: 27.33; H: 3.49; N: 7.97. Found: C: 27.55; H: 3.75; N: 7.62.

(3.46) 2-amino-5-cyclopropylmethoxycarbonyl-4- [2- (5-phosphono) furanyl] thiazole. Melting point 238 ° C (decomposition). Analytical calculation for C ₁₂ H ₁₃ N ₂ O ₆ PS: C: 41.86; H: 3.81; N: 8.14. Found: C: 41.69; H: 3.70; N: 8.01.

(3.47) Salt of 2-amino-5-methylthio-4- [2- (5-phosphono) furanyl] thiazole N, N-dicyclohexylammonium. Melting point> 250 ° C. Analytical calculation for C ₈ H ₉ N ₂ O ₄ PS + 1.15 C ₁₂ H ₂₃ N: C: 52.28; N:

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. Analytical calculation for C ₂₃ H ₂₆ N ₃ O ₆ PS ₂ +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. Analytical calculation for C ₉ H ₈ N ₂ F ₃ O 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- (5-phosphono) furanyl] thiazole. Analytical calculation 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] thiazolammonium salt. Analytical calculation for C ₈ H ₁₂ N ₃ O ₄ PS ₂ : 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. Analytical calculation 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. Analytical calculation 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. Analytical calculation for C ₁₂ H ₁₃ N ₂ O ₄ SP + 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. Analytical calculation for C ₁₀ H ₁₄ BrN ₂ O ₄ PS ₂ : 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. Analytical calculation for C ₁₃ H ₁₁ N ₂ O ₄ PS ₂ : C: 44.07; H: 3.13; N: .91. Found: C: 43.83; H: 3.07; N: 7.74.

(3.57) 2-amino-5-tert-butylthio-4- [2- (5-phosphono) furanyl] thiazole. Analytical calculation 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.

(3.58) Hydrobromide 2-amino-5-propiotio-4- [2- (5-phosphono) furanyl] thiazole. Analytical calculation for C ₁₀ H ₁₄ 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. Analytical calculation for C ₉ H ₁₁ N ₂ O ₄ PS 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. Analytical calculation for C ₁₄ H ₁₉ N ₂ O ₇ PS: C: 43.08; H: 4.91; N: 7.18. Found: C: 42.69; H: 4.58; N: 7.39.

(3.61) 2-Hydroxy-4- [2- (5-phosphono) furanyl] thiazole. Analytical calculation 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-Hydroxy-5-ethyl-4- [2- (5-phosphono) furanyl] thiazole. Analytical calculation 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-Hydroxy-5-isopropyl-4- [2- (5-phosphono) furanyl] thiazole. Analytical calculation 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-Hydroxy-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole. Analytical calculation 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. Analytical calculation for C ₁₀ H ₁₀ NO ₆ 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. Analytical calculation for C ₉ H ₉ N ₂ O ₄ PS + 0.2 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) furanyl] thiazole. Analytical calculation for C ₁₂ H ₁₆ NO ₄ PS ₂ : C: 43.24; 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. Analytical calculation 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- (5-phosphono) furanyl] selenazole. Analytical calculation for C ₁₁ H ₁₅ N ₂ O 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. Analytical calculation for C ₈ H ₉ N ₂ O ₄ PSSe + 0.7 HBr + 0.2 EtOAc: C: 25.57; 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. Analytical calculation for C ₉ H ₁₁ N ₂ O4Pse + 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

Stage A. A solution of 2-bromo-5-isobutyl-4- [2- (5-diethylphosphono) -furanyl] thiazole (1 mmol obtained by processing a solution of 2-amino-5-isobutyl-4- [2- (5-diethylphosphono ) furanyl] thiazole (obtained as described for stage B of example 3) (1 mmol) in acetonitrile with copper (II) bromide (1.2 mmol) and isoamyl nitrite (1.2 mmol) at 0 ° C for 1 hour, followed by extraction and chromatography to obtain a brown solid) in DMF, treated with tributyl (vinyl) tin (5 mmol) and bis (triphenylphosphine) palladium dichloride (0.05 mmol) at 100 ° C under nitrogen atmosphere. After 5 hours, the cooled reaction mixture was evaporated 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-5-isobutyl-4- [2- (5-diethylphosphono) furanyl) thiazole was subjected to the procedures of step C of Example 3 to obtain 2-vinyl-5-isobutyl-4- [2- (5- phosphono) furanyl] thiazole (4.1) as a yellow solid. Analytical calculation 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.

The described method can also be used to obtain 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 was subjected to the procedures of step A using 2-tributylstannylfuran as a partner in the coupling reaction to obtain 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 the procedures of step C of Example 3 to obtain 2-amino-5- (2-furanyl) - 4- [2- (5-phosphono) furanyl] thiazole (4.2). Melting point 190-210 ° C. Analytical calculation for C ₁₁ H ₉ N ₂ O ₅ PS + 0.25 HBr: C: 39.74; H: 2.80; N: 8.43. Found: C: 39.38; H: 2.92; N: 8.46.

The following compound was obtained in accordance with the described method:

(4.3) 2-amino-5- (2-thienyl) -4- [2- (5-diethylphosphono) furanyl] thiazole. Analytical calculation for C ₁₁ H ₉ N ₂ O ₄ PS ₂ +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) furayail] oxaaols and 4- [2- (5-phosphono) furanyl] imidazoles

Stage 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) under 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 the procedures of step C of example 3 to obtain 2-amino-5-isobutyl-4- [2- (5- phosphono) furanyl] oxazole (5.1). Melting point 250 ° C (decomposition). Analytical calculation 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 the procedures of step C of Example 3 to obtain 2-hydroxy-5-isobutyl-4- [2- (5-phosphono ) -furanyl] imidazole (5.14). Melting point 205 ° C (decomposition). Analytical calculation for C ₁₁ H ₁₅ N ₂ O ₅ P: C: 46.16; H: 5.28; N: 9.79. Found: C; 45.80; H: 4.90; N: 9.73.

Alternatively, 4- [2- (5-phosphono) furanyl] oxazole and 4- [2- (5-phosphono) furanyl] imidazole can be prepared as follows:

Stage 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 the procedures of step C of example 3 to obtain the following compounds:

(5.18) 2-Methyl-4-isobutyl-5- [2- (5-phosphono) furanyl] oxazole hydrobromide. Melting point> 230 ° C; analytical calculation 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 hydrobromide. Analytical calculation for C ₁₂ H ₁₇ 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 hydrobromide. Analytical calculation for C ₁₂ H ₁₈ BrN ₂ O ₄ P + 0.2 NH ₄ Br: C: 37.46; H: 4.93; N: 8.01. Found: C: 37.12; H: 5.11; N: 8.28.

Alternatively, 4- [2- (5-phosphono) furanyl] imidazoles can 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) furanyl] imidazole was treated according to the method of Step C of Example 3 to obtain 2-trifluoromethyl-4- [2- (5-phosphono) furanyl] imidazole (5.22). Melting point 188 ° C (decomposition); analytical calculation for C ₈ H ₆ F ₃ N ₂ O ₄ 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:

Stage N. A solution of 5-diethylphosphono-2-furaldehyde (1 mmol), ammonium acetate (1.4 mmol), 3,4-butanedione (3 mmol) and isobutylamine (3 mmol) in glacial acetic acid was heated at 100 ° C in within 24 hours. Evaporation and chromatography gave 4,5-dimethyl-1-isobutyl-2- [2- (5-diethylphosphono) furanyl] imidazole as a yellow solid.

Stage I. 4,5-Dimethyl-1-isobutyl-2- [2- (5-diethylphosphono) -furanyl] imidazole was subjected to the procedures of stage C of example 3 to obtain 4,5-dimethyl-1-isobutyl-2- [2 - (5-phosphono) furanyl] imidazole (5.23); analytical calculation 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.

In accordance with the methods described above or, in some cases, with small modifications of the described methods, the following compounds were obtained:

(5.2) 2-amino-5-propyl-4- [2- (5-phosphono) furanyl] oxazole. Melting point 250 ° C (decomposition); analytical calculation 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. Analytical calculation for C ₉ H ₁₁ N ₂ O ₅ P + 0.4 N 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-phosphono) furanyl] oxazole. Analytical calculation for C ₈ H ₉ N ₂ O ₅ P + 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. Analytical calculation 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 hydrobromide. Analytical calculation for C ₁₁ H ₁₆ N ₂ O ₅ BrP + 0.4 H ₂ O: C: 35.29; H: 4.52; N: 7.48. Found: C: 35.09; H: 4.21; N: 7.34.

Example 6

A. Obtaining various phosphoramides as prodrugs.

Step A. A suspension of 2-methyl-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole (1 mmol) in thionyl chloride (5 ml) was heated under reflux for 4 hours. The cooled reaction mixture was evaporated to dryness and the resulting yellow residue was dissolved in methylene chloride and treated with a solution of the corresponding benzyl alcohol (4 mmol) and pyridine (2.5 mmol) in methylene chloride. After stirring at 25 ° C. for 24 hours, the reaction mixture was extracted and chromatographed to obtain the title compound.

Step B. A solution of 2-methyl-5-isopropyl-4- [2- (5-phosphono) furanyl] thiazole dichloridate (prepared as described for 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 reaction solution was stirred at 0 ° C. for 1 hour, and then a solution of ammonia (excess) in THF was added. After stirring at room temperature for 16 hours, the reaction mixture was evaporated to dryness and the residue was purified by chromatography to give 2-methyl-5-isopropyl-4- [2- (5-phosphonomonoamido) furanyl] thiazole (6.1) as a yellow solid resin and 2-methyl-5-isopropyl-4- [2- (5-phosphorodiamido) furanyl] thiazole (6.2) as a yellow solid resin.

(6.1) 2-methyl-5-isopropyl-4- [2- (5-phosphonomonoamido) 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, to obtain other phosphoramides used a different method, which is shown as the following example:

Step C. A suspension of 2-amino-5-methylthio-4- [2- (5-phosphono) furanyl] thiazole dichloridate (prepared as described for Step A) (1 mmol) in dichloromethane (5 ml) was cooled to 0 ° C. and ammonia (excess) was bubbled through the reaction mixture for 10 minutes. After stirring at room temperature for 16 hours, 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 foam. Analytical calculation 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 methods described above or, in some cases, with minor modifications of the methods described:

(6.4) 2-amino-5-isobutyl-4- [2- (5-phosphonomonoamido) furanyl] thiazole. Melting point 77-81 ° C. Analytical calculation for C ₁₁ H ₁₆ N ₃ O ₃ PS + H ₂ O + 0.8 Et ₃ H: 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. Analytical calculation 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) phosphorodiamido] furanyl} thiazole. Melting point 182-183 ° C. Analytical calculation for C ₁₉ H ₃₃ N ₄ O ₄ 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- [5- (N, N '- (1,3-ethoxycarbonyl) -1-propyl) phosphorodiamido] furanyl} thiazole. Analytical calculation for C ₂₉ H ₄₅ 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. Analytical calculation for C ₃₁ H ₃₇ N ₄ 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. Analytical calculation 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.

(6.32) 2-amino-5-isobutyl-4- {2- [5- (M, N'-2- (1-ethoxycarbonyl) propyl) phosphorodiamido] furanyl} thiazole. Analytical calculation 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.

Monophenyl-monophosphonamide derivatives of the compounds of formula I can also be prepared in accordance with the methods described above:

Stage 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 N., 1 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 adding 6 N HCl. The resulting white solid was collected by filtration to obtain 2-amino-5-isobutyl-4- [2- (5-phenylphosphono) furanyl] thiazole.

Stage E. A suspension of 2-amino-5-isobutyl-4- [2- (5-phenylphosphono) furanyl] thiazole (1 mmol) in thionyl chloride (3 ml) was heated to boiling under 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 0 ° FROM. 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. Analytical calculation for C ₂₁ H ₂₆ N ₃ O 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 obtained in accordance with the methods described above:

(6.7) 2-amino-5-isobutyl-4- {2- [5- (0-phenylphosphonamido)] - furanyl} thiazole. Melting point 205 ° C (decomposition). Analytical calculation for C ₁₇ H ₂₀ N ₃ O ₃ PS + 0.3 H ₂ O + 0.3 HCl: C: 51.88; 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) phosphonamido] furanyl} thiazole. Analytical calculation 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-M-isobutyl) phosphonamido] furanyl} thiazole. Melting point 151-152 ° C. Analytical calculation 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. Analytical calculation for C ₂₈ H ₃₂ N ₃ O ₃ 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. Analytical calculation 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. Analytical calculation 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. Analytical calculation 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. Analytical calculation 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 (ethoxycarbonyl) methyl) phosphonamido)] furanyl} thiazole. Analytical calculation for C ₂₄ H ₃₀ N ₃ O ₇ PS: C: 53.83; 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. Analytical calculation 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-benzyl-hydroxycarbonyl) ethyl) phosphonamido)] furanyl} thiazole. Analytical calculation for C ₂₇ H ₃₀ N ₃ O ₅ PS: 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-benzyloxy-carbonylmethyl) phosphonamido)] furanyl} thiazole. Analytical calculation for C ₂₆ H ₂₈ N ₃ O ₅ 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. Analytical calculation for C ₂₂ 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-methoxy-carbonyl) propyl) phosphonamido)] furanyl} thiazole. Analytical calculation 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-ethoxy-carbonyl) phosphonamido)] furanyl} thiazole. Analytical calculation 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.

The reaction of dichlorophosphonate with 1-amino-3-propanol in the presence of a suitable base (e.g., pyridine, triethylamine) can also be used to produce cyclic phosphoramidates as phosphonate prodrugs. The following compounds were obtained by the indicated method.

(6.10) 2-Methyl-5-isobutyl-4- {2- [5- (1-phenyl-1,3-propyl) phosphonamido] furanyl} thiazole, minor isomer. Analytical calculation for C ₂₁ P 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 - !, 3-propyl) -phosphonamido] furanyl} thiazole, the main isomer. Analytical calculation for C ₂₁ H ₂₅ N ₂ O ₃ PS + 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, the main isomer. Analytical calculation 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. 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. Analytical calculation 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, a less polar isomer. Analytical calculation for C ₁₇ H ₁₈ N ₃ O ₃ PS ₂ +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) phosphonamido] furanyl} thiazole, the more polar isomer. Analytical calculation for C ₁₇ H ₁₈ N ₃ O ₃ PS ₂ : C: 50.11; H: 4.45; N: 10.31. Found: C: 49.84; 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. Analytical calculation for C ₁₈ H ₂₀ N ₃ O 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-1,3-propyl) -N-acetylphosphonamido] furanyl} thiazole. Analytical calculation for C ₂₂ H ₂₆ N ₃ O ₄ PS + 1.25 H ₂ O: C: 54.82; H: 5.96; N: 8.72. Found: C: 55.09; H: 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 , main isomer. Melting point 233-234 ° C. Analytical calculation for C ₂₁ H ₂₄ N ₃₀ 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 Calculation of C ₂₁ H ₂₄ N ₃₀ O ₅ PS + H: 462, 462 found.

(6.34) 2-amino-5-isobutyl-4- {2- [5- (3- (3,5-dichlorophenyl) -1,3-propyl) phosphonamido] furanyl} thiazole. Analytical calculation 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. Analytical calculation for C ₁₈ H ₂₀ N ₃ O ₃ PS + 0.7 H ₂ O: C: 53.78; H: 5.37; N: 10.45. Found: C: 53.63; H: 5.13; N: 10.36.

Section 2

The synthesis of compounds of formula X

Example 7

Preparation of 2-amino-4-phosphonomethyloxy-6-bromobenzothiazole

Stage 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 0-5 ° C for 2 hours. Evaporation and extraction gave 2-amino-4-hydroxybenzothiazole as a white solid.

Stage 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 minutes, and then treated with diethylphosphonomethyl trifluromethyl sulfonate (1.2 mmol ) After stirring at room temperature for 8 hours, the reaction mixture was extracted and chromatographed to obtain 2-amino-4-diethylphosphono-methoxybenzothiazole as an oil.

Stage 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 mixture was stirred at room temperature for 2.5 hours. The yellow precipitate was collected by filtration and washed with CH ₂ Cl ₂ to give 2-amino-4-diethylphosphonomethyloxy-6-bromobenzothiazole.

Stage D. A solution of 2-amino-4-diethylphosphonomethyloxy-6-bromobenzothiazole (1 mmol) in CH ₂ Cl ₂ (4 ml) was treated with TMSBr (10 mmol) at 0 ° C. After stirring for 8 hours at room temperature, the reaction mixture was evaporated to dryness and the residue was taken up in water (5 ml). The resulting precipitate was collected by filtration and washed with water to obtain 2-amino-4-phosphonomethyloxy-6-bromobenzothiazole (7.1) as a white solid. Melting point> 220 ° C (decomposition). Analytical calculation for C ₈ H ₈ N ₂ O ₄ PSBr: C: 28.34; H: 2.38; N: 8.26. Found: C: 28.32; H: 2.24; N: 8.06.

Similarly, the following compounds were obtained in accordance with the methods described above:

(7.2) 2-amino-4-phosphonomethyloxybenzothiazole. Melting point> 250 ° C. Analytical calculation for C ₈ H ₉ N ₂ O ₄ PS +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

Stage A. The solution of 1- (2-methoxy-5-chlorophenyl) -2-thiourea

(1 mmol) in chloroform (10 ml) was cooled to 10 ° C and treated with bromine (2.2 mmol) in chloroform (10 ml). The reaction mixture was stirred at 10 ° C. for 20 minutes and at room temperature for 0.5 hour. The resulting suspension was heated at reflux for 0.5 hours. The precipitate was collected by filtration (washed with CH ₂ Cl ₂ ) to obtain 2-amino-4-methoxy-7-chlorobenzothiazole, which was processed according to the methods of stages A, B, C and D of example 34 to obtain 2-amino-4-phosphonomethoxy- 6-bromo-7-chlorobenzothiazole (8.1). Melting point> 220 ° C (decomposition). Analytical calculation for C ₈ H ₇ N ₂ O ₄ PSClBr: C: 25.72; H: 1.89; N: 7.50. Found: C: 25.66; H: 1.67; N: 7.23.

Similarly, the following compounds were prepared according to the methods described above:

(8.2) 2-amino-4-phosphonomethoxy-6-bromo-7-methylbenzothiazole. Melting point> 220 ° C (decomposition). Analytical calculation for C ₉ H ₁₀ 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. Melting point> 220 ° C (decomposition). Analytical calculation for C ₉ H ₁₁ N ₂ O ₄ PS + 1.0 N ₁ 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. Melting point> 220 ° C (decomposition). Analytical calculation for C ₈ H ₈ N ₂ O ₄ PSCl +0.1 H ₂ O: C: 32.41; H: 2.79; N: 9.45. Found: C: 32.21; H: 2.74; N: 9.22.

Example 9

Preparation of 2-amino-7-ethyl-6-thiocyano-4-phosphonomethoxy-benzothiazole:

Stage A. A solution of 2-diethylphosphonomethyloxy-5-bromonitro-benzene (1 mmol, obtained as described in example 7, stage B) in DMF (5 ml) was treated with tributyl (vinyl) tin (1.2 mmol) and bis (triphenylphosphine ) -palladium dichloride (0.1 mmol) and the mixture was heated at 60 ° C in 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 a freshly prepared solution of methanol-HCl (10 ml) was added to a cold (0 ° C) solution of 2-diethylphosphonomethyloxy-5-vinyl nitrobenzene (1 mmol) in MeOH (5 ml). The mixture was warmed to room temperature and stirred for 3 hours. Evaporation, extraction and chromatography provided 2-diethylphosphonomethyloxy-5-vinylaniline.

A solution of KSCN (16 mmol) and CuSO ₄ (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 at reflux for 2 hours. Filtration, extraction and chromatography yielded a product that was subjected to the processing according to the method of step D of example 7 to obtain 2-amino-7-ethyl-6-thiocyano-4-phosphonomethoxybenzothiazole (9.1). Melting point> 167 ° C (decomposition). Analytical calculation 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

Obtaining various prodrugs of benzothiazoles.

Stage 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) and then 3 - (3,5-dichloro) phenyl-1,3-propanediol (1.1 mmol). The resulting mixture was heated at 80 ° C for 8 hours. Evaporation followed by column chromatography gave 2-amino-4 - {[3- (3,5-dichlorophenyl) propan-1,3-diyl] phosphonomethoxy} -5,6,7,8-tetrahydronaphtho [1,2-d] thiazole (10.1) as a solid. Melting point> 230 ° C. Analytical calculation for C ₂₁ H ₂₁ N ₂ O ₄ PSCl 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 (prepared as described for Step A of Example 6) (1 mmol) in dichloromethane (5 ml) was cooled to 0 ° C and was 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. After stirring at room temperature for 16 hours, the reaction mixture was evaporated to dryness and the residue was purified by chromatography to give 4-phosphonomonoamidomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d) thiazole.

Alternatively, to obtain other phosphoramides used another method, which is given as an example in the following method:

Step C. A suspension of 4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d) thiazole dichloridate (prepared as described for Step A of Example 6) (1 mmol) in dichloromethane (5 ml) was cooled to

0 ° C and ammonia (excess) was bubbled through the reaction mixture for 10 minutes. After stirring at room temperature for 16 hours, the reaction mixture was evaporated to dryness and the residue was purified by chromatography to give 4- (phosphorodiamido) methoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole.

Monophenyl-monophosphonamide derivatives of the compounds of formula X can also be prepared in accordance with the methods described above:

Stage 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 the pH of the solution was adjusted to 4 using 6 N. HCl. The resulting white solid was collected by filtration to obtain 4-phenylphosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole.

Stage E. A suspension of 4-phenylphosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole (1 mmol) in thionyl chloride (3 ml) was heated under 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 0 ° FROM. 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-5,6,1, 8-tetrahydro-naphtho [1,2-d] thiazole (1 mmol) in DMF was treated with N.N'-dicyclohexyl-4-morpholincarboxamidine (5 mmol) and ethylpropyloxycarbonyloxymethyl iodide (5 mmol), which was obtained from chloromethylchloroformate according to the described method (Nishimura 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-tetrahydronaphtho [1,2-d] thiazole also obtained by a similar method.

Example 11

A General Method for the Preparation of Bis-Phosphoroamide Prodrugs

Dichloridate formation

To a suspension of 1 mmol of phosphoric 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 heated under reflux for 2.5 hours. The solvent and excess thionyl chloride were removed under reduced pressure and dried to obtain a dichloridate.

Binding Reaction:

Method A: The crude dichloridate was placed in 5 ml of dry CH ₂ Cl ₂ and 8 mmol of amino acid ester was added at 0 ° C. The resulting mixture was left to reach room temperature, then was stirred for 16 hours. The reaction mixture was subjected to water treatment and chromatographic.

Method B: The crude dichloridate was placed in 5 ml of dry CH ₂ Cl ₂ and 4 mmol of amino acid ester and 4 mmol of N-methylimidazole were added at 0 ° C. The resulting mixture was left to reach room temperature, then was stirred for 16 hours. The reaction mixture was subjected to water treatment and chromatographic.

The following compounds were obtained in this way:

(11.1) 2-amino-5-isobutyl-4- [2- (5-N.N'-bis (L-glutamic acid diester) phosphonoamido) furanyl] thiazole. Analytical calculation for C ₂₉ H ₄₅ N ₄ O 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-alanine amino acid dibenzyl ester) phosphonoamido) furanyl] thiazole. Analytical calculation for C ₃₁ H ₃₇ N ₄ O ₆ PS: C: 59.60; H: 5.97; N: 8.97. Found: C: 59.27; H: 5.63; N: 8.74.

(11.3) 2-amino-5-isobutyl-4- {2- (5-N, N'-bis (benzyloxycarbonylmethyl) phosphonodiamido] furanyl} thiazole. Analytical calculation 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: 46.92; H: 5.00; N: 11.22.

(11.4) 2-amino-5-isobutyl-4- {2- (5-N, N'-bis (benzyloxycarbonylmethyl) phosphonodiamido] furanyl} thiazole. Analytical calculation for C ₂₉ H ₃₃ N ₄ O ₆ PS: C: 58 , 38; H: 5.57; N: 9.39. Found: C: 58.20; H: 5.26; N: 9.25.

(11.5) 2-amino-5-isobutyl-4- {2- (5-N, N'-bis (R) -1-methoxy-carbonyl) ethyl) phosphonamido] furanyl} thiazole. Analytical calculation for 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. Melting point 164-165 ° C. Analytical calculation 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. Analytical calculation for C ₂₃ H ₃₇ N ₄ O ₆ PS +0.15 CH ₂ Cl 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. Analytical calculation for C ₁₉ H ₂₉ N ₄ O ₆ PS + 0.1 EtOAc + 0.47 CH ₂ Cl 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. Melting point 142-145 ° C; analytical calculation for C ₂₃ H ₃₇ N ₄ O ₆ PS: C: 52.26; H: 7.06; N; 10.60. Found: C: 52.21; H: 6.93; N: 10.62.

(11.10) 2-amino-5-isobutyl-4- {2- (5-N, N'-bis (ethoxycarbonylmethyl) -N, N'-dimethylphosphonamido)] furanyl} thiazole. Analytical calculation for C ₂₁ H ₃₃ N ₄ O 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. Analytical calculation for C ₃₅ H ₄₅ N ₄ O _b PS +0.5 H ₂ O: C: 60.94; H: 6.72; N: 8.12. Found: C: 61.01; H: 6.48; N: 7.82.

(11.12) 2-amino-5-isobutyl-4- {2- (5-N, N'-bis ((S) -1-methoxycarbonyl-3-methyl) butyl) phosphonamido] furanyl} thiazole. Analytical calculation for C ₂₅ H ₄₁ N ₄ O ₆ PS: C: 53.94; H: 7.42; 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- (S-benzyl)) ethyl) phosphonamido] furanyl} thiazole. Analytical calculation for C ₃₅ H ₄₅ N ₄ O 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.

(11.14) 2-amino-5-isobutyl-4- {2- (5-N, N'-bis ((S) -1-ethoxycarbonyl-3- (S-methyl)) butyl) phosphonamido] furanyl} thiazole. Analytical calculation 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 '- (S) -ethoxycarbonyl) ethyl) phosphonamido] furanyl} thiazole. Analytical calculation for C ₂₀ H ₃₁ N ₄ O ₆ PS ₂ : C: 46.32; H: 6.03; N: 10.80. Found: C: 46.52; H: 6.18; N: 10.44.

(11.16) 2-amino-5-isobutyl-4- {2- (5-N, N'-bis (S) -1-benzyloxycarbonyl-2-methyl) isobutyl) phosphonamido] furanyl} thiazole. Analytical calculation for C ₃₇ H ₄₉ N ₄ O ₆ PS: C: 62.69; H: 6.97; N: 7.90. Found: C: 62.85; H: 7.06; N: 7.81.

(11.17) 2-amino-5-isobutyl-4- {2- (5-N, N'-bis (S) -1-ethoxycarbonyl-3-methyl) butyl) phosphonamido] furanyl} thiazole. Analytical calculation 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-ethoxy-carbonyl-2-methyl) propyl) phosphonamido] furanyl} thiazole. Analytical calculation 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. Analytical calculation for C ₃₃ H ₄₁ N ₄ O ₆ PS + 0.15 CH ₂ Cl ₂ : C: 59.83; H: 6.28; N: 8.42. Found: C: 59.88; H: 6.28; N: 8.32.

(11.20) 2-amino-5-propylthio-4- {2- (5-N, N '- (1-methyl-1-ethoxy-carbonyl) ethyl) phosphonamido] furanyl} thiazole. Melting point 110-115 ° C; Analytical calculation 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. Found: C: 48.38; H: 6.60; N: 8.98.

(11.21) 2-amino-5-methylthio-4- {2- (5-N, N'-bis (1-methyl -! - ethoxycarbonyl) ethyl) phosphonamido] furanyl} thiazole. Analytical calculation for C ₂₀ H ₃₁ N ₄ O ₆ 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 method. A suspension of compound 3.1 (1 mmol), oxalyl chloride (3.2 mmol) and DMF (1.1 mmol) in anhydrous toluene was heated under reflux to a boiling point 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. Then the mixture was stirred at 0 ° C for 2 hours and 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 under reflux to boiling point for 16 hours.

Extraction and crystallization gave compound 11.6 as an off-white solid

Example 12

General Method for Mixed Bis-Phosphoamidate Prodrugs

To a solution of the crude dichloridate (1 mmol obtained as described in Example 40) in 5 ml of dry CH ₂ Cl _{2 was} added an amine (1 mmol) followed by 4-dimethylaminopyridine (3 mmol) at 0 ° C. The resulting mixture was allowed to warm to room temperature and was stirred for 1 hour. Before adding the amino acid ester (2 mmol), the reaction mixture was again cooled to 0 ° C and left at room temperature for 16 hours. The reaction mixture was subjected to water treatment and the mixed bisphosphoroamidate prodrug was purified by column chromatography.

The following compounds were prepared as described.

(12.1) 2-amino-5-isobutyl-4- {2- [5- (N-morpholino-N '- (1-methyl-1-ethoxycarbonyl) ethyl) phosphonamido] furanyl} thiazole. Melting point 182-183 ° C; analytical calculation for C ₂₁ H ₃₃ N ₄ O ₅ PS C: 52.05; H: 6.68; 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. Melting point 189-190 ° C; analytical calculation 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.

The synthesis of compounds of formula VII

Example 13

Obtaining 5- (3,5-dinitrophenyl) -2-furanphosphonic acid (compound No. 13.01)

1) A solution of furan (1 mmol) in 1 ml of 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 introduced through a cannula into a solution of diethyl chlorophosphate (1.33 mmol) in 1 ml of diethyl ether at -60 ° C and the reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. Extraction and distillation at 75 ° C / 0.2 mm gave diethyl 2-furanphosphonate as a clear oil.

2) A solution of diethyl 2-furanphosphonate (1 mmol) in 2 ml of THF was cooled to -78 ° C and added to a solution of lithium diisopropylamide (LDA) (1 mmol) in 5 ml of THF at -78 ° C for 20 minutes. The resulting mixture was stirred at -78 ° C for 20 minutes and added to a solution of tributyltin chloride (1 mmol) in 1 ml THF at -78 ° C for 20 minutes. Then the mixture was stirred at -78 ° C for 15 minutes and at 25 ° C for 1 hour. Extraction and chromatography afforded diethyl 5-tributylstannyl-2-furanphosphonate as a colorless oil.

3) A mixture of diethyl 5-tributylstannyl-2-furanphosphonate (1 mmol), 1-iodo-2,4-dinitrobenzene (1 mmol) and tetrakis- (triphenylphosphine) -palladium (0) (0.05 mmol) in 6 ml dioxane was heated at 80 ° C for 16 hours. Evaporation of the solvent and chromatography provided diethyl 5- (3,5-dinitrophenyl) -2-furanphosphonate as a foamy solid.

4) A mixture of diethyl 5- (3,5-dinitrophenyl) -2-furanphosphonate (1 mmol) and TMSBr (6 mmol) in 10 ml of CH ₂ Cl _{2 was} stirred at room temperature for 16 hours and then evaporated. The residue was dissolved in a mixture of 85/15 CH ₃ CN / water, and then the solvent was evaporated. The residue was suspended in CH ₂ Cl ₂ and the title compound (No. 13.01) was collected as a pale yellow solid: HPLC R _t (retention time) = 5.30 minutes; when MS M-1 with electrospray with a negative ion was found: 313.

The following reagents were used in reactions with diethyl 5-tributylstannyl-2-furanphosphonate and converted into the corresponding compounds of the examples (indicated in parentheses) in steps C and D as described in Example 13: 2-bromo-4,6-dinitroaniline (for 13.02); chloro-2-iodanisole (for 13.03); 2,5-dichloro-1-iodobenzene (for 13.04); N ¹ -methyl-2-iodo-4- (trifluoromethyl) benzene-1-sulfonamide (for 13.05); N ¹ -methyl-4-chloro-2-iodobenzene-1-sulfonamide (for 13.06); N ¹ -methyl-2-iodobenzene-1-sulfonamide (for 13.07); N ¹ -methyl-4-chloro-2-iodobenzene-1-sulfonamide (for 13.08); 2-iodophenol (for 13.09); 5-iodo-m-xylene (for 13.10); 1-bromo-3-iodobenzene (for 13.11); 4-iodaniline (for 13.12); 2,5-dimethoxy-4-iodochlorobenzene (for 13.13); N ¹ - (4-chlorobenzyl) -2-iodobenzamide (for 13.14); N ¹ - (4-chlorophenethyl) -2-iodobenzamide (for 13.15); N ^1- benzyl-2-iodobenzene-1-sulfonamide (for 13.16); 2-iodobenzenesulfonamide (for 13.17); 1-iodo-2,3,4,5,6-pentamethylbenzene (for 13.18); 3-iodophthalic acid (iodoethane and diisopropylamine were included in step C for 13.19); 4-iodo-2-methylacetanilide (for 13.20); 3,5-dichloro-2-iodotoluene (for 13.21); methyl 5-hydroxy-2-iodobenzoate (for 13.22); 2-iodo-5-methylbenzamide (for 13.23); 5-hydroxy-2-iodobenzoic acid (iodoethane and diisopropylamine were included in step C for 13.24); 1-iodo-4-nitrobeneol (for 13.25); N1- (2,4-difluorophenyl) -2-iodobenzamide (for 13.26); 3,5-dichloro ~ 1-iodobenzene (13.27); 3-iodophenol (for 13.28); 3-bromo-5-iodobenzoic acid (for 13.29); 3-iodo-4,5-dimethoxybenzaldehyde (for 13.30); 1-iodo-2-nitrobenzene (for 13.31); 2-iodobiphenyl (for 13.32); 2-iodobenzoic acid (iodoethane and diisopropylamine were included in stage C for 13.33); 1-bromo-4-iodobenzene (for 13.34); 3'-bromopropiophenone (for 13.35); Z-bromo-4-methoxybenzonitrile (for 13.36); 1-ethyl-2-iodobenzene (for 13.37); 2-bromo-3-nitrotoluene (for 13.38); 4-iodoacetamide (for 13.39); 2,3,4,5-tetramethyliodobenzene (for 13.40); 3-bromobiphenyl (for 13.41); 4-chloro-2-iodobenzenesulfonamide (for 13.42); N1- (4-iodophenyl) -2-tetrahydro-1H-pyrrole-1ylacetamide (for 13.43); 3,4-dimethyliodobenzene (for 13.44); 2,4-dinitroiodobenzene (for 13.45); 3-iodobenzylamine (for 13.46); 2-fluoro-4-iodaniline (for 13.47); 3-iodobenzyl alcohol (for 13.48); 2-bromo-1-iodobenzene (for 13.49); 2-bromophenethyl alcohol (for 13.50); 4-iodobenzamide (for 13.51); 4-bromobenzonitrile (for 13.52); 3-bromobenzonitrile (for 13.53); 2-bromobenzonitrile (for 13.54); 4-bromo-2-nitroaniline (for 13.55); 2-iodisopropylbenzene (for 13.56); 6-amino-2-chloro-3-bromopyridine (obtained by reacting 6-amino-2-chlorobeneol (1 mmol) with bromine (1 mmol) in acetic acid (4 ml) for 2 hours at room temperature, followed by evaporation and chromatography to obtain 6-amino-2-chloro-3-bromopyridine) (for 13.57); 3-bromo-4-methylthiophene (for 13.58); 2-bromo-4-chloroaniline (for 13.59); 1-bromo-3-chloro-5-fluoroaniline (for 13.60); 2-bromo-4-cyanoanisole (for 13.61); 2-bromo-4-nitrotoluene (for 13.62); 3-nitro-5-fluoro-1-iodobenzene (for 13.63); 2-iodo-4-carbomethoxyaniline (for 13.64); 2-bromo-4-nitroanisole (for 13.65); 2-chloro-1-iodo-5-trifluoromethyl-benzene (for 13.66) and 1-bromo-2,5-bis- (trifluoromethyl) benzene (for 13.67).

Example 14

Preparation of 5- (4-fluorophenyl) -2-furanphosphonic acid (Compound No. 14.01).

1) A solution of diethyl 2-furanphosphonate (prepared as described for Step A, Example 13) (1 mmol) in 2 ml THF was cooled to -78 ° C and added to a solution of lithium isopropylcyclohexylamide (LICA) (1 mmol) in 2 ml THF at -78 ° C for 20 minutes. The resulting mixture was stirred at -78 ° C for 20 minutes and added to a solution of iodine (1 mmol) in 1 ml of THF at -78 ° C for 20 minutes. Then the mixture was stirred at -78 ° C for 20 minutes. Extraction and chromatography provided 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 (DISA) (4 mmol) and bis (acetonitrile) dichloropalladium (II) (0.05 mmol) 6 ml of DMF was heated at 75 ° C for 16 hours. Extraction and chromatography provided diethyl 5- (4-fluorophenyl) -2-furanphosphonate as an oil.

Application of the method of Step D, Example 13, to this material provided the title compound (No. 14.01) as a white solid. HPLC Rt = 5.09 minutes; when MS M-1 with elektrosprey negative ion found: 241.

Substitution of 2,4-dichlorophenylboronic acid in the described method provided compound No. 14.02. Substitution of 3-amino-5-carbomethoxyphenylboronic acid in the described method provided compound No. 14.03.

Example 15

Preparation of 5- (4-Bromo-3-aminophenyl) -2-furanphosphonic acid (Compound No. 15.01).

The reaction of 3-aminophenylboronic acid hydrochloride with diethyl 5-iodo-2-furanphosphonate, which is described in step B of Example 14, provides diethyl-5- (3-aminophenyl) -2-furanphosphonate as an oil.

A mixture of diethyl 5- (3-aminophenyl) -2-furanphosphonate (1 mmol), NBS (0.9 mmol) and AIBN (0.1 mmol) in 30 ml of CCl _{4 was} stirred at room temperature for 2 hours. Extraction and chromatography provided diethyl 5- (4-bromo-3-aminophenyl) -2-furansulfonate as an oil.

Application of the methods of step D, Example 13, to this material provided the title compound (No. 15.01) as a white solid. HPLC R _t = 4.72 min; when MS M-1 with elektrosprey with a negative ion found: 316/318.

BIOLOGICAL EXAMPLES

The following examples can be used to identify compounds that: 1) inhibit FBPase and gluconeogenesis in cellular and animal models of diabetes; or 2) increase insulin sensitivity in cell cultures and animal models of diabetes; or 3) exhibit higher pharmacological activity in the form of combinations of FBPase inhibitors and insulin secretion enhancing agents compared to any single agent.

In some Biological examples, the following compounds AK were used, which are:

Compound F was obtained in Example 5.6, compound G was obtained in Example 3.26, compound H was obtained in example 3.69, compound I was obtained in example 3.58, compound J was obtained in example 11.6, and compound K was obtained in example 11.2.

Example A: Inhibition of human liver FBPs

The E. coli strain BL21, transformed with a plasmid encoding human liver FBPase, was obtained from Dr. MR El-Maghrabi, State University of New York at Stony Brook. HlFBPase was usually purified from 10 liters of E. coli culture as described by Gidh-Jain et al., J. Biol. Chem. 269, 27732-27738 (1994). Enzymatic activity was measured spectrophotometrically in reactions in which the formation of the product (fructose-6-phosphate) was associated with the reduction of dimethylthiazole diphenyltetrazolium bromide (MTT) using NADP and phenazine methosulfate (PMS) using glucose phosphate isomerase and glucose-phosphate-glucose binding enzymes. Reaction mixtures (200 μl) were prepared in 96-well microtiter plates 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 BSA, 1 mM MTT, 0.6 mM PMS, 1 unit / ml glucose-phosphate isomerase, 2 units / ml glucose-6-phosphate dehydrogenase and 0.150 mm substrate (fructose-1,6-bisphosphate). Inhibitor concentrations ranged from 0.01 μM to 10 μM. Reactions were initiated by the addition of 0.002 units of pure HlFBPase and recorded for 7 minutes at 590 nm in a molecular reader plate (37 ° C).

The effectiveness of the selected compounds against FBP-basics of human liver are presented in table 1 below:

Table 1 Compound IC ₅₀ μm AMF 1.3 E 0,055 D 1,0

AT 5,0 FROM thirty F 0.12 G 0.015 N 0,025 I 0.018

Example B: Inhibition of rat liver and mouse liver FBPs

Strain BL21 of E. coli transformed with a plasmid encoding human liver FBPase was obtained from Dr. MR El-Maghrabi, University of New York at Stone Brook, and purified as described (El-Maghrabi, MR, and Pilkis, SJ (1991) Biochem. Biophys. Res. Commun. 176: 137-144). Mouse liver FBPase was obtained by homogenizing fresh isolated mouse liver in 100 mM Tris-HCl buffer, pH 7.4, containing 1 mM EGTA and 10% glycerol. The homogenate was clarified by centrifugation and a fraction precipitated with ammonium sulfate was obtained at 45-75% saturation. The resulting fraction was redissolved in a homogenization buffer and desalted by gel filtration on a PD-10 column (Biorad), eluting with the same buffer. The obtained partially purified fraction was used for enzyme studies. FBPase from both rat liver and mouse liver was analyzed as described for FBPase from the human liver in Example A. In general, enzymes from rat liver and mouse are less sensitive to inhibition by the test compounds than the enzyme from human liver, which is reflected at higher values of IC ₅₀ .

In the following table 2, the IC ₅₀ values for some compounds obtained in the examples are presented:

table 2 Compound IC ₅₀ Rat Liver (μM) IC ₅₀ Mouse Liver (μM) AMF 25 fifteen AT 140 33 D 1.25 55 FROM > 100 > 100 E 0.4 1,1 F 2.0 G 0.25 N 0.175 I 0.05

Example C: Inhibition of gluconeogenesis by an FBPase inhibitor in rat hepatocytes

Hepatocytes were obtained from fed Sprague-Dawley rats (250-300 g) according to the method of Berry and Friend (Berry, MH, Friend, DS, 1969, J. Cell. Biol. 43,506-520) in the modification of Groen (Groen, A.K. , Sips, HJ, Vervoorn, RC, Tager, JM, 1982, Eur. J. Biochem. 122, 87-93). Hepatocytes (75 mg wet weight / ml) were incubated in 1 ml of Krebs bicarbonate buffer containing 10 mm lactate, 1 mm pyruvate, 1 mg / ml BSA and the concentration of test compounds from 0 to 500 μm. Incubation was carried out in an atmosphere of 95% oxygen, 5% carbon dioxide in closed 50-ml Falcon tubes, immersed in a rapidly shaking water bath (37 ° C). After 1 hour, aliquots (0.25 ml) were taken, transferred to Eppendorf tubes and centrifuged. Then, glucose was examined in 50 μl of the supernatant using the glucose oxidase kit, Sigma, according to the manufacturer's instructions.

The following table 3 presents the IC ₅₀ values for some of the compounds obtained in the examples:

Table 3 Compound IC ₅₀ (μm) Compound A fifty Compound D 4,5 Compound E 2,5 Compound C > 100 Compound F fifteen Compound G 10 Compound H 2,5 Compound I 2.0 Compound J 2.0 Compound K 2.1

FBPase from rat liver turned out to be less sensitive to AMP than the enzyme from human liver. IC ₅₀ values in rat hepatocytes are therefore higher than expected in human hepatocytes.

It turned out to be especially advisable to test the compounds of formula I on hepatocytes, such as those described in examples C and D, since the compounds are phosphorylated by hepatocytes and, therefore, become FBPase inhibitors.

Example D: Inhibition of glucose production and increased levels of fructoeo-1,6-bisphosphate in rat hepatocytes treated with FBPase inhibitors.

Rat hepatocytes were isolated and incubated as described in example C. The glucose content was analyzed in cell extracts as described in example C, as well as the content of fructose-1,6-bisphosphate. Fructose-1,6-bisphosphate was determined spectrophotometrically, linking its enzymatic conversion to glocerol-3-phosphate with NADH oxidation, which was recorded at 340 nm.

The reaction mixtures (1 ml) consisted of 200 mM Tris-HCl, pH 7.4, 0.3 mM NADH, 2 units / ml glycerol-3-phosphate dehydrogenase, 2 units / ml triose phosphate isomerase and 50-100 μl cell extract. After 30 minutes of incubation at 37 ° C, 1 unit / ml aldolase was added and the change in optical density was measured until a stable value was obtained. 2 mol of NADH was oxidized in the described reaction to a mole of fructose-1,6-bisphosphate present in the cell extract.

Compound A and compound E inhibited glucose production in a dose-dependent manner with IC ₅₀ 50 and 2.5 μM, respectively. A dose-dependent increase in intracellular fructose 1,6-bisphosphate consistent with inhibition of FBPase was observed for both compounds.

Example E: Analysis of drug and plasma metabolite levels in the liver and plasma, blood glucose, and 1,6-bisphosphate fructose levels in the liver after oral administration of Compound A to normal rats.

Compound A was administered orally through a probe to Sprague-Dawley rats (250-300 g) under free feeding. The compound was prepared as a suspension in carboxymethyl cellulose and administered at a dose of 250 mg / kg. To determine hepatic metabolites, rats were sterilely killed within 24 hours after drug administration. The liver was fixed by freezing, homogenized in perchloric acid, neutrolized, and then analyzed relative to compound B using anion exchange HPLC.

To determine plasma metabolites, rats were catheterized into the carotid artery prior to oral administration of the compound. Blood samples were taken through a catheter at appropriate time points over a period of 8 hours after drug administration. Plasma was obtained from blood samples by centrifugation, and plasma proteins were precipitated by the addition of methanol to 60%. The metabolites of compound A were quantified by RP-HPLC in deproteinized plasma samples. Column C18 (1.4 cm x 250 mm) was equilibrated with 10 mM sodium phosphate, pH 5.5, and eluted with a gradient of the indicated buffer in acetonitrile. The measurement was carried out at 254 nm.

The effect of Compound A on blood glucose and fructose 1,6-phosphate levels in the liver was determined in Sprague-Dawley rats (250-300 g), starving for 18 hours. The compound was dosed to the animals as described above. At appropriate time points after drug administration, rats were anesthetized with halothane and a liver biopsy was performed (approximately 1 g), as well as a blood sample (2 ml) from the posterior vena cava. A heparin-washed syringe and needles were used to collect blood. Liver samples were immediately homogenized in ice-cold 10% perchloric acid (3 ml), centrifuged, and the supernatant was neutrolized 1/3 of a volume of 3 M KOH / 3 M KH ₂ CO ₃ . After centrifugation and filtration, the fructose 1,6-bisphosphate was analyzed in a neutrolized extract as described for isolated hepatocytes in Example C. Blood glucose was determined using a Hemocue analyzer (Hemocue Inc., Mission Viejo, CA).

Analysis of hepatic metabolites has shown that compound A is effectively converted to compound B at levels of the latter in the liver, reaching 3 μmol / g for 1 hour. Although levels slowly decreased over time, Compound B was determined to a final time point of 24 hours. In plasma, 5-bromo-1-pD-ribofuranosyl-imidazole-carboxamide was determined rather than compound A, suggesting that compound A was rapidly deacetylated in all three positions.

A single dose of 250 mg / kg of compound A significantly reduced blood glucose levels for approximately 8 hours, the time by which the levels in the treated animals slowly returned to the levels of the controls that received the vehicle. Drug treatment led to increased levels of fructose 1,6-bisphosphate in the liver. The time period for an increase in this gluconeogenesis intermediate correlated well with the time period for a decrease in glucose. The peak of the increase in the intermediate was observed close to the maximum decrease in glucose, as well as the ricocheted blood glucose levels, the fructose levels of 1,6-bisphosphate were slowly returning to normal. Recent observations are consistent with inhibition of gluconeogenesis by compound A at the level of fructose-1,6-bisphosphatase.

Example F: Analysis of drug levels in the liver and plasma after administration of compounds D, E, F, and G intraperitoneally to normal starving rats.

Sprague-Dawley rats (250-300 g) were kept hungry for 18 hours, and then a dose of either saline or an FBPase inhibitor was administered intraperitoneally. The excipient used during drug administration was 10 mM bicarbonate. One hour after the injection, the rats were anesthetized with halothane, liver and blood samples were taken and processed as described in Example E. In neutralized liver extracts, the content of the FBPase inhibitor was examined by HPLC. A YMC ODS AQ reverse phase column (250 x 4.6 cm) was used and was eluted with a gradient of 10 mM sodium phosphate pH 5.5 to 75% acetonitrile. The optical density was recorded at 310 nm. Glucose was determined in blood samples as described in Example C. Plasma was obtained by centrifugation and extracted with methanol to 60% (v / v). The methanol extract was clarified by centrifugation and filtration, and then analyzed by HPLC as described above.

The results for the selected compounds obtained in the examples are presented in table 4 below.

Table 4 Compound Decrease in glucose,% Conc. in plasma (μM) Conc. in the liver (nmol / g) D 31 8.8 27,2 E 44,4 79.2 38,4 F 51 eighteen 35 G 73 56.1

Example G: Determination of the oral bioavailability of compounds G, H, I and J and the oral glucose-lowering activity of compounds G and J

The oral bioavailability of prodrugs and parent compounds was determined in rats by urine determination. Prodrugs were dissolved in a mixture of 10% ethanol / 90% polyethylene glycol (molar mass 400) and administered orally through a probe in doses of 10 to 40 mg / kg equivalents of the starting compound to Sprague-Dawley rats (220-240 g) starving 6 hours. The starting compounds were usually dissolved in deionized water, neutralized with sodium hydroxide, and then administered orally at a dose of 10-40 mg / kg or intravenously ~ 10 mg / kg.

Subsequently, rats were placed in metabolic cells and urine was collected within 24 hours. The amount of the parent compound excreted in the urine was determined by HPLC analysis as described in Example F. The analysis was performed as described in Example F. For prodrugs, the percentage of oral bioavailability was estimated by comparing the excretion of the parent compound formed from the oral prodrug into the urine. with excretion in urine after intravenous administration of the corresponding starting compound. For parent compounds, the percentage of oral bioavailability was assessed by comparing the urinary excretion of the parent compound when administered orally with the amount excreted when administered intravenously.

The calculated% oral bioavailability of selected prodrugs and starting compounds is presented below.

Table 5A Compound Oral bioavailability,% G eighteen N four I 5 J 21

The oral efficacy of compound J was evaluated in Sprague-Dawley rats starving all night. Compound G or J was administered orally through a tube in suspension in 0.1% carboxymethyl cellulose at a concentration of 0, 10 or 30 mg / kg. 1.5 hours or 4 hours after administration, blood samples were taken from the tail vein and blood glucose was examined using an automatic glucose analyzer (HemoCue, HemoCue Inc, Mission Viejo, CA). The following results were obtained:

Table 5B Decrease in glucose,% Dose mg / kg Compound G (4 hours) Compound J (1.5 hours) 0 0 0 10 48 66% thirty > 70 85%

Example H: Insulin secretion from pancreatic islets (insulin secretion enhancing agents)

Pancreatic islets were isolated from healthy and diabetic rats or healthy or diabetic mice by collagenase treatment. The islands were used either immediately after preparation or were 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 ranging from 0 to 100 micromoles. Insulin secretion from fresh single islets was determined using a perfusion microsystem [(Bergsten P and Hellman In Diabetes 42; 670-674 (1993)], and from cultured islets was determined as described by Frodin et al., J. Biol. Chem. 270, 7882-7889 (1995). Insulin was determined by radioimmunoassay using, for example, Amerlex (Amersham Life Science) magnetic separation of insulin or rat or mouse, respectively. Preferred insulin secretion enhancing agents used in the invention increased insulin release during physiological glucose levels by at least 20% and preferably more than 100% in concentrations of <10 micromoles, preferably <1 micromoles.

Example I: Decrease in glucose in hungry rats (glucose secretion enhancing agents)

Adult Sprague-Dawley or Wistar rats (200-220 g) were fed, as desired, standard rat food and provided a 12/12 hour light / dark cycle (light from 7 am to 7 pm). Feeding was stopped 24 hours before the start of the studies, which were usually carried out starting at 8 a.m. The compounds were suspended in methylcellulose or another excipient and administered orally through a tube. Blood samples were taken from conscious animals during drug administration and from then on hourly through an incision in the tail vein. Blood glucose was tested using standard manual and automatic methods. The maximum percentage reduction in blood glucose observed within 4 hours is an indicator of the activity of a blood glucose lowering compound. The ED ₅₀ values for the active compounds were calculated and determined as the dose that causes the half-maximal effect of the compound. Statistical significance was evaluated using Student's test. The preferred insulin secretion enhancers used in the invention had an ED ₅₀ <30 mg / kg (preferably <5 mg / kg) and reduced blood glucose by more than 10% at a dose of ED ₅₀ .

Typical research results are presented below (Grell W. et al., J. Med. Chem. 41: 5219-5246 (1998):

Table 6

Dose Decrease in glucose,% ED ₅₀ mg / kg Glibenclamide 0.3 -25 0.255 (2 hours) Glimepiride 0.1 -eighteen 0.182 (2 hours) Repaglinide 0.01 -21 0.01 (2 hours)

Example J: Intravenous glucose tolerance in fasting rats (insulin secretion enhancing agent)

Adult Sprague-Dawley or Wistar rats (200-220 g) were fed, as desired, standard rat food and provided a 12/12 hour light / dark cycle (light from 7 am to 7 pm). Feeding was stopped 24 hours before the start of the studies, which were usually carried out starting at 8 a.m. Rats were anesthetized with intraperitoneal administration of sodium pentobarbital (60 mg / kg) and anesthesia was maintained with additional doses (15 mg / kg), if necessary. Cannulas were inserted into the right jugular vein to administer the drug and into the left carotid artery to take blood samples. Rats received an intravenous glucose bolus (0.5 g / kg in 20% w / v solution) with and without test compound (0-100 mg / kg). Blood samples were taken immediately before glucose / compound administration and 2, 5, 10, 20, 30, 40, and 60 minutes after administration. Blood glucose was determined by standard manual or automated methods. Preferred insulin secretion enhancing agents used in the invention reduced blood glucose AUC by time by more than 5%.

Example K: Oral glucose tolerance in obese rats with diabetes mellitus (insulin secretion enhancing agent)

Obese rats with diabetes mellitus (9.5 weeks old) were starving for 6 hours starting at 8 a.m. Glucose (1g / kg) and the test compound (0.01-100 mg / kg) were simultaneously administered orally through a tube. Control animals were given only glucose. Blood samples were taken through an incision in the tail vein just before the introduction of glucose / test compound and from that moment at hourly intervals for 6 hours. Blood glucose was examined by standard manual or automated methods. Plasma was obtained from blood samples and insulin was determined. Insulin was determined by radioimmunoassay using, for example, the magnetic separation method of Amerlex (Amersham Life Science) with rat insulin as a standard. Active compounds decreased glucose AUC over time and temporarily increased plasma insulin levels. The preferred insulin secretion enhancers used in the invention reduced glucose AUC over time by> 5% (preferably> 10%) and increased insulin levels by> 20% (preferably> 50%).

Example L: Rat Insulin Secretion (Insulin Secretion Enhancing Agents)

Adult Sprague-Dawley or Wistar rats (200-220 g) were fed, as desired, standard rat food and provided a 12/12 hour light / dark cycle (light from 7 am to 7 pm). Feeding was stopped 24 hours before the start of the studies, which were usually carried out starting at 8 a.m. Rats were anesthetized with intraperitoneal administration of sodium pentobarbital (60 mg / kg) and, if necessary, anesthesia was maintained with additional doses (15 mg / kg). Cannulas were inserted into the right jugular vein to administer the drug and into the left carotid artery to take blood samples. Arterial blood glucose concentrations were maintained at 6 mM by intermittent intravenous infusion of a 10% (w / v) glucose solution using a syringe pump. A drug (0-100 mg / kg) or excipient was administered intravenously as soon as blood glucose was stabilized, and blood samples were taken 2, 5, 10, 20, 30 40 and 60 minutes after administration. Plasma insulin was determined by radioimmunoassay using, for example, the magnetic separation method of Amerlex (Amersham Life Science) with rat insulin as a standard. The insulin response was calculated as an increase in the area above basal for arterial plasma insulin concentrations at 0-10 (first phase), 10-60 (second phase) and 0-60 (total). Preferred insulin secretion enhancers used in the invention increased the first or second phase or total insulin concentration by> 10%, preferably> 50%.

Example M: Inhibition of CATR channels in beta cells of the mouse pancreas (Tools that enhance insulin secretion)

Mouse beta cells were isolated by collagenase treatment and cultured in RPMI 1640 modified medium containing 5.5 mM glucose and 10% fetal calf serum. The contents of the “patches” of the cells were obtained and the electrophysiological assessment of potential fixation (“patch clamp”) was performed using a microflow system as described [Schwanstecher et al. Br. J. Pharmacol. 113: 903-911 (1999)]. The membrane potential was closed at -50 mV and internal membrane fluxes passing through the CATR channels were measured. Zero flow level was set to 1 mm ATP. The activity of the KATP channel was standardized by activity during the control periods (the presence of ADP, the absence of the drug) before and after the use of the drug (0-100 μM) in each study. Preferred insulin secretion enhancing agents used in the present invention inhibited potassium channel activity with an IC ₅₀ <10 micromoles, preferably <100 nanomoles.

Example N: Sulfonylurea Receptor Binding (Insulin Secretion Enhancing Agents)

The sulfonylurea receptor, SUR1, was cloned and transfected into Cos-7 cells as described [Aguilar-Bryan et al. Science 268: 423-426 (1995)]. Membranes were obtained from cells 60-72 hours after transfection. To determine binding to SUR1, resuspended membranes were incubated in the presence of a fixed concentration of [3H] -glibenclamide (or another suitable standard) and varying concentrations of the test sample. Nonspecific binding was determined by 100 nM unlabeled standard. Incubation was carried out for 1 hour at room temperature and stopped by rapid filtration of aliquots through Whatman GF / B filters. The filters were washed and the 3H content was determined in a liquid scintillation counter. Receptor binding was indicated by a decrease in count, i.e., a substitution of the labeled standard. Preferred insulin secretion enhancing agents used in the present invention have a Cd (dissociation constant) of <10 micromoles, preferably <100 nanomoles.

Example O: Inhibition of dipeptidyl peptididase IV (DPP-IV inhibitors)

This study was performed as described by Deacon CF, Hughes TE, Hoist JJ, Diabetes 47: 764-769 (1998), using H-glycine-proline-7-amino-4-methylcoumarin as a synthetic substrate and human plasma as an enzyme source. Preferred DPP-IV inhibitors inhibit the activity of the enzyme with an IC ₅₀ <10 micromoles, preferably <500 nanomoles.

Example P: Alpha Glucosidase Assay

Sugarase and maltase obtained from the membranes of the brush border of the small intestine of adult Sprague-Dawley rats were examined by determining glucose production from sucrose and maltose, respectively. Samulitis VK, Goda T, Lee SM, Koldowsky O, Drugs Exp. Clin Res 133: 517-24 (1987). Formed glucose was quantified using a commercial assay kit (glucose oxidase method, Sigma Chemical Co.). Preferred alpha glucosidase inhibitors inhibit enzyme activity with an IC _{50 of} from 1 nM to 1 μM. More preferred have an IC ₅₀ between 1 nM and 1 μM.

Example Q: Research glycogen phosphoryl

Glycogen phosphorylase derived from human liver was tested for glycogen synthesis by releasing glucose 1-phosphate into a buffered reaction mixture containing 0.5 mM glucose 1-phosphate and 1 mg / ml glycogen. Phosphate was determined by the addition of hydrochloric acid containing ammonium molybdate and malachite green. The optical density was measured at 620 nm. Test compounds were added to DMSO. Martin WH, Hoover DJ, Armento SJ et al., PNAS 95: 1776-1781 (1998). Preferred glycogen phosphorylase inhibitors have an IC _{50 of} from 1 nM to 10 μM. More preferred have an IC ₅₀ between 1 nM and 1 μM.

Example R: Investigation of glucose-6-phosphatase inhibitors

Glucose-6-phosphatase activity was determined by recording the release of phosphate from glucose 6-phosphate. Microsomes were obtained from starving rats and incubated at room temperature in a buffer containing 1 mM glucose 6-phosphate. Released phosphate was determined by adding hydrochloric acid containing ammonium molybdate and malachite green. The optical density was measured at 620 nm. Test compounds were added to DMSO before enzyme addition. Parker JC, van Volkenburg A, Levy CB et al., Diabetes 47; 1630-1636 (1998). Preferred glucose-6-phosphatase inhibitors have an IC _{50 of} from 1 nM to 10 μM. More preferred have an IC ₅₀ between 0.1 nM to 300 nM.

Example S: Study of glucagon antagonists

Glucagon antagonist activity was assessed by measuring the release of iodinated glucagon from plasma membrane membranes of hamster baby kidney cells expressing a human cloned receptor. Madsen P, Knudsen LB, Wiberg FC, Carr RD, J. Med. Chem. 41: 5150-5157 (1998). Studies were performed in microtiter plates with filters. Test compound at various concentrations, a fixed amount of glucagon label, and buffer were added to each well. Nonspecific binding was evaluated in the presence of a large amount of unlabeled ligand. Bound and unbound tags were separated by vacuum filtration. The plates were washed and the filters were counted in a gamma counter. The value of non-specific binding was subtracted from the account. To determine the binding constants, a Scatchard saturation graph was plotted and analyzed by standard methods. Antagonism was evaluated as the ability of compounds to displace a labeled glucagon label from filters. Preferred antagonists have an IC ₅₀ between 0.1 nM and 100 μM. More preferred compounds inhibit binding to an IC ₅₀ between 0.1 nM and 100 μM.

Example T: Amylin Agonist Assay

Membranes were obtained from nuclear clusters and surrounding areas of the rat basal forebrain. Amylin agonist activity was evaluated by measuring the release of iodinated human amylin from membrane preparations. Studies were performed in microtiter plates with filters. Test compound at various concentrations, a specific amount of amylin label and buffer was added to each well. Nonspecific binding was evaluated in the presence of a large amount of unlabeled ligand. Bound and unbound tags were separated by vacuum filtration. The plates were washed and the filters were counted in a gamma counter. The value of non-specific binding was subtracted from the account. To determine the binding constants, a Scatchard saturation graph was plotted and analyzed by standard methods. Preferred agonists have a K _i between 0.001 nM and 1 microM. More preferred compounds inhibit binding to K _i between 0.001 nM and 10 nM.

Example U: Study of fatty acid oxidation inhibitors

Isolated hepatocytes were obtained from starving rats by collagenase treatment according to the method of Berry and Friend. Cells were incubated in Krebs c. Bicarbonate buffer. the absence and in the presence of inhibitors at a number of concentrations. Reactions were initiated by the addition of ¹⁴ C-palmitate, 0.05 Ci / mol, 0.5 mM final concentration bound to albumin. After 10 minutes of incubation, the reactions were stopped with perchloric acid and the oxidation products were extracted. Guzman M, Geelen MJH, Biochem J, 287, 487-492 (1992). Total oxidation products were calculated as the sum of acid-soluble products (ketone bodies) and CO _{2 released} . Preferred fatty acid oxidation inhibitors block the oxidation of fatty acids with IC ₅₀ or 10 nM to 300 microM. More preferred have an IC _{50 of} from 10 nM to 30 microM.

Example V: Decrease in glucose in db / db mice (FBP-aa inhibitors)

Male db / db mice, a widely used NIDDM model, were purchased from Jackson Labs (Bar Harbor, Maine) at 8 weeks of age. The mice were kept under standard vivarium conditions (25 ° C., 12-hour light / 12-hour dark cycle) and Purina 5008 powder food and water were provided as desired. At the age of 10 weeks, animals with blood glucose levels> 400 mg / dl and <900 mg / dl were divided into 2 treatment groups (n = 5-6 / group). The treatment was carried out for 18 days. Blood glucose levels were measured in tail vein samples using a HemoCue glucose analyzer (HemoCue Inc., Mission Viejo, CA). Values were presented as mean plus or minus standard deviation from mean. Differences between groups were evaluated by student criterion. The results were considered significant with p <0.05.

As can be seen from the table below, on the last day of treatment (day 18), blood glucose levels in the compound G group were significantly lower than the levels in the control group:

Table 7 Blood glucose, mg / dl Treatment 0 day 18 day The control
Compound G 707 ± 65 708 ± 55 870 ± 32 646 ± 37 * p <0.05 against control

Example W: Decrease in glucose in rats ZDF (Compounds G and J)

Rats with diabetes mellitus and obesity (ZDF) are widely used as a human NIDDM model, since in these rodents the disease progression is similar to the development of the disease described for humans in 1983 patients. A mature ZDF rat not only exhibits obesity, hyperglycemia, insulin resistance, and increased glucose production in the liver, but also develops some macro- and microsodule complications associated with NIDDM. dark JB, Palmer CJ, (1982) Diabetes 30; 126A; Terrettaz J, Jeanrenaud B (1983) Endocrinology 112: 1346-1351.

(a) Compound G Protocol: Male ZDF rats at 8 weeks of age were purchased from Genetics Models Inc. (Indianapolis, Indiana). The rats were kept under standard vivarium conditions (25 ° C., 12-hour light / 12-hour dark cycle) and gave Purina 5008 food powder and water as desired. At the age of 11 weeks, animals with a blood glucose level> 500 mg / dl were selected and divided into 2 treatment groups (n = 8 / group). Treatment groups included control and treatment with compound G (administered as a 0.2% dietary supplement for 14 days. Blood glucose levels were measured in tail vein samples from a HemoCue glucose analyzer (HemoCue Inc., Mission Viejo, CA). Values were presented as mean plus or minus the standard deviation from the mean. Differences between groups were evaluated by Student's test. The results were considered significant with p <0.05.

(b) Compound J Protocol: This study was performed exactly as described above in the section for compound G with two modifications: the treatment period was 21 days and the dose of compound J used was 0.4%.

(c) Results:

Both compound G and J significantly improved glycemic control in ZDF rats. The results showed that FBPase inhibitors can be used clinically to treat NIDDM.

Example X: Short-term combination treatment with an agent that enhances insulin secretion and an FBPase inhibitor (compound J) of ZDP rats

Experimental protocol: Rats with diabetes mellitus and obesity (9.5 weeks old) were fasted for 5 hours, starting at 8 a.m. Then the animals were divided into 4 treatment groups with statistically similar basic blood glucose levels. Test compounds were administered orally through a tube. The treatment was carried out as follows:

Table 10 Group Drug Dose one saline on 2 glyburide 100 mg / kg 3 compound J 300 mg / kg four glyburyl + compound J 100 + 300 mg / kg

One hour after the administration of saline or drug, all animals were given simulated food in the form of an oral glucose bolus (1 g / kg). Then, blood glucose was determined at specific time intervals over 3 hours. Test compounds were prepared as a suspension in 0.1% carboxymethyl cellulose. Blood samples were obtained by sectioning the tail vein. Blood glucose was measured in a HemoCue glucose analyzer according to the manufacturer's instructions (HemoCue Inc., Mission Viejo, CA). The results were presented as mean values +/- standard deviation from the average for all values.

Results: In experimental studies, it was found that glyburide and compound J showed maximum efficiency in the model used at doses of 100 and 300 mg / kg, respectively. In this study, both glyburide and compound J suppressed an increase in blood glucose levels induced by an oral glucose load; in the case of compound J, the decrease in blood glucose was below baseline levels (see figure 1 below). Combined treatment was better than any monotherapy, as indicated by increased recovery of the area under the curve (AUC) of blood glucose during the first 4 hours after drug administration.

Table 11 Medicine AUC of glucose, mg / dl * hour The control 1463 ± 99 Gliburide 1324 ± 132 Compound J 1121 ± 82 Combination 895 ± 74

Combination treatment also reduces the increase in blood lactate levels observed in the monotherapy group with compound J (p = 0.01 for a 0 hour time point, Figure 2).

The study showed that combined treatment with an agent that enhances insulin secretion and an FBPase inhibitor provides significantly improved glycemic control compared to treatment with any one agent. It is possible that improved glycemic control leads to a reduced incidence of complications associated with NIDDM. In addition, in acute cases, combination treatment attenuates the side effects associated with therapy with an FBPase inhibitor, an increase in blood lactate. In chronic cases, the marked attenuation is more pronounced.

Figure 1: OGTT in ZDF rats

* p <0.05 for all groups: ANOVA with Dunnet post hoc test

+ p <0.05 relative to vehicle: ANOVA with Dunnett post hoc test;

Figure 2: OGTT in ZDF rats

Example Y: Long-term combination treatment with an agent that enhances insulin secretion and an FBPase inhibitor of ZDF rats

7-week old male ZDF rats were purchased from Genetics Models Inc. (Indianapolis, Indiana). The rats were kept under standard vivarium conditions (25 ° C., 12-hour light / 12-hour dark cycle) and gave Purina 5008 food powder and water as desired. At the age of 8 weeks, the animals were divided into 4 treatment groups (n = 8 / group). The treatment was carried out: control, compound J, glyburide and combined treatment with compound J and glyburide. Compound J and glyburide were administered at maximum doses by oral feeding through a tube, with drinking water, or as a dietary supplement for 2 to 12 weeks. Blood glucose levels were measured in tail vein samples using a HemoCue glucose analyzer (HemoCue Inc., Mission Viejo, CA). Other parameters determined using standard methods include: lactate, glycerol, alanine, triglycerides, free fatty acids, ketone bodies, liver and muscle glycogen, cholesterol, VLDL, HDL, Ale hemoglobin, body weight and water intake, as well as other indicators metabolism of carbohydrates, lipids and proteins. Values were presented as mean plus or minus standard deviation from mean. Differences between groups were evaluated by ANOVA using the appropriate post hoc test. The results were considered significant at p <0.05.

Control animals progressively developed hyperglycemia during the study period, while there was a significant improvement in glycemic control in the case of all three drug treatment groups in the initial stage. The combined group showed a significantly greater decrease in glucose than the monotherapy groups, either with compound J, or glyburide. Due to the progressive depletion of pancreatic beta cells and resulting from a violation of insulin secretion, glyburide therapy became less and less effective over time, and severe hyperglycemia developed in animals, that is, a secondary disturbance appeared. Compound J treatment was more effective than glyburide, which impairs pancreatic function. However, combination therapy led to a significant improvement in glycemic control throughout the study period.

Example Z: Short-term combination treatment with insulin and an FBPase inhibitor (Compound G) of db / db mice.

5 week old male C57BL / Ksj db / db mice were purchased from Clea Japan, Inc. (Tokyo, Japan). Mice were kept under standard vivarium conditions (24-26 ° C, 12-hour light / 12-hour dark cycle) and given standard food and water as desired. At the age of 20 weeks, the animals were divided into 4 treatment groups (n = 6 / group). The treatment groups were control, compound G group, insulin group and combination treatment group with compound G and insulin. Compound G was administered orally at a dose of 200 mg / kg. Insulin (recombinant human insulin, Penfill R300, Novo Nordisk, Denmark) was administered subcutaneously at a dose of 1.5 U / kg. Feeding was stopped after the start of treatment. Blood glucose levels were measured in tail vein samples using a Glucoloader-F automatic glucose analyzer (A&T Co., LTD., Tokyo, Japan). Values were presented as mean plus or minus the standard deviation from the mean.

The following table shows blood glucose levels relative to pre-treatment values:

Table 12 Plasma glucose levels before and after treatment Treatment Plasma glucose (mg / dl) BEFORE (0 hours) AFTER 1 hour 2.5 h 4 h The control 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, b
(79.3 +/- 3.7) Compound G 774 +/- 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 +/- 15.2 (100.0 +/- 0.0) 410.8 +/- 34.4 (54.2 +/- 4.1) 46.2 +/- 40.2 (61.1 +/- 4.9) 540.3 +/- 35.9 (71.4 +/- 4.1) Combination 728.0 +/- 29.8 (100.0 +/- 0.0) 378.0 + 7-43.8 (51.9 +/- 5.5) 243.0 +/- b0.5 (33.7 +/- 8.5) 130.8 +/- 53.9 (18.3 +/- 7.5) () average% values before treatment

In control animals, glucose levels improved to some extent due to starvation. Insulin treatment showed a positive trend in hyperglycemia within 2.5 hours after administration. However, no differences were observed in plasma glucose levels between the control and the groups treated with insulin by 4 hours. Compound G progressively reduced plasma glucose levels, and a more pronounced decrease in glucose at a 4 hour time point was found than with insulin treatment. The combination group showed a significantly greater decrease in the glucose of the monotherapy group with compound G or insulin.

Example AA: Effective effect of long-term combination therapy with insulin and an FBPase inhibitor (Compound G) on db / db mice.

5 week old male C57BL / Ksj db / db mice were purchased from Clea Japan, Inc. (Tokyo, Japan). Mice were kept under standard vivarium conditions (24-26 ° C, 12-hour light / 12-hour dark cycle) and given standard food and water as desired. At the age of 16 weeks, the animals were divided into 2 treatment groups (n = 5 or 9-10 / group). Recombinant human insulin (Penfill N300, Novo Nordisk, Denmark) was subcutaneously administered to both groups on a daily basis to bring plasma glucose levels to the intended range of 250 to 300 mg / dl. Compound G was given to one group as a dietary supplement containing 0.2% of compound G. Blood glucose levels in tail vein samples were measured using a Glu-test ace automatic glucose analyzer (Sanwa Kagaku Kenkyusho Co., Ltd., Nagoya, Japan). Values were presented as mean plus or minus the standard deviation from the mean.

As shown in the table below, the plasma glucose levels of the two groups were kept within the range of 250-300 mg / dl.

Table 13 Plasma glucose levels before and after treatment Treatment Plasma glucose (mg / dl) BEFORE
(0 weeks) AFTER 1 Week 2 weeks 3 weeks Insulin one 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, 273.8 +/- 55.9

The following table shows the changes in body weight.

Table 14 Body weight before and after treatment Treatment Body weight (g) BEFORE
(0 weeks) AFTER 1 Week 2 weeks 3 weeks Insulin one 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 experienced a significant increase in body weight, in the combined treatment group, the rate and degree of weight gain were significantly reduced.

The following table shows the doses of insulin for each group required to regulate plasma glucose to the intended level (250-300 mg / dl).

Table 15 Treatment The dose of insulin (units / kg) BEFORE (0 weeks) AFTER 1 Week 2 weeks 3 weeks Insulin one 548 +/- 18 753 +/- 72 492 +/- 68 306 +/- 67 Combination 501 +/- 47 494 +/- 108 252 +/- 78 114 +/- 37

In the combination treatment group, simultaneous administration of compound G significantly reduced the dose of insulin required to lower plasma glucose to the intended range.

Example BB: Effective effect of long-term combination therapy with insulin and an EBPase inhibitor (compound J) on db / db mice.

5 week old male C57BL / Ksj db / db mice were purchased from Clea Japan, Inc. (Tokyo, Japan). Mice were kept under standard vivarium conditions (24-26 ° C, 12-hour light / 12-hour dark cycle) and given standard food and water as desired. At the age of 19 weeks, the animals were divided into 2 treatment groups (n = 6 / group). Recombinant human insulin (Penfill N300, Novo Nordisk, Denmark) was subcutaneously administered to both groups to bring plasma glucose levels to the target value of 300 mg / dL every day. Compound J was given to one group as a dietary supplement containing 0.2% of compound J. Blood glucose levels in tail vein samples were measured using a Glucoloader-F automatic glucose analyzer (A&T Co., Ltd., Tokyo, Japan). Values were presented as mean plus or minus the standard deviation from the mean.

The following table shows plasma glucose levels.

In both groups, plasma glucose levels remained at about 300 mg / dl for 4 weeks of treatment.

The following table shows the changes in body weight in each treatment group:

While insulin treatment led to an increase in body weight, combination therapy with insulin and compound J significantly reduced the increase in body weight during 4 weeks of treatment.

As shown in the table below, compound J significantly reduced the insulin dose required to lower blood glucose to target levels in almost 40% of the combination treatment group.

Table 18 Doses of insulin required to achieve target blood glucose levels Treatment The dose of insulin (units / kg) BEFORE AFTER (0 weeks) 1 Week 2 weeks 3 weeks 4 weeks Insulin one 0 + \ - 0 495 + \ - 32 699 + V-63 7b0 + \ - 95 802 + \ - 129 Combination 0 + \ - 0 303 + \ - 31 411 + \ - 62 440 + \ - 80 491 + \ - 112

Example SS: Short-term combination treatment with Goto-Kakizaki rat insulin and FBPase inhibitor

Male 9-week-old Goto-Kakizaki (GK) rats were purchased from Charles River Japan, Inc. (Tokyo, Japan). Rats were kept under standard vivarium conditions (24-26 ° C, 12-hour light / 12-hour dark cycle) and given standard food and water as desired. At the age of 48 weeks, the animals were divided into 4 treatment groups (n = 6 / group). The treatment groups were control, the compound J treatment group, the insulin group and the compound J and insulin treatment group. Compound J was administered orally at a dose of 50 mg / kg. Insulin (recombinant human insulin, Penfill N300, Novo Nordisk, Denmark) was administered subcutaneously at a dose of 1.5 U / kg. Blood glucose levels in tail vein samples were measured using a Glucoloader-F automatic glucose analyzer (A&T Co., Ltd., Tokyo, Japan). Values were presented as mean plus or minus the standard deviation from the mean.

The following table shows plasma glucose levels before and after drug administration for each treatment group.

Table 19 Plasma glucose levels before and after treatment, mg / dd or (% of baseline) Treatment Plasma glucose (mg / dl)

BEFORE (0 hour) AFTER 2 hours 4 hours 6 o'clock

The control 160.5 +/- 16.3 (100.0 +/- 0.0) 189.5 + 7-15.8 (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 +/- 10.8 (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) () - average% before treatment; ND - not determined

Plasma glucose levels in control animals did not change during the study. Treatment with compound J or insulin reduced plasma glucose within 2 hours after administration. No differences were observed in plasma glucose levels between treatment groups with compound J and insulin at 2 and 4 hours. Compound J progressively decreased plasma glucose and showed a more potent hypoglycemic effect than with insulin by 6 hours. The combined group showed a more significant decrease in glucose than monotherapy groups with compound J or insulin after 2 hours of action. The magnitude of the effect indicates that significantly lower doses of insulin can be used. Thus, it is possible that compound J exhibits an insulin-saving effect when used in combination therapy with insulin. Perhaps a decrease in insulin reduces the frequency and severity of side effects associated with insulin monotherapy (for example, weight gain).

Example DD: Short-term combination treatment with biguanide and an FBPase inhibitor of db / db mice.

5 week old male C57BL / KsJ db / db mice were purchased from Clea Japan, Inc. (Tokyo, Japan). Mice were kept under standard vivarium conditions (24-26 ° C, 12-hour light / 12-hour dark cycle) and given standard food and water as desired. At the age of 10 weeks, the animals were divided into 4 treatment groups (n = 6 / group). Treatment groups comprised control, a compound J treatment group, a metformin group, and a combined compound J and metformin treatment group. Compound J and / or metformin (Sigma) was administered orally at a dose of 150 mg / kg. After the introduction of drugs stopped feeding. Blood glucose levels in tail vein samples were measured using a Glucoloader-F automatic glucose analyzer (A&T Co., Ltd., Tokyo, Japan). Values were presented as mean plus or minus the standard deviation from the mean.

As shown in the table below, plasma glucose levels in control animals decreased progressively during the fasting period. Metmorphine and compound J in monotherapy significantly reduced blood glucose compared to control. The strongest decrease in blood glucose levels was observed in the combination therapy group. Unexpectedly, despite the general mechanism of action (inhibition of gluconeogenesis), combination therapy with metformin and an FBPase inhibitor provided a significant positive dynamics of glycemic control compared to the use of any drug alone.

Table 20 Plasma glucose levels before and after treatment Treatment Plasma glucose (mg / dl) BEFORE AFTER (0 hour) 2 hours 4 hours 6 o'clock 8 ocloc'k The control 541.3 +/- 10.0 (100.0 +/- 0.0) 465.5 +/- 23.2 (85.8 +/- 3.2) 468.8 +/- 10.0 (8b, 5 +/- 3.3) 460.5 +/- 29.3 (85.0 +/- 5.0) 495.8 +/- 28.1 (91.5 +/- 4.6) Compound J 514.3 +/- 23.0 (100.0 +/- 0.0) 448.6 +/- 42.5 376.7 +/- 39.9 (70.2 +/- 14.6) (72.4 +/- 5.0) 357.7 +/- 40.4 (68.7 +/- 5.5) 386.5 +/- 43.1 (74.2 +/- 5.8) Metformin 515.7 +/- 37.0 (100.0 +/- 0.0) 347.0 +/- 21.2 (b7.7 +/- 1.9) 346.5 +/- 34.6 (6b, 4 +/- 3.1) 348.3 +/- 30.7 (67.7 +/- 4.1) 407.8 +/- 40.0 (79.1 +/- 5.6) Combination 538.4 +/- 20.2 (100.0 +/- 0.0) 317.2 +/- 21.0 (59.9 +/- 2.1) 265.4 +/- 31.0 (49.3 +/- 3.3) 253.4 +/- 32.7 (45.9 +/- 3.6) 289.2 +/- 49.3 (53.4 +/- 5.5) () average% of value before treatment

Example EE: Short-term combination treatment with an alpha-glucoeidase inhibitor and a Gb-Kakizaki rat PBPase inhibitor.

Goto-Kakizaki rats, an animal model of NIDDM thin, 5 weeks old, were purchased from Charles River Japan, Inc., (Tokyo, Japan). Rats were kept under standard vivarium conditions (24-26 ° C, 12-hour light / 12-hour dark cycle) and given standard food and water as desired. At the age of 18 weeks, the animals were divided into 4 groups (n = 5 / group). The treatment groups were control, compound J group, acarbose group (Bayer, Japan) and combination treatment group with compound J and acarbose. All animals were given corn starch 1 g / kg orally through a tube. Compound J was administered orally at a dose of 10 mg / kg 1 hour before the introduction of starch. Acarbose was administered orally at a dose of 1 mg / kg simultaneously with starch. Blood glucose levels in tail vein samples were measured using a Glucoloader-F automatic glucose analyzer (A&T Co., Ltd., Tokyo, Japan). Values were presented as mean plus or minus the standard deviation from the mean.

The following table shows the time profile of plasma glucose values for each treatment group.

Table 21 Plasma glucose levels before and after treatment Treatment Plasma glucose (mg / dl) -60 min 0 min 30 minutes 60 min 120 min 240 min Glucose plaza (mg / dl) or relative value (%) The control 148.6 +/- 8.1
(100.0 +/- 0.0) 211.4 +/- 9.6
(142.6 +/- 2.2) 291.0 +/- 10.4 (197.0 +/- 7.4) 342.4 +/- 4.0
(233.7 +/- 15.1) 248.6 +/- 9.8
(168.9 +/- 9.8) 165.4 +/- 9.5
(111.9 +/- 5.8) 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) Metformin 175.4 +/- 5.9
(100.0 +/- 0.0) 226.4 +/- 5.3
(129.4 +/- 2.8) 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) Combination 164.4 +/- 3.6
(100.0 +/- 0.0) 198.2 +/- 9.7
(120.4 +/- 4.4) 150.0 +/- 11.2
(91.1 +/- 6.0) 129.4 +/- 9.6
(78.6 +/- 5.3) 103.0 +/- 9.1
(62.7 +/- 5.5) 111.2 +/- 12.1
(67.8 +/- 7.7) () average% of value before treatment

In control animals, plasma glucose levels increased up to 1.6 times after starch administration. Treatment with both compound J and acarbose attenuated plasma glucose abnormalities after starch administration. The combination treatment group showed a significantly greater decrease in glucose than the monotherapy groups with either compound J or acarbose. Thus, the combination of an FBPase inhibitor and an alpha glucosidase inhibitor provides a significant positive dynamics of glycemic control in the postprandial state. It turned out that both gluconeogenesis and carbohydrate absorption are important factors that determine blood glucose levels after eating.

Example FF: Short-term combination treatment with a glycogenphosphorylase inhibitor and an FBPase inhibitor of db / db or ob / ob mice.

5 week old db / db or ob / ob mice were purchased from Jackson Laboratories (Bar Harbor, Maine). Mice were kept under standard vivarium conditions (24-26 ° C, 12-hour light / 12-hour dark cycle) and given standard food and water as desired. At the age of more than 10 weeks, animals were divided into 4 groups (n = 5-7 / group). The treatment groups were control, Compound J treatment group, CP-91149 group (Pfizer), and Compound J combined treatment group and CP-91149. After a 0-48 hour fasting period, compound J and / or CP-91149 was orally administered at a dose of 0.5 to 300 mg / kg. After drug administration, food was given. Blood glucose levels in tail vein samples were measured using standard manual and automated methods. Values were presented as mean plus or minus the standard deviation of the mean.

Monotherapy with both compound J and CP-91149 significantly reduced blood glucose compared to control values.

The decrease in glucose in the combination therapy group was significantly more pronounced than the decrease in any monotherapy group.

Example GG: Short-term combination treatment with a glucose-6-phosphatase inhibitor and a PBPase inhibitor of db / db or ob / ob mice.

5 week old db / db or ob / ob mice were purchased from Jackson Laboratories (Bar Harbor, Maine). Mice were kept under standard vivarium conditions (24-26 ° C, 12-hour light / 12-hour dark cycle) and given standard food and water as desired. At the age of more than 10 weeks, animals were divided into 4 groups (n = 5-7 / group). The treatment groups were control, the compound J treatment group, the glucose-6-phosphatase inhibitor treatment group, and the compound J treatment group and the glucose-6-phosphatase inhibitor. After a 0-48 hour fasting period, compound J and / or a glucose-6-phosphatase inhibitor was orally administered at a dose of 0.5 to 300 mg / kg. After drug administration, food was either not given or given. Blood glucose levels in tail vein samples were measured using standard manual and automated methods. Values were presented as mean plus or minus the standard deviation of the mean.

Monotherapy with both compound J and a glucose-6-phosphatase inhibitor significantly reduced blood glucose compared to control values. The decrease in glucose in the combination therapy group was significantly more pronounced than the decrease in any monotherapy group.

Example HH: Short-term combination treatment with an FBPase inhibitor and an amylin agonist.

Two to three weeks after the induction of diabetes by intravenous administration of 65 mg / kg of streptozotocin, Sprague-Dawley rats were starved overnight, and then the rats were given intravenous saline or pramlintide (10 micrograms) or compound J (300 mg) orally / kg). Then, when feeding through a probe, animals were injected with 1 ml of 50% glucose and access to food was left at will. Blood glucose was determined in samples taken from the tail vein at 0, 30, 60, 120, 180 and 240 minutes after glucose administration. Both pramlintide and compound J attenuated postprandial glucose deflection. Combination therapy led to a significant improvement in postprandial glycemic control compared with any monotherapy.

Example JJ: Long-term combination treatment with a fatty acid oxidation inhibitor and an FBPase inhibitor of rats with streptozotocin-induced diabetes.

Male Sprague-Dawley rats (Charles Rives Laboratories), weighing approximately 120 g, were placed at the beginning of the study under standard conditions in a vivarium and fed standard food (Purina 5001). In rats, injection of 55 mg / kg body weight of streptozotocin (STZ) in citrate buffer, pH 4.7, induced diabetes. Three days later, fasting blood glucose was determined, and rats with a glucose level> 250 mg / dl were divided into 4 groups: control, etomoxir, compound J, etomoxir + compound J. Ethomoxir (3-300 mg / kg) was administered subcutaneously once in a day.

Compound J was administered as a dietary supplement (0.2% w / w). Drug treatment was continued for 2-6 weeks. Blood glucose levels were examined at specific intervals during the treatment period. At the end of the study, rats were anesthetized and catheters were inserted into the jugular vein and carotid artery. Liver glucose production was determined using an initial continuous infusion of ( ³ H) -6-glucose. Blood samples were taken after two hours and the specific activity of glucose was determined using gas chromatography-mass spectrometry. The rate of glucose production in the liver was calculated by standard methods.

Throughout the study, control animals progressively developed hyperglycemia. Blood glucose was significantly reduced when monotherapy with etomoxir or compound J. Combination therapy showed significantly more pronounced positive dynamics of glycemic control compared with therapy or etomoxir or compound J alone. Liver glucose production rates were also significantly lower in the combination therapy group compared to the monotherapy groups.

It is clear that none of the references cited in the description refers to the prior art in this field, and all references are included in the description by quoting in full. Various modifications and aspects of the invention, in addition to those described in the description, are obvious to experts in this field.

While the content of the patents, the description of various aspects and conditions of receipt are presented, the scope of the invention is not limited to them. Modifications and changes to this invention without deviating from the scope and ideas of the invention will be apparent to those skilled in the art. Therefore, it is clear that the scope of the present invention should be determined rather by the attached claims, rather than specific examples, which are presented as examples.

Claims (142)

1. A pharmaceutical composition for the prevention and treatment of diabetes and related disorders and conditions, comprising a pharmaceutically effective amount of at least one insulin secretion enhancing agent and a pharmaceutically effective amount of at least one FBPase inhibitor, wherein an FBPase inhibitor is a compound selected from formulas I and IA, and pharmaceutically acceptable prodrugs and salts thereof, wherein formulas I and IA are as follows:

and

where in vivo or in vitro the compounds of formulas I and IA are converted to M-PO ₃ ^2- , which inhibits FBP-ase, and where Y is independently selected from —O— and —NR ⁶ , provided that: when Y is —O—, then R ¹ attached to —O— is independently selected from —H, alkyl, optionally substituted aryl, optionally substituted alicyclic, where the cyclic moiety contains carbonate or thiocarbonate, optionally substituted α-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 -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 , then R ¹ attached to —NR ⁶ is independently selected from —H, - [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 , where q is 1 or 2; when only one Y is —O—, where —O— is not part of a cyclic group containing another Y, then 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 and form a cyclic group, or R ¹ and R ¹ together form

or

or

Where a) V is selected from the group comprising aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl; or V and Z are joined together by an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is condensed with an aryl group at the beta and gamma positions of Y adjacent to V; or Z is selected from the group consisting of —CHR ² H, —CHR ² OC (O) R ³ , —CHR ² OC (S) R ³ , —CHR ² CO (S) OR ³ , —CHR ² C (O) SR ³ , —CHR ² CO 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 , -SCO ₂ R ³ , -NHCOR ² , -NHCO ₂ R ³ , -CH ₂ NH- aryl, - (CH ₂ ) _p OR ² and - (CH ₂ ) _p -SR ² , where p is the integer 2, or Z and W are joined together by additional 3-5 atoms to form a cyclic group optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl; or W and W ′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or W and W ′ are joined together by an additional 2-5 atoms to form a cyclic group optionally containing 0-2 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 —H, 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 (O) SR ³ , -CHR ² OS (S) OR ³ , -CH (aryl) OH, -CH (CH = CR ² ₂ ) OH, -CH (C≡CR ² ) OH, -SR ² , -CH ₂ NH-aryl, - CH ₂ -aryl; or V ² and Z ^{2 are} joined together by an additional 3-5 atoms to form a cyclic group containing 5-7 atoms in the ring, optionally containing 1 heteroatom and substituted by hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom, which is three atoms from 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 —H; D ″ is selected from the group consisting of —H, alkyl, —OR ² , —OH and —OC (O) R ³ ; each W ^{3 is} independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; provided that V, Z, W, W '- all do not mean -H, and V ² , Z ² , W ² , W'', all do not mean -H; and R ^{2 is} selected from R ³ and —H; R ³ selected from alkyl, aryl, alicyclic or aralkyl. each R ^{4 is} independently selected from the group —H, alkyl, alkylene aryl and aryl, or together R ⁴ and R ^{4 are} connected through 2-6 atoms, optionally including one heteroatom selected from O, S and N; R ^{6 is} selected from —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl; R ^{18 is} independently selected from H, lower alkyl, aryl and aralkyl, or R ¹² and R ^{18 are} joined together by 1-4 carbon atoms to form a cyclic group; each R ¹² and each R ^{13 is} independently selected from H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R ¹² and R ^{13 are} joined together by 2-6 carbon atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S, with the formation of a cyclic group; each R ^{14 is} independently selected from —OR ¹⁷ , —N (R ¹⁷ ) ₂ , —NHR ¹⁷ , —SR ^17, and —NR ² R ²⁰ ; R ^{15 is} selected from —H, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together by 2-6 atoms to form a cyclic group, wherein the cyclic group optionally contains one heteroatom selected from O, N and S; R ^{16 is} selected from - (CR ¹² R ¹³ ) _n —C (O) —R ¹⁴ , —H, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together by 2-6 atoms to form a cyclic group where the cyclic group optionally contains one heteroatom selected from O, N and S; each R ^{17 is} independently selected from lower alkyl, lower aryl and lower aralkyl, or when R ¹⁴ is —N (R ¹⁷ ) ₂ , then two R ^{17 are} joined together by 2-6 atoms to form a cyclic group, where the cyclic group optionally contains one a heteroatom selected from O, N and S; R ^{20 is} selected from the group consisting of —H, lower R ³ and —C (O) —lower — R ³ ; where M means:

where U ⁶ and V ^{6 are} independently selected from hydrogen, hydroxy and acyloxy, or U ⁶ and V ⁶ taken together form a lower cyclic ring containing at least one oxygen; W ^{6 is} selected from amino and lower alkylamino; and Z ^{6 is} selected from alkyl and halogen; or where M means

where A ^{2 is} selected from —NR ⁸ ₂ , —NHSO ₂ R ³ , —OR ²⁵ , —SR ²⁵ , halogen, lower alkyl, —CON (R ⁴ ) 2, guanidine, amidine, —H, and perhaloalkyl; E ^{2 is} selected from —H, halogen, lower alkylthio, lower perhaloalkyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, —CN and —NR ⁷ ₂ ; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; 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 P ² ₂ ; Y ^{3 is} selected from —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C (O) R ³ , —S (O) ₂ R ³ , —C (O) —R ¹¹ , - CONHR ³ , —NR ² _2, and —OR ³ , all except H, are optionally substituted; —OR ³ all except H are optionally substituted; each R ^{4 is} independently selected from —H and alkyl, or together two R ⁴ form a cyclic alkyl group; R ^{25 is} selected from —H, lower alkyl, lower aryl, lower aralkyl, and lower alicyclic; each R ^{7 is} independently selected from H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and —C (O) R ¹⁰ ; each R ^{8 is} independently selected from H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl and —C (O) R ¹⁰ or together two R ⁸ form bidentant alkyl; R ¹⁰ selected from —H, lower alkyl, lower aryl and lower perhaloalkyl, NH ₂ ; R ^{11 is} selected from alkyl, aryl, NR ² ₂ and OR ² ; where M means

where A, E and L are independently selected from —NR ⁸ ₂ , —NO ₂ , —H, —OR ⁷ , —SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —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, C ₂ -C ₅ - alkynyl and a 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 heterocycle; J is selected from —NR ⁸ ₂ , —NO ₂ , —H, —OR ⁷ , —SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —COR ¹¹ , —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy , alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or J and Y together form a cyclic group selected from the group consisting of aryl, cyclic alkyl and heterocyclic alkyl; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; 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 —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C (O) R ³ , —S (O) ₂ R ³ , —C (O) —R ¹¹ , - CONHR ³ , —NR ² _2, and —OR ³ , all except H, are optionally substituted; each R ^{4 is} independently selected from —H and alkyl, or together R ⁴ form a cyclic alkyl group; R ^{25 is} selected from lower alkyl, lower aryl, lower aralkyl and lower alicyclic; each R ^{7 is} independently selected from H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and —C (O) R ¹⁰ ; each R ^{8 is} independently selected from H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl and —C (O) R ¹⁰ or together two R ⁸ form bidentant alkyl; R ¹⁰ selected from —H, lower alkyl, lower aryl and lower perhaloalkyl, NH ₂ ; and R ^{11 is} selected from alkyl, aryl, NR ² ₂ and OR ² ; where M means

where B ^{5 is} selected from —NH—, —N = and CH =; D ^{5 is} selected from

and

Q ^{5 is} selected from —C = and —N—; provided that when B ⁵ means —NH— then Q ⁵ means —C = and D ⁵ means

when B ⁵ means —CH =, then Q ⁵ means —N— and D ⁵ means

and when B ⁵ means -N =, then D ⁵ means

and Q ⁵ means —C =; A, E and L are independently selected from —NR ⁸ ₂ , —NO ₂ , —H, —OR ⁷ , —SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —COR ¹¹ , —SO ₂ R ³ , guanidine , amidine, —NHSO ₂ R ²⁵ , —SO ₂ NR ⁴ ₂ , —CN, sulfoxide, perhalogenacyl, perhaloalkyl, perhaloalkoxy, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl and a lower alicycle, 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 heterocycle; J is selected from —NR ⁸ ₂ , —NO ₂ , —H, —OR ⁷ , —SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —COR ¹¹ , —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or J and Y together form a cyclic group selected from the group consisting of aryl, cyclic alkyl and heterocyclic alkyl; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; 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 - H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C (O) R ³ , -S (O) ₂ R ³ , -C (O) -R ¹¹ , - CONHR ³ , —NR ² ₂ and —OR ³ , all except H, are optionally substituted; each R ^{4 is} independently selected from —H and alkyl; or R ⁴ and R ⁴ form a cyclic alkyl group; R ^{25 is} selected from lower alkyl, lower aryl, lower aralkyl and lower alicyclic; each R ^{7 is} independently selected from H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and —C (O) R ¹⁰ ; each R ^{8 is} independently selected from H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl and —C (O) R ¹⁰ or together two R ⁸ form bidentant alkyl; R ^{10 is} selected from - H, lower alkyl, NH ₂ , lower aryl and lower perhaloalkyl; R ^{11 is} selected from alkyl, aryl, NR ² ₂ and OR ³ ; where M means —XR ⁵ , where R ⁵ means

where each G is independently selected from C, N, O, S, and Se, and where not more than one G is O, S, or Se, and not more than one G is N; And selected from —H, —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 or absent; B is independently selected from —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, —C (O) R ¹¹ , —C (O) SR ³ , SO ₂ R ¹¹ , —S (O) R ³ , —CN, —NR ⁹ ₂ , —OR ³ , —SR ³ , perhalogen-alkyl, halogen, —NO ₂ or is absent, with the exception of —H, —CN, perhaloalkyl, —NO ₂ and halogen, all optionally substituted; J is selected from —H or absent; X is an optionally substituted linking group that binds R ⁵ to a phosphorus atom through 2-4 atoms including 0-1 heteroatoms selected from N, O and S, except that when X is urea or carbamate, then there are 2 heteroatoms located along the shortest path between R ⁵ and the phosphorus atom, and where the atom attached to the phosphorus is a carbon atom, and where X is selected from furan-2,5-diyl, alkyl (hydroxy) -; alkynyl; heteroaryl; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; alkylthioalkyl-; alkylalkyl; -alkylaminocarbonyl-; alkylcarbonylamino; alkoxycarbonyl-; -carbonyloxyalkyl-; alkoxycarbonylamino and -alkylaminocarbonylamino, all optionally substituted, provided 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 —H; R ^{3 is} selected from alkyl, aryl, alicyclic, and aralkyl; each R ^{4 is} independently selected from —H and alkyl, or together R ⁴ and R ⁴ form a cyclic alkyl group; each R ^{9 is} independently selected from —H, alkyl, aralkyl, and alicyclic, or together R ⁹ and R ⁹ form a cyclic alkyl group or heterocyclic group, wherein the heteroatom is selected from O, S, and N; R ^{11 is} selected from alkyl, aryl, —NR ₂ , and OR ₂ ; provided that: 1) at least one of A and B is not selected from —H or absent; 2) when G is N, then the corresponding A or B does not mean a halogen or a group directly bonded to G via a heteroatom; 3) when X is not an aryl group, then R ^{5 is} not substituted with two or more aryl groups. 2. The pharmaceutical composition according to claim 1, where the specified insulin secretion enhancing agent is an sulfonylurea-based antidiabetic agent. 3. The pharmaceutical composition of claim 2, wherein said sulfonylurea antidiabetic agent is a compound of formula XV

where A is selected from hydrogen, halogen, alkyl, alkanoyl, aryl, aralkyl, heteroaryl and cycloalkyl and B is selected from alkyl, cycloalkyl and heterocyclic alkyl. 4. The pharmaceutical composition according to claim 2, wherein said sulfonylurea antidiabetic agent is selected from glyburide, glyoxoxide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, glyclazide, glychidone, glyhexamide, fenbutamide, tolcylamide and. 5. The pharmaceutical composition according to claim 1, wherein said insulin secretion enhancing agent is a derivative that is not sulfonylurea. 6. The pharmaceutical composition according to claim 5, wherein said agent that enhances the secretion of insulin, which is a non-sulfonylurea, is selected from benzoic acid derivatives, phenylpropionic acid derivatives and imidazoline derivatives. 7. The pharmaceutical composition according to claim 6, wherein said non-sulfonylurea is selected from mitiglinide, BTS-67582, nateglinide repaglinide, midaglizole, isaglidol, dariglidol, idazoxane, efaroxane or fluparoxane. 8. The pharmaceutical composition according to claim 1, wherein said insulin secretion enhancing agent is a dipeptidyl peptidase-IV inhibitor (DPP-IV). 9. The pharmaceutical composition of claim 8, where the specified dipeptidyl peptidase-IV inhibitor (DPP-IV) is selected from the group comprising NVP-DPP728 and P32 / 98. 10. The pharmaceutical composition according to claim 1, wherein said insulin secretion enhancing agent is a glucagon-like peptide-1 receptor agonist (GLP-1). 11. The pharmaceutical composition of claim 10, wherein said glucagon receptor-like peptide-1 (GLP-1) agonist is NN-2211, an exendin, or an exendin agonist. 12. The pharmaceutical composition according to claim 1, where M means:

where U ⁶ and V ^{6 are} independently selected from hydrogen, hydroxy and acyloxy, or U ⁶ and V ⁶ taken together form a lower cyclic ring containing at least one oxygen; W ^{6 is} selected from amino and lower alkylamino; and Z ^{6 is} selected from alkyl and halogen. 13. The pharmaceutical composition of claim 12, wherein said insulin secretion enhancing agent is a sulfonylurea-based antidiabetic agent. 14. The pharmaceutical composition according to claim 1, where M means

where A ^{2 is} selected from —NR ⁸ ₂ , —NHSO ₂ R ³ , —OR ²⁵ , —SR ²⁵ , halogen, lower alkyl, —CON (R ⁴ ) ₂ , guanidine, amidine, —H, and perhaloalkyl; E ^{2 is} selected from —H, halogen, lower alkylthio, lower perhaloalkyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, —CN and —NR ⁷ ₂ ; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; 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 —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C (O) R ³ , —S (O) ₂ R ³ , —C (O) —R ¹¹ , - CONHR ³ , —NR ² _2, and —OR ³ , all except H, are optionally substituted; each R ^{4 is} independently selected from —H and alkyl, or two R ⁴ together form a cyclic alkyl group; R ^{25 is} selected from lower alkyl, lower aryl, lower aralkyl and lower alicyclic; each R ^{7 is} independently selected from —H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and —C (O) R ¹⁰ ; each R ^{8 is} independently selected from —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —C (O) R ^10, or two R ⁸ together form a bidentate alkyl; R ^{10 is} selected from —H, lower alkyl, —NH ₂ , lower aryl, and lower perhaloalkyl; R ^{11 is} selected from alkyl, aryl, —NR ² _2, and —OR ² . 15. The pharmaceutical composition of claim 14, wherein said insulin secretion enhancing agent is an sulfonylurea-based antidiabetic agent. 16. The pharmaceutical composition according to claim 1, where M means

where A, E and L are independently selected from —NR ⁸ ₂ , —NO ₂ , —H, —OR ⁷ , —SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —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, C ₂ -C ₅ - alkynyl and a 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 heterocycle; J is selected from —NR ⁸ ₂ , —NO ₂ , —H, —OR ⁷ , —SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —COR ¹¹ , —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or J and Y together form a cyclic group selected from the group consisting of aryl, cyclic alkyl and heterocyclic alkyl; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; 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 —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C (O) R ³ , —S (O) ₂ R ³ , —C (O) —R ¹¹ , - CONHR ³ , —NR ² _2, and —OR ³ , all except H, are optionally substituted; each R ^{4 is} independently selected from —H and alkyl, or two R ⁴ together form a cyclic alkyl group; R ^{25 is} selected from lower alkyl, lower aryl, lower aralkyl and lower alicyclic; each R ^{7 is} independently selected from —H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and —C (O) R ¹⁰ ; each R ^{8 is} independently selected from —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —C (O) R ^10, or two R ⁸ together form a bidentate alkyl; R ^{10 is} selected from —H, lower alkyl, —NH ₂ , lower aryl, and lower perhaloalkyl; and R ^{11 is} selected from alkyl, aryl, —NR ² _2, and —OR ² . 17. The pharmaceutical composition according to clause 16, where the specified agent that enhances the secretion of insulin, is an antidiabetic agent based on sulfonylurea. 18. The pharmaceutical composition of claim 17, wherein said sulfonylurea antidiabetic agent is selected from glyburide, glisoxepide, acetohexamide, chlorpropapamide, glibornuride, tolbutamide, tolazamide, glipizide, glyclazide, glychidone, glyhexamide, fenbutamide, tolcylamide. 19. The pharmaceutical composition of claim 16, wherein said insulin secretion enhancing agent is selected from mitiglinide, BTS-67582, repaglinide, nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitors, and glucagon-like peptide-1 receptor agonists (GLP-1) . 20. The pharmaceutical composition according to claim 1, where M means

where B ^{5 is} selected from —NH—, —N = and CH =; D ^{5 is} selected from

and

Q ^{5 is} selected from —C = and —N—; provided that when B ⁵ means —NH— then Q ⁵ means —C = and D ⁵ means

when B ⁵ means —CH =, then Q ⁵ means —N— and D ⁵ means

and when B ⁵ means -N =, then D ⁵ means

and Q ⁵ means —C =; A, E and L are independently selected from —NR ⁸ ₂ , —NO ₂ , —H, —OR ⁷ , —SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —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, C ₂ -C ₅ alkynyl and a lower alicycle, 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 heterocycle; J is selected from —NR ⁸ ₂ , —NO ₂ , —H, —OR ⁷ , —SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —COR ¹¹ , —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or together with Y forms a cyclic group selected from the group consisting of aryl, cyclic alkyl and heterocyclic alkyl; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; 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 —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C (O) R ³ , S (O) ₂ R ³ , —C (O) —R ¹¹ , —CONHR ³ , —NR ² ₂ and —OR ³ , all except H, are optionally substituted; R ^{4 is} independently selected from —H and alkyl; or R ⁴ and R ⁴ together form a cyclic alkyl group; R ^{25 is} selected from lower alkyl, lower aryl, lower aralkyl and lower alicyclic; R ^{7 is} independently selected from —H, 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 together they form a bidentate alkyl; R ^{10 is} selected from —H, lower alkyl, —NH ₂ , lower aryl, and lower perhaloalkyl; and R ^{11 is} selected from alkyl, aryl, —NR ² _2, and —OR ² . 21. The pharmaceutical composition of claim 20, wherein said insulin secretion enhancing agent is a sulfonylurea-based antidiabetic agent. 22. The pharmaceutical composition according to claim 1, where M means -XR ⁵ where R ⁵ selected from

where each G is independently selected from C, N, O, S, and Se, and where not more than one G is O, S, or Se, and not more than one G is N; And selected from —H, —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 or absent; B is independently selected from —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, —C (O) R ¹¹ , —C (O) SR ³ , —SO ₂ R ¹¹ , —S (O) R ³ , -CN, -NR ⁹ ₂ , -OR ³ , -SR ³ , perhalogen-alkyl, halogen, -NO ₂ or absent, with the exception of -H, -CN, perhalogenated, -NO ₂ and halogen, all but hydrogen, optionally substituted; J is selected from —H or absent; X is an optionally substituted linking group that binds R ⁵ to a phosphorus atom through 2-4 atoms including 0-1 heteroatoms selected from N, O and S, except that when X is urea or carbamate, then there are 2 heteroatoms located along the shortest path between R ⁵ and the phosphorus atom, and where the atom attached to the phosphorus is a carbon atom, and where X is selected from furan-2,5-diyl, alkyl (hydroxy) -; alkynyl; heteroaryl; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; alkylthioalkyl-; alkylalkyl; -alkylaminocarbonyl-; alkylcarbonylamino; alkoxycarbonyl-; -carbonyloxyalkyl-; alkoxycarbonylamino and -alkylaminocarbonylamino, all optionally substituted, provided 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 —H; R ³ selected from alkyl, aryl, alicyclic and aralkyl; each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group; each R ^{9 is} independently selected from —H, alkyl, aralkyl and alicyclic, R ⁹ and R ⁹ together form a cyclic alkyl group or heterocyclic group, wherein the heteroatom is selected from the group consisting of O, S and N; R ^{11 is} selected from alkyl, aryl, —NR ² ₂ and —OR ² ₂ ; and provided that: 1) at least one of A and B is not selected from —H or absent; 2) when G is N, then the corresponding A or B does not mean a halogen or a group directly bonded to G via a heteroatom; 3) when X is not an aryl group, then R ^{5 is} not substituted with two or more aryl groups. 23. The pharmaceutical compositions of claim 22, wherein R ^{5 is} selected from 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-thidiazolyl, 1,3,4-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl and 1,3-selenazolyl, all of which contain at least one substituent. 24. The pharmaceutical composition according to item 22, where R ⁵ does not mean 2-thiazolyl or 2-oxazolyl. 25. The pharmaceutical composition according to item 22, where R ⁵ selected from the group including

where A ″ is selected from —H, —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 , -N ₃ , -NHC (S) NR ⁴ ₂ and -NHAc; B '' is selected from —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, —C (O) R ¹¹ , —C (O) SR ³ , —SO ₂ R ¹¹ , —S (O) R ³ , —CN, —NR ⁹ ₂ , —OR ³ , —SR ³ , perhaloalkyl, halogen, with the exception of —H, —CN, perhaloalkyl and halogen, are all optionally substituted; each R ^{3 is} independently selected from C ₁ -C ₆ alkyl, C ₆ aryl, C ₃ -C ₆ heteroaryl, C ₃ -C ₈ alicyclic, C ₂ -C ₇ heteroalicycle, C ₇ -C ₁₀ aralkyl and C ₄ -C ₉ heteroaryl; each R ⁴ and R ^{9 is} independently selected from —H and C ₁ -C ₂ alkyl; X is selected from -heteroaryl-, -alkylcarbonylamino, alkylaminocarbonyl- and -alkoxycarbonyl-; each R ^{11 is} selected from —NR ⁴ ₂ , —OH, —OR ³ , C ₁ -C ₆ alkyl and C ₆ aryl, C ₃ -C ₆ heteroaryl; 26. The pharmaceutical composition according A.25, where X is selected from -heteroaryl- and -alkoxycarbonyl-. 27. The pharmaceutical composition of claim 25, wherein said FBPase inhibitor is a compound of formula XII, XIII or XIV:

28. The pharmaceutical composition of claim 25, wherein A ″ is selected from —NH ₂ , —Cl, —Br, and CH ₃ ; each B ″ is selected from —H, —C (O) OR ³ , —C (O) SR ³ , C ₁ –C ₆ alkyl, alicyclic, halogen, heteroaryl, and —SR ³ . 29. The pharmaceutical composition according to item 27, where R ^{18 is} selected from —H, methyl and ethyl, each R ¹² and R ^{13 is} independently selected from —H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, —CH ₂ CH ₂ SCH ₃ , phenyl and benzyl or R ¹² and R ^{13 are} joined together by a chain of 2-5 carbon atoms to form a cycloalkyl group; n is 1 or 2; each R ^{14 is} independently selected from —OR ¹⁷ where R ^{17 is} selected from methyl, ethyl, propyl, and benzyl; and R ¹⁵ and R ^{16 are} independently selected from lower alkyl and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together by a chain of 2-6 atoms, optionally containing 1 heteroatom selected from O, N and S. 30. The pharmaceutical composition according to item 27, where R ¹⁶ means - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ . 31. The pharmaceutical composition according to item 27, where R is selected from —H, methyl, and ethyl; R ¹² and R ^{13 are} independently selected from —H, methyl, isopropyl, isobutyl and benzyl, or are joined together by a chain of 2-5 carbon atoms to form a cycloalkyl group; R ¹⁴ is —OR ¹⁷ ; R ¹⁷ selected from methyl, ethyl, propyl, tert-butyl and benzyl and R ¹⁵ and R ^{16 are} independently selected from lower alkyl and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together by a chain of 2-6 atoms, optionally including 1 heteroatom selected from O and N. 32. The pharmaceutical composition of claim 22, wherein said FBPase inhibitor is a compound of the formula

where X is selected from furan-2,5-diyl, alkoxycarbonyl and alkylaminocarbonyl. 33. The pharmaceutical composition according p, where n is 1; R ¹² and R ^{13 are} independently selected from —H, methyl, isopropyl, isobutyl and benzyl, or R ¹² and R ^{13 are} joined together by a chain of 2-5 carbon atoms to form a cycloalkyl group, and when R ¹² and R ¹³ are not the same, then H ₂ N-CR ¹² R ¹³ -C (O) -R ¹⁴ means an ester or thioester of a natural amino acid; R ^{14 is} selected from —OR ¹⁷ and —SR ¹⁷ ; R ¹⁷ selected from methyl, ethyl, propyl, tert-butyl and benzyl and R ^{18 is} selected from —H, methyl, and ethyl. 34. The pharmaceutical composition according A.25, where R ⁵ means

A ″ is selected from —NH ₂ , —CONH ₂ , halogen, —CH ₃ , —CF ₃ , —CH ₃ halogen, —CN, —OCH ₃ , —SCH ₃ , and —H; B is selected from —H, —C (O) R ¹¹ , —C (O) SR ³ , alkyl, aryl, alicyclic, halogen, —CN, —SR ³ , —OR ³ and —NR ⁹ ₂ ; and X is selected from -heteroaryl-, -alkoxycarbonyl- and -alkylaminocarbonyl-, all optionally substituted. 35. The pharmaceutical compositions of claim 34, wherein said FBPase inhibitor is a compound of formula IA and where

selected from

and

where C * is the S-configuration; R ¹⁸ and R ^{15 are} independently selected from H and methyl; R ¹² and R ^{13 are} independently selected from —H, methyl, isopropyl, isobutyl and benzyl, or R ¹² and R ^{13 are} joined together by a chain of 2-5 carbon atoms to form a cycloalkyl group; n is 1; R ¹⁴ is —OR ¹⁷ ; R ¹⁶ means - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ and R ^{17 is} selected from methyl, ethyl, propyl, phenyl and benzyl. 36. The pharmaceutical composition according to clause 34, where A "means -NH ₂ , X means furan-2,5-diyl and B" means -3 (CH ₂ ) ₂ CH ₃ . 37. The pharmaceutical composition according to claim 34, wherein A ″ is —NH ₂ , X is furan-2,5-diyl and B ″ is —CH ₂ CH (CH ₃ ) ₂ . 38. The pharmaceutical composition according to clause 37, where the specified FBPase inhibitor is a compound of formula 1A and where

means

39. The pharmaceutical composition according to clause 37, where the specified FBPase inhibitor is a compound of formula 1A and where

means

where C ^* is the S-configuration. 40. The pharmaceutical composition of claim 23, wherein said insulin secretion enhancing agent is an sulfonylurea-based antidiabetic agent. 41. The pharmaceutical composition according to claim 40, wherein said sulfonylurea-based antidiabetic agent is selected from glyburide, glisoxepide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, glyclazide, glychidone, glyhexamide, fenbutamide, tolcylamide. 42. The pharmaceutical composition according to claim 22, wherein said insulin secretion enhancing agent is selected from mitiglinide, BTS-67582, hepatlinide, nateglinide, dipeptidyl peptidase-IV inhibitors (DPP-IV) and glucagon receptor agonists like peptide-1 ( GLP-1). 43. A method of treating a mammal having diabetes or diabetes-related diseases, comprising administering to said mammal a pharmaceutically effective amount of a composition, said composition comprising component (a) comprising at least one insulin secretion enhancing agent and a pharmaceutically effective amount of the component (b) containing at least one FBPase inhibitor, said FBPase inhibitor is a compound selected from formulas I and IA, and pharmaceutically acceptable prodrugs, and x salts, where formulas I and IA are as follows:

and

where the compounds of formulas I and IA in vivo or in vitro are converted to M-PO ₃ ^2- , which inhibits FBP-ase, and where Y is independently selected from —O— and —NR ⁶ , provided that: when Y is —O—, then R ¹ attached to —O— is independently selected from —H, alkyl, optionally substituted aryl, optionally substituted alicyclic, where the cyclic moiety contains carbonate or thiocarbonate, optionally substituted α-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 -OC (O) OR ³ , -C (R ² ) ₂ OC (O) SR ³ , -alkyl-SC (O) R ³ , -alkyl-SS-alkyl hydroxy and -alkyl-SSS-alkyl hydroxy; when Y is —NR ⁶ , then R ¹ attached to —NR ⁶ is independently selected from —H, - [C (R ² ) ₂ ] _q —COOR ³ , —C (R ⁴ ) ₂ COOR ³ , - [C (R ² ) ₂ ] q-C (O) S) and cycloalkylene-COOR ³ , where q is 1 or 2; when only one Y is —O—, where —O— is not part of a cyclic group containing another Y, then 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 and form a cyclic group, or R ¹ and R ¹ together form

or

or

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 by an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is condensed with an aryl group at the beta and gamma positions of Y adjacent to V; or Z is selected from the group consisting of —CHR ² OH, —CHR ² C (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 = R ² ₂ ) OH, -CH (C ≡CR ² ) OH, -R ² , -NR ² ₂ , -OCOR ³ , -OCO ₂ R ³ , -SCOR ³ , -SCO ₂ R ³ , -NHCOR ² , -NHCO ₂ R ³ , -CH ₂ NH- aryl, - (CH ₂ ) _p OR ² and - (CH ₂ ) _p -SR ² , where p is an integer of 2 or 3; or Z and W are joined together by additional 3-5 atoms to form a cyclic group optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl; or W and W ′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or W and W ′ are joined together by an additional 2-5 atoms to form a cyclic group optionally containing 0-2 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 —H, 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 (O) SR ³ , -CHR ² C (S) OR ³ , -CH (aryl) OH, -CH (CH = CR ² ₂ ) OH, -CH (C≡CR ² ) OH, -SR ² , -CH ₂ NH-aryl, - CH ₂ aryl; or V ² and Z ^{2 are} joined together by an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally containing 1 heteroatom and substituted by hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom, which is three atoms from 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 —H; D ″ is selected from the group consisting of —H, alkyl, —OR ² , —OH and —OC (O) R ³ ; each W ^{3 is} independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; provided that V, Z, W, W '- all do not mean -H, and V ² , Z ² , W ² , W' - all do not mean -H; and R ^{2 is} selected from R ³ and —H; R ³ selected from alkyl, aryl, alicyclic and aralkyl; each R ^{4 is} independently selected from the group consisting of —H, alkylene, α-alkylenearyl and aryl, or R ⁴ and R ^{4 are} joined together by 2-6 atoms optionally containing one heteroatom selected from the group consisting of O, N and S; R ^{6 is} selected from —H, 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 and aralkyl, or R ¹² and R ^{18 are} joined together by 1-4 carbon atoms to form a cyclic group; each R ¹² and each R ^{13 is} independently selected from H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R ¹² and R ^{13 are} joined together by 2-6 carbon atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S, with the formation of a cyclic group; each R ^{14 is} independently selected from —OR ¹⁷ , —N (R ¹⁷ ) ₂ , —NHR ¹⁷ , —SR ^17, and —NR ² R ²⁰ ; R ^{15 is} selected from —H, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together by 2-6 atoms to form a cyclic group, wherein the cyclic group optionally contains one heteroatom selected from O, N and S; R ^{16 is} selected from - (CR ¹² R ¹³ ) _n —C (O) —R ¹⁴ , —H, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together by 2-6 atoms to form a cyclic group where the cyclic group optionally contains one heteroatom selected from O, N and S; each R ^{17 is} independently selected from lower alkyl, lower aryl and lower aralkyl, or when R ¹⁴ is —N (R ¹⁷ ) ₂ , then two R ^{17 are} joined together by 2-6 atoms to form a cyclic group, where the cyclic group optionally contains one a heteroatom selected from O, N and S; R ^{20 is} selected from the group consisting of —H, lower R ³ and —C (O) —lower — R ³ ; where M means

where A ^{2 is} selected from —NR ⁸ ₂ , —NHSO ₂ R ³ , —OR ²⁵ , —SR ²⁵ , halogen, lower alkyl, —CON (R ⁴ ) ₂ , guanidine, amidine, —H, and perhaloalkyl; E ^{2 is} selected from —H, halogen, lower alkylthio, lower perhaloalkyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, —CN and —NR ⁷ ₂ ; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; 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 —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C (O) R ³ , —S (O) ₂ R ³ , —C (O) —R ¹¹ , —CONHR ³ , —NR ² _2, and —OR ³ , all except H, are optionally substituted; each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group; R ^{25 is} selected from lower alkyl, lower aryl, lower aralkyl and lower alicyclic; each R ^{7 is} independently selected from —H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and —C (O) R ¹⁰ ; each R ^{8 is} independently selected from —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —C (O) R ^10, or two R ⁸ together form a bidentate alkyl; R ^{10 is} selected from —H, lower alkyl, —NHs, lower aryl, and lower perhaloalkyl; R ¹¹ selected from alkyl, aryl, -NR ² and -OR ₂ , and where M means:

where A, E and L are independently selected from —NR ⁸ ₂ , —NO ₂ , —H, —OR ⁷ , —SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —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, C ₂ -C ₅ - alkynyl and a 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 heterocycle; J is selected from —NR ⁸ ₂ , —NO ₂ , —H, —OR ⁷ , —SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —COR ¹¹ , —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or together with Y forms a cyclic group selected from the group consisting of aryl, cyclic alkyl and heterocyclic alkyl; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; 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 —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C (O) R ³ , —S (O) ₂ R ³ , —C (O) —R ¹¹ , - CONHR ³ , —NR ² _2, and —OR ³ , all except H, are optionally substituted; each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group; R ^{25 is} selected from lower alkyl, lower aryl, lower aralkyl and lower alicyclic; R ^{7 is} independently selected from —H, 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 two R ⁸ together form a bidentate alkyl; R ^{10 is} selected from —H, lower alkyl, —NH ₂ , lower aryl, and lower perhaloalkyl; R ^{11 is} selected from alkyl, aryl, —NR ² _2, and —OR ² ; where M means

where B ^{5 is} selected from —NH—, —N = and —CH =; D ^{5 is} selected from

and

Q ^{5 is} selected from —C = and —N—; provided that: when B ⁵ means —NH— then Q ⁵ means —C = and D ⁵ means

when B ⁵ means —CH =, then Q ⁵ means —N— and D ⁵ means

and when B ⁵ means -N =, then D ⁵ means

and Q ⁵ means —C =; A, E and L are independently selected from —NR ⁸ ₂ , —NO ₂ , —H, —OR ⁷ , —SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —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, 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 heterocycle; J is selected from —NR ⁸ ₂ , —NO ₂ , —H, —OR ⁷ , —SR ⁷ , —C (O) NR ⁴ ₂ halogen, —COR ¹¹ , —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or together with Y forms a cyclic group selected from the group consisting of aryl, cyclic alkyl and heterocyclic alkyl; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; 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 —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C (O) R ³ , S (O) ₂ R ³ , —C (O) —R ¹¹ , —CONHR ³ , —NR ² ₂ and —OR ³ , all except H, are optionally substituted; each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group; R ^{25 is} selected from lower alkyl, lower aryl, lower aralkyl and lower alicyclic; R ^{7 is} independently selected from —H, 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 together they form a bidentate alkyl; R ^{10 is} selected from —H, lower alkyl, —NH ₂ , lower aryl, and lower perhaloalkyl; and R ^{11 is} selected from alkyl, aryl, —NR ² _2, and —OR ³ ; and where M means -XR ⁵ where R ⁵ selected from

where each G is independently selected from C, N, O, S, and Se, and where at most one G is O, S, or Se, and at most one G is N; And selected from —H, —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 or absent; B is selected from —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, —C (O) R ¹¹ , —C (O) SR ³ , —SO ₂ R ¹¹ , —S (O) R ³ , -CN, -NR ⁹ ₂ , -OR ³ , -SR ³ , perhalogenated, halogen and -NO ₂ or absent, with the exception of -H, -CN, perhalogenated, -NO ₂ and halogen, all except -H, -CN , —NO ₂ and halogen are optionally substituted; J is selected from —H or absent; X is an optionally substituted linking group that binds R ⁵ to a phosphorus atom through 2-4 atoms including 0-1 heteroatoms selected from N, O and S, except that when X is urea or carbamate, then there are 2 heteroatoms located along the shortest path between R ⁵ and the phosphorus atom, and where the atom attached to the phosphorus means a carbon atom, and where X is selected from -alkyl (hydroxy) -; alkynyl; heteroaryl; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; -alkylaminocarbonyl-; -alkylcarbonylamino; alkoxycarbonyl-; -carbonyloxyalkyl-; -alkoxycarbonylamino and -alkylamino-carbonylamino, all optionally substituted, provided that X is not substituted -COOR ² , -SO ₃ H or -RO ₃ R ² ₂ ; R ^{2 is} selected from R ³ and —H; R ³ selected from alkyl, aryl, alicyclic and aralkyl; each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group; each R ^{9 is} independently selected from —H, alkyl, aralkyl and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group; R ^{11 is} selected from alkyl, aryl, —NR ² _2, and —OR ² ; and provided that: 1) at least one of A and B is not selected from —H or absent; 2) when G is N, then the corresponding A or B does not mean a halogen or a group directly bonded to G via a heteroatom; 3) when X is not an aryl group, then R ^{5 is} not substituted with two or more aryl groups. 44. The method of claim 43, wherein said insulin secretion enhancing agent is an sulfonylurea-based antidiabetic agent. 45. The method according to claim 44, wherein said sulfonylurea antidiabetic agent is selected from glyburide, glisoxepide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, glyclazide, glychidone, glyhexamide, fenbutamide, tolcylamide and. 46. The method of claim 43, wherein said insulin secretion enhancing agent is selected from mitiglinide, BTS-67582, replaglinide, nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitors, and glucagon-like peptide-1 receptor agonists (GLP-1). 47. The method according to item 43, where M means

where A ^{2 is} selected from —NR ⁸ ₂ , —NHSO ₂ R ³ , —OR ²⁵ , —SR ²⁵ , halogen, lower alkyl, —CON (R ⁴ ) ₂ , guanidine, amidine, —H, and perhaloalkyl; E ^{2 is} selected from —H, halogen, lower alkylthio, lower perhaloalkyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, —CN and —NR ⁷ ₂ ; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; 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 —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C (O) R ³ , —S (O) ₂ R ³ , —C (O) —R ¹¹ , - CONHR ³ , —NR ² _2, and —OR ³ , all except H, are optionally substituted; each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group; R ^{25 is} selected from lower alkyl, lower aryl, lower aralkyl and lower alicyclic; each R ^{7 is} independently selected from —H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and —C (O) R ¹⁰ ; each R ^{8 is} independently selected from —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —C (O) R ^10, or two R ⁸ together form a bidentate alkyl; R ^{10 is} selected from —H, lower alkyl, —NH ₂ , lower aryl, and lower perhaloalkyl; R ^{11 is} selected from alkyl, aryl, —NR ² _2, and —OR ₂ . 48. The method of claim 47, wherein said insulin secretion enhancing agent is an sulfonylurea-based antidiabetic agent. 49. The method of claim 48, wherein said sulfonylurea antidiabetic agent is selected from glyburide, glisoxepide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, glyclazide, glychidone, glyhexamide, fenbutamide, tolcylamide and. 50. The method of claim 47, wherein said insulin secretion enhancing agent is selected from mitiglinide, BTS-67582, replaglinide, nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitors, and glucagon-like peptide-1 receptor agonists (GLP-1). 51. The method according to item 43, where M means

where A, E and L are independently selected from —NR ⁸ ₂ —NO ₂ , —H, —OR ⁷ , —SR ⁷ , —C (O) NR ⁴ ₂ halogen, —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, 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 heterocycle; J is selected from —NR ⁸ ₂ , —NO ₂ , —H, —OR ⁷ , —SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —COR ¹¹ , —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or together with Y forms a cyclic group selected from the group consisting of aryl, cyclic alkyl and heterocyclic alkyl; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; 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 —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C (O) R ³ , —S (O) ₂ R ³ , —C (O) —R ¹¹ , - CONHR ³ , —NR ² _2, and —OR ³ , all except H, are optionally substituted; each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group; R ^{25 is} selected from lower alkyl, lower aryl, lower aralkyl and lower alicyclic; R ^{7 is} independently selected from —H, 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 two R ⁸ together form a bidentate alkyl; R ^{10 is} selected from —H, lower alkyl, —NH ₂ , lower aryl, and lower perhaloalkyl; R ^{11 is} selected from alkyl, aryl, —NR ² _2, and —OR ² . 52. The method of claim 51, wherein said insulin secretion enhancing agent is an sulfonylurea-based antidiabetic agent. 53. The method of claim 52, wherein said sulfonylurea antidiabetic agent is selected from glyburide, glycosoxide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, glyclazide, glychidone, glyhexamide, fenbutamide, tolcylamide and. 54. The method of claim 53, wherein said insulin secretion enhancing agent is selected from mitiglinide, BTS-67582, replaglinide, nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitors, and glucagon-like peptide-1 receptor agonists (GLP-1). 55. The method according to item 43, where M means

where B ^{5 is} selected from —NH—, —N = and —CH =; D ^{5 is} selected from

and

Q ^{5 is} selected from —C = and —N—; provided that: when B ⁵ means —NH— then Q ⁵ means —C = and D ⁵ means

when B ⁵ means —CH =, then Q ⁵ means —N— and D ⁵ means

and when B ⁵ means -N =, then D ⁵ means

and Q ⁵ means —C =; A, E and L are independently selected from —NR ⁸ ₂ , —NO ₂ , —H, —OR ⁷ , —SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —COR ¹¹ , —SO ₂ R ³ , guanidine , amidine, —NHSO ₂ R ²⁵ , —SO ₂ NR ⁴ ₂ , —CN, sulfoxide, perhalogenacyl, perhaloalkyl, perhaloalkoxy, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl and a lower alicycle, 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 heterocycle; J is selected from —NR ⁸ ₂ , —NO ₂ , —H, —OR ⁷ , —SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —COR ¹¹ , —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or together with Y forms a cyclic group selected from the group consisting of aryl, cyclic alkyl and heterocyclic alkyl; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; -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 —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C (O) R ³ , S (O) ₂ R ³ , —C (O) —R ¹¹ , —CONHR ³ , —NR ² ₂ and —OR ³ , all except H, are optionally substituted; each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group; R ^{25 is} selected from lower alkyl, lower aryl, lower aralkyl and lower alicyclic; R ^{7 is} independently selected from —H, 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 together they form a bidentate alkyl; R ^{10 is} selected from —H, lower alkyl, —NH ₂ , lower aryl, and lower perhaloalkyl; and R ^{11 is} selected from alkyl, aryl, —NR ² _2, and —OR ² . 56. The method of claim 55, wherein said insulin secretion enhancing agent is an sulfonylurea-based antidiabetic agent. 57. The method of claim 56, wherein said sulfonylurea antidiabetic agent is selected from glyburide, glisoxepide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, glyclazide, glychidone, glyhexamide, fenbutamide, tolcylamide and. 58. The method of claim 55, wherein said insulin secretion enhancing agent is selected from mitiglinide, BTS-67582, replaglinide, nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1). 59. The method according to item 43, where M means -XR ⁵ where R ⁵ represents

where each G is independently selected from C, N, O, S, and Se, and where not more than one G is O, S, or Se, and not more than one G is N; And selected from —H, —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 or absent; B is independently selected from —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, —C (O) R ¹¹ , —C (O) SR ³ , —SO ₂ R ¹¹ , —S (O) R ³ , -CN, -NR ⁹ ₂ , -OR ³ , -SR ³ , perhalogenated, halogen and -NO ₂ or absent, with the exception of -H, -CN, perhalogenated, -NO ₂ and halogen, all optionally substituted; J is selected from —H or absent; X is an optionally substituted linking group that binds R ⁵ to a phosphorus atom through 2-4 atoms including 0-1 heteroatoms selected from N, O and S, except that when X is urea or carbamate, then there are 2 heteroatoms located along the shortest path between R ⁵ and the phosphorus atom, and where the atom attached to the phosphorus means a carbon atom, and where X is selected from furan-2,5-diyl, -alkyl (hydroxy) -; alkynyl; heteroaryl; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; -alkylaminocarbonyl-; -alkylcarbonylamino; alkoxycarbonyl-; -carbonyloxyalkyl-; -alkoxycarbonylamino and -alkylamino-carbonylamino, all optionally substituted, provided that X is not substituted -COOR ² , -SO ₃ H or -PO ₃ R ² ₂ ; R ^{2 is} selected from R ³ and —H; R ³ selected from alkyl, aryl, alicyclic and aralkyl; each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group; each R ^{9 is} independently selected from —H, alkyl, aralkyl and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group; R ^{11 is} selected from alkyl, aryl, —NR ² _2, and —OR ² ; and provided that: 1) at least one of A and B is not selected from —H or absent; 2) when G is N, then the corresponding A or B does not mean a halogen or a group directly bonded to G via a heteroatom; 3) when X is not an aryl group, then R ^{5 is} not substituted with two or more aryl groups. 60. The method of claim 59, wherein said insulin secretion enhancing agent is an sulfonylurea-based antidiabetic agent. 61. The method of claim 60, wherein said sulfonylurea antidiabetic agent is selected from glyburide, glisoxepide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, glyclazide, glychidone, glyhexamide, fenbutamide, tolcylamide and. 62. The method of claim 59, wherein said insulin secretion enhancing agent is selected from mitiglinide, BTS-67582, replaglinide, nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1). 63. The method according to item 43, where the specified composition is administered orally. 64. The method according to item 43, where the specified disease is characterized by hyperglycemia. 65. The method according to item 43, where the specified disease is obesity. 66. The method according to item 43, where the specified mammal is administered from about 100 to 2000 mg of the aforementioned FBPase inhibitor and from about 3 to 250 mg of the aforementioned antidiabetic agent. 67. A pharmaceutical composition for the prevention and treatment of diabetes and related disorders and conditions, which comprises a pharmaceutically effective amount of insulin or an insulin analogue and a pharmaceutically effective amount of an FBPase inhibitor, wherein said FBPase inhibitor is a compound according to claim 1. 68. The pharmaceutical composition according p, where the specified insulin or insulin analogue is selected from insulin, insulin lispro, insulin aspart and insulin garglin. 69. A pharmaceutical composition for the prevention and treatment of diabetes and related disorders and conditions, which comprises a pharmaceutically effective amount of biguanide and a pharmaceutically effective amount of an FBPase inhibitor, wherein the FBPase inhibitor is a compound of formula I or formula IA according to claim 1. 70. The pharmaceutical composition according p, where the specified biguanide selected from metformin, phenformin and buformin. 71. A pharmaceutical composition for the prevention and treatment of diabetes and related disorders and conditions, which comprises a pharmaceutically effective amount of an alpha glucosidase inhibitor and a pharmaceutically effective amount of an FBPase inhibitor, wherein the FBPase inhibitor is a compound of formula I or formula IA according to claim .one. 72. The pharmaceutical composition of claim 71, wherein the alpha glucosidase inhibitor is selected from acarbose, miglitol, and voglibose. 73. A pharmaceutical composition for the prevention and treatment of diabetes and related disorders and conditions, which comprises a pharmaceutically effective amount of an inhibitor of FBPase and a pharmaceutically effective amount of an inhibitor of glucose production in the liver, selected from glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists , amylin agonists and fatty acid oxidation inhibitors, wherein the FBPase inhibitor is a compound of formula I or formula IA according to claim 1. 74. The pharmaceutical composition according to p, where the specified amylin agonist is pramlintide. 75. The pharmaceutical composition according to PP, 68, 73 and 74, where M means

where Z ^{6 is} selected from alkyl or halogen; U ⁶ and V ^{6 are} independently selected from hydrogen, hydroxy, acyloxy or, taken together, form a lower cyclic ring containing at least one oxygen; W ^{6 is} selected from amino and lower alkylamino, and their pharmaceutically acceptable prodrugs and salts. 76. The pharmaceutical composition according to PP, 68, 70 and 73, where M means

where A ^{2 is} selected from —NR ⁸ ₂ , —NHSO ₂ R ³ , —OR ²⁵ , —SR ²⁵ , halogen, lower alkyl, —CON (R ⁴ ) ₂ , guanidine, amidine, —H, and perhaloalkyl; E ^{2 is} selected from —H, halogen, lower alkylthio, lower perhaloalkyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, —CN and —NR ⁷ ₂ ; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; -alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; -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 —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C (O) R ³ , —S (O) ₂ R ³ , —C (O) —R ¹¹ , —CONHR ³ , —NR ² _2, and —OR ³ , all except H, are optionally substituted; each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group; R ^{25 is} selected from lower alkyl, lower aryl, lower aralkyl and lower alicyclic; R ^{7 is} independently selected from —H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and —C (O) R ¹⁰ ; each R ^{8 is} independently selected from —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —C (O) R ^10, or two R ⁸ together form a bidentate alkyl; R ^{10 is} selected from —H, lower alkyl, —NH ₂ , lower aryl, and lower perhaloalkyl; and R ^{11 is} selected from alkyl, aryl, —NR ² _2, and —OR ² . 77. The pharmaceutical composition according to PP, 69, 71 and 73, where M means

where A, E and L are independently selected from —NR ⁸ ₂ , —NO ₂ , —H, —OR ⁷ , —SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —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, 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, including aryl, cyclic alkyl and heterocycle; J is selected from —NR ⁸ ₂ , —NO ₂ , —H, —OR ⁷ , —SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —COR ¹¹ , —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or together with Y forms a cyclic group, including aryl, cyclic alkyl and heterocyclic alkyl; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; 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 —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C (O) R ³ , S (O) ₂ R ³ , —C (O) —R ¹¹ , —CONHR ³ , —NR ² ₂ and —OR ³ , all except H, are optionally substituted; R ^{4 is} independently selected from —H and alkyl; or R ⁴ and R ⁴ together form a cyclic alkyl group; R ^{25 is} selected from lower alkyl, lower aryl, lower aralkyl and lower alicyclic; R ^{7 is} independently selected from —H, 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 two R ⁸ together form a bidentate alkyl; R ^{10 is} selected from —H, lower alkyl, —NH ₂ , lower aryl, and lower perhaloalkyl; and R ^{11 is} selected from alkyl, aryl, —NR ² _2, and —OR ² . 78. The pharmaceutical composition according to PP, 69, 71 and 73, where M means

where B ^{5 is} selected from —NH—, —N = and —CH =; D ^{5 is} selected from

and

Q ^{5 is} selected from —C = and —N—; provided that: when B ⁵ means —NH— then Q ⁵ means —C = and D ⁵ means

when B ⁵ means —CH =, then Q ⁵ means —N— and D ⁵ means

and when B ⁵ means -N =, then D ⁵ means

and Q ⁵ means —C =; A, E and L are independently selected from —NR ⁸ ₂ , NO ₂ , —H, —OR ⁷ , —SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —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, 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 including aryl, cyclic alkyl and heterocycle; J is selected from —NR ⁸ ₂ , —NO ₂ , —H, —OR ⁷ , —SR ⁷ , —C (O) NR ⁴ ₂ halogen, —COR ¹¹ , —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or together with Y forms a cyclic group, including aryl, cyclic alkyl and heterocyclic alkyl; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; 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 —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C (O) R ³ , S (O) ₂ R ³ , —C (O) —R ¹¹ , —CONHR ³ , —NR ² ₂ and —OR ³ , all except H, are optionally substituted; R ^{4 is} independently selected from —H and alkyl; or R ⁴ and R ⁴ together form a cyclic alkyl group; R ^{25 is} selected from lower alkyl, lower aryl, lower aralkyl and lower alicyclic; R ^{7 is} independently selected from —H, 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 together they form a bidentate alkyl; R ^{10 is} selected from —H, lower alkyl, —NH ₂ , lower aryl, and lower perhaloalkyl; R ^{11 is} selected from alkyl, aryl, —NR ² _2, and —OR ³ . 79. The pharmaceutical composition according to claims 67, 69, 71 and 73, wherein M is —XR ⁵ , where R ⁵ is

where each G is independently selected from C, N, O, S, and Se, and where at most one G is O, S, or Se, and at most one G is N; And selected from —H, —NR ⁴ ₂ , —CONR ⁴ ₂ , —CO ₃ 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 or absent; B is independently selected from —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, —C (O) R ¹¹ , —C (O) SR ³ , —SO ₂ R ¹¹ , —S (O) R ³ , -CN, -NR ⁹ ₂ , -OR ³ , -SR ³ , perhalogenated, halogen, -NO ₂ or absent, all, with the exception of -H, -CN, perhalogenated, -NO ₂ and halogen, are optionally substituted; J is selected from —H or absent; X is an optionally substituted linking group that binds R ⁵ to a phosphorus atom through 2-4 atoms including 0-1 heteroatoms selected from N, O and S, except that when X is urea or carbamate, then there are two heteroatoms located along the shortest path between R ⁵ and the phosphorus atom, and where the atom attached to the phosphorus means a carbon atom, and where X is selected from -alkyl (hydroxy) -; alkynyl; heteroaryl; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; -alkylaminocarbonyl-; -alkylcarbonylamino; alkoxycarbonyl-; -carbonyloxyalkyl-; -alkoxycarbonylamino and alkylaminocarbonylamino, all optionally substituted, provided 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 —H; R ³ selected from alkyl, aryl, alicyclic and aralkyl; each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group; each R ^{9 is} independently selected from —H, alkyl, aralkyl, and alicyclic; R ⁹ and R ⁹ together form a cyclic alkyl group; R ^{11 is} selected from alkyl, aryl, —NR ² ₂ and —OR ² ₂ ; provided that 1) at least one of A and B is not selected from —H or absent; 2) when G is N, then the corresponding A or B does not mean a halogen or a group directly bonded to G via a heteroatom; 3) when X is not an aryl group, then R ^{5 is} not substituted with two or more aryl groups. 80. The pharmaceutical composition of claim 79, wherein R ^{5 is} selected from 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, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl and 1,3-selenazolyl, all of which contain at least one substituent. 81. The pharmaceutical composition according p, where R ⁵ selected from

where A ″ is selected from —H, —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 -perhalogenated, C ₁ -C ₆ -halogenated, 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 and -NHAc; B '' is selected from —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, —C (O) R ¹¹ , —C (O) SR ³ , —SO ₂ R ¹¹ , —S (O) R ³ , —CN, —NR ⁹ ₂ , —OR ³ , —SR ³ , perhaloalkyl and halogen, all except —H, —CN, perhaloalkyl and halogen are optionally substituted; each R ^{3 is} independently selected from C ₁ -C ₆ 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 ₉ heteroaryl; each R ⁴ and R ^{9 is} independently selected from —H and C ₁ -C ₂ alkyl; X is selected from -heteroaryl-, -alkylcarbonylamino, -alkylaminocarbonyl- and -alkoxycarbonyl-; each R ^{11 is} selected from —NR ⁴ ₂ , —OH, —OR ³ , C ₁ -C ₆ alkyl and C ₆ aryl, C ₃ -C ₆ heteroaryl; 82. The pharmaceutical composition of claim 81, wherein said FBPase inhibitor is a compound of formula IA and where R ⁵ is

A ″ is selected from —NH ₂ , —CONH ₂ , halogen, —CH ₃ , —CF ₃ , —CH ₂ halogen, —CN, —OCH ₃ , —SCH ₃ and —H; each B ″ is selected from —H, —C (O) R ¹¹ , —C (O) SR ³ , alkyl, aryl, alicyclic, halogen, —CN, —SR ³ , —OR ³ and —NR ⁹ ₂ ; X is selected from -heteroaryl-, -alkoxycarbonyl- and -alkylaminocarbonyl-, all optionally substituted; and Where

selected from

and

where C * is the S-configuration; R ¹⁸ and R ^{15 are} each independently selected from H and methyl; each R ¹² and R ^{13 is} independently selected from —H, methyl, isopropyl, isobutyl and benzyl, or R ¹² and R ^{13 are} joined together by 2-5 carbon atoms to form a cycloalkyl group; n is 1; R ¹⁴ is —OR ¹⁷ ; R ¹⁶ means - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ and R ^{17 is} selected from methyl, ethyl, propyl, phenyl and benzyl. 83. The pharmaceutical composition of claim 82, wherein said composition comprises insulin or an insulin analog selected from insulin, insulin lispro, insulin aspart and insulin garglin. 84. The pharmaceutical composition according p, where the specified composition contains a biguanide selected from metformin, phenformin and buformin. 85. The pharmaceutical composition of claim 82, wherein said composition comprises an alpha glucosidase inhibitor selected from acarbose, miglitol and voglibose. 86. A method of treating a mammal with diabetes, comprising administering to said mammal: a pharmaceutically effective amount of component (a) containing at least one agent from insulin, an insulin analog, a biguanide, an inhibitor of glucose production in the liver, or an alpha glucosidase inhibitor; and a pharmaceutically effective amount of component (b) containing at least one FBPase inhibitor, which is a compound of formulas I and IA and its pharmaceutically acceptable prodrugs and salts, where formulas I and IA are as follows:

and

wherein in vivo or in vitro of formulas I and IA compounds are converted to M-PO _of ^2- which inhibits FBP-ase, and wherein Y is independently selected from —O— and —NR ⁶ , provided that: when Y is —O—, then R ¹ attached to —O— is independently selected from —H, alkyl, optionally substituted aryl, optionally substituted alicyclic, where the cyclic moiety contains carbonate or thiocarbonate, optionally substituted α-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 -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 , then R ¹ attached to —NR ⁶ is independently selected from —H, - [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 , where q is 1 or 2; when only one Y is —O—, where —O— is not part of a cyclic group containing another Y, then 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 and form a cyclic group, or R ¹ and R ¹ together form

or

or

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 by an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is condensed with an aryl group at the beta and gamma positions of Y adjacent 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 C (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 , -SCO ₂ R ³ , -NHCOR ² , -NHCO ₂ R ³ , -CH ₂ NH- aryl, - (CH ₂ ) _p OR ² and - (CH ₂ ) _p —SR ² , where p is an integer of 2 or 3; or Z and W are joined together by additional 3-5 atoms to form a cyclic group optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl or substituted heteroaryl; or W and W ′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or W and W ′ are joined together by an additional 2-5 atoms to form a cyclic group optionally containing 0-2 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 —H, 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 (O) SR ³ , -CHR ² OC (S) OR ³ , -CH (aryl) OH, -CH (CH = CR ² ₂ ) OH, -CH (C≡CR ² ) OH, -SR ² , -CH ₂ NH-aryl, - CH ₂ -aryl; or V ² and Z ^{2 are} joined together by an additional 3-5 atoms to form a cyclic group containing 5-7 atoms in the ring, optionally containing 1 heteroatom and substituted by hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom, which is three atoms from 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 —H; D ″ is selected from the group consisting of —H, alkyl, —OR ² , —OH and —OC (O) R ³ ; each W ^{3 is} independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; provided that V, Z, W, W '- all do not mean - H, and V ² , Z ² , W ² , W''- all do not mean -H; and R ^{2 is} selected from R ³ and —H; R ³ selected from alkyl, aryl, alicyclic or aralkyl; each R ^{4 is} independently selected from the group —H, alkyl, alkylene aryl and aryl, or together R ⁴ and R ^{4 are} connected through 2-6 atoms, optionally including one heteroatom selected from O, S and N. R ^{6 is} selected from —H, 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 and aralkyl, or R ¹² and R ^{18 are} joined together by 1-4 carbon atoms to form a cyclic group; each R ¹² and each R ^{13 is} independently selected from H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R ¹² and R ^{13 are} joined together by 2-6 carbon atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S, with the formation of a cyclic group; each R ^{14 is} independently selected from —OR ¹⁷ , —N (R ¹⁷ ) ₂ , —NHR ¹⁷ , —SR ^17, and —NR ² R ²⁰ ; R ^{15 is} selected from —H, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together by 2-6 atoms to form a cyclic group, wherein the cyclic group optionally contains one heteroatom selected from O, N and S; R ^{16 is} selected from - (CR ¹² R ¹³ ) _n —C (O) —R ¹⁴ , —H, lower alkyl, lower aryl and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together by 2-6 atoms to form a cyclic group where the cyclic group optionally contains one heteroatom selected from O, N and S; each R ^{17 is} independently selected from lower alkyl, lower aryl and lower aralkyl, or when R ¹⁴ is —N (R ¹⁷ ) ₂ , then two R ^{17 are} joined together by 2-6 atoms to form a cyclic group, where the cyclic group optionally contains one a heteroatom selected from O, N and S; where M is selected from the group including M means

where A, E and L are independently selected from —NR ⁸ ₂ , —NO ² , —H, —OR ⁷ , —SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —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, C ₂ -C ₅ - alkynyl and a 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 heterocycle; J is selected from —NR ⁸ ₂ , —NO ₂ , —H, —OR ⁷ , —SR ⁷ , —C (O) NR ⁴ ₂ , halogen, —COR ¹¹ , —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy , alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or J and Y together form a cyclic group selected from the group consisting of aryl, cyclic alkyl and heterocyclic alkyl; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; 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 - H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C (O) R ³ , -S (O) ₂ R ³ , -C (O) -R ¹¹ , - CONHR ³ , —NR ² _2, and —OR ³ , all except H, are optionally substituted; each R ^{4 is} independently selected from —H and alkyl, or together R ⁴ and R ⁴ form a cyclic alkyl group; R ^{25 is} selected from lower alkyl, lower aryl, lower aralkyl, lower alicyclic; each R ^{7 is} independently selected from H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and —C (O) R ¹⁰ ; each R ^{8 is} independently selected from H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl and —C (O) R ¹⁰ or together two R ⁸ form bidentant alkyl; R ¹⁰ selected from —H, lower alkyl, lower aryl and lower perhaloalkyl, NH ₂ ; R ^{11 is} selected from alkyl, aryl, NR ² ₂ and OR ² ; where M represents -XR ₅ where R ₅ means

where each G is independently selected from C, N, O, S, and Se, and where no more than one G is O, S, or Se, and no more than one G is N; And selected from —H, —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 or absent; B is selected from —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, —C (O) R ¹¹ , —C (O) SR ³ , —SO ₂ R ¹¹ , —S (O) R ³ , —CN, —NR ⁹ ₂ , —OR ³ , —SR ³ , perhaloalkyl, halogen, —NO ₂ or is absent, with the exception of —H, —CN, perhaloalkyl, —NO ₂ and halogen, all optionally substituted; J is selected from —H or absent; X is an optionally substituted linking group that binds R ⁵ to a phosphorus atom through 2-4 atoms including 0-1 heteroatoms selected from N, O and S, except that when X is urea or carbamate, then there are 2 heteroatoms located along the shortest path between R ⁵ and the phosphorus atom, and where the atom attached to the phosphorus means a carbon atom, and where X is selected from furan-2,5-diyl, alkyl (hydroxy) -; alkynyl; heteroaryl; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; alkylthioalkyl-; alkylalkyl; -alkylaminocarbonyl-; alkylcarbonylamino; alkoxycarbonyl-; -carbonyloxyalkyl-; alkoxycarbonylamino and -alkylaminocarbonylamino, all optionally substituted, provided 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 —H; R ^{3 is} selected from alkyl, aryl, alicyclic, and aralkyl; each R ^{4 is} independently selected from —H and alkyl, or together R ⁴ and R ⁴ form a cyclic alkyl group; each R ^{9 is} independently selected from —H, alkyl, aralkyl and alicyclic, or both together R ⁹ and R ⁹ form a cyclic alkyl group; R ^{11 is} selected from alkyl, aryl, —NR ₂ , and OR ₂ ; provided that 1) at least one of A and B is not selected from - H or absent; 2) when G is N, then the corresponding A or B does not mean a halogen or a group directly bonded to G via a heteroatom; 3) when X is not an aryl group, then R ^{5 is} not substituted with two or more aryl groups. 87. The method according to p, where the specified insulin or insulin analogue is selected from insulin, insulin lispro, insulin aspart and insulin garglin. 88. The method of claim 86, wherein said biguanide is selected from metformin, phenformin, and buformin. 89. The method of claim 86, wherein said liver glucose production inhibitor is selected from glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists, amylin agonists and fatty acid oxidation inhibitors. 90. The method of claim 88, wherein said amylin agonist is pramlintide. 91. The method of claim 86, wherein said alpha glucosidase inhibitor is selected from acarbose, miglitol, and voglibose. 92. The pharmaceutical composition according to claim 1, where M means X ⁴ -R ⁵⁵ where R ⁵⁵ represents

where G ² selected from the group of C, O and S; G ³ and G ^{4 are} independently selected from the group C, N, O, and S; where a) not more than one of G ² , G ³ and G ⁴ means O or S; b) if G ² means O or S, then not more than one of G ³ and G ⁴ means N; c) at least one of G ² , G ³ and G ⁴ means C and d) G ² , G ³ and G ⁴ - all do not mean C; J ³ , J ⁴ , J ⁵ , J ⁶ and J ^{7 are} independently selected from the group of —H, —NR ⁴ ₂ , —CONR ⁴ ₂ , —CO ₂ R ³ , halogen, —S (O) ₂ NR ⁴ ₂ , -S (O) R ³ , -SO ₂ R ³ , alkyl, alkenyl, alkynyl, alkylene aryl, perhaloalkyl, haloalkyl, aryl, heteroaryl, alkylene-OH, -C (O) R ¹¹ , -OR ¹¹ , -alkylene-NR ⁴ ₂ , -alkylene-CN, -CN, -C (S) NR ⁴ ₂ , -OR ² , -SR ² , -N ₃ , -NO ₂ , -NHC (S) NR ⁴ ₂ and -NR ²¹ COR ² ; X ^{4 is} selected from: i) a linking group having 2-4 atoms located on the smallest number of atoms connecting the carbon of the aromatic ring and the phosphorus atom, which is selected from the group consisting of -furanyl-, -thienyl-, -pyridyl-, -oxazolyl-, -imidazolyl- , -phenyl-, -pyrimidinyl-, -pyrazinyl- and -alkynyl-, all of which are optionally substituted; and ii) a linking group that contains 3-4 atoms located on the smallest number of atoms connecting the carbon of the aromatic ring and the phosphorus atom, and is selected from the group of alkylenecarbonylamino, alkyleneaminocarbonyl-, alkyleneoxycarbonyl-, alkyleneoxy and alkyleneoxyalkylene, all of which optionally substituted; R ^{11 is} selected from the group consisting of alkyl, aryl, —NR ² _2, and —OR ² ; R ^{20 is} selected from the group consisting of —H, lower R ³ and —C (O) - (lower R ³ ); R ^{21 is} selected from —H and lower R ³ ; provided that: 1) when X ⁴ is substituted furanyl, then at least one of J ³ , J ⁴ , J ⁵ and J ⁶ cannot mean —H or be absent; 2) when X ⁴ does not mean substituted furanyl, then at least two of J ³ , J ⁴ , J ⁵ and J ⁶ in formula VII-5 cannot mean —H or be absent; 3) when G ² , G ³ or G ⁴ means O or S, then the corresponding J ³ , J ⁴ or J ^{5 is} absent; 4) when G ³ or G ⁴ means N, then the corresponding J ⁴ or J ⁵ does not mean halogen or a group directly bonded to G ³ or G ⁴ via a heteroatom; 5) when two Y groups mean —NR ⁶ -, and R ¹ and R ^{1 are} not connected to form a cyclic phosphoramidate, then at least one R ¹ means - (CR ¹² R ¹³ ) _n —C (O) —R ¹⁴ ; 6) when R ^{55 is} substituted with phenyl, then J ⁴ , J ⁵ and J ⁶ do not mean purinyl, purinylalkylene, deaza-purinyl or deazapurinylalkylene; 7) R ¹ can be selected from lower alkyl only when the other YR ¹ is —NR ¹⁸ —C (R ¹² R ¹³ ) _n —C (O) —R ¹⁴ ; 8) when R ^{55 is} substituted with phenyl and X ⁴ is 1,2-ethynyl, then J ⁴ or J ⁶ does not mean a heterocyclic group; 9) when X ⁴ is 1,2-ethynyl, then G ⁵ or G ⁷ cannot be N. 93. The pharmaceutical composition of claim 40, wherein the FBPase inhibitor is

94. The method according to item 43 or 86, where the specified component (a) and the specified component (b) are administered one after the other with an interval of within 1 hour 95. The method according to clause 94, wherein said component (a) and said component (b) are administered one after the other with an interval of 10 minutes. 96. The method according to item 43 or 86, where one of the specified component (a) and the specified component (b) is administered first and the other of the specified component (a) and the specified component (b) is administered after 1 to 12 hours 97. The method according to item 43 or 86, where the specified mammal suffers from labile diabetes. 98. The method according to item 43 or 86, where the specified mammal suffers from NIDDM. 99. The method according to item 43 or 86, where the specified mammal suffers IDDM. 100. The pharmaceutical composition of claim 10, wherein said glucagon-like peptide-1 receptor agonist (GLP-1) is NN-2211 or exendin. 101. A method of preventing diabetes in animals, comprising administering to animals at risk of developing diabetes a pharmaceutically effective amount of an insulin secretion stimulator and a pharmaceutically effective amount of at least one FBPase inhibitor, wherein said FBPase inhibitor is a compound according to claim 43 . 102. A method of treating reduced glucose tolerance, comprising administering to the patient, if necessary, such a treatment, a pharmaceutically effective amount of an insulin secretion stimulator and a pharmaceutically effective amount of at least one FBPase inhibitor, wherein said FBPase inhibitor is a compound according to claim 1. 43. 103. A method of treating insulin resistance, comprising administering to the patient, if necessary, such a treatment, a pharmaceutically effective amount of an insulin secretion promoter and a pharmaceutically effective amount of at least one FBPase inhibitor, wherein said FBPase inhibitor is a compound according to claim 43 . 104. The method of claim 101, wherein said animals at risk of developing diabetes suffer from a disease or condition selected from the group consisting of reduced glucose tolerance, insulin resistance, hyperglycemia, obesity, accelerated glyconeogenesis and increased liver glucose production. 105. The pharmaceutical composition of claim 25, wherein Y is O, R ¹ is —H, X is furan-2,5 = diyl, R ⁵ is

where A ″ represents —NHz, B ″ represents —C (O) R ^11, and R ¹¹ represents alkyl. 106. The pharmaceutical compositions of claim 35, wherein said FBPase inhibitor is a compound of formula IA and where

represents

107. The pharmaceutical compositions of claim 35, wherein X is furan-2,5-diyl, where A ″ is —NH ₂ , B ″ is —C (O) R ¹¹ , where R ¹¹ is alkyl . 108. The pharmaceutical compositions of claim 35, wherein said FBPase inhibitor is a compound of formula IA and where

represents

where C * has S-stereochemistry. 109. The pharmaceutical compositions of claim 22, wherein X is furan-2,5-diyl, wherein A ″ is —NH2, B ″ is alkyl. 110. The pharmaceutical compositions of claim 22, wherein the FBRase inhibitor is

111. The pharmaceutical compositions of claim 22, wherein the FBRase inhibitor is

112. The pharmaceutical composition of claim 1 wherein the FBP-ase inhibitor is a compound of formula I, wherein M is XR ^5; R ⁵ represents

A ″ is selected from the group consisting of —H, —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 , -N ₃ , -NHC (S) NR ⁴ ₂ and -NHAc; B ″ represents —H, alkyl, alkenyl, alkynyl, aryl, alicyclic group, aralkyl, alkoxyalkyl, —C (O) R ¹¹ , —C (O) SR ³ , —SO ₂ R ¹¹ , —S (O) R ³ , —CN, —NR ⁹ ₂ , —OR ³ , —SR ³ , perhaloalkyl and halogen, with all groups except —H, —CN, perhaloalkyl and halogen optionally substituted; X is selected from the group consisting of methyleneoxycarbonyl and furan-2,5-diyl; and YR ¹ is OH or Y is NR ⁶ , wherein R ^{6 is} selected from H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, or lower acyl; and R ^{1 is} independently selected from the group consisting of —H, - [C (R ² ) ₂ ] _q —COOR ³ , —C (R ⁴ ) ₂ COOR ³ , - [C (R ² ) ₂ ] _q —C ( O) SR ³ and β-cycloalkylene-COOR ³ , wherein R ^{4 is} independently alkyl or H and R ³ is an alkyl, aryl, alicyclic or aralkyl group. 113. The pharmaceutical composition according p, where A ″ represents —NH ₂ , —Cl, —Br or —CH ₃ ; B ″ represents —H, —C (O) OR ³ , —C (O) SR ³ , C ₁ -C ₆ alkyl, C (O) R ¹¹ , an alicyclic group, halogen, heteroaryl, or —SR ^3, and wherein all groups except -H and halogen are optionally substituted. 114. The pharmaceutical composition according p, where A "represents -NH ₂ ; B" represents C ₁ -C ₆ alkyl or C (O) R ¹¹ and R ¹¹ represents alkyl. 115. The pharmaceutical composition according p, where X is furan-2,5-diyl. 116. The pharmaceutical composition according p, where Y is NR ⁶ , R ⁶ selected from H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl or lower acyl; and R ^{1 is} independently selected from the group consisting of —H, - [C (R ² ) ₂ ] _q —COOR ³ , —C (R ⁴ ) ₂ COOR ³ , - [C (R ² ) ₂ ] _q —C ( O) SR ³ and β-cycloalkylene-COOR ³ , wherein R ^{4 is} independently alkyl or H and R ³ is an alkyl, aryl, alicyclic or aralkyl group. 117. The pharmaceutical composition according p, where Y is NR ⁶ , R ⁶ represents H and R ¹ represents -C (R ⁴ ) ₂ COOR ³ , and R ^{4 is} independently selected from H or methyl and R ³ represents alkyl. 118. The pharmaceutical composition according p, where A "represents -NH ₂ ; B ″ is C ₁ -C ₆ alkyl or C (O) R ¹¹ where R ¹¹ is alkyl and X is selected from the group consisting of methyleneoxycarbonyl and furan-2,5-diyl. 119. The pharmaceutical composition according p, where X is furan-2,5-diyl. 120. The pharmaceutical composition according p, where A "represents -NH ₂ ; In "represents C ₁ -C ₆ alkyl or C (O) R ¹¹ and R ¹¹ represents alkyl and YR ¹ represents OH. 121. The pharmaceutical composition according p, where A "represents -NH ₂ ; B" represents C ₁ -C ₆ alkyl or C (O) R ¹¹ and R ¹¹ represents alkyl; Y represents NR ⁶ and R ⁶ is H; and R ¹ is —C (R ⁴ ) ₂ COOR ³ , wherein R ⁴ is independently H or methyl and R ³ is alkyl. 122. The pharmaceutical composition of Claim 112, wherein X is furan-2,5-diyl and YR ¹ is OH. 123. The pharmaceutical composition according p, where X is furan-2,5-diyl; Y is NR ⁶ and R ⁶ is H and R ¹ is —C (R ⁴ ) ₂ COOR ³ , wherein R ^{4 is} independently H or methyl and R ³ is alkyl. 124. The pharmaceutical composition of Claim 112, wherein A ″ is —NH ₂ , B ″ is C ₁ -C ₆ alkyl or C (O) R ¹¹ , wherein R ¹¹ is alkyl; X is selected from the group consisting of methyleneoxycarbonyl and furan-2,5-diyl; and YR ¹ is OH. 125. The pharmaceutical composition according p, where X is furan-2,5-diyl. 126. The pharmaceutical composition according p, where A "represents -NH ₂ ; B ″ is C ₁ -C ₆ alkyl or C (O) R ¹¹ , wherein R ¹¹ is alkyl; X is selected from the group consisting of methyleneoxycarbonyl and furan-2,5-diyl; Y represents NR ⁶ and R ⁶ represents H; and R ¹ is —C (R ⁴ ) ₂ COOR ³ , wherein R ^{4 is} independently H or methyl and R ³ is alkyl. 127. The pharmaceutical composition according p, where X is furan-2,5-diyl. 128. The pharmaceutical composition of Claim 112, wherein said FBRase inhibitor is compound J

. 129. The pharmaceutical composition according to claims 112-128, wherein said insulin secretion stimulator is an sulfidylurea-based antidiabetic agent. 130. The pharmaceutical composition of claim 129, wherein said sulfonylurea antidiabetic agent is a compound of formula XV

where A is selected from hydrogen, halogen, alkyl, alkanoyl, aryl, aralkyl, heteroaryl and cycloalkyl; and B is selected from alkyl, cycloalkyl and heterocyclic alkyl. 131. The pharmaceutical composition of claim 130, wherein said sulfonylurea antidiabetic agent is selected from glyburide, glyxoxepide, acetohexamide, chloropropamide, glibornuride, tolbutamide, tolazamide, glipizide, glyclazide, glycuidone, glyhexamide, fenbutamide or tolamide, tolamide or tolamide. 132. The pharmaceutical composition according to claims 112-128, wherein said insulin secretion stimulator is non-sulfonylurea. 133. The pharmaceutical composition according p, where the aforementioned non-sulfonylurea is selected from mitiglinide, BTS-67582, repaglinide or nateglinide. 134. The pharmaceutical composition according to claims 112-128, wherein said insulin secretion stimulator is a dipeptidyl peptidase-IV inhibitor (DPP-IV). 135. The pharmaceutical composition according p, where the said dipeptidyl peptidase-IV inhibitor (DPP-IV) is NVP-DPP728 or P32 / 98. 136. The pharmaceutical composition according to claims 112-128, wherein said insulin secretion stimulator is a glucagon-like peptide-1 (GLP-1), a receptor antagonist. 137. The pharmaceutical composition according p, where the aforementioned glucagon-like peptide-1 (GLP-1) receptor antagonist is NN-2211, an exendin or an exendin antagonist. 138. The pharmaceutical composition of claim 112, wherein said sulfonylurea as an antidiabetic agent is glyburide and said FBRase inhibitor is compound J

139. A method of treating animals having diabetes, comprising administering to them a composition according to claims 112-138. 140. A method of reducing the activity of FBR-basics in animals, comprising administering a composition according to any one of paragraphs 112-138. 141. A method for the prevention of diabetes in animals, comprising administering a composition according to any one of paragraphs 112-138. 142. A method for the prevention and treatment of diseases and conditions associated with diabetes in an animal, comprising administering a composition according to any one of paragraphs 112-138.