FBPase inhibitors of the formula I and X

This invention relates to novel heteroaromatic compounds that possess a phosphonate group that are inhibitors of Fructose-1,6-bisphosphatase. The invention also relates to the preparation and use of these compounds in the treatment of diabetes, and other diseases where the inhibition of gluconeogenesis, control of blood glucose levels, reduction in glycogen storage, or reduction in insulin levels is beneficial.
The following description of the background of the invention is provided to aid in understanding the invention, but is not admitted to be, or to describe, prior art to the invention. All cited publications are incorporated by reference in their entirety.
Diabetes mellitus (or diabetes) is one of the most prevalent diseases in the world today. Diabetic patients have been divided into two classes, namely type I or insulin-dependent diabetes mellitus and type II or non-insulin dependent diabetes mellitus (NIDDM). NIDDM accounts for approximately 90% of all diabetics and is estimated to affect 12-14 million adults in the U.S. alone (6.6% of the population). NIDDM is characterized by both fasting hyperglycemia and exaggerated postprandial increases in plasma glucose levels. NIDDM is associated with a variety of long-term complications, including microvascular diseases such as retinopathy, nephropathy and neuropathy, and macrovascular diseases such as coronary heart disease. Numerous studies in animal models demonstrate a causal relationship between long term hyperglycemia and complications. Results from the Diabetes Control and Complications Trial (DCCT) and the Stockholm Prospective Study demonstrate this relationship for the first time in man by showing that insulin-dependent diabetics with tighter glycemic control are at substantially lower risk for the development and progression of these complications. Tighter control is also expected to benefit NIDDM patients.
Current therapies used to treat NIDDM patients entail both controlling lifestyle risk factors and pharmaceutical intervention. First-line therapy for NIDDM is typically a tightly-controlled regimen of diet and exercise since an overwhelming number of NIDDM patients are overweight or obese (67%) and since weight loss can improve insulin secretion, insulin sensitivity and lead to normoglycemia. Normalization of blood glucose occurs in less than 30% of these patients due to poor compliance and poor response. Patients with hyperglycemia not controlled by diet alone are subsequently treated with oral hypoglycemics or insulin. Until recently, the sulfonylureas were the only class of oral hypoglycemic agents available for NIDDM. Treatment with sulfonylureas leads to effective blood glucose lowering in only 70% of patients and only 40% after 10 years of therapy. Patients that fail to respond to diet and sulfonylureas are subsequently treated with daily insulin injections to gain adequate glycemic control.
Although the sulfonylureas represent a major therapy for NIDDM patients, four factors limit their overall success. First, as mentioned above, a large segment of the NIDDM population do not respond adequately to sulfonylurea therapy (i.e. primary failures) or become resistant (i.e. secondary failures). This is particularly true in NIDDM patients with advanced NIDDM since these patients have severely impaired insulin secretion. Second, sulfonylurea therapy is associated with an increased risk of severe hypoglycemic episodes. Third, chronic hyperinsulinemia has been associated with increased cardiovascular disease although this relationship is considered controversial and unproven. Last, sulfonylureas are associated with weight gain, which leads to worsening of peripheral insulin sensitivity and thereby can accelerate the progression of the disease.
Results from the U.K. Diabetes Prospective Study also showed that patients undergoing maximal therapy of a sulfonylurea, metformin, or a combination of the two, were unable to maintain normal fasting glycemia over the six year period of the study. U.K. Prospective Diabetes Study 16. Diabetes, 44:1249-158 (1995). These results further illustrate the great need for alternative therapies.
Gluconeogenesis from pyruvate and other 3-carbon precursors is a highly regulated biosynthetic pathway requiring eleven enzymes. Seven enzymes catalyze reversible reactions and are common to both gluconeogenesis and glycolysis. Four enzymes catalyze reactions unique to gluconeogenesis, namely pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase and glucose-6-phosphatase. Overall flux through the pathway is controlled by the specific activities of these enzymes, the enzymes that catalyzed the corresponding steps in the glycolytic direction, and by substrate availability. Dietary factors (glucose, fat) and hormones (insulin, glucagon, glucocorticoids, epinephrine) coordinatively regulate enzyme activities in the gluconeogenesis and glycolysis pathways through gene expression and post-translational mechanisms.
Of the four enzymes specific to gluconeogenesis, fructose-1,6-bisphosphatase (hereinafter xe2x80x9cFBPasexe2x80x9d) is the most suitable target for a gluconeogenesis inhibitor based on efficacy and safety considerations. Studies indicate that nature uses the FBPase/PFK cycle as a major control point (metabolic switch) responsible for determining whether metabolic flux proceeds in the direction of glycolysis or gluconeogenesis. Claus, et al., Mechanisms of Insulin Action, Belfrage, P. editor, pp.305-321, Elsevier Science 1992; Regen, et al. J. Theor. Biol., 111:635-658 (1984); Pilkis, et al. Annu. Rev. Biochem, 57:755-783 (1988). FBPase is inhibited by fructose-2,6-bisphosphate in the cell. Fructose-2,6-bisphosphate binds to the substrate site of the enzyme. AMP binds to an allosteric site on the enzyme.
Synthetic inhibitors of FBPase have also been reported. McNiel reported that fructose-2,6-bisphosphate analogs inhibit FBPase by binding to the substrate site. J. Am. Chem. Soc., 106:7851-7853 (1984); U.S. Pat. No. 4,968,790 (1984). These compounds, however, were relatively weak and did not inhibit glucose production in hepatocytes presumably due to poor cell penetration.
Gruber reported that some nucleosides can lower blood glucose in the whole animal through inhibition of FBPase. These compounds exert their activity by first undergoing phosphorylation to the corresponding monophosphate. EP 0 427 799 B1.
Gruber et al. U.S. Pat. No. 5,658,889 described the use of inhibitors of the AMP site of FBPase to treat diabetes. WO 98/39344, WO/39343, and WO 98/39342 describe specific inhibitors of FBPase to treat diabetes.
The present invention is directed towards novel heteroaromatic compounds containing a phosphonate group and are potent FBPase inhibitors. In another aspect, the present invention is directed to the preparation of this type of compound and to the in vitro and in vivo FBPase inhibitory activity of these compounds. Another aspect of the present invention is directed to the clinical use of these FBPase inhibitors as a method of treatment or prevention of diseases responsive to inhibition of gluconeogenesis and in diseases responsive to lowered blood glucose levels.
The compounds are also useful in treating or preventing excess glycogen storage diseases and diseases such as cardiovascular diseases including atherosclerosis, myocardial ischemic injury, and diseases such as metabolic disorders such as hypercholesterolemia, hyperlipidemia which are exacerbated by hyperinsulinema and hyperglycemia.
The invention also comprises the novel compounds and methods of using them as specified below in formulae I and X. Also included in the scope of the present invention are prodrugs of the compounds of formulae I and X.
Since these compounds may have asymmetric centers, the present invention is directed not only to racemic mixtures of these compounds, but also to individual stereoisomers. The present invention also includes pharmaceutically acceptable and/or useful salts of the compounds of formulae I and X, including acid addition salts. The present inventions also encompass prodrugs of compounds of formulae I and X.
Definitions
In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.
X and X2 group nomenclature as used herein in formulae I and X describes the group attached to the phosphonate and ends with the group attached to the heteroaromatic ring. For example, when X is alkylamino, the following structure is intended:
(heteroaromatic ring)-NR-alk-P(O)(OR1)2
Likewise, A, B, C, D, E, Axe2x80x3, Bxe2x80x3, Cxe2x80x3, Dxe2x80x3, Exe2x80x3, A2, L2, E2, and J2 groups and other substituents of the heteroaromatic ring are described in such a way that the term ends with the group attached to the heteroaromatic ring. Generally, substituents are named such that the term ends with the group at the point of attachment.
The term xe2x80x9carylxe2x80x9d refers to aromatic groups which have 5-14 ring atoms and at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted. Suitable aryl groups include phenyl and furan-2,5-diyl.
Carbocyclic aryl groups are groups wherein the ring atoms on 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 are groups having from 1 to 4 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include oxygen, sulfur, nitrogen, and selendum. Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, and the like, all optionally substituted.
The term xe2x80x9cannulationxe2x80x9d or xe2x80x9cannulatedxe2x80x9d refers to the formation of an additional cyclic moiety onto an existing aryl or heteroaryl group. The newly formed ring may be carbocyclic or heterocyclic, saturated or unsaturated, and contains 2-9 new atoms of which 0-3 may be heteroatoms taken from the group of N, O, and S. The annulation may incorporate atoms from the X group as part of the newly formed ring. For example, the phrase xe2x80x9ctogether L2 and E2 form an annulated cyclic group,xe2x80x9d includes
The term xe2x80x9cbiarylxe2x80x9d represents aryl groups containing more than one aromatic ring including both fused ring systems and aryl groups substituted with other aryl groups. Such groups may be optionally substituted. Suitable biaryl groups include naphthyl and biphenyl.
The term xe2x80x9calicyclicxe2x80x9d means compounds which combine the properties of aliphatic and cyclic compounds. Such cyclic compounds include but are not limited to, aromatic, cycloalkyl and bridged cycloalkyl compounds. The cyclic compound includes heterocycles. Cyclohexenylethyl and cyclohexylethyl are suitable alicyclic groups. Such groups may be optionally substituted.
The term xe2x80x9coptionally substitutedxe2x80x9d or xe2x80x9csubstitutedxe2x80x9d includes groups substituted by one to four substituents, independently selected from lower alkyl, lower aryl, lower aralkyl, lower alicyclic, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, amino, guanidino, amidino, halo, lower alkylthio, oxo, acylalkyl, carboxy esters, carboxyl, -carboxamido, nitro, acyloxy, aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl, arylamino, aralkylamino, phosphono, sulfonyl, -carboxamidoalkylaryl, -carboxamidoaryl, hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy-, aminocarboxamidoalkyl-, cyano, lower alkoxyalkyl, lower perhaloalkyl, and arylalkyloxyalkyl. xe2x80x9cSubstituted arylxe2x80x9d and xe2x80x9csubstituted heteroarylxe2x80x9d preferably refers to aryl and heteroaryl groups substituted with 1-3 substituents. Preferably these substituents are selected from the group consisting of lower alkyl, lower alkoxy, lower perhaloalkyl, halo, hydroxy, and amino. xe2x80x9cSubstitutedxe2x80x9d when describing an R5 group does not include annulation.
The term xe2x80x9caralkylxe2x80x9d refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like, and may be optionally substituted. The term xe2x80x9c-aralkyl-xe2x80x9d refers to a divalent group -aryl-alkylene-. xe2x80x9cHeteroarylalkylxe2x80x9d refers to an alkylene group substituted with a heteroaryl group.
The term xe2x80x9c-alkylaryl-xe2x80x9d refers to the group -alk-aryl- where xe2x80x9calkxe2x80x9d is an alkylene group. xe2x80x9cLower -alkylaryl-xe2x80x9d refers to such groups where alkylene is lower alkylene.
The term xe2x80x9clowerxe2x80x9d referred to herein in connection with organic radicals or compounds respectively defines such as with up to and including 10, preferably up to and including 6, and advantageously one to four carbon atoms. Such groups may be straight chain, branched, or cyclic.
The terms xe2x80x9carylaminoxe2x80x9d (a), and xe2x80x9caralkylaminoxe2x80x9d (b), respectively, refer to the group xe2x80x94NRRxe2x80x2 wherein respectively, (a) R is aryl and Rxe2x80x2 is hydrogen, alkyl, aralkyl or aryl, and (b) R is aralkyl and Rxe2x80x2 is hydrogen or aralkyl, aryl, alkyl.
The term xe2x80x9cacylxe2x80x9d refers to xe2x80x94C(O)R where R is alkyl and aryl.
The term xe2x80x9ccarboxy estersxe2x80x9d refers to xe2x80x94C(O)OR where R is alkyl, aryl, aralkyl, and alicyclic, all optionally substituted.
The term xe2x80x9ccarboxylxe2x80x9d refers to xe2x80x94C(O)OH.
The term xe2x80x9coxoxe2x80x9d refers to xe2x95x90O in an alkyl group.
The term xe2x80x9caminoxe2x80x9d refers to xe2x80x94NRRxe2x80x2 where R and Rxe2x80x2 are independently selected from hydrogen, alkyl, aryl, aralkyl and alicyclic, all except H are optionally substituted; and R and R1 can form a cyclic ring system.
The term xe2x80x9ccarbonylaminoxe2x80x9d and xe2x80x9c-carbonylamino-xe2x80x9d refers to RCONRxe2x80x94 and xe2x80x94CONRxe2x80x94, respectively, where each R is independently hydrogen or alkyl.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refers to xe2x80x94F, xe2x80x94Cl, xe2x80x94Br and xe2x80x94I.
The term xe2x80x9c-oxyalkylamino-xe2x80x9d refers to xe2x80x94O-alk-NRxe2x80x94, where xe2x80x9calkxe2x80x9d is an alkylene group and R is H or alkyl.
The term xe2x80x9c-alkylaminoalkylcarboxy-xe2x80x9d refers to the group -alk-NR-alk-C(O)xe2x80x94Oxe2x80x94 where xe2x80x9calkxe2x80x9d is an alkylene group, and R is a H or lower alkyl.
The term xe2x80x9c-alkylaminocarbonyl-xe2x80x9d refers to the group -alk-NRxe2x80x94C(O)xe2x80x94 where xe2x80x9calkxe2x80x9d is an alkylene group, and R is a H or lower alkyl.
The term xe2x80x9c-oxyalkyl-xe2x80x9d refers to the group xe2x80x94O-alk- where xe2x80x9calkxe2x80x9d is an alkylene group.
The term xe2x80x9c-alkylcarboxyalkyl-xe2x80x9d refers to the group -alk-C(O)xe2x80x94O-alk- where each alk is independently an alkylene group.
The term xe2x80x9calkylxe2x80x9d refers to saturated aliphatic groups including straight-chain, branched chain and cyclic groups. Alkyl groups may be optionally substituted. Suitable alkyl groups include methyl, isopropyl, and cyclopropyl.
The term xe2x80x9ccyclic alkylxe2x80x9d or xe2x80x9ccycloalkylxe2x80x9d refers to alkyl groups that are cyclic. Suitable cyclic groups include norbornyl and cyclopropyl. Such groups may be substituted.
The term xe2x80x9cheterocyclicxe2x80x9d and xe2x80x9cheterocyclic alkylxe2x80x9d refer to cyclic groups of 3 to 10 atoms, more preferably 3 to 6 atoms, containing at least one heteroatom, preferably 1 to 3 heteroaroms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. Heterocyclic groups may be attached through a nitrogen or through a carbon atom in the ring. Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl, and pyridyl.
The term xe2x80x9cphosphonoxe2x80x9d refers to xe2x80x94PO3R2, where R is selected from the group consisting of xe2x80x94H, alkyl, aryl, aralkyl, and alicyclic.
The term xe2x80x9csulphonylxe2x80x9d or xe2x80x9csulfonylxe2x80x9d refers to xe2x80x94SO3R, where R is H, alkyl, aryl, aralkyl, and alicyclic.
The term xe2x80x9calkenylxe2x80x9d refers to unsaturated groups which contain at least one carbonxe2x80x94carbon double bond and includes straight-chain, branched-chain and cyclic groups. Alkenyl groups may be optionally substituted. Suitable alkenyl groups include allyl. xe2x80x9c1-alkenylxe2x80x9d refers to alkenyl groups where the double bond is between the first and second carbon atom. If the 1-alkenyl group is attached to another group, e.g. it is a W substituent attached to the cyclic phosph(oramid)ate, it is attached at the first carbon.
The term xe2x80x9calkynylxe2x80x9d refers to unsaturated groups which contain at least one carbonxe2x80x94carbon triple bond and includes straight-chain, branched-chain and cyclic groups. Alkynyl groups may be optionally substituted. Suitable alkynyl groups include ethynyl. xe2x80x9c1-alkynylxe2x80x9d refers to alkynyl groups where the triple bond is between the first and second carbon atom. If the 1-alkynyl group is attached to another group, e.g. it is a W substituent attached to the cyclic phosph(oramid)ate, it is attached at the first carbon.
The term xe2x80x9calkylenexe2x80x9d refers to a divalent straight chain, branched chain or cyclic saturated aliphatic group.
The term xe2x80x9c-cycloalkylene-COOR3xe2x80x9d refers to a divalent cyclic alkyl group or heterocyclic group containing 4 to 6 atoms in the ring, with 0-1 heteroatoms selected from O, N, and S. The cyclic alkyl or heterocyclic group is substituted with xe2x80x94COOR3.
The term xe2x80x9cacyloxyxe2x80x9d refers to the ester group xe2x80x94Oxe2x80x94C(O)R, where R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or alicyclic.
The term xe2x80x9caminoalkyl-xe2x80x9d refers to the group NR2-alk- wherein xe2x80x9calkxe2x80x9d is an alkylene group and R is selected from H, alkyl, aryl, aralkyl, and alicyclic.
The term xe2x80x9c-alkyl(hydroxy)-xe2x80x9d refers to an xe2x80x94OH off the alkyl chain. When this term is an X group, the xe2x80x94OH is at the position a to the phosphorus atom.
The term xe2x80x9calkylaminoalkyl-xe2x80x9d refers to the group alkyl-NR-alk- wherein each xe2x80x9calkxe2x80x9d is an independently selected alkylene, and R is H or lower alkyl. xe2x80x9cLower alkylaminoalkyl-xe2x80x9d refers to groups where each alkylene group is lower alkylene.
The term xe2x80x9carylaminoalkyl-xe2x80x9d refers to the group aryl-NR-alk- wherein xe2x80x9calkxe2x80x9d is an alkylene group and R is H, alkyl, aryl, aralkyl, and alicyclic. In xe2x80x9clower arylaminoalkyl-xe2x80x9d, the alkylene group is lower alkylene.
The term xe2x80x9calkylaminoaryl-xe2x80x9d refers to the group alkyl-NR-aryl- wherein xe2x80x9carylxe2x80x9d is a divalent group and R is H, alkyl, aralkyl, and alicyclic. In xe2x80x9clower alkylaminoaryl-xe2x80x9d, the alkylene group is lower alkyl.
The term xe2x80x9calkyloxyaryl-xe2x80x9d refers to an aryl group substituted with an alkyloxy group. In xe2x80x9clower alkyloxyaryl-xe2x80x9d, the alkyl group is lower alkyl.
The term xe2x80x9caryloxyalkyl-xe2x80x9d refers to an alkyl group substituted with an aryloxy group.
The term xe2x80x9caralkyloxyalkyl-xe2x80x9d refers to the group aryl-alk-O-alk- wherein xe2x80x9calkxe2x80x9d is an alkylene group. xe2x80x9cLower aralkyloxyalkyl-xe2x80x9d refers to such groups where the alkylene groups are lower alkylene.
The term xe2x80x9c-alkoxy-xe2x80x9d or xe2x80x9c-alkyloxy-xe2x80x9d refers to the group -alk-O- wherein xe2x80x9calkxe2x80x9d is an alkylene group. The term xe2x80x9calkoxy-xe2x80x9d refers to the group alkyl-Oxe2x80x94.
The term xe2x80x9c-alkoxyalkyl-xe2x80x9d or xe2x80x9c-alkyloxyalkyl-xe2x80x9d refer to the group -alk-O-alk- wherein each xe2x80x9calkxe2x80x9d is an independently selected alkylene group. In xe2x80x9clower -alkoxyalkyl-xe2x80x9d, each alkylene is lower alkylene.
The terms xe2x80x9calkylthio-xe2x80x9d and xe2x80x9c-alkylthio-xe2x80x9d refer to the groups alkyl-Sxe2x80x94, and -alk-Sxe2x80x94, respectively, wherein xe2x80x9calkxe2x80x9d is alkylene group.
The term xe2x80x9c-alkylthioalkyl-xe2x80x9d refers to the group -alk-S-alk- wherein each xe2x80x9calkxe2x80x9d is an independently selected alkylene group. In xe2x80x9clower -alkylthioalkyl-xe2x80x9d each alkylene is lower alkylene.
The term xe2x80x9calkoxycarbonyloxy-xe2x80x9d refers to alkyl-Oxe2x80x94C(O)xe2x80x94Oxe2x80x94.
The term xe2x80x9caryloxycarbonyloxy-xe2x80x9d refers to aryl-Oxe2x80x94C(O)xe2x80x94Oxe2x80x94.
The term xe2x80x9calkylthiocarbonyloxy-xe2x80x9d refers to alkyl-Sxe2x80x94C(O)xe2x80x94Oxe2x80x94.
The term xe2x80x9c-alkoxycarbonylamino-xe2x80x9d refers to -alk-Oxe2x80x94C(O)xe2x80x94NR1xe2x80x94, where xe2x80x9calkxe2x80x9d is alkylene and R1 includes xe2x80x94H, alkyl, aryl, alicyclic, and aralkyl.
The term xe2x80x9c-alkylaminocarbonylamino-xe2x80x9d refers to -alk-NR1xe2x80x94C(O)xe2x80x94NR1xe2x80x94, where xe2x80x9calkxe2x80x9d is alkylene and R1 is independently selected from H, alkyl, aryl, aralkyl, and alicyclic.
The terms xe2x80x9camidoxe2x80x9d or xe2x80x9ccarboxamidoxe2x80x9d refer to NR2xe2x80x94C(O)xe2x80x94 and RC(O)xe2x80x94NR1xe2x80x94, where R and R1 include H, alkyl, aryl, aralkyl, and alicyclic. The term does not include urea, xe2x80x94NRxe2x80x94C(O)xe2x80x94NRxe2x80x94.
The terms xe2x80x9ccarboxamidoalkylarylxe2x80x9d and xe2x80x9ccarboxamidoarylxe2x80x9d refers to an aryl-alk-NR1xe2x80x94C(O)xe2x80x94, and an xe2x80x94NR1xe2x80x94C(O)-alk-, respectively, where xe2x80x9carxe2x80x9d is aryl, and xe2x80x9calkxe2x80x9d is alkylene, Rxe2x80x2 and R include H, alkyl, aryl, aralkyl, and aliyclic.
The term xe2x80x9c-alkylcarboxamido-xe2x80x9d or xe2x80x9c-alkylcarbonylamino-xe2x80x9d refers to the group -alk-C(O)N(R)xe2x80x94 wherein xe2x80x9calkxe2x80x9d is an alkylene group and R is H or lower alkyl.
The term xe2x80x9c-alkylaminocarbonyl-xe2x80x9d refers to the group -alk-NRxe2x80x94C(O)xe2x80x94 wherein xe2x80x9calkxe2x80x9d is an alkylene group and R is H or lower alkyl.
The term xe2x80x9caminocarboxamidoalkyl-xe2x80x9d refers to the group NR2xe2x80x94C(O)xe2x80x94N(R)-alk- wherein R is an alkyl group or H and xe2x80x9calkxe2x80x9d is an alkylene group. xe2x80x9cLower aminocarboxamidoalkyl-xe2x80x9d refers to such groups wherein xe2x80x9calkxe2x80x9d is lower alkylene.
The term xe2x80x9cthiocarbonatexe2x80x9d refers to xe2x80x94Oxe2x80x94C(S)xe2x80x94Oxe2x80x94 either in a chain or in a cyclic group.
The term xe2x80x9chydroxyalkylxe2x80x9d refers to an alkyl group substituted with one xe2x80x94OH.
The term xe2x80x9chaloalkylxe2x80x9d refers to an alkyl group substituted with one halo, selected from the group I, Cl, Br, F.
The term xe2x80x9ccyanoxe2x80x9d refers to xe2x80x94Cxe2x80x94N.
The term xe2x80x9cnitroxe2x80x9d refers to xe2x80x94NO2.
The term xe2x80x9cacylalkylxe2x80x9d refers to an alkyl-C(O)-alk-, where xe2x80x9calkxe2x80x9d is alkylene.
The term xe2x80x9cheteroarylalkylxe2x80x9d refers to an alkyl group substituted with a heteroaryl group.
The term xe2x80x9c-1,1-dihaloalkyl-xe2x80x9d refers to an X group where the 1 position and therefore halogens are a to the phosphorus atom.
The term xe2x80x9cperhaloxe2x80x9d refers to groups wherein every Cxe2x80x94H bond has been replaced with a C-halo bond on an aliphatic or aryl group. Suitable perhaloalkyl groups include xe2x80x94CF3 and xe2x80x94CFCl2.
The term xe2x80x9cguanidinoxe2x80x9d refers to both xe2x80x94NRxe2x80x94C(NR)xe2x80x94NR2 as well as xe2x80x94Nxe2x95x90C(NR2)2 where each R group is independently selected from the group of xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, and alicyclic, all except xe2x80x94H are optionally substituted.
The term xe2x80x9camidinoxe2x80x9d refers to xe2x80x94C(NR)xe2x80x94NR2 where each R group is independently selected from the group of xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, and alicyclic, all except xe2x80x94H are optionally substituted.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d includes salts of compounds of formula I and its prodrugs derived from the combination of a compound of this invention and an organic or inorganic acid or base. Suitable acids include HCl.
The term xe2x80x9cprodrugxe2x80x9d as used herein refers to any compound that when administered to a biological system generates the xe2x80x9cdrugxe2x80x9d substance (a biologically active compound) as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s). Standard prodrugs are formed using groups attached to functionality, e.g. HOxe2x80x94, HSxe2x80x94, HOOCxe2x80x94, R2Nxe2x80x94, associated with the FBPase inhibitor, that cleave in vivo. Standard prodrugs include but are not limited to carboxylate esters where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of hydroxyl, thiol and amines where the group attached is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate. Standard prodrugs of phosphonic acids are also included and may be represented by R1 in formulae I and X. The groups illustrated are exemplary, not exhaustive, and one skilled in the art could prepare other known varieties of prodrugs. Such prodrugs of the compounds of formulae I and X, fall within the scope of the present invention. Prodrugs must undergo some form of a chemical transformation to produce the compound that is biologically active or is a precursor of the biologically active compound. In some cases, the prodrug is biologically active usually less than the drug itself, and serves to imprive efficacy or safety through improved oral bioavailability, pharmacodynamic half-life, etc.
The term xe2x80x9cprodrug esterxe2x80x9d as employed herein includes, but is not limited to, the following groups and combinations of these groups:
[1] Acyloxyalkyl esters which are well described in the literature (Farquhar et al., J. Pharm. Sci. 72, 324-325 (1983)) and are represented by formula A
wherein
R, Rxe2x80x2, and Rxe2x80x3 are independently H, alkyl, aryl, alkylaryl, and alicyclic; (see WO 90/08155; WO 90/10636).
[2] Other acyloxyalkyl esters are possible in which an alicyclic ring is formed such as shown in formula B. These esters have been shown to generate phosphorus-containing nucleotides inside cells through a postulated sequence of reactions beginning with deesterification and followed by a series of elimination reactions (e.g. Freed et al., Biochem. Pharm. 38: 3193-3198 (1989)).
wherein
R is xe2x80x94H, alkyl, aryl, alkylaryl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino, cycloalkyl, or alicyclic.
[3] Another class of these double esters known as alkyloxycarbonyloxymethyl esters, as shown in formula A, where R is alkoxy, aryloxy, alkylthio, arylthio, alkylamino, and arylamino; Rxe2x80x2, and Rxe2x80x3 are independently H, alkyl, aryl, alkylaryl, and alicyclic, have been studied in the area of -lactam antibiotics (Tatsuo Nishimura et al. J. Antibiotics, 1987, 40(1), 81-90; for a review see Ferres, H., Drugs of Today, 1983,19, 499.). More recently Cathy, M. S., et al. (Abstract from AAPS Western Regional Meeting, April, 1997) showed that these alkyloxycarbonyloxymethyl ester prodrugs on (9-[(R)-2-phosphonomethoxy)propyl]adenine (PMPA) are bioavailable up to 30% in dogs.
[4] Aryl esters have also been used as phosphonate prodrugs (e.g. Erion, DeLambert et al., J. Med. Chem. 37: 498, 1994; Serafinowska et al., J. Med. Chem. 38: 1372, 1995). Phenyl as well as mono and poly-substituted phenyl proesters have generated the parent phosphonic acid in studies conducted in animals and in man (Formula C). Another approach has been described where Y is a carboxylic ester ortho to the phosphate. Khamnei and Torrence, J. Med. Chem.; 39:4109-4115 (1996).
wherein
Y is H, alkyl, aryl, alkylaryl, alkoxy, acyloxy, halogen, amino, alkoxycarbonyl, hydroxy, cyano, and alicyclic.
[5] Benzyl esters have also been reported to generate the parent phosphonic acid. In some cases, using substituents at the para-position can accelerate the hydrolysis. Benzyl analogs with 4-acyloxy or 4-alkyloxy group [Formula D, Xxe2x95x90H, OR or O(CO)R or O(CO)OR] can generate the 4-hydroxy compound more readily through the action of enzymes, e.g. oxidases, esterases, etc. Examples of this class of prodrugs are described in Mitchell et al., J. Chem. Soc. Perkin Trans. I 2345 (1992); Brook, et al. WO 91/19721.
wherein
X and Y are independently H, alkyl, aryl, alkylaryl, alkoxy, acyloxy, hydroxy, cyano, nitro, perhaloalkyl, halo, or alkyloxycarbonyl; and
Rxe2x80x2 and Rxe2x80x3 are independently H, alkyl, aryl, alkylaryl, halogen, and alicyclic.
[6] Thio-containing phosphonate proesters have been described that are useful in the delivery of FBPase inhibitors to hepatocytes. These proesters contain a protected thioethyl moiety as shown in formula E. One or more of the oxygens of the phosphonate can be esterified. Since the mechanism that results in de-esterification requires the generation of a free thiolate, a variety of thiol protecting groups are possible. For example, the disulfide is reduced by a reductase-mediated process (Puech et al., Antiviral Res., 22: 155-174 (1993)). Thioesters will also generate free thiolates after esterase-mediated hydrolysis. Benzaria, et al., J. Med. Chem., 39:4958 (1996). Cyclic analogs are also possible and were shown to liberate phosphonate in isolated rat hepatocytes. The cyclic disulfide shown below has not been previously described and is novel.
wherein
Z is alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, or alkylthio.
Other examples of suitable prodrugs include proester classes exemplified by Biller and Magnin (U.S. 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 EPO patent application 0 632 048 A1. Some of the structural classes described are optionally substituted, including fused lactones attached at the omega position (formulae E-1 and E-2) and optionally substituted 2-oxo-1,3-dioxolenes attached through a methylene to the phosphorus oxygen (formula E-3) such as:
wherein
R is xe2x80x94H, alkyl, cycloalkyl, or alicyclic; and
wherein
Y is xe2x80x94H, alkyl, aryl, alkylaryl, cyano, alkoxy, acyloxy, halogen, amino, alicyclic, and alkoxycarbonyl.
The prodrugs of Formula E-3 are an example of xe2x80x9coptionally substituted alicyclic where the cyclic moiety contains a carbonate or thiocarbonate.xe2x80x9d
[7] Propyl phosphonate proesters can also be used to deliver FBPase inhibitors into hepatocytes. These proesters may contain a hydroxyl and hydroxyl group derivatives at the 3-position of the propyl group as shown in formula F. The R and X groups can form a cyclic ring system as shown in formula F. One or more of the oxygens of the phosphonate can stefied.
wherein
R is alkyl, aryl, heteroaryl;
X is hydrogen, alkylcarbonyloxy, alkyloxycarbonyloxy; and
Y is alkyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, halogen, hydrogen, hydroxy, acyloxy, amino.
[8] Phosphoramidate derivatives have been explored as phosphate prodrugs (e.g. McGuigan et al., J. Med. Chem., 1999, 42: 393 and references cited therein) as shown in Formula G.
Cyclic phosphoramidates have also been studied as phosphonate prodrugs because of their speculated higher stability compared to non-cyclic phosphoramidates (e.g. Starrett et al., J. Med. Chem., 1994, 37: 1857.
Another type of nucleotide prodrug was reported as the combination of S-acyl-2-thioethyl ester and phosphoramidate (Egron et al., Nucleosides and Nucleotides, 1999, 18, 981) as shown in Formula H.
Other prodrugs are possible based on literature reports such as substituted ethyls for example, bis(trichloroethyl)esters as disclosed by McGuigan, et al. Bioorg Med. Chem. Lett., 3:1207-1210 (1993), and the phenyl and benzyl combined nucleotide esters reported by Meier, C. et al. Bioorg. Med. Chem. Lett., 7:99-104 (1997).
The structure
has a plane of symmetry running through the phosphorus-oxygen double bond when R6xe2x95x90R6, Vxe2x95x90W, Wxe2x80x2xe2x95x90H, and V and W are either both pointing up or both pointing down. The same is true of structures where each xe2x80x94NR6 is replaced with xe2x80x94Oxe2x80x94.
The term xe2x80x9ccyclic 1xe2x80x2,3xe2x80x2-propane esterxe2x80x9d, xe2x80x9ccyclic 1,3-propane esterxe2x80x9d, xe2x80x9ccyclic 1xe2x80x2,3xe2x80x2-prop anyl esterxe2x80x9d, and xe2x80x9ccyclic 1,3-propanyl esterxe2x80x9d refers to the following:
The phrase xe2x80x9ctogether V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally containing 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorusxe2x80x9d includes the following:
The structure shown above (left) has an additional 3 carbon atoms that forms a five member cyclic group. Such cyclic groups must possess the listed substitution to be oxidized.
The phrase xe2x80x9ctogether V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, that is fused to an aryl group attached at the beta and gamma position to the Y attached to the phosphorusxe2x80x9d includes the following:
The phrase xe2x80x9ctogether V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxy carbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorusxe2x80x9d includes the following:
The structure above has an acyloxy substituent that is three carbon atoms from a Y, and an optional substituent, xe2x80x94CH3, on the new 6-membered ring. There has to be at least one hydrogen at each of the following positions: the carbon attached to Z; both carbons alpha to the carbon labelled xe2x80x9c3xe2x80x9d; and the carbon attached to xe2x80x9cOC(O)CH3xe2x80x9d above.
The phrase xe2x80x9ctogether W and Wxe2x80x2 are connected 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 heteroarylxe2x80x9d includes the following:
The structure above has V=aryl, and a spiro-fused cyclopropyl group for W and Wxe2x80x2.
The term xe2x80x9ccyclic phosph(oramid)atexe2x80x9d refers to
where Y is independently xe2x80x94Oxe2x80x94 or xe2x80x94NR6xe2x80x94. The carbon attached to V must have a Cxe2x80x94H bond. The carbon attached to Z must also have a Cxe2x80x94H bond.
The term xe2x80x9cliverxe2x80x9d refers to liver and to like tissues and cells that contain the CYP3A4 isozyme or any other P450 isozyme found to oxidize the phosph(oramid)ate esters of the invention. Based on Example F, we have found that prodrugs of formula VI and VIII are selectively oxidized by the cytochrome P450 isoenzyme CYP3A4. According to DeWaziers et al (J. Pharm. Exp. Ther., 253, 387-394 (1990)), CYP3A4 is located in humans in the following tissues (determined by immunoblotting and enzyme measurements):
Thus, xe2x80x9cliverxe2x80x9d more preferably refers to the liver, duodenum, jejunum, ileum, colon, stomach, and esophagus. Most preferably, liver refers to the liver organ.
The term xe2x80x9cenhancingxe2x80x9d refers to increasing or improving a specific property.
The term xe2x80x9cliver specificityxe2x80x9d refers to the ratio:       [drug or a drug metabolite in liver tissue]        [drug or a drug metabolite in blood or another tissue]
as measured in animals treated with the drug or a prodrug. The ratio can be determined by measuring tissue levels at a specific time or may represent an AUC based on values measured at three or more time points.
The term xe2x80x9cincreased or enhanced liver specificityxe2x80x9d refers to an increase in the liver specificity ratio in animals treated with the prodrug relative to animals treated with the parent drug.
The term xe2x80x9cenhanced oral bioavailabilityxe2x80x9d refers to an increase of at least 50% of the absorption of the dose of the parent drug or prodrug(not of this invention) from the gastrointestinal tract. More preferably it is at least 100%. Measurement of oral bioavailability usually refers to measurements of the prodrug, drug, or drug metabolite in blood, tissues, or urine following oral administration compared to measurements following systemic administration.
The term xe2x80x9cparent drugxe2x80x9d refers to any compound which delivers the same biologically active compound. The parent drug form is R5xe2x80x94Xxe2x80x94P(O)(OH)2 and standard prodrugs, such as esters.
The term xe2x80x9cdrug metabolitexe2x80x9d refers to any compound produced in vivo or in vitro from the parent drug, which can include the biologically active drug.
The term xe2x80x9cpharmacodynamic half-lifexe2x80x9d refers to the time after administration of the drug or prodrug to observe a diminution of one half of the measured pharmacological response. Pharmacodynamic half-life is enhanced when the half-life is increased by preferably at least 50%.
The term xe2x80x9cpharmacokinetic half-lifexe2x80x9d refers to the time after administration of the drug or prodrug to observe a dimunition of one half of the drug concentration in plasma or tissues.
The term xe2x80x9ctherapeutic indexxe2x80x9d refers to the ratio of the dose of a drug or prodrug that produces a therapeutically beneficial response relative to the dose that produces an undesired response such as death, an elevation of markers that are indicative of toxicity, and/or pharmacological side effects.
The term xe2x80x9csustained deliveryxe2x80x9d refers to an increase in the period in which there is adequate blood levels of the biologically active drug to have a therapeutic effect.
The term xe2x80x9cbypassing drug resistancexe2x80x9d refers to the loss or partial loss of therapeutic effectiveness of a drug (drug resistance) due to changes in the biochemical pathways and cellular activities important for producing and maintaining the biologically active form of the drug at the desired site in the body and to the ability of an agent to bypass this resistance through the use of alternative pathways and cellular activities.
The term xe2x80x9cbiologically active drug or agentxe2x80x9d refers to the chemical entity that produces a biological effect. Thus, active drugs or agents include compounds which as R5xe2x80x94Xxe2x80x94P(O)(OH)2 are biologically active.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d refers to an amount that has any beneficial effect in treating a disease or condition.
Suitable alkyl groups include groups having from 1 to about 20 carbon atoms. Suitable aryl groups include groups having from 1 to about 20 carbon atoms. Suitable aralkyl groups include groups having from 2 to about 21 carbon atoms. Suitable acyloxy groups include groups having from 1 to about 20 carbon atoms. Suitable alkylene groups include groups having from 1 to about 20 carbon atoms. Suitable alicyclic groups include groups having 3 to about 20 carbon atoms. Suitable heteroaryl groups include groups having from 1 to about 20 carbon atoms and from 1 to 4 heteroatoms, preferably independently selected from nitrogen, oxygen, phosphorous, and sulfur. Suitable heteroalicyclic groups include groups having from 2 to about twenty carbon atoms and from 1 to 5 heteroatoms, preferably independently selected from nitrogen, oxygen, phosphorous, and sulfur.
In the method claims, preferred are the following compounds of formula (I):
wherein:
each G is independently selected from the group consisting of C, N, O, S and Se, and wherein only one G may be O, S, or Se;
each Gxe2x80x2 is independently selected from the group consisting of C and N and wherein no more than two Gxe2x80x2 groups are N;
A is selected from the group consisting of xe2x80x94H, xe2x80x94NR42, xe2x80x94CONR42, xe2x80x94CO2R3, halo, xe2x80x94S(O)R3, xe2x80x94SO2R3, alkyl, alkenyl, alkynyl, perhaloalkyl, haloalkyl, aryl, xe2x80x94CH2OH, xe2x80x94CH2NR42, xe2x80x94CH2CN, xe2x80x94CN, xe2x80x94C(S)NH2, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94N3, xe2x80x94NHC(S)NR42, xe2x80x94NHAc, and null;
each B and D are independently selected from the group consisting of xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, xe2x80x94SO2R11, xe2x80x94S(O)R3, xe2x80x94CN, xe2x80x94NR92, xe2x80x94OR3, xe2x80x94SR3, perhaloalkyl, halo, xe2x80x94NO2, and null, all except xe2x80x94H, xe2x80x94CN, perhaloalkyl, xe2x80x94NO2, and halo are optionally substituted;
E is selected from the group consisting of xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, xe2x80x94C(O)OR3, xe2x80x94CONR42, xe2x80x94CN, xe2x80x94NR92, xe2x80x94NO2, xe2x80x94OR3, xe2x80x94SR3, perhaloalkyl, halo, and null, all except xe2x80x94H, xe2x80x94CN, perhaloalkyl, and halo are optionally substituted;
J is selected from the group consisting of xe2x80x94H and null;
X is an optionally substituted linking group that links R5 to the phosphorus atom via 2-4 atoms, including 0-1 heteroatoms selected from N, O, and S, except that if X is urea or carbamate there is 2 heteroatoms, measured by the shortest path between R5 and the phosphorus atom, and wherein the atom attached to the phosphorus is a carbon atom, and wherein there is no N in the linking group unless it is connected directly to a carbonyl or in the ring of a heterocycle; and wherein X is not a 2 carbon atom -alkyl- or -alkenyl- group; with the proviso that X is not substituted with xe2x80x94COOR2, xe2x80x94SO3R1, or xe2x80x94PO3R12;
Y is independently selected from the group consisting of xe2x80x94Oxe2x80x94, and xe2x80x94NR6xe2x80x94;
when Y is xe2x80x94Oxe2x80x94, then R1 attached to xe2x80x94Oxe2x80x94 is independently selected from the group consisting of xe2x80x94H, alkyl, optionally substituted aryl, optionally substituted alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, xe2x80x94C(R2)2OC(O)NR22, xe2x80x94NR2xe2x80x94C(O)xe2x80x94R3, xe2x80x94C(R2)2xe2x80x94OC(O)R3, xe2x80x94C(R2)2xe2x80x94Oxe2x80x94C(O)OR3, xe2x80x94C(R2)2OC(O)SR3, -alkyl-Sxe2x80x94C(O)R3, -alkyl-Sxe2x80x94S-alkylhydroxy, and -alkyl-Sxe2x80x94Sxe2x80x94S-alkylhydroxy,
when Y is xe2x80x94NR6xe2x80x94, then R1 attached to xe2x80x94NR6xe2x80x94 is independently selected from the group consisting of xe2x80x94H, [C(R2)2]qxe2x80x94COOR3, xe2x80x94C(R4)2COOR3, xe2x80x94[C(R2)2]qxe2x80x94C(O)SR, and -cycloalkylene-COOR3;
or when either Y is independently selected from xe2x80x94Oxe2x80x94 and xe2x80x94NR6xe2x80x94, then together R1 and R1 are -alkyl-Sxe2x80x94S-alkyl- to form a cyclic group, or together R1 and R1 are
wherein
V, W, and Wxe2x80x2 are independently selected from the group consisting of xe2x80x94H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus;
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;
together Z and W are connected via 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;
together W and Wxe2x80x2 are connected 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;
Z is selected from the group consisting of xe2x80x94CHR2OH, xe2x80x94CHR2OC(O)R3, xe2x80x94CHR2OC(S)R3, xe2x80x94CHR2OC(S)OR3, xe2x80x94CHR2OC(O)SR3, xe2x80x94CHR2OCO2R3, xe2x80x94OR2, xe2x80x94SR2, xe2x80x94CHR2N3, xe2x80x94CH2aryl, xe2x80x94CH(aryl)OH, xe2x80x94CH(CHxe2x95x90CR22)OH, xe2x80x94CH(Cxe2x89xa1CR2)OH, xe2x80x94R2, xe2x80x94N22, xe2x80x94OCOR3, xe2x80x94OCO2R3, xe2x80x94SCOR3, xe2x80x94SCO2R3, xe2x80x94NHCOR2, xe2x80x94NHCO2R3, xe2x80x94CH2NHaryl, xe2x80x94(CH2)pxe2x80x94OR2, and xe2x80x94(CH2)pxe2x80x94SR2;
p is an integer 2 or 3;
q is an integer 1 or 2;
with the provisos that:
a) V, Z, W, Wxe2x80x2 are not all xe2x80x94H; and
b) when Z is xe2x80x94R2, then at least one of V, W, and Wxe2x80x2 is not xe2x80x94H, alkyl, aralkyl, or alicyclic;
R2 is selected from the group consisting of R3 and xe2x80x94H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
each R4 is independently selected from the group consisting of xe2x80x94H, and alkyl, or together R4 and R4 form a cyclic alkyl group;
R6 is selected from the group consisting of xe2x80x94H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
each R9 is independently selected from the group consisting of xe2x80x94H, alkyl, aralkyl, and alicyclic, or together R9 and R9 form a cyclic alkyl group;
R11 is selected from the group consisting of alkyl, aryl, xe2x80x94NR22, and xe2x80x94OR2; and with the provisos that:
1) when Gxe2x80x2 is N, then the respective A, B, D, or E is null;
2) at least one of A and B, or A, B, D, and E is not selected from the group consisting of xe2x80x94H or null;
3) when R5 is a six-membered ring, then X is not any 2 atom linker, an optionally substituted -alkyl-, an optionally substituted -alkenyl-, an optionally substituted -alkyloxy-, or an optionally substituted -alkylthio-;
4) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom;
5) R1 is not unsubstituted C1-C10 alkyl;
6) when X is not an -aryl- group, then R1 is not substituted with two or more aryl groups;
and pharmaceutically acceptable prodrugs and salts thereof.
In the methods of using such compounds, preferred R5 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, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3,4-tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, and 1,3-selenazolyl, all of which contain at least one substituent.
More preferred are compounds where R5 is:
wherein
Axe2x80x3 is selected from the group consisting of xe2x80x94H, xe2x80x94NR42, xe2x80x94CONR42, xe2x80x94CO2R3, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl, C1-C6 haloalkyl, aryl, xe2x80x94CH2OH, xe2x80x94CH2NR42, xe2x80x94CH2CN, xe2x80x94CN, xe2x80x94C(S)NH2, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94N3, xe2x80x94NHC(S)NR42, and xe2x80x94NHAc;
Bxe2x80x3 and Dxe2x80x3 are independently selected from the group consisting of xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, xe2x80x94SO2R11, xe2x80x94S(O)R3, xe2x80x94CN, xe2x80x94NR92, xe2x80x94OR3, xe2x80x94SR3, perhaloalkyl, and halo, all except xe2x80x94H, xe2x80x94CN, perhaloalkyl, and halo are optionally substituted;
Exe2x80x3 is selected from the group consisting of xe2x80x94H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, C4-C6 alicyclic, alkoxyalkyl, xe2x80x94C(O)OR, xe2x80x94CONR42, xe2x80x94CN, xe2x80x94NR92, xe2x80x94OR3, xe2x80x94SR3, C1-C6 perhaloalkyl, and halo, all except xe2x80x94H, xe2x80x94CN, perhaloalkyl, and halo are optionally substituted; and
Cxe2x80x3 is selected from the group consisting of xe2x80x94H, alkyl, alkylalkenyl, alkylalkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, and alkoxyalkyl, all optionally substituted;
R4 is selected from the group consisting of xe2x80x94H and C1-C2 alkyl.
Particularly preferred are such compounds where R5 is:
wherein
Axe2x80x3 is selected from the group consisting of xe2x80x94H, xe2x80x94NR42, xe2x80x94CONR42, xe2x80x94CO2R3, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl, C1-C6 haloalkyl, aryl, xe2x80x94CH2OH, xe2x80x94CH2NR42, xe2x80x94CH2CN, xe2x80x94CN, xe2x80x94C(S)NH2, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94N3, xe2x80x94NHC(S)NR42, and xe2x80x94NHAc;
Bxe2x80x3 and Dxe2x80x3 are independently selected from the group consisting of xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, xe2x80x94SO2R11, xe2x80x94S(O)R3, xe2x80x94CN, xe2x80x94NR92, xe2x80x94OR3, xe2x80x94SR3, perhaloalkyl, and halo, all except xe2x80x94H, xe2x80x94CN, perhaloalkyl, and halo are optionally substituted;
Exe2x80x3 is selected from the group consisting of xe2x80x94H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C4-C6 alicyclic, alkoxyalkyl, xe2x80x94C(O)OR3, xe2x80x94CONR42, xe2x80x94CN, xe2x80x94NR92, xe2x80x94OR3, xe2x80x94SR3, C1-C6 perhaloalkyl, and halo, all except H, xe2x80x94CN, perhaloalkyl, and halo are optionally substituted; and
each R4 is independently selected from the group consisting of xe2x80x94H and C 1-C2 alkyl.
In the methods, preferred X groups include -alkyl(hydroxy)-, -alkyl-, -alkynyl-, xe2x80x94aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, xe2x80x94alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, xe2x80x94alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, xe2x80x94alkylaminocarbonylamino-, -alkylamino-, and -alkenyl-, all optionally substituted.
In the compound and method claims, preferred are novel compounds of formula (I):
wherein R5 is selected from the group consisting of:
wherein:
each G is independently selected from the group consisting of C, N, O, S, and Se, and wherein only one G may be O, S, or Se, and at most one G is N;
each Gxe2x80x2 is independently selected from the group consisting of C and N and wherein no more than two Gxe2x80x2 groups are N;
A is selected from the group consisting of xe2x80x94H, xe2x80x94NR42, xe2x80x94CONR42, xe2x80x94CO2R3, halo, xe2x80x94S(O)R3, xe2x80x94SO2R3, alkyl, alkenyl, alkynyl, perhaloalkyl, haloalkyl, aryl, xe2x80x94CH2OH, xe2x80x94CH2NR42, xe2x80x94CH2CN, xe2x80x94CN, xe2x80x94C(S)NH2, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94N3, xe2x80x94NHC(S)NR42, xe2x80x94NHAc, and null;
each B and D are independently selected from the group consisting of xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, xe2x80x94SO2R11, xe2x80x94S(O)R3, xe2x80x94CN, xe2x80x94NR92, xe2x80x94OR3, xe2x80x94SR3, perhaloalkyl, halo, xe2x80x94NO2, and null, all except xe2x80x94H, xe2x80x94CN, perhaloalkyl, xe2x80x94NO2, and halo are optionally substituted;
E is selected from the group consisting of xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, xe2x80x94C(O)OR3, xe2x80x94CONR42, xe2x80x94CN, xe2x80x94NR92, xe2x80x94NO2, xe2x80x94OR3, xe2x80x94SR3, perhaloalkyl, halo, and null, all except xe2x80x94H, xe2x80x94CN, perhaloalkyl, and halo are optionally substituted;
J is selected from the group consisting of xe2x80x94H and null;
X is an optionally substituted linking group that links R5 to the phosphorus atom via 2-4 atoms, including 0-1 heteroatoms selected from N, O, and S, except that if X is urea or carbamate there is 2 heteroatoms, measured by the shortest path between R5 and the phosphorus atom, and wherein the atom attached to the phosphorus is a carbon atom, and wherein there is no N in the linking group unless it is connected directly to a carbonyl or in the ring of a heterocycle; and wherein X is not a 2 carbon atom -alkyl- or -alkenyl- group; with the proviso that X is not substituted with xe2x80x94COOR2, xe2x80x94SO3R1, or xe2x80x94PO3R12;
Y is independently selected from the group consisting of xe2x80x94Oxe2x80x94, and xe2x80x94NR6xe2x80x94;
when Y is xe2x80x94Oxe2x80x94, then R1 attached to xe2x80x94Oxe2x80x94 is independently selected from the group consisting of xe2x80x94H, alkyl, optionally substituted aryl, optionally substituted alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, xe2x80x94C(R2)2OC(O)NR22, xe2x80x94NR2xe2x80x94C(O)xe2x80x94R3, xe2x80x94C(R2)2xe2x80x94OC(O)R3, xe2x80x94C(R2)2xe2x80x94Oxe2x80x94C(O)OR3, xe2x80x94C(R2)2OC(O)SR3, -alkyl-Sxe2x80x94C(O)R3, -alkyl-Sxe2x80x94S-alkylhydroxy, and -alkyl-Sxe2x80x94Sxe2x80x94S-alkylhydroxy,
when Y is xe2x80x94NR6xe2x80x94, then R1 attached to xe2x80x94NR6xe2x80x94 is independently selected from the group consisting of xe2x80x94H, xe2x80x94[C(R2)2]qxe2x80x94COOR3, xe2x80x94C(R4)2COOR3, xe2x80x94[C(R2)2]qxe2x80x94C(O)SR, and -cycloalkylene-COOR3;
or when either Y is independently selected from xe2x80x94Oxe2x80x94 and xe2x80x94NR6xe2x80x94, then together R1 and R1 are -alkyl-Sxe2x80x94S-alkyl- to form a cyclic group, or together R1 and R1 are
wherein
V, W, and Wxe2x80x2 are independently selected from the group consisting of xe2x80x94H, alky, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus;
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;
together Z and W are connected via 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;
together W and Wxe2x80x2 are connected 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;
Z is selected from the group consisting of xe2x80x94CHR2OH, xe2x80x94CHR2OC(O)R3, xe2x80x94CHR2OC(S)R3, xe2x80x94CHR2OC(S)OR3, xe2x80x94CHR2OC(O)SR3, xe2x80x94CHR2OCO2R3, xe2x80x94OR2, xe2x80x94SR2, xe2x80x94CHR2N3, xe2x80x94CH2aryl, xe2x80x94CH(aryl)OH, xe2x80x94CH(CHxe2x95x90CR22)OH, xe2x80x94CH(Cxe2x89xa1CR2)OH, xe2x80x94R2, xe2x80x94NR22, xe2x80x94OCOR3, xe2x80x94OCO2R3, xe2x80x94SCOR3, xe2x80x94SCO2R3, xe2x80x94NHCOR2, xe2x80x94NHCO2R3, xe2x80x94CH2NHaryl, xe2x80x94(CH2)pxe2x80x94OR2, and xe2x80x94(CH2)pxe2x80x94SR2;
p is an integer 2 or 3;
q is an integer 1 or 2;
with the provisos that:
a) V, Z, W, Wxe2x80x2 are not all xe2x80x94H; and
b) when Z is xe2x80x94R2, then at least one of V, W, and Wxe2x80x2 is not xe2x80x94H, alkyl, aralkyl, or alicyclic;
R2 is selected from the group consisting of R3 and xe2x80x94H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
each R4 is independently selected from the group consisting of xe2x80x94H, and alkyl, or together R4 and R4 form a cyclic alkyl group;
R6 is selected from the group consisting of xe2x80x94H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
each R9 is independently selected from the group consisting of xe2x80x94H, alkyl, aralkyl, and alicyclic, or together R9 and R9 form a cyclic alkyl group;
R11 is selected from the group consisting of alkyl, aryl, xe2x80x94NR22, and xe2x80x94OR2; and with the provisos that:
1) when Gxe2x80x2 is N, then the respective A, B, D, or E is null;
2) at least one of A and B, or A, B, D, and E is not selected from the group consisting of xe2x80x94H or null;
3) when R5 is a six-membered ring, then X is not any 2 atom linker, an optionally substituted -alkyl-, an optionally substituted -alkenyl-, an optionally substituted -alkyloxy-, or an optionally substituted -alkylthio-;
4) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom;
5) R1 is not unsubstituted C1-C10 alkyl;
6) when X is not an -aryl- group, then R5 is not substituted with two or more aryl groups;
and pharmaceutically acceptable prodrugs and salts thereof.
Preferred R5 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.
In one aspect, preferred are compounds of formula I where:
A is selected from the group consisting of xe2x80x94H, xe2x80x94NR42, xe2x80x94CONR42, xe2x80x94CO2R3, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl, C1-C6 haloalkyl, aryl, xe2x80x94CH2OH, xe2x80x94CH2NR42, xe2x80x94CH2CN, xe2x80x94CN, xe2x80x94C(S)NH2, xe2x80x94OR4, xe2x80x94SR4, xe2x80x94N3, xe2x80x94NHC(S)NR42, xe2x80x94NHAc, and null;
each B and D are independently selected from the group consisting of xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, xe2x80x94SO2R11, xe2x80x94S(O)R3, xe2x80x94CN, xe2x80x94NR22, xe2x80x94OR3, xe2x80x94SR3, perhaloalkyl, halo, and null, all except xe2x80x94H, xe2x80x94CN, perhaloalkyl, and halo are optionally substituted;
E is selected from the group consisting of xe2x80x94H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, C4-C6 alicyclic, alkoxyalkyl, xe2x80x94C(O)OR3, xe2x80x94CONR42, xe2x80x94CN, xe2x80x94NR92, xe2x80x94OR3, xe2x80x94SR3, C1-C6 perhaloalkyl, halo, and null, all except xe2x80x94H, xe2x80x94CN, perhaloalkyl, and halo are optionally substituted; and
each R4 is independently selected from the group consisting of xe2x80x94H, and C1-C2 alkyl.
In another preferred aspect, R5 is:
In another preferred aspect, R5 is:
In another preferred aspect, R5 is selected from the group consisting of:
wherein
Axe2x80x3 is selected from the group consisting of xe2x80x94H, xe2x80x94NR42, xe2x80x94CONR42, xe2x80x94CO2R3, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl, C1-C6 haloalkyl, aryl, xe2x80x94CH2OH, xe2x80x94CH2NR42, xe2x80x94CH2CN, xe2x80x94CN, xe2x80x94C(S)NH2, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94N3, xe2x80x94NHC(S)NR42, and xe2x80x94NHAc;
Bxe2x80x3 and Dxe2x80x3 are independently selected from the group consisting of xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, xe2x80x94SO2R11, xe2x80x94S(O)R3, xe2x80x94CN, xe2x80x94NR92, xe2x80x94OR3, xe2x80x94SR3, perhaloalkyl, and halo, all except xe2x80x94H, xe2x80x94CN, perhaloalkyl, and halo are optionally substituted;
Exe2x80x3 is selected from the group consisting of xe2x80x94H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C4-C6 alicyclic, alkoxyalkyl, xe2x80x94C(O)OR3, xe2x80x94CONR42, xe2x80x94CN, xe2x80x94NR92, xe2x80x94OR3, xe2x80x94SR3, C1-C6 perhaloalkyl, and halo, all except H, xe2x80x94CN, perhaloalkyl, and halo are optionally substituted; and
each R4 is independently selected from the group consisting of xe2x80x94H and C1-C2 alkyl.
More preferred are such where Rs is selected from the group consisting of:
Also more preferred are such where R5 is selected from the group consisting of:
Also more preferred are such where R5 is selected from the group consisting of:
Preferred X groups include -alkyl(hydroxy)-, -alkyl-, -alkynyl-, -aryl-, xe2x80x94carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, xe2x80x94alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, xe2x80x94alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted.
More preferred X groups include -heteroaryl-, -alkylcarbonylamino-, -alkylaminocarbonyl-, -alkoxycarbonyl-, and -alkoxyalkyl-.
Particularly preferred X groups include -heteroaryl-, and -alkoxycarbonyl-. Especially preferred are furan-3,5-diyl, -methylaminocarbonyl-, and methyloxycarbonyl-.
Also particularly preferred are compounds where X is as shown in formulae II, III, or IV
Especially preferred are compounds where X is as shown in formulae II and IV.
Preferred A groups include xe2x80x94H, xe2x80x94NR42, xe2x80x94CONR42, xe2x80x94CO2R3, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl, C1-C6 haloalkyl, aryl, xe2x80x94CH2OH, xe2x80x94CH2NR42, xe2x80x94CH2CN, xe2x80x94CN, xe2x80x94C(S)NH2, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94N3, xe2x80x94NHC(S)NR42, null, and xe2x80x94NHAc. More preferred A groups include xe2x80x94NH2, xe2x80x94CONH2, halo, xe2x80x94CH3, xe2x80x94CF3, xe2x80x94CH2-halo, xe2x80x94CN, xe2x80x94OCH3, xe2x80x94SCH3, null, and xe2x80x94H. Especially preferred A groups include xe2x80x94NH2, xe2x80x94Cl, xe2x80x94Br, null, and xe2x80x94CH3.
Preferred Axe2x80x3 groups include xe2x80x94H, xe2x80x94NR42, xe2x80x94CONR42, xe2x80x94CO2R3, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl, C1-C6 haloalkyl, aryl, xe2x80x94CH2OH, xe2x80x94CH2NR42, xe2x80x94CH2CN, xe2x80x94CN, xe2x80x94C(S)NH2, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94N3, xe2x80x94NHC(S)NR42, and xe2x80x94NHAc. More preferred Axe2x80x3 groups include xe2x80x94NH2, xe2x80x94CONH2, halo, xe2x80x94CH3, xe2x80x94CF3, xe2x80x94CH2-halo, xe2x80x94CN, xe2x80x94OCH3, xe2x80x94SCH3, and xe2x80x94H. Especially preferred Axe2x80x3 groups include xe2x80x94NH2, xe2x80x94Cl, xe2x80x94Br, and xe2x80x94CH3.
Preferred B groups include xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, xe2x80x94SO2R11, xe2x80x94S(O)R3, xe2x80x94CN, xe2x80x94NR92, xe2x80x94OR3, xe2x80x94SR3, perhaloalkyl, halo, and null, all except xe2x80x94H, xe2x80x94CN, perhaloalkyl, null, and halo are optionally substituted. More preferred B groups include xe2x80x94H, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, alkyl, aryl, alicyclic, halo, xe2x80x94NR92, xe2x80x94OR3, null and xe2x80x94SR3. Especially preferred B groups include xe2x80x94H, xe2x80x94C(O)OR3, xe2x80x94C(O)SR3, C1-C6 alkyl, alicyclic, halo, heteroaryl, null, and xe2x80x94SR3.
Preferred Bxe2x80x3 groups include xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, xe2x80x94SO2R11, xe2x80x94S(O)R3, xe2x80x94CN, xe2x80x94NR92, xe2x80x94OR3, xe2x80x94SR3, perhaloalkyl, and halo, all except xe2x80x94H, xe2x80x94CN, perhaloalkyl, and halo are optionally substituted. More preferred Bxe2x80x3 groups include xe2x80x94H, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, alkyl, aryl, alicyclic, halo, xe2x80x94NR92, xe2x80x94OR3, and xe2x80x94SR3. Especially preferred Bxe2x80x3 groups include xe2x80x94H, xe2x80x94C(O)OR3, xe2x80x94C(O)SR3, C1-C6 alkyl, alicyclic, halo, heteroaryl, and xe2x80x94SR3.
Preferred D groups include xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, xe2x80x94SO2R11, xe2x80x94S(O)R3, xe2x80x94CN, NR22, xe2x80x94OR3, xe2x80x94SR3, perhaloalkyl, halo, and null, all except xe2x80x94H, xe2x80x94CN, perhaloalkyl, null, and halo are optionally substituted. More preferred D groups include xe2x80x94H, xe2x80x94C(O)R11, alkyl, xe2x80x94C(O)SR3, aryl, alicyclic, halo, xe2x80x94NR92, null and xe2x80x94SR3. Especially preferred D groups include xe2x80x94H, xe2x80x94C(O)OR3, lower alkyl, alicyclic, null, and halo.
Preferred Dxe2x80x3 groups include xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, xe2x80x94SO2R11, xe2x80x94S(O)R3, xe2x80x94CN, xe2x80x94NR22, xe2x80x94OR3, xe2x80x94SR3, perhaloalkyl, and halo, all except xe2x80x94H, xe2x80x94CN, perhaloalkyl, and halo are optionally substituted. More preferred Dxe2x80x3 groups include xe2x80x94H, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, alkyl, aryl, alicyclic, halo, xe2x80x94NR92, and xe2x80x94SR3. Especially preferred Dxe2x80x3 groups include xe2x80x94H, xe2x80x94C(O)OR3, lower alkyl, alicyclic, and halo.
Preferred E groups include xe2x80x94H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, C4-C6 alicyclic, alkoxyalkyl, xe2x80x94C(O)OR3, xe2x80x94CONR42, xe2x80x94CN, xe2x80x94NR92, xe2x80x94OR3, xe2x80x94SR3, C1-C6 perhaloalky, halo, and null, all except xe2x80x94H, xe2x80x94CN, perhaloalkyl, null, and halo are optionally substituted. More preferred E groups include xe2x80x94H, C1-C6 alkyl, lower alicyclic, halogen, xe2x80x94CN, xe2x80x94C(O)OR3, xe2x80x94SR3, xe2x80x94CONR42, and null. Especially preferred E groups include xe2x80x94H, xe2x80x94Br, xe2x80x94Cl, and null.
Preferred Exe2x80x3 groups include xe2x80x94H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, C4-C6 alicyclic, alkoxyalkyl, xe2x80x94C(O)OR3, xe2x80x94CONR42, xe2x80x94CN, xe2x80x94NR92, xe2x80x94OR3, xe2x80x94SR3, C1-C6 perhaloalky, and halo, all except xe2x80x94H, xe2x80x94CN, perhaloalkyl, and halo are optionally substituted. More preferred Exe2x80x3 groups include xe2x80x94H, C1-C6 alkyl, lower alicyclic, halogen, xe2x80x94CN, xe2x80x94C(O)OR3, xe2x80x94SR3, and xe2x80x94CONR42. Especially preferred Exe2x80x3 groups include xe2x80x94H, xe2x80x94Br, and xe2x80x94Cl.
In one preferred aspect,
Axe2x80x3 is selected from the group consisting of xe2x80x94NH2, xe2x80x94CONH2, halo, xe2x80x94CH3, xe2x80x94CF3, xe2x80x94CH2-halo, xe2x80x94CN, xe2x80x94OCH3, xe2x80x94SCH3, and xe2x80x94H;
Bxe2x80x3 is selected from the group consisting of xe2x80x94H, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, alkyl, aryl, alicyclic, halo, xe2x80x94CN, xe2x80x94SR3, OR3 and xe2x80x94NR92;
Dxe2x80x3 is selected from the group consisting of xe2x80x94H, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, xe2x80x94NR92, alkyl, aryl, alicyclic, halo, and xe2x80x94SR3;
Exe2x80x3 is selected from the group consisting of xe2x80x94H, C1-C6 alkyl, lower alicyclic, halo, xe2x80x94CN, xe2x80x94C(O)OR3, and xe2x80x94SR3.
X is selected from the group consisting of -alkyl(hydroxy)-, -alkyl-, -alkynyl-, xe2x80x94aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, xe2x80x94alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, xe2x80x94alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted;
when both Y groups are xe2x80x94Oxe2x80x94, then R1 is independently selected from the group consisting of optionally substituted aryl, optionally substituted benzyl, xe2x80x94C(R2)2OC(O)R3, xe2x80x94C(R2)2OC(O)OR3, and xe2x80x94H; or
when one Y is xe2x80x94Oxe2x80x94, then R1 attached to xe2x80x94Oxe2x80x94 is optionally substituted aryl; and the other Y is xe2x80x94NR6xe2x80x94, then R1 attached to xe2x80x94NR6xe2x80x94 is selected from the group consisting of xe2x80x94C(R4)2COOR3, and xe2x80x94C(R2)2COOR3; or
when Y is xe2x80x94Oxe2x80x94 or xe2x80x94NR6xe2x80x94, then together R1 and R1 are
wherein
V, W, and Wxe2x80x2 are independently selected from the group consisting of xe2x80x94H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl, or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;
together Z and W are connected via 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;
together W and Wxe2x80x2 are connected 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;
Z is selected from the group consisting of xe2x80x94CHR2OH, xe2x80x94CHR2OC(O)R3, xe2x80x94CHR2OC(S)R3, xe2x80x94CHR2OC(S)OR3, xe2x80x94CHR2OC(O)SR3, xe2x80x94CHR2OCO2R3, xe2x80x94OR2, xe2x80x94SR2, xe2x80x94R2, xe2x80x94NHCOR2, xe2x80x94NHCO2R3, xe2x80x94(CH2)pxe2x80x94OR2, and xe2x80x94(CH2)pxe2x80x94SR2;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, Wxe2x80x2 are not all xe2x80x94H;
b) when Z is xe2x80x94R2, then at least one of V, W, and Wxe2x80x2 is not xe2x80x94H, alkyl, aralkyl, or alicyclic; and
c) both Y groups are not xe2x80x94NR6xe2x80x94;
R2 is selected from the group consisting of R3 and xe2x80x94H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R6 is selected from the group consisting of xe2x80x94H, and lower alkyl.
In one particularly preferred aspect, R5 is
X is selected from the group consisting of methylenoxycarbonyl, and furan-2,5-diyl; at least one Y group is xe2x80x94Oxe2x80x94; and pharmaceutically acceptable salts and prodrugs thereof. More preferred are such compounds wherein when Y is xe2x80x94Oxe2x80x94, then R1 attached to xe2x80x94Oxe2x80x94 is independently selected from the group consisting of xe2x80x94H, optionally substituted phenyl, xe2x80x94CH2OC(O)-tBu, xe2x80x94CH2OC(O)Et and xe2x80x94CH2OC(O)-iPr;
when Y is xe2x80x94NR6xe2x80x94, then R1 is attached to xe2x80x94NR6xe2x80x94 independently selected from the group consisting of xe2x80x94C(R2)2COOR3, xe2x80x94C(R4)2COOR3, or
when Y is xe2x80x94Oxe2x80x94 or xe2x80x94NR6xe2x80x94, and at least one Y is xe2x80x94Oxe2x80x94, then together R1 and R1 are
wherein
V is selected from the group consisting of optionally substituted aryl, and optionally substituted heteroaryl; and Z, Wxe2x80x2, and W are H; and
R6 is selected from the group consisting of xe2x80x94H, and lower alkyl.
The following such compounds and their salts are most preferred:
1) Axe2x80x3 is xe2x80x94NH2, X is furan-2,5-diyl, and Bxe2x80x3 is xe2x80x94CH2xe2x80x94CH(CH3)2;
2) Axe2x80x3 is xe2x80x94NH2, X is furan-2,5-diyl, and Bxe2x80x3 is xe2x80x94COOEt;
3) Axe2x80x3 is xe2x80x94NH2, X is furan-2,5-diyl, and Bxe2x80x3 is xe2x80x94SCH3;
4) Axe2x80x3 is xe2x80x94NH2, X is furan-2,5-diyl, and Bxe2x80x3 is xe2x80x94SCH2CH2SCH3;
5) Axe2x80x3 is xe2x80x94NH2, X is methyleneoxycarbonyl, and Bxe2x80x3 is xe2x80x94CH(CH3)2.
In another particularly preferred aspect, R5 is
X is furan-2,5-diyl, and methyleneoxycarbonyl, and Axe2x80x3 is xe2x80x94NH2; at least one Y group is xe2x80x94Oxe2x80x94; and pharmaceutically acceptable salts and prodrugs thereof. Especially preferred are such compounds wherein
when Y is xe2x80x94Oxe2x80x94, then each R1 is independently selected from the group consisting of xe2x80x94H, optionally substituted phenyl, xe2x80x94CH2OC(O)-tBu, xe2x80x94CH2OC(O)Et, and xe2x80x94CH2OC(O)-iPr;
or when Y is xe2x80x94NR6xe2x80x94, then each R1 is independently selected from the group consisting of xe2x80x94C(R2)2C(O)OR3, and xe2x80x94C(R4)2COOR3;
or when Y is independently selected from xe2x80x94Oxe2x80x94 and xe2x80x94NR6xe2x80x94, then together R1 and R1 are
wherein
V selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; and Z, Wxe2x80x2, and W are H. Also especially preferred are such compounds wherein Bxe2x80x3 is xe2x80x94SCH2CH2CH3.
In another particularly preferred aspect, R5 is
Axe2x80x3 is xe2x80x94NH2, Exe2x80x3 and Dxe2x80x3 are xe2x80x94H, Bxe2x80x3 is n-propyl and cyclopropyl, X is furan-2,5-diyl and methyleneoxycarbonyl; at least one Y group is xe2x80x94Oxe2x80x94; and pharmaceutically acceptable salts and prodrugs thereof. Especially preferred are such compounds wherein R1 is selected from the group consisting of xe2x80x94H, optionally substituted phenyl xe2x80x94CH2OC(O)-tBu, xe2x80x94CH2OC(O)Et, and xe2x80x94CH2OC(O)-iPr,
or when Y is xe2x80x94NR6xe2x80x94, then each R1 is independently selected from the group consisting of xe2x80x94C(R2)2C(O)OR3, and xe2x80x94C(R4)2COOR3;
or when either Y is independently selected from xe2x80x94Oxe2x80x94 and xe2x80x94NR6xe2x80x94, and at least one Y is xe2x80x94Oxe2x80x94, then together R1 and R1 are
wherein
V is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; and Z, Wxe2x80x2, and W are H.
In another particularly preferred aspect, R5 is
Axe2x80x3 is xe2x80x94NH2, Dxe2x80x3 is xe2x80x94H, Bxe2x80x3 is n-propyl and cyclopropyl, X is furan-2,5-diyl and methyleneoxycarbonyl; at least one Y group is xe2x80x94Oxe2x80x94; and pharmaceutically acceptable salts and prodrugs thereof. Especially preferred are such compounds wherein when Y is xe2x80x94Oxe2x80x94 then R1 is selected from the group consisting of xe2x80x94H, optionally substituted phenyl, xe2x80x94CH2OC(O)-tBu, xe2x80x94CH2OC(O)Et, and xe2x80x94CH2OC(O)-iPr;
or when one Y is xe2x80x94Oxe2x80x94 and its corresponding R1 is -phenyl while the other Y is xe2x80x94NHxe2x80x94 and its corresponding R1 is xe2x80x94CH(Me)C(O)OEt, or
when at least one Y group is xe2x80x94Oxe2x80x94, then together R1 and R1 are
wherein
V is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; and Z, Wxe2x80x2, and W are H.
Preferred are compounds of formula (X):
wherein:
Gxe2x80x3 is selected from the group consisting of xe2x80x94Oxe2x80x94 and xe2x80x94Sxe2x80x94;
A2, L2, E2, and J2 are selected from the group consisting of xe2x80x94NR42, xe2x80x94NO2, xe2x80x94H, xe2x80x94OR2, xe2x80x94SR2, xe2x80x94C(O)NR42, halo, xe2x80x94COR11, xe2x80x94SO2R3, guanidinyl, amidinyl, aryl, aralkyl, alkyoxyalkyl, xe2x80x94SCN, xe2x80x94NHSO2R9, xe2x80x94SO2NR42, xe2x80x94CN, xe2x80x94S(O)R3, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together L2 and E2 or E2 and J2 form an annulated cyclic group;
X2 is an optionally substituted linking group that links R5 to the phosphorus atom via 1-3 atoms, including 0-1 heteroatoms, selected from N, O, and S, and wherein in the atom attached to the phosphorus is a carbon atom;
with the proviso that X2 is not substituted with xe2x80x94COOR2, xe2x80x94SO3R1, or xe2x80x94PO3R12;
Y is independently selected from the group consisting of xe2x80x94Oxe2x80x94, and xe2x80x94NR6xe2x80x94;
when Y is xe2x80x94Oxe2x80x94, then R1 attached to xe2x80x94Oxe2x80x94 is independently selected from the group consisting of xe2x80x94H, alkyl, optionally substituted aryl, optionally substituted alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, xe2x80x94C(R2)2OC(O)NR22, xe2x80x94NR2xe2x80x94C(O)xe2x80x94R3, xe2x80x94C(R2)2xe2x80x94OC(O)R3, xe2x80x94C(R2)2xe2x80x94Oxe2x80x94C(O)OR3, xe2x80x94C(R2)2OC(O)SR3, -alkyl-Sxe2x80x94C(O)R3, -alkyl-Sxe2x80x94S-alkylhydroxy, and -alkyl-Sxe2x80x94Sxe2x80x94S-alkylhydroxy,
when Y is xe2x80x94NR6xe2x80x94, then R1 attached to xe2x80x94NR6xe2x80x94 is independently selected from the group consisting of xe2x80x94H, xe2x80x94[C(R2)2]qxe2x80x94COOR3, xe2x80x94C(R4)2COOR3, [C(R2)2]qxe2x80x94C(O)SR, and -cycloalkylene-COOR3;
or when either Y is independently selected from xe2x80x94Oxe2x80x94 and xe2x80x94NR6xe2x80x94, then together R1 and R1 are -alkyl-Sxe2x80x94S-alkyl- to form a cyclic group, or together R1 and R1 are
wherein
V, W, and Wxe2x80x2 are independently selected from the group consisting of xe2x80x94H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus;
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;
together Z and W are connected via 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;
together W and Wxe2x80x2 are connected 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;
Z is selected from the group consisting of xe2x80x94CHR2OH, xe2x80x94CHR2OC(O)R3, xe2x80x94CHR2OC(S)R3, xe2x80x94CHR2OC(S)OR3, xe2x80x94CHR2OC(O)SR3, xe2x80x94CHR2OCO2R3, xe2x80x94OR2, xe2x80x94SR2, xe2x80x94CHR2N3, xe2x80x94CH2aryl, xe2x80x94CH(aryl)OH, xe2x80x94CH(CHxe2x95x90CR22)OH, xe2x80x94CH(Cxe2x89xa1CR2)OH, xe2x80x94R2, xe2x80x94NR22, xe2x80x94OCOR3, xe2x80x94OCO2R3, xe2x80x94SCOR3, xe2x80x94SCO2R3, xe2x80x94NHCOR2, xe2x80x94NHCO2R3, xe2x80x94CH2NHaryl, xe2x80x94(CH2)pxe2x80x94OR2, and xe2x80x94(CH2)pxe2x80x94SR2;
p is an integer 2 or 3;
q is an integer 1 or 2;
with the provisos that:
a) V, Z, W, Wxe2x80x2 are not all xe2x80x94H; and
b) when Z is xe2x80x94R2, then at least one of V, W, and Wxe2x80x2 is not xe2x80x94H, alkyl, aralkyl, or alicyclic;
R2 is selected from the group consisting of R3 and xe2x80x94H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
each R4 is independently selected from the group consisting of xe2x80x94H, alkyl, or together R4 and R4 form a cyclic alkyl;
R6 is selected from the group consisting of xe2x80x94H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
each R9 is independently selected from the group consisting of xe2x80x94H, alkyl, aralkyl, and alicyclic, or together R9 and R9 form a cyclic alkyl group;
R11 is selected from the group consisting of alkyl, aryl, xe2x80x94NR22, and xe2x80x94OR2; and pharmaceutically acceptable prodrugs and salts thereof
The preferred Gxe2x80x3 group is xe2x80x94Sxe2x80x94.
Preferred A2, L2, E2, and J2 groups include xe2x80x94H, xe2x80x94NR42, xe2x80x94Sxe2x80x94CN, halogen, xe2x80x94OR3, hydroxy, -alkyl(OH), aryl, alkyloxycarbonyl, xe2x80x94SR3, lower perhaloalkyl, and C1-C5 alkyl, or together L2 and E2 form an annulated cyclic group. More preferred A2, E2, E2 and J2 groups include xe2x80x94H, xe2x80x94NR42, xe2x80x94Sxe2x89xa1CN, halogen, lower alkoxy, hydroxy, lower alkyl(hydroxy), lower aryl, and C1-C5 alkyl, or together L2 and E2 form an annulated cyclic group. Particularly preferred J2 groups are xe2x80x94H, and lower alkyl. Particularly preferred A2 groups include xe2x80x94NH2, xe2x80x94H, halo, and C1-C5 alkyl.
Particularly preferred compounds include those where L2 and E2 are independently selected from the group consisting of xe2x80x94H, xe2x80x94Sxe2x80x94Cxe2x89xa1N, lower alkoxy, C1-C5 alkyl, lower alkyl(hydroxy), lower aryl, and halogen or together L2 and E2 form an annulated cyclic group containing an additional 4 carbon atoms.
Preferred X2 groups include -alkyl-, -alkenyl-, -alkynyl-, -alkylene-NR4xe2x80x94, xe2x80x94alkylene-Oxe2x80x94, alkylene-Sxe2x80x94, xe2x80x94C(O)-alkylene-, and -alkylene-C(O)xe2x80x94. More preferred X2 groups include -alkylene-Oxe2x80x94, alkylene-Sxe2x80x94, and -alkyl-. Especially preferred X2 groups include -methyleneoxy-.
In one aspect, preferred are compounds of formula X wherein A2 is selected from the group consisting of xe2x80x94H, xe2x80x94NH2, xe2x80x94CH3, Cl, and Br;
L2 is xe2x80x94H, lower alkyl, halogen, lower alkyloxy, hydroxy, -alkenylene-OH, or together with E2 forms a cyclic group including aryl, cyclic alkyl, heteroaryls, heterocyclic alkyl;
E2 is selected from the groups consisting of H, lower alkyl, halogen, SCN, lower alkyloxycarbonyl, lower alkyloxy, or together with L2 forms a cyclic group including aryl, cyclic alkyl, heteroaryl, or heterocyclic alkyl;
J2 is selected from the groups consisting of H, halogen, and lower alkyl;
Gxe2x80x3 is xe2x80x94Sxe2x80x94;
X2 is xe2x80x94CH2Oxe2x80x94; and
at least one Y group is xe2x80x94Oxe2x80x94; and pharmaceutically acceptable salts and prodrugs thereof. Also particularly preferred are such compounds where A2 is NH2, Gxe2x80x3 is xe2x80x94Sxe2x80x94, L2 is Et, E2 is SCN, and J2 is H. More preferred are such compounds wherein one Y is xe2x80x94Oxe2x80x94 and its corresponding R1 is optionally substituted phenyl, while the other Y is xe2x80x94NHxe2x80x94, and its corresponding R1 is xe2x80x94C(R2)2xe2x80x94COOR3. When R1 is xe2x80x94CHR3COOR3, then the corresponding xe2x80x94NR6xe2x80x94*CHR3COOR3, preferably has L stereochemistry.
Also more preferred are such compounds wherein one Y is xe2x80x94Oxe2x80x94, and its corresponding R1 is -phenyl, while the other Y is xe2x80x94NHxe2x80x94 and its corresponding R1 is xe2x80x94CH(Me)CO2Et.
In compounds of formula I and X, preferably both Y groups are xe2x80x94Oxe2x80x94; or one Y is xe2x80x94Oxe2x80x94 and one Y is xe2x80x94NR6xe2x80x94. When only one Y is xe2x80x94NR6xe2x80x94, preferably the Y closest to W and Wxe2x80x2 is xe2x80x94Oxe2x80x94. Most preferred are prodrugs where both Y groups are xe2x80x94Oxe2x80x94;
In another particularly preferred aspect, both Y groups are xe2x80x94Oxe2x80x94, and R1 and R1 together are
and V is phenyl substituted with 1-3 halogens. Especially preferred are such 3-bromo-4-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, and 3,5-dichlorophenyl.
In another particularly preferred aspect, one Y is xe2x80x94Oxe2x80x94 and its corresponding R1 is phenyl, or phenyl substituted with 1-2 substituents selected from xe2x80x94NHC(O)CH3, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94C(O)OCH2CH3, and xe2x80x94CH3; while the other Y is xe2x80x94NR6xe2x80x94 and its corresponding R1 is xe2x80x94C(R2)COOR3; each R2 is independently selected from xe2x80x94H, xe2x80x94CH3, and xe2x80x94CH2CH3. More preferred R6 is xe2x80x94H, and R1 attached to xe2x80x94NHxe2x80x94 is xe2x80x94CH(Me)CO2Et.
In general, preferred substituents, V, Z, W, and Wxe2x80x2 of formulae I and X are chosen such that they exhibit one or more of the following properties:
(1) enhance the oxidation reaction since this reaction is likely to be the rate determining step and therefore must compete with drug elimination processes.
(2) enhance stability in aqueous solution and in the presence of other non-p450 enzymes;
(3) enhance cell penetration, e.g. substituents are not charged or of high molecular weight since both properties can limit oral bioavailability as well as cell penetration;
(4) promote the xcex2-elimination reaction following the initial oxidation by producing ring-opened products that have one or more of the following properties:
a) fail to recyclize;
b) undergo limited covalent hydration;
c) promote xcex2-elimination by assisting in the proton abstraction;
d) impede addition reactions that form stable adducts, e.g. thiols to the initial hydroxylated product or nucleophilic addition to the carbonyl generated after ring opening; and
e) limit metabolism of reaction intermediates (e.g. ring-opened ketone);
(5) lead to a non-toxic and non-mutagenic by-product with one or more of the following characteristics. Both properties can be minimized by using substituents that limit Michael additions, reactions, e.g.
a) electron donating Z groups that decrease double bond polarization;
b) W groups that sterically block nucleophilic addition to xcex2-carbon;
c) Z groups that eliminate the double bond after the elimination reaction either through retautomerization (enol-xe2x86x92keto) or hydrolysis (e.g. enamine);
d) V groups that contain groups that add to the xcex1,xcex2-unsaturated ketone to form a ring;
e) Z groups that form a stable ring via Michael addition to double bond; and
f) groups that enhance detoxification of the by-product by one or more of the following characteristics:
(i) confine to liver; and
(ii) make susceptible to detoxification reactions (e.g. ketone reduction); and
(6) capable of generating a pharmacologically active product.
In another aspect, it is preferred when Y is xe2x80x94Oxe2x80x94, then R1 attached to xe2x80x94Oxe2x80x94 is independently selected from the group consisting of xe2x80x94H, optionally substituted aryl, optionally substituted alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, xe2x80x94C(R2)2OC(O)R3, xe2x80x94C(R2)2xe2x80x94Oxe2x80x94C(O)OR3, xe2x80x94C(R2)2OC(O)SR3, -alkyl-Sxe2x80x94C(O)R3, and -alkyl-Sxe2x80x94S-alkylhydroxy;
when Y is xe2x80x94NR1xe2x80x94, then R1 attached to xe2x80x94NR6xe2x80x94 is independently selected from the group consisting of xe2x80x94H, xe2x80x94[C(R2)2]qxe2x80x94COOR3, xe2x80x94[C(R2)2]qxe2x80x94C(O)SR3, xe2x80x94C(R4)2COOR3, and -cycloalkylene-COOR3;
or when either Y is independently selected from xe2x80x94Oxe2x80x94 and xe2x80x94NR6xe2x80x94, then together R1 and R1 are
wherein
V, W, and Wxe2x80x2 are independently selected from the group consisting of xe2x80x94H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl, or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;
together Z and W are connected via 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;
together W and Wxe2x80x2 are connected 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;
Z is selected from the group consisting of xe2x80x94CHR2OH, xe2x80x94CHR2OC(O)R3, xe2x80x94CHR2OC(S)R3, xe2x80x94CHR2OC(S)OR3, xe2x80x94CHR2OC(O)SR3, xe2x80x94CHR2OCO2R3, xe2x80x94OR2, xe2x80x94SR2, xe2x80x94R2, xe2x80x94NHCOR2, xe2x80x94NHCO2R3, xe2x80x94(CH2)pxe2x80x94OR2, and xe2x80x94(CH2)pxe2x80x94SR2;
p is an integer 2 or 3;
q is an integer 1 or 2;
with the provisos that:
a) V, Z, W, Wxe2x80x2 are not all xe2x80x94H;
b) when Z is xe2x80x94R2, then at least one of V, W, and Wxe2x80x2 is not xe2x80x94H, alkyl, aralkyl, or alicyclic; and
c) both Y groups are not xe2x80x94NR6xe2x80x94;
R2 is selected from the group consisting of R3 and xe2x80x94H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R6 is selected from the group consisting of xe2x80x94H, and lower alkyl.
More preferred are such compounds wherein when both Y groups are xe2x80x94Oxe2x80x94, then R1 is independently selected from the group consisting of optionally substituted aryl, optionally substituted benzyl, xe2x80x94C(R2)2OC(O)R3, xe2x80x94C(R2)2OC(O)OR3, and xe2x80x94H; and
when Y is xe2x80x94NR6xe2x80x94, then the R1 attached to said xe2x80x94NR6xe2x80x94 group is selected from the group consisting of xe2x80x94C(R4)2xe2x80x94COOR3, and xe2x80x94C(R2)2COOR3; and the other Y group is xe2x80x94Oxe2x80x94 and then R1 attached to said xe2x80x94Oxe2x80x94 is selected from the group consisting of optionally substituted aryl, xe2x80x94C(R2)2OC(O)R3, and xe2x80x94C(R2)2OC(O)OR3.
In another aspect, when one Y is xe2x80x94Oxe2x80x94, then its corresponding R1 is phenyl, and the other Y is xe2x80x94NHxe2x80x94, and its corresponding R1 is xe2x80x94CH2CO2Et.
In another preferred aspect, when one Y is xe2x80x94Oxe2x80x94, its corresponding R1 is phenyl, and the other Y is xe2x80x94NHxe2x80x94 and its corresponding R1 is xe2x80x94C(Me)2CO2Et.
In another preferred aspect, when one Y is xe2x80x94Oxe2x80x94, its corresponding R1 is 4-NHC(O)CH3-phenyl, and the other Y is xe2x80x94NHxe2x80x94, and its corresponding R1 is xe2x80x94CH2COOEt.
In another preferred aspect, when one Y is xe2x80x94Oxe2x80x94, its corresponding R1 is 2-CO2Et-phenyl, and the other Y is xe2x80x94NHxe2x80x94 and its corresponding R1 is xe2x80x94CH2CO2Et.
In another preferred aspect, when one Y is xe2x80x94Oxe2x80x94, then its corresponding R1 is 2-CH3-phenyl, and the other Y is xe2x80x94NH, and its corresponding, R1 is xe2x80x94CH2CO2Et.
In another aspect, preferred are compounds wherein both Y groups are xe2x80x94Oxe2x80x94, and R1 is aryl, or xe2x80x94C(R2)2-aryl.
Also preferred are compounds wherein both Y groups are Oxe2x80x94, and at least one R1 is selected from the group consisting of xe2x80x94C(R2)2xe2x80x94OC(O)R3, and xe2x80x94C(R2)2xe2x80x94C(O)OR3.
In another aspect, preferred are compounds wherein both Y groups are xe2x80x94Oxe2x80x94 and at least one R1 is -alkyl-Sxe2x80x94S-alkylhydroxyl, -alkyl-Sxe2x80x94C(O)R3, and -alkyl-Sxe2x80x94Sxe2x80x94S-alkylhydroxy, or together R1 and R1 are -alkyl-Sxe2x80x94S-alkyl- to form a cyclic group.
In one aspect, particularly preferred are compounds wherein both Y groups are xe2x80x94Oxe2x80x94, and R1 is H.
In another aspect, particularly preferred are compounds where both Y groups are xe2x80x94Oxe2x80x94, and R=is xe2x80x94CH2OC(O)OEt.
More preferred are compounds wherein at least one Y is xe2x80x94Oxe2x80x94, and together R1 and R1 are
wherein
V, W, and Wxe2x80x2 are independently selected from the group consisting of xe2x80x94H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl, or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;
together Z and W are connected via 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;
together W and Wxe2x80x2 are connected 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;
Z is selected from the group consisting of xe2x80x94CHR2OH, xe2x80x94CHR2OC(O)R3, xe2x80x94CHR2OC(S)R3, xe2x80x94CHR2OC(S)OR3, xe2x80x94CHR2OC(O)SR3, xe2x80x94CHR2OCO2R3, xe2x80x94OR2, xe2x80x94SR2, xe2x80x94R2, xe2x80x94NHCOR2, xe2x80x94NHCO2R3, xe2x80x94(CH2)pxe2x80x94OR2, and xe2x80x94(CH2)pxe2x80x94SR2;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, Wxe2x80x2 are not all xe2x80x94H;
b) when Z is xe2x80x94R2, then at least one of V, W, and Wxe2x80x2 is not xe2x80x94H, alkyl, aralkyl, or alicyclic; and
c) both Y groups are not xe2x80x94NR6xe2x80x94;
R2 is selected from the group consisting of R3 and xe2x80x94H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R6 is selected from the group consisting of xe2x80x94H, and lower alkyl.
In an other aspect, more preferred are compounds wherein one Y is xe2x80x94Oxe2x80x94, and R1 is optionally substituted aryl; and the other Y is xe2x80x94NR6xe2x80x94, where R1 on said xe2x80x94NR6xe2x80x94 is selected from the group consisting of xe2x80x94C(R4)2COOR3, and xe2x80x94C(R2)2C(O)OR3. Particularly preferred are such compounds where R1 attached to xe2x80x94Oxe2x80x94 is -phenyl, and R1 to xe2x80x94NHxe2x80x94 is xe2x80x94CH(Me)CO2Et, and xe2x80x94NH*CH(Me)CO2Et is in the L configuration.
Especially preferred are such compounds where R1 attached to xe2x80x94Oxe2x80x94 is selected from the group consisting of phenyl and phenyl substituted with 1-2 substituents selected from the group consisting of xe2x80x94NHAc, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94COOEt, and xe2x80x94CH3; and R1 attached to xe2x80x94NR6, is xe2x80x94C(R2)2COOR3 where R2 and R3 independently is xe2x80x94H, xe2x80x94CH3, and -Et. Of such compounds, when R1 attached to xe2x80x94Oxe2x80x94 is phenyl substituted with xe2x80x94NHAc or xe2x80x94COOEt, then preferably any xe2x80x94NHAc is at the 4-position, and any xe2x80x94COOEt is at the 2-position. More preferred are such compounds where the substituents on the substituted phenyl is 4-NHC(O)CH3, xe2x80x94Cl, xe2x80x94Br, 2-C(O)OCH3CH3, or xe2x80x94CH3.
More preferred V groups of formula VI are aryl, substituted aryl, heteroaryl, and substituted heteoaryl. Preferably Y is xe2x80x94Oxe2x80x94. Particularly preferred aryl and substituted aryl groups include phenyl, and phenyl substituted with 1-3 halogens. Especially preferred are 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 3-chlorophenyl, and 3-bromophenyl.
It is also especially preferred when V is selected from the group consisting of monocyclic heteroaryl and monocyclic substituted heteroaryl containing at least one nitrogen atom. Most preferred is when such heteroaryl and substituted heteroaryl is 4-pyridyl, and 3-bromopyridyl, respectively.
It is also preferred when together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma positions to the Y attached to phosphorus. In such compounds preferably said aryl group is an optionally substituted monocyclic aryl group and the connection between Z and the gamma position of the aryl group is selected from the group consisting of O, CH2, CH2CH2, OCH2 or CH2O.
In another aspect, it is preferred when together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and monosubstituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkosycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus. In such compounds, it is more preferred when together V and W form a cyclic group selected from the group consisting of xe2x80x94CH2xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94, CH2CH(OCOR3)xe2x80x94CH2xe2x80x94, and xe2x80x94CH2CH(OCO2)R3)xe2x80x94CH2xe2x80x94.
Another preferred V group is 1-alkene. Oxidation by p450 enzymes is known to occur at benzylic and allylic carbons.
In one aspect, a preferred V group is xe2x80x94H, when Z is selected from the group consisting of xe2x80x94CHR2OH, xe2x80x94CHR2OCOR3, and xe2x80x94CHR2OCO2R3.
In another aspect, when V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, preferred Z groups include xe2x80x94OR2, xe2x80x94SR2, xe2x80x94CHR2N3, xe2x80x94R2, xe2x80x94NR22, xe2x80x94OCOR2, xe2x80x94OCO2R3, xe2x80x94SCOR3, xe2x80x94SCO2R3, xe2x80x94NHCOR2, xe2x80x94NHCO2R3, xe2x80x94CH2NHaryl, xe2x80x94(CH2)pxe2x80x94OR2, and xe2x80x94(CH2)pxe2x80x94SR2. More preferred Z groups include xe2x80x94OR2, xe2x80x94R2, xe2x80x94OCOR2, xe2x80x94OCO2R3, xe2x80x94CH3, xe2x80x94NHCOR2, xe2x80x94NHCO2R3, xe2x80x94(CH2)pxe2x80x94OR2, and, xe2x80x94(CH2)pxe2x80x94SR2. Most preferred Z groups include xe2x80x94OR2, xe2x80x94H, xe2x80x94OCOR2, xe2x80x94OCO2R3, and xe2x80x94NHCOR2.
Preferred W and Wxe2x80x2 groups include H, R3, aryl, substituted aryl, heteroaryl, and substituted aryl. Preferably, W and Wxe2x80x2 are the same group. More preferred is when W and Wxe2x80x2 are H.
In one aspect, prodrugs of formula VI are preferred:
wherein
V is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl, 1-alkenyl, and 1-alkynyl. More preferred V groups of formula VI are aryl, substituted, heteroaryl, and substituted heteoaryl. Preferably Y is xe2x80x94Oxe2x80x94. Particularly preferred aryl and substituted aryl groups include phenyl and substituted phenyl. Particularly preferred heteroaryl groups include monocyclic substiutted and unsubstituted heteroaryl groups. Especially preferred are 4-pyridyl and 3-bromopyridyl.
In one aspect, the compounds of formula VI preferably have a group Z which is H, alkyl, alicyclic, hydroxy, alkoxy,
or NHCOR. Preferred are such groups in which Z decreases the propensity of the byproduct, vinyl aryl ketone to undergo Michael additions. Preferred Z groups are groups that donate electrons to the vinyl group which is a known strategy for decreasing the propensity of xcex1,xcex2-unsaturated carbonyl compounds to undergo a Michael addition. For example, a methyl group in a similar position on acrylamide results in no mutagenic activity whereas the unsubstituted vinyl analog is highly mutagenic. Other groups could serve a similar function, e.g. Zxe2x95x90OR, NHAc, etc. Other groups may also prevent the Michael addition especially groups that result in removal of the double bond altogether such as Zxe2x95x90OH, xe2x80x94OC(O)R, xe2x80x94OCO2R, and NH2, which will rapidly undergo retautomerization after the elimination reaction. Certain W and Wxe2x80x2 groups are also advantageous in this role since the group(s) impede the addition reaction to the xcex2-carbon or destabilize the product. Another preferred Z group is one that contains a nucleophilic group capable of adding to the xcex1,xcex2-unsaturated double bond after the elimination reaction i.e. (CH2)pSH or (CH2)nOH where p is 2 or 3. Yet another preferred group is a group attached to V which is capable of adding to the xcex1,xcex2-unsaturated double bond after the elimination reaction:
In another aspect, prodrugs of formula VII are preferred:
wherein
Z is selected from the group consisting of:
xe2x80x94CHR2H, xe2x80x94CHR2OCOR3, xe2x80x94CHR2OC(S)R3, xe2x80x94CHR2OCO2R3, xe2x80x94CHR2OC(O)SR3, and xe2x80x94CHR2OC(S)OR3. Preferably Y is xe2x80x94Oxe2x80x94. More preferred groups include xe2x80x94CHR2OH, xe2x80x94CHR2OC(O)R3, and xe2x80x94CHR2OCO2R3.
In another aspect, prodrugs of formula VIII are preferred:
wherein
Zxe2x80x2 is selected from the group consisting of xe2x80x94OH, xe2x80x94OC(O)R3, xe2x80x94OCO2R3, and xe2x80x94OC(O)SR3;
D4 and D3 are independently selected from the group consisting of xe2x80x94H, alkyl, OR2, xe2x80x94OH, and xe2x80x94OC(O)R3; with the proviso that at least one of D4 and D3 are xe2x80x94H. Preferably Y is xe2x80x94Oxe2x80x94.
In one preferred embodiment, Wxe2x80x2 and Z are xe2x80x94H, W and V are both the same aryl, substituted aryl, heteroaryl, or substituted heteroaryl such that the phosphonate prodrug moiety:
has a plane of symmetry. Preferably Y is xe2x80x94Oxe2x80x94.
In another preferred embodiment, W and Wxe2x80x2 are H, V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, and Z is selected from the group consisting of xe2x80x94H, ORxe2x80x2, and xe2x80x94NHCOR2. More preferred are such compounds where Z is xe2x80x94H.
Preferably, oral bioavailability is at least 5%. More preferably, oral bioavailability is at least 10%.
p450 oxidation can be sensitive to stereochemistry which might either be at phosphorus or at the carbon bearing the aromatic group. The prodrugs of the present invention have two isomeric forms around the phosphorus. Preferred is the stereochemistry that enables both oxidation and the elimination reaction. Preferred is the cis-stereochemistry.
The preferred compounds of formula VIII utilize a Zxe2x80x2 group that is capable of undergoing an oxidative reaction that yields an unstable intermediate which via elimination reactions breaks down to the corresponding R5xe2x80x94Xxe2x80x94PO32xe2x88x92, R5xe2x80x94Xxe2x80x94P(O)(NHR6)2, or R5xe2x80x94Xxe2x80x94P(O)(Oxe2x88x92)(NHR6). Especially preferred Zxe2x80x2 groups is OH. Groups D4 and D3 are preferably hydrogen, alkyl, and xe2x80x94OR2, xe2x80x94OC(O)R3, but at least one of D4 or D3 must be H.
In the following examples of preferred compounds, the following prodrugs are preferred:
Acyloxyalkyl esters;
Alkoxycarbonyloxyalkyl esters;
Aryl esters;
Benzyl and substituted benzyl esters;
Disulfide containing esters;
Substituted (1,3-dioxolen-2-one)methyl esters;
Substituted 3-phthalidyl esters;
Cyclic-[5-hydroxycyclohexan-1,3-diyl] diesters and hydroxy protected forms;
Cyclic-[2-hydroxymethylpropan-1,3-diyl] diesters and hydroxy protected forms;
Cyclic-(1-arylpropan-1,3-diyl);
Monoaryl ester N-substituted mono phosphoramidates;
Bis Omega substituted lactone esters; and all mixed esters resulted from possible combinations of above esters;
More preferred are the following:
Bis-pivaloyloxymethyl esters;
Bis-isobutyryloxymethyl esters;
Cyclic-[1-(3-chlorophenyl)propan-1,3-diyl] diesters;
Cyclic-[1-(3,5-dichlorophenyl)propan-1,3-diyl] diester;
Cyclic-[1-(3-bromo-4-fluorophenyl)propan-1,3-diyl] diester;
Cyclic-[2-hydroxymethylpropan-1,3-diyl] diester;
Cyclic-[2-acetoxymethylpropan-1,3-diyl] diester;
Cyclic-[2-methyloxycarbonyloxymethylpropan-1,3-diyl] diester;
Cyclic-[1-phenylpropan-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-hydroxycyclohexan-1,3-diyl] diesters and hydroxy protected forms;
Bis-benzoylthiomethyl esters;
Bis-benzoylthioethyl esters;
Bis-benzoyloxymethyl esters;
Bis-p-fluorobenzoyloxymethyl esters;
Bis-6-chloronicotinoyloxymethyl esters;
Bis-5-bromonicotinoyloxymethyl esters;
Bis-thiophenecarbonyloxymethyl esters;
Bis-2-furoyloxymethyl esters;
Bis-3-furoyloxymethyl esters;
Diphenyl 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-triazolophenyl) esters;
Bis-(3-N,N-dimethylaninophenyl) esters;
Bis-(1,2,3,4-tetrahydronapthalen-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-(6xe2x80x2-hydroxy-3xe2x80x2,4xe2x80x2-dithia)hexyl esters;
Bis-(6xe2x80x2-acetoxy-3xe2x80x2,4xe2x80x2-dithia)hexyl esters;
(3,4-dithiahexan-1,6-diyl) esters;
Bis-(5-methyl-1,3-dioxolen-2-one-4-yl)methyl esters;
Bis-(5-ethyl-1,3-dioxolen-2-one-4-yl)methyl esters;
Bis-(5-tert-butyl-1,3-dioxolen-2-one-4-yl)methyl esters;
Bis-3-(5,6,7-trimethoxy)phthalidyl esters;
Bis-(cyclohexyloxycarbonyloxymethyl) esters;
Bis-(isopropyloxycarbonyloxymethyl) esters;
Bis-(ethyloxycarbonyloxymethyl) esters;
Bis-(methyloxycarbonyloxymethyl) esters;
Bis-(isopropythiocarbonyloxymethyl) 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-(-chlorophenoxycarbonyloxymethyl) esters;
Bis-(1,4-biphenoxycarbonyloxymethyl) esters;
Bis-[(2-phthalimidoethyl)oxycarbonyloxymethyl]esters;
Bis-(N-phenyl-N-methylcarbamoyloxymethyl) 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)]carbamoylmethylesters;
Bis-(2-aminoethyl) esters;
Bis-(2-methyl-5-thiazolomethyl) esters;
Bis-(bis-2-hydroxyethylcarbamoylmethyl) esters.
O-phenyl-[-(1-ethoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh)N(H)xe2x80x94CH(Me)CO2Et)
O-phenyl-[N-(1-methoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh)(N(H)xe2x80x94CH(Me)CO2Me)
O-(3-chlorophenyl)-[N -(1-ethoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-3-Cl)(NHxe2x80x94CH(Me)CO2Et)
O-(2-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-2-Cl)(NHxe2x80x94CH(Me)CO2Et)
O-(4-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-4-Cl)(NHxe2x80x94CH(Me)CO2Et)
O-(4-acetamidophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-4xe2x80x94NHAc)(NHxe2x80x94CH(Me)CO2Et)
O-(2-ethoxycarbonylphenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-2-CO2Et)(NHxe2x80x94CH(Me)CO2Et)
O-phenyl-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh)(NHxe2x80x94C(Me)2CO2Et)
O-phenyl-[N-(1-methoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh)(NHxe2x80x94C(Me)2CO2Me)
O-(3-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-3-Cl)(NHxe2x80x94C(Me)2CO2Et)
O-(2-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-2-Cl)(NHxe2x80x94C(Me)2CO2Et)
O-(4-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-4-Cl)(NHxe2x80x94C(Me)2CO2Et)
O-(4-acetamidophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-4-NHAc)(NHxe2x80x94C(Me)2CO2Et)
O-(2-ethoxycarbonylphenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-2-CO2Et)(NHxe2x80x94C(Me)2CO2Et)
O-phenyl-[N-(ethoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh)(NHxe2x80x94CH2CO2Et)
O-phenyl-[N-(methoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh)(NHxe2x80x94CH2CO2Me)
O-(3-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh-3-Cl)(NHxe2x80x94CH2CO2Et)
O-(2-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh-2-Cl)(NHxe2x80x94CH2CO2Et)
O-(4-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh-4-Cl)(NHxe2x80x94CH2CO2Et)
O-(4-acetamidophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh-4-NHAc)(NHxe2x80x94CH2CO2Et)
O-(2-ethoxycarbonylphenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh-2-CO2Et)(NHxe2x80x94CH2CO2Et)
Most preferred are the following:
Bis-pivaloyloxymethyl esters;
Bis-isobutyryloxymethyl esters;
Cyclic-[1-(3-chlorophenyl)propan-1,3-diyl] diesters;
Cyclic-[1-3,5-dichlorophenyl)propan-1,3-diyl] diester;
Cyclic-[1-(3-bromo-4-fluorophenyl)propan-1,3-diyl] diester;
Cyclic-(2-hydroxymethylpropan-1,3-diyl) ester;
Cyclic-(2-acetoxymethylpropan-1,3-diyl) ester;
Cyclic-(2-methyloxycarbonyloxymethylpropan-1,3-diyl) ester;
Cyclic-(2-cyclohexylcarbonyloxymethylpropan-1,3-diyl) ester;
Cyclic-[phenylpropan-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-hydroxycyclohexan-1,3-diyl] diesters and hydroxy protected forms;
Bis-benzoylthiomethyl esters;
Bis-benzoylthioethylesters;
Bis-benzoyloxymethyl esters;
Bis-p-fluorobenzoyloxymethyl esters;
Bis-6-chloronicotinoyloxymethyl esters;
Bis-5-bromonicotinoyloxymethyl esters;
Bis-thiophenecarbonyloxymethyl esters;
Bis-2-furoyloxyethyl 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)oxycarbonyloxymethyl]esters;
Bis-(6-hydroxy-3,4-dithia)hexyl esters;
Cyclic-(3,4-dithiahexan-1,6-diyl) esters;
Bis-(2-bromoethyl) esters;
Bis-(2-aminoethyl) esters;
Bis-(2-N,N-dianinoetlyl) esters;
O-phenyl-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh)(NHxe2x80x94*CH(Me)CO2Et)
O-phenyl-[N-(1-methoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh)(NHxe2x80x94*CH(Me)CO2Me)
O-(3-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-3-Cl)(NHxe2x80x94*CH(Me)CO2Et)
O-(2-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-2-Cl)(NHxe2x80x94*CH(Me)CO2Et)
O-(4-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-4-Cl)(NHxe2x80x94*CH(Me)CO2Et)
O-(4-acetamidophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-4-NHAc)(NHxe2x80x94*CH(Me)CO2Et)
O-(2-ethoxycarbonylphenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-2-CO2Et)(NHxe2x80x94*CH(Me)CO2Et)
O-phenyl-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh)(NHxe2x80x94C(Me)2CO2Et)
O-phenyl-[N-(1-methoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh)(NHxe2x80x94C(Me)2CO2Me)
O-(3-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-3-Cl)(NHxe2x80x94C(Me)2CO2Et)
O-(2-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-2-Cl)(NHxe2x80x94C(Me)2CO2Et)
O-(4-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-4-Cl)(NHxe2x80x94C(Me)2CO2Et)
O-(4-acetamidophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-4-NHAc)(NHxe2x80x94C(Me)2CO2Et)
O-(2-ethoxycarbonylphenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-2-CO2Et)(NHxe2x80x94C(Me)2CO2Et)
In the above prodrugs an asterisk (*) on a carbon refers to the L-configuration.
O-phenyl-[N-(ethoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh)(NHxe2x80x94CH2CO2Et)
O-phenyl-[N-(methoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh)(NHxe2x80x94CH2CO2Me)
O-(3-chlorophenyl)[N-((ethoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh-3-Cl)(NHxe2x80x94CH2CO2Et)
O-(2-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh-2-Cl)(NHxe2x80x94CH2CO2Et)
O-(4-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh-4-Cl)(NHxe2x80x94CH2CO2Et)
O-(4-acetamidophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh-4-NHAc)(NHxe2x80x94C H2CO2Et)
O-(2-ethoxycarbonylphenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh-2-CO2Et)(NHxe2x80x94CH2CO2Et)
The following compounds of formula I wherein R5 is a thiazolyl, or an oxazolyl, or a selenazolyl, or a pyrazolyl, or an imidazolyl or an isoxazolyl or a 1,2,4-triazolyl, or a 1,2,4-thiadiazolyl, or a 1,2,4-oxadiazolyl, and pharmaceutically acceptable salts and prodrugs thereof are preferred. These preferred compounds are shown in structures (i)-(iv), below:
The preferred compounds are listed in Table 1 by designated numbers assigned to A, B, X and Yxe2x80x2 moieties in the above formulae i-iv according to the following convention: A.B.X.Yxe2x80x2. For each moiety, structures are assigned to a number shown in the following tables for A, B, X, and Yxe2x80x2. The following terms are used: Pr-c is cyclopropyl, Pr-n is n-propyl, Pr-i is isopropyl, Bu-n is n-butyl, Bu-I is isobutyl, Bu-c is cyclobutyl, Bu-s is sec-butyl, Bu-t is tert-butyl and hexyl-c is cyclohexyl.
Variable A is selected from seven different substituents.
The A groups are assigned the following numbers:
Variable B is divided into four Groups, each listing nine different substituents.
The Group 1 substituents for variable B are assigned the following numbers:
The Group 2 substituents for variable B are assigned the following numbers:
The Group 3 substituents for variable B are assigned the following numbers:
The Group 4 substituents for variable B are assigned the following numbers:
Variable X is selected from nine different substituents.
The X groups are assigned the following numbers:
The direction of X groups is defined as going from the heterocycle to the phosphorus atom as shown in formula (i), (ii), (iii) and (iv).
Variable Yxe2x80x2 is selected from six different substituents.
The Yxe2x80x2 groups are assigned the following numbers:
Therefore, compounds named in Table 1 of formula (i) having xe2x80x94Sxe2x80x94 as Yxe2x80x2 are compounds with a thiazolyl as R5 in formula I. For example, using Group 1 for variable B, the compound named 22.214.171.124 specifies xe2x80x94NH2 as A, -Pr-c as B, furan-2,5-diyl as X and xe2x80x94Sxe2x80x94 as Yxe2x80x2, and this compound is 2-amino-5-cyclopropyl-4-[2-(5-phosphono)furanyl]thiazole prepared in Example 3 as compound 3.27. Analogously, compounds named in Table 1 of formula (i) having xe2x80x94Oxe2x80x94 as Yxe2x80x2 are compounds with an oxazolyl as R5 in formula I. For example, using group 1 for variable B, the compound named 184.108.40.206 in Table 1 of formula (i) has the structure of 2-amino-5-propyl-4-[2-(phosphono)furanyl]oxazole prepared in Example 10 as compound 10.2. Similarly, compounds named in Table 1 of formula (i) having xe2x80x94Sexe2x80x94 as Yxe2x80x2 are compounds with a selenazolyl as R5 in formula I. Thus, using Group 1 for variable B, the compound named 22.214.171.124 in Table 1 of formula (i) has the structure of 2-amino-5-ethyl-4-[2-(5-phosphono)furanyl]selenazole prepared in Example 3 as compound 3.72.
Likewise, using Group 2 for variable B, the compound named in Table 1 of formula (i) as 126.96.36.199 is 2-amino-5-methylthio-4-[2-(5-phosphono)furanyl]thiazole prepared in Example 3 as compound 3.26. Using Group 3 for variable B, the compound named in Table 1 of formula (i) as 18.104.22.168 is 2-amino-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole prepared in Example 3 as compound 3.1.
Using Group 4 for variable B, the compound named in Table 1 of formula (i) as 18.104.22.168 is 2-amino-5-(2-thienyl)-4-[2-(5-phosphono)furanyl]thiazole prepared in Example 6 a compound 6.3.
Some of the exemplary embodiments of the compounds named in Table 1 using Groups 1-4 for variable B in the compounds of formulae (i), (ii), (iii) and (iv) are listed in Table 2.
The following compounds of formula I wherein R5 is a pyridinyl, or a pyrimidinyl, or a pyrazinyl or a pyridazinyl, and pharmaceutically acceptable salts and prodrugs thereof are preferred. These preferred compounds are shown in structures (v)-(ix), below:
The preferred compounds of formula (v)-(ix) are listed in Table 3 by designated numbers assigned to A, B, X, D and E in the above formulae (v)-(ix) according to the following convention: A.B.X.D.E. For compounds of formula (vi) D is null and designated with number 0, for compounds of formula (vii) E is null and designated with number 0, and for compounds of formula (viii) B is null and designated with number 0. For example, all compounds named in Table 3 of formula (vi) are assigned as A.B.X.0.E, all compounds named in Table 3 of formula (vii) are assigned as A.B.X.D.0, all compounds named in Table 3 of formula (viii) are assigned as A.0.X.D.E, and all compounds named in Table 3 of formula (ix) are assigned as 0.B.X.D.E. For each moiety, structures are assigned to a number shown in the following tables for A, B, X, D, and E.
Variable A is selected from eight different sub stituents.
The A groups are assigned the following numbers:
Variable B is divided into four Groups, each listing eight different substituents.
The Group 1 substituents for variable B are assigned the following numbers:
The Group 2 substituents for variable B are assigned the following numbers:
The Group 3 substituents for variable B are assigned the following numbers:
The Group 4 substituents for variable B are assigned the following numbers:
Variable X is divided into two Groups, each listing four different substituents.
The Group 1 substituents for variable X are assigned with the following numbers:
The direction of X groups is defined as going from the heterocycle to the phosphorus atom as shown in formula (v), (vi), (vii), (viii) and (ix).
The Group 2 substituents for variable X are assigned the following numbers:
Variable D is divided into two groups, each listing eight different substituents.
The D groups are assigned the following numbers:
The Group 2 substituents for variable D are assigned the following numbers:
Variable E is divided into three Groups, each listing four different substituents.
The Group 1 substituents for variable E are assigned the following numbers:
The Group 2 substituents for variable E are assigned the following numbers:
The Group 3 substituents for variable E are assigned the following numbers:
Thus, the compound named in Table 3 of formula (v) having substituents from Group 1 of each variable B, X, D, and E named 184.108.40.206.1 specifies xe2x80x94NH2 as A, -Pr-n as B, furan-2,5-diyl as X, xe2x80x94H as D and xe2x80x94H as E, and this compound is 2-amino-5-propyl-6-[2-(5-phosphono)furanyl]pyridine prepared in Example 15 as compound 15.14. Compounds named in Table 3 of formula (v) are compounds with a pyridinyl as R5 in formula I. Analogously, the compound named 188.8.131.52.3 in Table 3 of formula (v) using substituents of Group 1 of each variable B, X, D, and E has the structure of 2-amino-3-ethyl-6-[2-(5-phosphono)furanyl]pyridine and was prepared in Example 15 as compound 15.12.
Compounds named in Table 3 of formula (vi) are compounds with a pyrazinyl as R1 in formula I. One preferred pyrazinyl compound named in Table 3 of formula (vi) is 18.104.22.168.4. Using Group 1 of each variable, 126.96.36.199.4 has the structure of 2-amino-3-propyl-6-[2-(phosphono)furanyl]pyrazine and was prepared in Example 17 as compound 17.3. Similarly, compounds named in Table 3 of formula (vii) are compounds with a pyrimidinyl as R5 in formula I. The formula (vii) compound named 18.104.22.168.0 in Table 3 using all Group 1 variables has the structure of 2-amino-5-propyl-6-[2-(phosphono)furanyl]pyrimidine and was prepared in Example 16 as compound 16.1. Similarly, compounds named in Table 3 of formula (viii) are compounds with a pyrimidinyl as R5 in formula I. Thus, using Group 1 variable, the compound named 220.127.116.11.1 in Table 3 has the structure of 2-[2-(5-phosphono)furanyl]pyrimidine and was prepared in Example 16 as compound 16.5.
Some of the exemplary embodiments of the compounds named in Table 3 using Groups 1-4 for variable B, Groups 1-2 for variable X, Groups 1-2 for variable D, and Groups 1-3 for variable E in the compound of formulae (v), (vi), (vii), (viii) and (ix) are listed in Table 4.
The numbers designated in Table 3 also refer to preferred benzothiazole and benzoxazole compounds of formula X. These preferred compounds are shown in structures (x) and (xi), below:
The preferred compounds of formula (x) and formula (xi) are listed in Table 3 by designated numbers assigned to B, X, A, D and E in the above formulae (x) and (xi) according to the following convention: B.X.A.D.E. For each moiety, structures are assigned to a number shown in the following tables for B, X, A, D, and E.
Variable B is divided into two Groups, each listing eight different substituents.
The substituents for variable B of formula (x) and formula (xi) in Table 3 are assigned the following numbers:
The Group 1 substituents for variable B in Table 3 for formulae (x) and (xi) are assigned the following numbers:
The Group 2 substituents for variable B are assigned the following numbers:
Variable X is selected from eight different substituents, assigned with the following numbers:
The direction of X groups is defined as going from the heterocycle to the phosphorus atom as shown in formula (x) and formula (xi).
Variable A is selected from four different substituents assigned with the following numbers:
Variable D is selected from eight different substituents, assigned with the following numbers:
Variable E is selected from four different substituents assigned with the following numbers:
Thus, using Group 1 for variable B, the compound of formula (x) named in Table 3 as 126.96.36.199.1 specifies xe2x80x94H as B, xe2x80x94OCH2xe2x80x94 as X, xe2x80x94NH2 as A, xe2x80x94H as D and xe2x80x94H as E, and this compound is 2-amino-4-phosphonomethoxybenzothiazole prepared in Example 34 as compound 34.2. Similarly, using group 1 for variable B, the compound named in Table 3 of formula (x) as 188.8.131.52.1 specifies xe2x80x94H as B, xe2x80x94SCH2xe2x80x94 as X, xe2x80x94NH2 as A, xe2x80x94H as D and xe2x80x94H as E, and this compound is 2-amino-4-phosphonomethylthiobenzothiazole in Example 46 as compound 46.1.
Likewise, using Group 2 for variable B, the compound named 188.8.131.52.1 in Table 3 of formula (x) is 2-amino-7-ethoxycarbonyl-4-phosphonomethoxybenzothiazole in Example 37 prepared as compound 37.4.
Examples of preferred compounds of formula X also include, but not limited to the pharmaceutically acceptable salts and prodrugs of the compounds named in Table 5:
The numbers designated in Table 1 also represent preferred prodrugs of compounds of formula I as shown in formula (xii) and (xiii), below:
In the above formulae (xii) and (xiii), Ar stands for aryl including heteroaryl and is substituted by R25. The preferred compounds of formula (xii) and formula (xiii) are listed in Table 1 designated by numbers assigned to X, R5, R25, and Ar in the above formulae (xii) and (xiii) according to the following convention: X.R5.R25.Ar.
Variable X is selected from seven different substituents, assigned the following numbers:
Variable R5 is selected from nine different substituents assigned the following numbers:
Variable R25 is selected from nine different substituents assigned the following numbers:
Variable Ar is selected from six different substituents assigned the following numbers:
The compounds named in Table 1 of formula (xii) or formula (xiii) each number listed in Table 1 of formula (xii) or formula (xiii) are shown without depictions of stereochemistry since the compounds are biologically active as the diastereomeric mixture or as a single stereoisomer.
Using the variable for X, R5, R25, and Ar, the compound of formula (xii) named 184.108.40.206 in Table 1 specifies furan-2,5-diyl as X, 4-(2-amino-5-isobutyl)thiazolyl as R5, chloro as R25, and 3-chlorophenyl as Ar, and this compound is the diastereomers of 2-amino-5-isobutyl-4-{2-[5-(1-(3-chlorophenyl)-1,3-propyl)phosphono]furanyl}thiazole prepared in Example 19 as compound 19.46 (major isomer) and 19.45 (minor isomer).
The numbers designated in Table 3 also represent preferred prodrugs of compounds of formula I as shown in the following formulae (xiv) and (xv):
In the compounds of formulae (xiv) and (xv), Ar represents aryl and heteroaryl and is substituted by R25. The preferred compounds of formula (xiv) and formula (xv) are listed named in Table 3 by designated numbers assigned to R5, R23, Ar, R25 and X in the above formulae (xiv) and (xv) according to the following convention: R5.R23.Ar.R25.X. For each moiety, structures are assigned to a number shown in the following tables for R5, R23, Ar, R25 and X.
The Variable R5 is selected from eight different substituents assigned the following numbers:
The variable R23 is selected from eight different substituents assigned the following numbers:
The variable Ar is selected from four different substituents assigned the following numbers:
The variable R25 is selected from eight different substituents assigned the following numbers:
The variable X is selected from four different substituents assigned the following numbers:
Thus, using the variables for R5, R23, Ar, R25, and X, the compound of formula (viv) named in Table 3 as 184.108.40.206.1 specifies 4-(2-amino-5-isobutyl)thiazolyl as R5, xe2x80x94CH(Me)CO2Me as R23, 3-chlorophenyl as Ar, chloro as R25, and furan-2,5-diyl as X, and this compound is 2-amino-5-isobutyl-4-{2-[5-(O-phenyl-N-(1-(1-methoxycarbonyl)ethyl)phosphono]furanyl}thiazole prepared in Example 31 as compound 31.6.
The numbers designated in Table 3 also represent preferred prodrugs of compounds of formula I as shown in the following formulae (xvi) and (xvii):
In the above formuale (xvi) and (xvii), Ar stands for aryl including heteroaryl, and is substituted by R24 and R25. The preferred compounds of formula (xvi) and formula (xvii) are listed in Table 3 by designated numbers assigned to R24, R25, Ar, R5, and R23 in the above formula according to the following convention, R24.R25.Ar.R5.R23. For each moiety, structures are assigned to a number shown in the following tables for R24, R25, Ar, R5 and R23.
Variable R24 is selected from eight different substituents assigned the following numbers:
Variable R25 is selected from eight different substituents assigned the following numbers:
Variable Ar is divided into two Groups, each listing four different subsituents. The Group 1 substituents for variable Ar are assigned the following numbers:
The Group 2 substituents for variable Ar are assigned the following numbers:
Variable R5 is selected from eight different substituents assigned the following numbers:
Variable R23 is divided into two Groups, each listing four different substituents. The Group 1 substituents for variable R23 are assigned the following numbers:
The Group 2 substituents for variable R23 are assigned the following numbers:
Variable R5 is selected from eight different substituents assigned the following numbers,
Variable X is selected from four different substituents assigned the following numbers:
Examples of preferred prodrugs of compounds of formula I are named in Table 6 as shown in the following prodrug formula (xi):
R5xe2x80x94Xxe2x80x94Pxe2x80x2xe2x80x83xe2x80x83(xix)
The preferred compounds of formula (xix) are listed in Table 6 by designated numbers assigned to Pxe2x80x2, R5, and X in the above formula (xix) according to the following convention, Pxe2x80x2.R5.X. For each moiety, structures are assigned to a number in the following tables for Pxe2x80x2, R5 and X.
Variable Pxe2x80x2 is divided into two Groups, each listing seven different substituents. The Group 1 substituents for variable Pxe2x80x2 are assigned the following numbers:
The Group 2 substituents for variable Pxe2x80x2 are assigned the following numbers:
Variable R5 is selected from nine different substituents assigned the following numbers:
Variable X is selected from six different substituents assigned the following numbers:
The numbers designated in Table 1 also represent preferred prodrugs of compounds of formula X as shown in the following formula (xx):
In the above formula (xx), Ar stands for aryl including heteroaryl, and is substituted with R25. The preferred compounds of formula (xx) are listed in Table 1 by designated numbers assigned to Arxe2x80x2, R25, R23, and Ar according to the following convention: Arxe2x80x2.R25.R23.Ar. For each moiety, structures are assigned to a number in the following tables for Arxe2x80x2, R25, R23 and Ar, wherein R25 is a substituent attached to Ar.
Variable Arxe2x80x2 is selected from seven different substituents assigned the following numbers:
Variable R25 is selected from nine different substituents assigned the following numbers:
Variable R23 is selected from nine different substituents assigned the following numbers:
Variable Ar is selected from six different substituents assigned the following numbers:
The numbers designated in Table 6 also represented preferred prodrugs of compounds of formula X as shown in the following formula (xxi):
In the above formula (xxi), Ar stands for aryl including heteroaryl, and is substituted by R25. The preferred compounds of formula (xxi) are listed in Table 6 by designated numbers assigned to Arxe2x80x2.R2, and Ar according to the following convention: Arxe2x80x2, R25, Ar. For each moiety, structures are assigned to a number in the following tables for Axe2x80x2, R25, and Ar.
Variable Arxe2x80x2 is selected from seven different substituents assigned the following numbers:
Variable R25 is selected from nine different substituents assigned the following numbers:
Variable Ar is selected from six different substituents assigned the following numbers:
The numbers designated in Table 6 also represent preferred prodrugs of compounds of formula X as shown in the following formula (xxii):
The preferred compounds of formula (xxii) are listed in Table 6 by designated numbers assigned to Pxe2x80x2, Rxe2x80x2 and Rxe2x80x3 according to the following convention, Pxe2x80x2.Rxe2x80x2.Rxe2x80x3. For each moiety, structures are assigned to a number in the following tables for Pxe2x80x2, Rxe2x80x2 and Rxe2x80x3.
Variable Pxe2x80x2 is divided into two Groups each listing seven different substituents. The Group 1 substituents for variable Pxe2x80x2 are assigned the following numbers: Table Pxe2x80x2.
The Group 2 substituents for variable Pxe2x80x2 are assigned the following numbers:
Variable Rxe2x80x2 is selected from nine different substituents assigned the following numbers:
Variable Rxe2x80x3 is selected from six different substituents assigned the following numbers:
Synthesis of compounds encompassed by the present invention typically includes some or all of the following general steps: (1) preparation of a phosphonate prodrug; (2) deprotection of a phosphonate ester; (3) modification of a heterocycle; (4) coupling of a heterocycle with a phosphonate component; (5) construction of a heterocycle; (6) ring closure to construct a heterocycle with a phosphonate moiety present and (7) preparation of useful intermediates. These steps are illustrated in the following scheme for compounds of formula I wherein R5 is a 5-membered heteroaromatic ring. Compounds of formula I wherein R5 is a 6-member heteroaromatic ring or other heteroaromatic rings are prepared in an analogous manner. The procedures are also generally applicable to compounds of formula I where both Y groups are not xe2x80x94O.
(1) Preparation of a Phosphonate Prodrug
Prodrugs can be introduced at different stages of the synthesis. Most often these prodrugs are made from the phosphonic acids of formula 2, because of their liability. Advantageously, these prodrugs can be introduced at an earlier stage, provided that it can withstand the reaction conditions of the subsequent steps.
Compounds of formula 2, can be alkylated with electrophiles (such as alkyl halides, alkyl sulfonates, etc) under nucleophilic substitution reaction conditions to give phosphonate esters. For example, compounds of formula I, wherein R1 is an acyloxyalkyl group can be synthesized through 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 suitable base (e.g. N,Nxe2x80x2-dicyclohexyl-4-morpholinecarboxamidine, triethylamine, Hunig""s base, etc.) in suitable solvents such as 1,1-dimethyl formamide (xe2x80x9cDMFxe2x80x9d) (Starrett, et al, J. Med. Chem., 1994, 1857). The carboxylate component of these acyloxyalkyl halides includes but is not limited to acetate, propionate, isobutyrate, pivalate, benzoate, and other carboxylates. When appropriate, further modification are envisioned after the formation of these acyloxyalkyl phosphonate esters such as reduction of a nitro group. For example, compounds of formula 3 wherein A is a NO2 group can be converted to compounds of formula 3 wherein A is an H2Nxe2x80x94 group under suitable reduction conditions (Dickson, et al, J. Med. Chem., 1996, 39: 661; Iyer, et al, Tetrahedron Lett., 1989, 30: 7141; Srivastva, et al, Bioorg. Chem., 1984, 12: 118). These methods can be extended to the synthesis of other types of prodrugs, such as compounds of formula I where R1 is a 3-phthalidyl, a 2-oxo-4,5-didehydro-1,3-dioxolanemethyl, or a 2-oxotetrahydrofuran-5-yl group (Biller et al., U.S. Pat. No. 5,157,027; Serafinowska et al., J. Med. Chem. 1995,38: 1372; Starrett et al., J. Med. Chem. 1994, 37: 1857; Martin et al., J. Pharm. Sci. 1987, 76: 180; Alexander et al., Collect. Czech. Chem. Commun, 1994, 59: 1853; EPO 0632048A1). N,N-Dimethylformamide dialkyl acetals can also be used to alkylate phosphonic acids (Alexander, P., et al Collect. Czech. Chem. Commun., 1994, 59, 1853). Compounds of formula I wherein R1 is a cyclic carbonate, a lactone or a phthalidyl group can also be synthesized via direct alkylation of the free phosphonic acid with appropriate halides in the presence of a suitable base (e.g. NaH or diisopropylethylamine, Biller et al., U.S. Pat. No. 5,157,027; Serafinowska et al., J. Med. Chem. 1995, 38: 1372; Starrett et al., J. Med. Chem. 1994, 37: 1857; Martin et al., J. Pharm. Sci. 1987, 76: 180; Alexander et al., Collect. Czech. Chem. Commun, 1994, 59: 1853;EPO 0632048A1).
Alternatively, these phosphonate prodrugs can also be synthesized by reactions of the corresponding dichlorophosphonates with an alcohol (Alexander et al, Collect. Czech. Chem. Commun., 1994, 59: 1853). For example, reactions of a dichlorophosphonate with substituted phenols and aralkyl alcohols in the presence of base (e.g. pyridine, triethylamine, etc) yield compounds of formula I where R1 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). The disulfide-containing prodrugs (Puech et al., Antiviral Res., 1993, 22: 155) can also be prepared from a dichlorophosphonate and 2-hydroxyethyl disulfide under standard conditions. Dichlorophosphonates are also useful for the preparation of various phosphoramides as prodrugs. For example, treatment of a dichlorophosphonate with ammonia gives both a monophosphonamide and a diphosphonamide; treatment of a dichlorophosphonate with a 1-amino-3-propanol gives a cyclic 1,3-propylphosphonamide; treatment of a chlorophosphonate monophenyl ester with an aminoacid ester in the presence of a suitable base gives a substituted monophenyl monophosphonamidate.
Such reactive dichlorophosphonates can be generated from the corresponding phosphonic acids with a chlorinating agent (e.g. thionyl chloride: Starrett et al., J. Med. Chem., 1994, 1857, oxalyl chloride: Stowell et al., Tetrahedron Lett., 1990, 31: 3261, and phosphorus pentachloride: Quast et al., Synthesis, 1974, 490). Alternatively, a dichlorophosphonate can also be generated from its corresponding disilyl phosphonate esters (Bhongle et al., Synth. Commun., 1987, 17: 1071) or dialkyl phosphonate esters (Still et al., Tetrahedron Lett., 1983, 24: 4405; Patois et al., Bull. Soc. Chim. Fr., 1993, 130: 485).
Chlorophosphonate monophenyl esters can be prepared from monophenyl phosphonate esters using the above described methods for dichlorophosphonate synthesis, and monophenyl phosphonate esters are easily made from their corresponding diphenyl phosphonate esters via base (e.g. sodium hydroxide) hydrolysis. Alternatively, treatment of a dichlorophosphonate with one equivalent of a phenol following by addition of an amine (e.g. alanine ethyl ester) in the presence of a suitable base (e.g. pyridine or triethylamine) will also give a monophenyl monophosphonamidate. When substituted phenols or other aryl-OH are used in place of phenol, then these methods are useful for the synthesis of various monoaryl monophosphonamidates as prodrugs for compounds of formula I.
Furthermore, these prodrugs can be prepared using Mitsunobu reactions (Mitsunobu, Synthesis, 1981, 1; Campbell, J. Org. Chem., 1992, 52: 6331), and other coupling reactions (e.g. using carbodiimides: Alexander et al., 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 benzotriazolyloxytris-(dimethylamino)phosphonium salts: Campagne et al., Tetrahedron Lett., 1993, 34: 6743).
R1 can also be introduced at an early stage of the synthesis provided that it is compatible with the subsequent reaction steps. For example, compounds of formula I where R1 is an aryl group can be prepared by metalation of a 2-furanyl heterocycle (e.g. using LDA) followed by trapping the anion with a diaryl chlorophosphate.
It is envisioned that compounds of formula I can be mixed phosphonate esters (e.g. phenyl and benzyl esters, or phenyl and acyloxyalkyl esters) including the chemically combined mixed esters such as the phenyl and benzyl combined prodrugs reported by Meier, et al. Bioorg. Med. Chem. Lett., 1997, 7: 99.
Cyclic propyl phosphonate esters can be synthesized by either reactions of the corresponding dichlorophosphonate with a substituted 1,3-propanediol or coupling reactions using suitable coupling reagents (e.g. DCC, EDCI, pyBOP: Hoffinan, Synthesis, 1988, 62). Some of these methods useful for the preparation of 1,3-propanediols are discussed below.
Various methods can be used to prepare 1,3-propanediols such as (i) 1-substituted, (ii) 2-substituted, (iii) 1,2- or 1,3-annulated 1,3-propanediols. Substituents on the prodrug moiety of compounds of formula I (i.e. substituents on the 1,3-propanediol moiety) can be introduced or modified either during the synthesis of these diols or after the synthesis of compounds of formula 2.
(i) 1-Substituted 1,3-propanediols.
1,3-Propanediols useful in the synthesis of compounds in the present invention can be prepared using various synthetic methods. Additions of a aryl Grignard to a 1-hydroxy-propan-3-al give 1-aryl-substituted 1,3-propanediols (path a). This method is suitable for the conversion of various aryl halides to 1-arylsubstituted-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 achieved using Heck reactions (e.g. couplings with a 1,3-diox-4-ene) followed by reductions 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 Grignard addition reactions followed by hydroboration-oxidation reactions (path b).
Aldol reactions between an enolate (e.g. lithium, boron, tin enolates) of a carboxylic acid derivative (e.g. tert-butyl acetate) and an aldehyde, and these reactions (e.g. the Evans""s aldol reactions) are specially useful for the asymmetric synthesis of chiral 1,3-propanediols. For example, reaction of a metal enolate of t-butyl acetate with an aromatic aldehyde followed by reduction of the ester (path e) gives a 1,3-propanediol (Turner., J. Org. Chem., 1990, 55 4744). Alternatively, epoxidation of cinnamyl alcohols using known methods (e.g. Sharpless epoxidations and other asymmetric epoxidation reactions) followed by reduction reactions (e.g. using Red-Al) give various 1,3-propanediols (path c). Enantiomerically pure 1,3-propanediols can be obtained via asymmetric reduction reactions (e.g. chiral borane reductions) of 3-hydroxy-ketones (Ramachandran et. al., Tetrahedron Lett., 1997, 38 761). Alternatively, resolution of racemic 1,3-propanediols using various methods (e.g. enzymatic or chemical methods) can also give enantiomerically pure 1,3-propanediol. Propan-3-ols with a 1-heteroaryl substituent (e.g. a pyridyl, a quinolinyl or an isoquinolinyl) can be oxygenated to give 1-substituted 1,3-propanediols using N-oxide formation reactions followed by a rearrangement reaction in acetic anhydride conditions (path d) (Yamamoto et. al., Tetrahedron, 1981, 37, 1871).
(ii) 2-Substituted 1,3-propanediols:
A variety of 2-substituted 1,3-propanediols useful for the synthesis of compounds of formula I can be prepared from various other 1,3-propanediols (e.g. 2-(hydroxymethyl)-1,3-propanediols) using conventional chemistry (Larock, Comprehensive Organic Transformations, VCH, New York, 1989).
For example, reductions of a trialkoxycarbonylmethane under known conditions give a triol via complete reduction (path a) or a bis(hydroxymethyl)acetic acid via selective hydrolysis of one of the ester groups followed by reduction of the remaining two other ester groups. Nitrotriols are also known to give triols via reductive elimination (path b) (Latour et. al., Synthesis, 1987, 8, 742). Furthermore, a 2-(hydroxymethyl)-1,3-propanediol can be converted to a mono acylated derivative (e.g. acetyl, methoxycarbonyl) using an acyl chloride or an alkyl chloroformate (e.g. acetyl chloride or methyl chloroformate) (path d) using known chemistry (Greene et al., Protective Groups In Organic Synthesis; Wiley, New York, 1990). Other functional group manipulations can also be used to prepare 1,3-propanediols such as oxidation of one the hydroxylmethyl groups in a 2-(hydroxymethyl)-1,3-propanediol to an aldehyde followed by addition reactions with an aryl Grignard (path c). Aldehydes can also be converted to alkyl amines via reductive amination reactions (path e).
(iii) Annulated 1,3-propane Diols:
Compounds of formula I wherein V and Z or V and W are connected by four carbons to form a ring can be prepared from a 1,3-cyclohexanediol. For example, cis, cis-1,3,5-cyclohexanetriol can be modified (as described in section (ii)) to give various other 1,3,5-cyclohexanetriols which are useful for the preparations of compounds of formula I wherein R1 and R1 together are
wherein together V and W are connected via 3 atoms to form a cyclic group containing 6 carbon atoms substituted with a hydroxy group. It is envisioned that these modifications can be performed either before or after formation of a cyclic phosphonate 1,3-propanediol ester. Various 1,3-cyclohexanediols can also be prepared using Diels-Alder reactions (e.g. using a pyrone as the diene: Posner et. al., Tetrahedron Lett., 1991, 32, 5295). 2-Hydroxymethylcyclohexanols and 2-hydroxymethylcyclopentanols are useful for the preparations of compounds of formula I wherein R1 and R1 together are
wherein together V and Z are connected via 2 or 3 atoms to form a cyclic group containing 5 or 6 carbon atoms. 1,3-Cyclohexanediol derivatives are also prepared via other cycloaddition reaction methodologies. For example, cycloadducts from the cycloadditon reactions of a nitrile oxide and an olefin can be converted to a 2-ketoethanol derivative which can be further converted to a 1,3-propanediol (includingl,3-cyclohexanediol, 2-hydroxymethylcyclohexanol and 2-hydroxymethylcyclopentanol) using known chemistry (Curran, et. al., J. Am. Chem. Soc., 1985, 107, 6023). Alternatively, precursors to 1,3-cyclohexanediol can be made from quinic acid (Rao, et. al., Tetrahedron Lett., 1991, 32, 547.)
2) Deprotection of a Phosphonate Ester
Compounds of formula I wherein R1 is H may be prepared from phosphonate esters using known phosphate and phosphonate ester cleavage conditions. Silyl halides are generally used to cleave various phosphonate esters, and subsequent mild hydrolysis of the resulting silyl phosphonate esters give the desired phosphonic acids. When required, acid scavengers (e.g. 1,1,1,3,3,3-hexamethyldisilazane, 2,6-lutidine, etc.) can be used for the synthesis of 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). Alternately, phosphonate esters can be cleaved under strong acidic conditions (e.g. HBr or HCl: Moffatt, et al, U.S. Pat. No. 3,524,846, 1970). These esters can also be cleaved via dichlorophosphonates, prepared by treating the esters with halogenating agents (e.g. phosphorus pentachloride, thionyl chloride, BBr3: Pelchowicz et al, J. Chem. Soc., 1961, 238) followed by aqueous hydrolysis to give phosphonic acids. Aryl and benzyl phosphonate esters can be cleaved under hydrogenolysis conditions (Lejczak, et al, Synthesis, 1982, 412; Elliott, et al, J. Med. Chem., 1985, 28: 1208; Baddiley, et al, Nature, 1953, 171: 76) or metal reduction conditions (Shafer, et al, J. Am. Chem. Soc., 1977, 99: 5118). Electrochemical (Shono, et al, J. Org. Chem., 1979, 44: 4508) and pyrolysis (Gupta, et al, Synth. Commun., 1980, 10: 299) conditions have also been used to cleave various phosphonate esters.
(3) Modification of an Existing Heterocycle
Syntheses of the heterocycles encompassed in the disclosed compounds have been well studied and described in numerous reviews (see section 4). Although it is advantageous to have the desired substituents present in these heterocycles before synthesis of compounds of formula 4, in some cases, the desired substituents are not compatible with subsequent reactions, and therefore modifications of an existing heterocycle are required late in the synthetic scheme using conventional chemistry (Larock, Comprehensive organic transformations, VCH, New York, 1989; Trost, Comprehensive organic synthesis; Pergamon press, New York, 1991). For example, compounds of formula I wherein A, Axe2x80x3, or B is a halo or a cyano group can be prepared from the corresponding amine group by conversion to the diazonium group and reaction with various copper (I) salts (e.g. Cul, CuBr, CuCl, CuCN). Halogens can also be introduced by direct halogenations of various heterocycles. For example, 5-unsubstituted-2-aminothiazoles can be converted to 2-amino-5-halothiazoles using various reagents (e.g. NIS, NBS, NCS). Heteroaryl halides are also useful intermediates and are often readily converted to other substituents (such as A, Axe2x80x3, B, Bxe2x80x3, Cxe2x80x3, D, Dxe2x80x3, E and Exe2x80x3) via transition metal assisted coupling reactions such as Suzuki, Heck or Stille reactions (Farina et al, Organic Reactions, Vol. 50; Wiley, New York, 1997; Mitchell, Synthesis, 1992, 808; Suzuki, Pure App. Chem., 1991, 63, 419; Heck Palladium Reagents in Organic Synthesis; Academic Press: San Diego, 1985). Compounds of formula I wherein A is a carbamoyl group can be made from their corresponding alkyl carboxylate esters via aminolysis with various amines, and conventional functional group modifications of the alkyl carboxylate esters are useful for syntheses of compounds of formula I wherein A is a xe2x80x94CH2OH group or a xe2x80x94CH2-halo group. Substitution reactions of haloheterocycles (e.g. 2-bromothiazole, 5-bromothiazole) with various nucleophiles (e.g. HSMe, HOMe, etc.) represents still another method for introducing substituents such as A, Axe2x80x3, B and Bxe2x80x3. For example, substitution of a 2-chlorothiazole with methanethiol gives the corresponding 2-methylthiothiazole.
It is envisioned that when necessary alkylation of nitrogen atoms in the heterocycles (e.g. imidazoles, 1,2,4-triazoles and 1,2,3,4-tetrazoles) can be readily performed using for example standard alkylation reactions (with an alkyl halide, an aralkyl halide, an alkyl sulfonate or an aralkyl sulfonate), or Mitsunobu reactions (with an alcohol).
(4) Coupling of a Heterocycle with a Phosphonate Component
When feasible compounds disclosed in the present invention are advantageously prepared via a convergent synthetic route entailing the coupling of a heterocycle with a phosphonate diester component.
Transition metal catalyzed coupling reactions such as Stille or Suzuki reactions are particularly suited for the synthesis of compounds of formula I. Coupling reactions between a heteroaryl halide or triflate (e.g. 2-bromopyridine) and a Mxe2x80x94PO3R1 wherein M is a 2-(5-tributylstannyl)furanyl or a 2-(5-boronyl)furanyl group 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) yield compounds of formula I wherein X is a furan-2,5-diyl group. It is envisioned that the nature of the coupling partners for these reactions can also be reversed (e.g. coupling of trialkylstannyl or boronyl heterocycles with a halo-Xxe2x80x94P(O)(O-alkyl)2). Other coupling reactions between organostannes and an alkenyl halide or an alkenyl triflate are also reported which may be used to prepared compounds of formula I wherein X is an alkenyl group. The Heck reaction may be used to prepare compounds of formula I wherein X is an alkynyl group (Heck Palladium Reagents in Organic Synthesis; Academic Press: San Diego, 1985). These reactions are particularly suited for syntheses of various heteroaromatics as R5 for compounds of formula I given the availability of numerous halogenated heterocycles, and these reactions are particularly suitable for parallel synthesis (e.g. combinatorial synthesis on solid phase(Bunin, B. A., The Combinatorial Index,; Academic press: San Diego, 1998) or in solution phase (Flynn, D. L. et al., Curr. Op. Drug. Disc. Dev., 1998, 1, 1367)) to generate large combinatorial libraries. For example, ethyl 5-iodo-2-furanylphosphonate can be coupled to Wang""s resin under suitable coupling reaction conditions. The resin-coupled 5-iodo-2-[5-(O-ethyl-O-Wang""s resin)phosphono]furan can then be subjected to transition metal catalyzed Suzuki and Stille reactions (as described above) with organoboranes and organotins in a parallel manner to give libraries of compounds of formula 3 wherein X is furan-2,5-diyl.
Substitution reactions are useful for the coupling of a heterocycle with a phosphonate diester component. For example, cyanuric chloride can be substituted with dialkyl mercaptoalkylphosphonates or dialkyl aminoalkylphosphonates to give compounds of formula I wherein R5 is a 1,3,5-triazine, X is an alkylthio or an alkylamino group. Alkylation reactions are also used for the coupling of a heterocycle with a phosphonate diester component. For example, a heteroaromatic thiol (e.g. a 1,3,4-thiadiazole-2-thiol) can be alkylated with a dialkyl methylphosphonate derivative (e.g. ICH2P(O)(OEt)2, TsOCH2P(O)(OEt)2, TfOCH2P(O)(OEt)2) to lead to compounds of formula I wherein X is an alkylthio group. In another aspect, alkylation reactions of a heteroaromatic carboxylic acid (e.g. a thiazole-4-carboxylic acid) with a dialkyl methylphosphonate derivative (e.g. ICH2P(O)(OEt)2, TsOCH2P(O)(OEt)2, TfOCH2P(O)(OEt)2) lead to compounds of formula I wherein X is an alkoxycarbonyl group, while alkylation reactions of a heteroaromatic thiocarboxylic acid (e.g. a thiazole-4-thiocarboxylic acid) with a dialkyl methylphosphonate derivative (e.g. ICH2P(O)(OEt)2, TsOCH2P(O)(OEt)2, TfOCH2P(O)(OEt)2) lead to compounds of formula I wherein X is an alkylthiocarbonyl group. Substitutions of haloalkyl heterocycles (e.g. 4-haloalkylthiazole) with nucleophiles containing the phosphonate group (diethyl hydroxymethylphosphonate) are useful for the preparation of compounds of formula I wherein X is an alkoxyalkyl or an alkylthioalkyl group. For example, compounds of formula I where X is a xe2x80x94CH2OCH2xe2x80x94 group can be prepared from 2-chloromethylpyridine or 4-chloromethylthiazole using dialkyl hydroxymethylphosphonates and a suitable base (e.g. sodium hydride). It is possible to reverse the nature of the nucleophiles and electrophiles for the substitution reactions, i.e. haloalkyl- and/or sulfonylalkylphosphonate esters can be substituted with heterocycles containing a nucleophile (e.g. a 2-hydroxyalkylpyridine, a 2-mercaptoalkylpyridine, or a 4-hydroxyalkyloxazole).
Known amide bond formation reactions (e.g. the acyl halide method, the mixed anhydride method, the carbodiimide method) can also be used to couple a heteroaromatic carboxylic acid with a phosphonate diester component leading to compounds of formula I wherein X is an alkylaminocarbonyl or an alkoxycarbonyl group. For example, couplings of a thiazole-4-carboxylic acid with a dialkyl aminoalkylphosphonate or a dialkyl hydroxyalkylphosphonate give compounds of formula I wherein R5 is a thiazole, and X is an alkylaminocarbonyl or an alkoxycarbonyl group. Alternatively, the nature of the coupling partners can be reversed to give compounds of formula I wherein X is an alkylcarbonylamino group. For example, 2-aminothiazoles can be coupled with (RO)2P(O)-alkyl-CO2H (e.g. diethylphosphonoacetic acid) under these reaction conditions to give compounds of formula I wherein R5 is a thiazole and X is an alkylcarbonylamino group. These reactions are also useful for parallel synthesis of compound libraries through combinatorial chemistry on solid phase or in solution phase. For example, HOCH2P(O)(OEt)(O-resin), H2NCH2P(O)(OEt)(O-resin) and HOOCCH2P(O)(OEt)(O-resin) (prepared using known methods) can be coupled to various heterocycles using the above described reactions to give libraries of compounds of formula 3 wherein X is a xe2x80x94C(O)OCH2xe2x80x94, or a xe2x80x94C(O)NHCH2xe2x80x94, or a xe2x80x94NHC(O)CH2xe2x80x94.
Rearrangement reactions can also be used to prepare compounds covered in the present invention. For example, the Curtius""s rearrangement of a thiazole-4-carboxylic acid in the presence of a dialkyl hydroxyalkylphosphonate or a dialkyl aminoalkylphosphonate lead to compounds of formula I wherein X is an alkylaminocarbonylamino or an alkoxycarbonylamino group. These reactions can also be adopted for combinatorial synthesis of various libraries of compounds of formula 3. For example, Curtius""s rearrangement reactions between a heterocyclic carboxylic acid and HOCH2P(O)(OEt)(O-resin), or H2NCH2P(O)(OEt)(O-resin) can lead to libraries of compounds of formula I wherein X is a xe2x80x94NHC(O)OCH2xe2x80x94, or a xe2x80x94NHC(O)NHCH2xe2x80x94.
For compounds of formula I wherein X is an alkyl group, the phosphonate group can be introduced using other common phosphonate formation methods such as Michaelis-Arbuzov reaction (Bhattacharya et al., Chem. Rev., 1981, 81: 415), Michaelis-Becker reaction (Blackburn et al., J. Organomet. Chem., 1988, 348: 55), and addition reactions of phosphorus to electrophiles (such as aldehydes, ketones, acyl halides, imines and other carbonyl derivatives).
Phosphonate component can also be introduced via lithiation reactions. For example, lithiation of an 2-ethynylpyridine using a suitable base followed by trapping the thus generated anion with a dialkyl chlorophosphonate lead to compounds of formula I wherein R5 is a pyridyl, X is a 1-(2-phosphono)ethynyl group.
(5) Construction of a Heterocycle
Although existing heterocycles are useful for the synthesis of compounds of formula I, when required, heterocycles can also be constructed leading to compounds in the current invention, and in some cases may be preferred for the preparations of certain compounds. The construction of heterocycles have been well described in the literature using a variety of reaction conditions (Joule et al., Heterocyclic Chemistry; Chapman hall, London, 1995; Boger, Weinreb, Hetero Diels-Alder Methodology In Organic Synthesis; Academic press, San Diego, 1987; Padwa, 1,3-Dipolar Cycloaddition Chemistry; Wiley, New York, 1984; Katritzsky et al., Comprehensive Heterocyclic Chemistry; Pergamon press, Oxford; Newkome et al., Contemporary Heterocyclic Chemistry: Syntheses, Reaction and Applications; Wiley, New York, 1982; Syntheses of Heterocyclic Compounds; Consultants Bureau, New York). Some of the methods which are useful to prepare compounds in the present invention are given as examples in the following discussion.
(i) Construction of a Thiazole Ring System
Thiazoles useful for the present invention can be readily prepared using a variety of well described ring-forming reactions (Metzger, Thiazole and its derivatives, part 1 and part 2; Wiley and Sons, New York, 1979). Cyclization reactions of thioamides (e.g. thioacetamide, thiourea) and alpha-halocarbonyl compounds (such as alpha-haloketones, alpha-haloaldehydes) are particularly useful 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 useful for the synthesis of compounds of formula I wherein R5 is a thiazole, A is an amino group and X is a furan-2,5-diyl group; cyclization reaction between thiourea and a bromopyruvate alkyl ester give a 2-amino-4-alkoxycarbonylthiazole which is useful for the preparations of compounds of formula I wherein R5 is a thiazole and X is an alkylaminocarbonyl, an alkoxycarbonyl, an alkylaminocarbonylamino, or an alkoxyacarbonylamino group. Thioamides can be prepared using reactions reported in the literature (Trost, Comprehensive organic synthesis, Vol. 6,; Pergamon press, New York, 1991, pages 419-434) and alpha-halocarbonyl compounds are readily accessible via 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 (e.g. NBS, CuBr2).
(ii) Construction of an Oxazole Ring System
Oxazoles useful for the present invention can be prepared using various methods in the literature (Turchi, Oxazoles; Wiley and Sons, New York, 1986). Reactions between isocyanides (e.g. tosylmethylisocyanide) and carbonyl compounds (e.g. aldehydes and acyl chlorides) can be used to construct oxazole ring systems (van Leusen et al, Tetrahedron Lett., 1972, 2369). Alternatively, cyclization reactions of amides (e.g. urea, carboxamides) and alpha-halocarbonyl compounds are commonly used for the construction of an oxazole ring system. For example, the reactions of urea and 5-diethylphosphono-2-[(-2-bromo-1-oxo)alkyl]furans are useful for the synthesis of compounds of formula I wherein R5 is an oxazole, A is an amino group and X is a furan-2,5-diyl group. Reactions between amines and imidates are also used to construct the oxazole ring system (Meyers et al, J. Org. Chem., 1986, 51(26), 5111).
(iii) Construction of a Pyridine Ring System
Pyridines useful for the synthesis of compounds of formula I can be prepared using various known synthetic methods (Klingsberg, Pyridine and Its Derivatives; Interscience Publishers, New York, 1960-1984). 1,5-Dicarbonyl compounds or their equivalents can be reacted with ammonia or compounds which can generate ammonia to produce 1,4-dihydropyridines which are easily dehydrogenated to pyridines. When unsaturated 1,5-dicarbonyl compounds, or their equivalents (e.g. pyrylium ions) are used to react with ammonia, pyridines can be generated directly. 1,5-Dicarbonyl compounds or their equivalents can be prepared using conventional chemistry. For example, 1,5-diketones are accessible via a number of routes, such as Michael addition of an enolate to an enone (or precursor Mannich base (Gill et al, J. Am. Chem. Soc., 1952, 74, 4923)), ozonolysis of a cyclopentene precursor, or reaction of silyl enol ethers with 3-methoxyaliylic alcohols (Duhamel et al, Tetrahedron, 1986, 42, 4777). When one of the carbonyl carbons is at the acid oxidation state, then this type of reaction produces 2-pyridones which can be readily converted to 2-halopyridines (Isler et al, Helv. Chim. Acta, 1955, 38, 1033) or 2-aminopyridines (Vorbruggen et al, Chem. Ber., 1984, 117, 1523). Alternatively, a pyridine can be prepared from an aldehyde, a 1,3-dicarbonyl compound and ammonia via the 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-amino-enones or 3-amino-nitriles have also been used to produce pyridines (such as the Guareschi synthesis, Mariella, Org. Synth., Coll. Vol. IV, 1963, 210). 1,3-Dicarbonyl compounds can be made via oxidation reactions on corresponding 1,3-diols or aldol reaction products (Mukaiyama, Org, Reactions, 1982, 28, 203). Cycloaddition reactions have also been used for the synthesis of pyridines, for example cycloaddition reactions between oxazoles and alkenes (Naito et al., Chem. Pharm. Bull., 1965, 13, 869), and Diels-Alder reactions between 1,2,4-triazines and enamines (Boger et al., J. Org. Chem., 1981, 46, 2179).
(iv) Construction of a Pyrimidine Ring System
Pyrimidine ring systems useful for the synthesis of compounds of formula I are readily available (Brown, The pyrimidines; Wiley, New York, 1994). One method for pyrimidine synthesis involves the coupling of a 1,3-dicarbonyl component (or its equivalent) with an Nxe2x80x94Cxe2x80x94N fragment. The selection of the Nxe2x80x94Cxe2x80x94N componentxe2x80x94urea (Sherman et al., Org. Synth., Coll. 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)xe2x80x94governs the substitution at C-2 in the pyrimidine products. This method is particular useful for the synthesis of compounds of formula I with various A groups. In another method, pyrimidines can be prepared via cycloaddition reactions such as aza-Diels-Alder reactions between a 1,3,5-triazine and an enamine or an ynamine (Boger et al., J. Org. Chem., 1992, 57, 4331 and references cited therein).
(v) Construction of an Imidazole Ring System
Imidazoles useful for the synthesis of compounds of formula I are readily prepared using a variety of different synthetic methodologies. Various cyclization reactions are generally used to synthesize imidazoles such as reactions between amidines and alpha-haloketones (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-haloketones, and reactions between aldehydes and 1,2-dicarbonyl compounds in the presence of amines.
(vi) Construction of an Isoxazole Ring System
Isoxazoles useful for the synthesis of compounds of formula I are readily synthesized using various methodologies (such as cycloaddition reactions between nitrile oxides and alkynes or active methylene compounds, oximation of 1,3-dicarbonyl compounds or alpha, beta-acetylenic carbonyl compounds or alpha,beta-dihalocarbonyl compounds, etc.) can be used to synthesize an isoxazole ring system (Grunanger et al., Isoxazoles; Wiley and Sons, New York, 1991). For example, reactions between alkynes and 5-diethylphosphono-2-chlorooximidofuran in the presence of base (e.g. triethylamine, Hunig""s base, pyridine) are useful for the synthesis of compounds of formula I wherein R5 is an isoxazole and X is a furan-2,5-diyl group.
(vii) Construction of a Pyrazole Ring System
Pyrazoles useful for the synthesis of compounds of formula I are readily prepared using a variety of methods (Wiley, Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles, and Condensed Rings; Interscience Publishers, New York, 1967) such as reactions between hydrazines and 1,3-dicarbonyl compounds or 1,3-dicarbonyl equivalents (e.g. one of the carbonyl group is masked as an enamine or ketal or acetal), and additions of hydrazines to acrylonitriles followed by cyclization reactions (Dorn et al, Org. Synth., 1973, Coll. Vol. V, 39). Reaction of 2-(2-alkyl-3-N,N-dimethylamino)acryloyl-5-diethylphosphonofurans with hydrazines are useful for the synthesis of compounds of formula I wherein R5 is a pyrazole, X is a furan-2,5-diyl group and Bxe2x80x3 is an alkyl group.
(viii) Construction of a 1,2,4-triazole Ring System
1,2,4-Triazoles useful for the synthesis of compounds of formula I are readily available via 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 to Construct a Heterocycle with a Phosphonate
Compounds of formula 4 can also be prepared using a ring closure reaction to construct the heterocycle from precursors that contain the phosphonate component. For example, cyclization reactions between thiourea and 5-diethylphosphono-2-[(-2-bromo-1-oxo)alkyl]furans are useful for the synthesis of compounds of formula I wherein R5 is a thiazole, A is an amino group and X is a furan-2,5-diyl group. Oxazoles of the present invention can also be prepared using a ring closure reaction. In this case, reactions of urea and 5-diethylphosphono-2-[(-2-bromo-1-oxo)alkyl]furans are useful for the synthesis of compounds of formula I wherein R5 is an oxazole, A is an amino group and X is a furan-2,5-diyl group. Reactions between 5-diethylphosphono-2-furaldehyde, an alkyl amine, a 1,2-diketone and ammonium acetate are useful to synthesize compounds of formula I wherein R5 is an imidazole and X is a furan-2,5-diyl group. These types of ring closure reactions can also be used for the synthesis of pyridines or pyrimidines useful in the present invention. For example, reaction of 5-diethylphosphono-2-[3-dimethylamino-2-alkyl)acryloyl]furans and cyanoacetamide in the presence of base gives 5-alkyl-3-cyano-6-[2-(5-diethylphosphono)furanyl]-2-pyridones (Jain et al., Tetrahedron Lett., 1995, 36, 3307). Subsequent conversion of these 2-pyridones to the corresponding 2-halopyridines (see references cited in section 3 for the modifications of heterocycles) will lead to compounds of formula I wherein R5 is a pyridine, A is a halo group, X is a furan-2,5-diyl group, and B is an alkyl group. Reactions of 5-diethylphosphono-2-[3-dimethylamino-2-alkyl)acryloyl]furans and amidines in the presence of base give 5-alkyl-6-[2-(5-diethylphosphono)-furanyl]pyrimidines which will lead to compounds of formula I wherein R5 is a pyrimidine, X is a furan-2,5-diyl group and B is an alkyl group.
(7) Preparation of Various Precursors Useful for Cyclization Reactions
Intermediates required for the synthesis of compounds in the present invention are generally prepared using either an existing method in the literature or a modification of an existing method. Syntheses of some of the intermediates useful for the synthesis of compounds in the present invention are described herein.
Various aryl phosphonate dialkyl esters are particularly useful for the synthesis of compounds of formula I. For example, compounds of formula I wherein X is a furan-2,5-diyl group can be prepared from a variety of furanyl precursors. It is envisioned that synthesis of other precursors may follow some or all of these reaction steps, and some modifications of these reactions may be required for different precursors. 5-Dialkylphosphono-2-furancarbonyl compounds (e.g. 5-diethylphosphono-2-furaldehyde, 5-diethylphosphono-2-acetylfuran) are well suited for the synthesis of compounds of formula I wherein X is a furan-2,5-diyl group. These intermediates are prepared from furan or furan derivatives using conventional chemistry such as lithiation reactions, protection of carbonyl groups and deprotection of carbonyl groups. For example, lithiation of furan using known methods (Gschwend Org. React. 1979, 26: 1) followed by addition of phosphorylating agents (e.g. ClPO3R2) gives 2-dialkylphosphono-furans (e.g. 2-diethylphosphonofuran). This method can also be applied to a 2-substituted furan (e.g. 2-furoic acid) to give a 5-dialkylphosphono-2-substituted furan (e.g. 5-diethylphosphono-2-furoic acid). It is envisioned that other aryl phosphonate 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 triflates (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) are used to prepare aryl phosphonates. Aryl phosphonate esters can also be prepared from aryl phosphates under anionic rearrangement conditions (Melvin, Tetrahedron Lett., 1981, 22: 3375; Casteel et al. Synthesis, 1991, 691). N-Alkoxy aryl salts with alkali metal derivatives of dialkyl phosphonate provide another general synthesis for heteroaryl-2-phosphonate esters (Redmore J. Org. Chem., 1970, 35: 4114).
A second lithiation step can be used to incorporate a second group on the aryl phosphonate dialkyl ester such as an aldehyde group, a trialkylstannyl or a halo group, although other methods known to generate these functionalities (e.g. aldehydes) can be envisioned as well (e.g. Vilsmeier-Hack reaction or Reimar-Teimann reaction for aldehyde synthesis). In the second lithiation step, the lithiated aromatic ring is treated with reagents that either directly generate the desired functional group (e.g. for an aldehyde using DMF, HCO2R, etc.) or with reagents that lead to a group that is subsequently transformed into the desired functional group using known chemistry (e.g. alcohols, esters, nitriles, alkenes can be transformed into aldehydes). For example, lithiation of a 2-dialkylphosphonofuran (e.g. 2-diethylphosphonofaran) under normal conditions (e.g. LDA in THF) followed by trapping of the thus generated anion with an electrophile (e.g. tributyltin chloride or iodine) produces a 5-functionalized-2-dialkylphosphonofuran (e.g. 5-tributylstannyl-2-diethylphosphonofuran or 5-iodo-2-diethylphosphonofuran). It is also envisioned that the sequence of these reactions can be reversed, i.e. the aldehyde moiety can be incorporated first followed by the phosphorylation reaction. The order of the reaction will be dependent on reaction conditions and protecting groups. Prior to the phosphorylation, it is also envisioned that it may be advantageous to protect some of these functional groups using a number of well-known methods (e.g. protection of aldehydes as acetals, aminals; protection of ketones as ketals). The protected functional group is then unmasked after phosphorylation. (Protective groups in Organic Synthesis, Greene, T. W., 1991, Wiley, New York). For example, protection of 2-furaldehyde as 1,3-propanediol acetal followed by a lithiation step (using for example LDA) and trapping the anion with a dialkyl chlorophosphate (e.g. diethyl chlorophosphate), and subsequent deprotection of the acetal functionality under normal deprotection conditions produces the 5-dialkylphosphono-2-furaldehyde (e.g. 5-diethylphosphono-2-furaldehyde). Another example is the preparation of 5-keto-2-dialkylphosphonofurans which encompass the following steps: acylations of furan under Friedel-Crafts reaction conditions give 2-ketofuran, subsequent protection of the ketone as ketals (e.g. 1,3-propanediol cyclic ketal) followed by a lithiation step as described above gives the 5-dialkylphosphono-2-furanketone with the ketone being protected as a 1,3-propanediol cyclic ketal, and final deprotection of the ketal under, for example, acidic conditions gives 2-keto-5-dialkylphosphonofurans (e.g. 2-acetyl-5-diethylphosphonofuran). Alternatively, 2-ketofurans can be synthesized via a palladium catalyzed reaction between 2-trialkylstannylfurans (e.g. 2-tributylstannylfuran) and an acyl chloride (e.g. acetyl chloride, isobutyryl chloride). It is advantageous to have the phosphonate moiety present in the 2-trialkylstannylfurans (e.g. 2-tributylstannyl-5-diethylphosphonofuran). 2-Keto-5-dialkylphosphonofurans can also be prepared from a 5-dialkylphosphono-2-furoic acid (e.g. 5-diethylphosphono-2-furoic acid) by conversion of the acid to the corresponding acyl chloride and followed by additions of a Grignard reagent.
Some of the above described intermediates can also be used for the synthesis of other useful intermediates. For example, a 2-keto-5-dialkylphosphonofuran can be further converted to a 1,3-dicarbonyl derivative which is useful for the preparation of pyrazoles, pyridines or pyrimidines. Reaction of a 2-keto-5-dialkylphosphonofuran (e.g. 2-acetyl-5-diethylphosphonofuran) with a dialkylformamide dialkyl acetal (e.g. dimethylformamide dimethyl acetal) gives a 1,3-dicarbonyl equivalent as a 2-(3-dialkylamino-2-alkyl-acryloyl)-5-dialkylphosphonofuran (e.g. 2-(3-dimethylaminoacryloyl)-5-diethylphosphonofuran).
It is envisioned that the above described methods for the synthesis of furan derivatives can be either directly or with some modifications applied to syntheses of various other useful intermediates such as aryl phosphonate esters (e.g. thienyl phosphonate esters, phenyl phosphonate esters or pyridyl phosphonate esters).
It is conceivable that when applicable the above described synthetic methods can be adopted for parallel synthesis either on solid phase or in solution to provide rapid SAR (structure activity relationship) exploration of FBPase inhibitors encompassed in the current invention, provided method development for these reactions are successful.
Synthesis of the compounds encompassed by the present invention typically includes some or all of the following general steps: (1) preparation of a phosphonate prodrug; (2) deprotection of a phosphonate ester; (3) construction of a heterocycle; (4) introduction of a phosphonate component; (5) synthesis of an aniline derivative. Step (1) and step (2) were discussed in section 1, and discussions of step (3), step (4) and step (5) are given below. These methods are also generally applicable to compounds of Formula X, where both Y groups are not xe2x80x94Oxe2x80x94.
(3) Construction of a Heterocycle
i. Benzothiazole ring system:
Compounds of formula 3 wherein Gxe2x80x3xe2x95x90S, i.e. benzothiazoles, can be prepared using various synthetic methods reported in the literature. Two of these methods are given as examples as discussed below. One method is the modification of commercially available benzothiazole derivatives to give the appropriate functionality on the benzothiazole ring. Another method is the annulation of various anilines (e.g. compounds of formula 4) to construct the thiazole portion of the benzothiazole ring. For example, compounds of formula 3 wherein Gxe2x80x3xe2x95x90S, Axe2x95x90NH2, L2,E2,J2xe2x95x90H, X2xe2x95x90CH2O, and Rxe2x80x2xe2x95x90Et can be prepared from the commercially available 4-methoxy-2-amino thiazole via a two-step sequence: conversion 4-methoxy-2-aminobenzothiazole to 4-hydroxy-2-aminobenzothiazole with reagents such as BBr3 (Node, M.; et al J. Org. Chem. 45, 2243-2246, 1980) or AlCl3 in presence of a thiol (e.g. EtSH) (McOmie, J. F. W.; et al. Org. Synth., Collect. Vol. V, 412, 1973) followed alkylation of the phenol group with diethylphosphonomethyl trifluoromethylsulfonate (Phillion, D. P.; et al. Tetrahedron Lett. 27, 1477-1484, 1986) in presence of a suitable base (e.g. NaH) in polar aprotic solvents (e.g. DMF) provide the required compound.
Several methods can be used to convert various anilines to benzothiazoles (Sprague, J. M.; Land, A. H. Heterocycle. Compd. 5, 506-13, 1957). For example, 2-aminobezothiazoles (formula 3 wherein Axe2x95x90NH2) can be prepared by annulation of compounds of formula 4 wherein W2xe2x95x90H, using various common methods. One method involves the treatment of a suitably substituted aniline with a mixture of KSCN and CuSO4 in methanol to give a substituted 2-aminobezothiazole (Ismail, I. A.; Sharp, D. E; Chedekel, M. R. J. Org. Chem. 45, 2243-2246, 1980). Alternatively, a 2-aminobenzothiazole can also be prepared by the treatment of Br2 in presence of KSCN in acetic acid (Patil, D. G.; Chedekel, M. R. J. Org. Chem. 49, 997-1000, 1984). This reaction can also be done in two step sequence. For example treatment of substituted phenylthioureas with Br2 in CHCl3 gives substituted 2-aminobenzothiazoles (Patil, D. G.; Chedekel, M. R. J. Org. Chem. 49, 997-1000, 1984). 2-Aminobenzothiazoles can also be made by condensation of ortho iodo anilines with thiourea in presence of Ni catalyst (NiCl2 (PPh3)2) (Takagi, K.Chem. Lett. 265-266, 1986).
Benzothiazoles can undergo electrophilic aromatic substitution to give 6-substituted benzothiazoles (Sprague, J. M.; Land, A. H. Heterocycle. Compd. 5, 606-13, 1957). For example bromination of formula 3 wherein Gxe2x80x3xe2x95x90S, Axe2x95x90NH2, L2,E2,J2xe2x95x90H, X2xe2x95x90CH2O and Rxe2x80x2xe2x95x90Et with bromine in polar solvents such as AcOH gave compound of formula 3 wherein E2xe2x95x90Br.
Furthermore, compounds of formula 3 wherein A is a halo, H, alkoxy, alkylthio or an alkyl can be prepared from the corresponding amino compound (Larock, Comprehensive organic transformations, VCH, New York, 1989; Trost, Comprehensive organic synthesis; Pergamon press, New York, 1991).
ii. Benzoxazoles:
Compounds of formula 3 wherein Gxe2x80x3xe2x95x90O, i.e. benzoxazoles, can be prepared by the annulation of ortho aminophenols with suitable reagent (e.g. cyanogen halide (Axe2x95x90NH2; Alt, K. O.; et al J. Heterocyclic Chem. 12, 775, 1975) or acetic acid (Axe2x95x90CH3; Saa, J. M.; J. Org. Chem. 57, 589-594, 1992) or trialkyl orthoformate (Axe2x95x90H; Org. Prep. Proced. Int., 22, 613, 1990)).
(4) Introduction of a Phosphonate Component:
Compounds of formula 4 (wherein X2xe2x95x90CH2O and Rxe2x80x2xe2x95x90alkyl) can made in different ways (e.g. using alkylation and nucleophilic substitution reactions). Typically, compounds of formula 5 wherein Mxe2x80x2xe2x95x90OH is treated with a suitable base (e.g. NaH) in polar aprotic solvent (e.g. DMF, DMSO) and the resulting phenoxide anion can be alkylated with a suitable electrophile preferably with a phosphonate component present (e.g. diethyl iodomethylphosphonate, diethyl trifluoromethylsulphonomethyl phosphonate, diethyl p-methyltoluenesulphonomethylphosphonate). The alkylation method can also be applied to the precursor compounds to compounds of formula 5 wherein a phenol moiety is present and it can be alkylated with a phosphonate containing component. Alternately, compounds of formula 4 can also be made from the nucleophilic substitution of the precursor compounds to compounds of formula 5 (wherein a halo group, preferably a fluoro or a chloro, is present ortho to a nitro group). For example, a compound of formula 4 (wherein X2xe2x95x90CH2O and Rxe2x80x2xe2x95x90Et) can be prepared from a 2-chloro-1-nitrobenzene derivative by treatment with NaOCH2P(O)(OEt)2 in DMF. Similarly, compounds of formula 4 where X2xe2x95x90-alkyl-Sxe2x80x94 or -alkyl-Nxe2x80x94 can also be made.
(5) Synthesis of an Aniline Derivative:
Numerous synthetic methods have been reported for the synthesis of aniline derivatives, these methods can be applied to the synthesis of useful intermediates which can lead to compounds of formula X. For example, various alkenyl or aryl groups can be introduced on to a benzene ring via transition metal catalyzed reactions (Kasibhatla, S. R., et al. WO 98/39343 and the references cited in); anilines can be prepared from their corresponding nitro derivatives via reduction reactions (e.g. hydrogenation reactions in presence of 10% Pd/C, or reduction reactions using SnCl2 in HCl (Patil, D. G.; Chedekel, M. R. J. Org. Chem. 49, 997-1000, 1984)).
A large number of synthetic methods are available for the preparation of substituted 1,3-hydroxyamines and 1,3-diamines due to the ubiquitous nature of these functionalities in naturally occurring compounds. Following are some of these methods organised into: 1. synthesis of substituted 1,3-hydroxy amines; 2. synthesis of substituted 1,3-diamines and 3. Synthesis of chiral substituted 1,3-hydroxyamines and 1,3-diamines.
i. Synthesis of Substituted 1,3-hydroxy Amines:
1,3-Diols described in the earlier section can be converted selectively to either hydroxy amines or to corresponding diamines by converting hydroxy functionaliy to a leaving group and treating with anhydrous ammonia or required primary or secondary amines (Corey, et al., Tetrahedron Lett., 1989, 30, 5207: Gao, et al., J. Org. Chem., 1988, 53, 4081). A similar transformation may also be achieved directly from alcohols in Mitsunobu type of reaction conditions (Hughes, D. L., Org. React., 1992, 42). A general synthetic procedure for 3-aryl-3-hydroxy-propan-1-amine type of prodrug moiety involves aldol type condensation of aryl esters with alkyl nitriles followed by reduction of resulting substituted benzoylacetonitrile (Shih et al., Heterocycles, 1986, 24, 1599). The procedure can also be adapted for formation 2-substitutedaminopropanols by using substituted alkylnitrile. In another approach, 3-aryl-3-amino-propan-1-ol type of prodrug groups are synthesized from aryl aldehydes by condensation of malonic acid in presence of ammonium acetate followed by reduction of resulting substituted aminoacids. Both these methods enable to introduce wide variety of substitution of aryl group (Shih, et al., Heterocycles., 1978, 9, 1277). In an alternate approach, -substituted organolithium compounds of 1-amino-1-aryl ethyl dianion generated from styrene type of compounds undergo addition with carbonyl compounds to give variety of W, Wxe2x80x2 substitution by variation of the carbonyl componds (Barluenga, et al., J. Org. Chem., 1979, 44, 4798).
ii. Synthesis of Substituted 1,3-diamines:
Substituted 1,3-diamines are synthesized starting from variety of substrates. Arylglutaronitriles can be transformed to 1-substituted diamines by hydrolysis to amide and Hoffinan rearrangement conditions (Bertochio, et al., Bull. Soc. Chim. Fr, 1962, 1809). Whereas, malononitrile substitution will enable variety of Z substitution by electrophile introduction followed by hydride reduction to corresponding diamines. In another approach, cinnamaldehydes react with hydrazines or substituted hydrazines to give corresponding pyrazolines which upon catalytic hydrogenation result in substituted 1,3-diamines (Weinhardt, et al., J. Med. Chem., 1985, 28, 694). High transdiastereoselectivity of 1,3-substitution is also attainable by aryl Grignard addition on to pyrazolines followed by reduction (Alexakis, et al., J. Org. Chem., 1992, 576, 4563). 1-Aryl-1,3-diaminopropanes are also prepared by diborane reduction of 3-amino-3-arylacrylonitriles which intum are made from nitrile substituted aromatic compounds (Domow, et al., Chem Ber., 1949, 82, 254). Reduction of 1,3-diimines obtained from corresponding 1,3-carbonyl compounds are another source of 1,3-diamine prodrug moiety which allows a wide variety of activating groups V and/or Z (Barluenga, et al., J. Org. Chem., 1983, 48, 2255).
iii. Synthesis of Chiral Substituted 1,3-hydroxyamines and 1,3-diamines.
Enantiomerically pure 3-aryl-3-hydroxypropan-1-amines are synthesized by CBS enantioselective catalytic reaction of -chloropropiophenone followed by displacement of halo group to make secondary or primary amines as required (Corey, et al., Tetrahedron Lett., 1989, 30, 5207). Chiral 3-aryl-3-amino propan-1-ol type of prodrug moiety may be obtained by 1,3-dipolar addition of chirally pure olefin and substituted nitrone of arylaldehyde followed by reduction of resulting isoxazolidine (Koizumi, et al., J. Org. Chem., 1982, 47, 4005). Chiral induction in 1,3-polar additions to form substituted isoxazolidines is also attained by chiral phosphine palladium complexes resulting in enatioselective formation of amino alcohols (Hori, et al., J. Org. Chem., 1999, 64, 5017). Alternatively, optically pure 1-aryl substituted amino alcohols are obtained by selective ring opening of corresponding chiral epoxy alcohols with desired amines (Canas et al., Tetrahedron Lett., 1991, 32, 6931).
Several methods are known for diastereoselective synthesis of 1,3-disubstituted aminoalcohols. For example, treatment of (E)-N-cinnamyltrichloroacetamide with hypochlorus acid results in trans-dihydrooxazine which is readily hydrolysed to erythro-chloro-hydroxy-phenylpropanamine in high diastereoselectivity (Commercon et al., Tetrahedron Lett., 1990, 31, 3871). Diastereoselective formation of 1,3-aminoalcohols is also achieved by reductive amination of optically pure 3-hydroxy ketones (Haddad et al., Tetrahedron Lett., 1997, 38, 5981). In an alternate approach, 3-aminoketones are transformed to 1,3-disubstituted aminoalcohols in high stereoslectivity by a selective hydride reduction (Barluenga et al., J. Org. Chem., 1992, 57, 1219). All the above mentioned methods may also be applied to prepare corresponding V-Z or V-W annulated chiral aminoalcohols. Furthermore, such optically pure amino alcohols are also a source to obtain optically pure diamines by the procedures described earlier in the section.
Formulations
Compounds of the invention are administered orally in a total daily dose of about 0.01 mg/kg/dose to about 100 mg/kg/dose, preferably from about 0.1 mg/kg/dose to about 10 mg/kg/dose. The use of time-release preparations to control the rate of release of the active ingredient may be preferred. The dose may be administered in as many divided doses as is convenient. When other methods are used (e.g. intravenous administration), compounds are administered to the affected tissue at a rate from 0.05 to 10 mg/kg/hour, preferably from 0.1 to 1 mg/kg/hour. Such rates are easily maintained when these compounds are intravenously administered as discussed below.
For the purposes of this invention, the compounds may be administered by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques. Intraarterial and intravenous injection as used herein includes administration through catheters. Oral administration is generally preferred.
Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
The pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.
The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions. It is preferred that the pharmaceutical composition be prepared which provides easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion should contain from about 3 to 330 xcexcg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
As noted above, formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach. This is particularly advantageous with the compounds of formulae I and X when such compounds are susceptible to acid hydrolysis.
Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of a fructose 1,6-bisphosphatase inhibitor compound.
It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those skilled in the art.
Utility
FBPase inhibitors may be used to treat diabetes mellitus, lower blood glucose levels, and inhibit gluconeogenesis.
FBPase inhibitors may also be used to treat excess glycogen storage diseases. Excessive hepatic glycogen stores are found in patients with some glycogen storage diseases. Since the indirect pathway contributes significantly to glycogen synthesis (Shulman, G. I. Phys. Rev. 72:1019-1035 (1992)), inhibition of the indirect pathway (gluconeogenesis flux) decreases glycogen overproduction.
FBPase inhibitors may also be used to treat or prevent diseases associated with increased insulin levels. Increased insulin levels are associated with an increased risk of cardiovascular complications and atherosclerosis (Folsom, et al., Stroke, 25:66-73 (1994); Howard, G. et al., Circulation 93:1809-1817 (1996)). FBPase inhibitors are expected to decrease postprandial glucose levels by enhancing hepatic glucose uptake. This effect is postulated to occur in individuals that are non-diabetic (or pre-diabetic, i.e. without elevated hepatic glucose output xe2x80x9chereinafter HGOxe2x80x9d or fasting blood glucose levels). Increased hepatic glucose uptake will decrease insulin secretion and thereby decrease the risk of diseases or complications that arise from elevated insulin levels.
One aspect of the invention is directed to the use of new cyclic 1,3-propanyl ester methodology which results in efficient conversion of the cyclic phosph(oramid)ate. The phosphonate containing compounds by p450 enzymes found in large amounts in the liver and other tissues containing these specific enzymes.
In another aspect of the invention, this prodrug methodology can also be used to prolong the pharmacodynamic half-life because the cyclic phosph(oramid)ates of the invention can prevent the action of enzymes which degrade the parent drug.
In another aspect of the invention, this prodrug methodology can be used to achieve sustained delivery of the parent drug because various novel prodrugs are slowly oxidized in the liver at different rates.
The novel cyclic 1,3-propanylester methodology of the present invention may also be used to increase the distribution of a particular drug to the liver which contains abundant amounts of the p450 isozymes responsible for oxidizing the cylic 1,3-propanylester of the present invention so that the free phosph(oramid)ate is produced.
In another aspect of the invention, the cyclic phosph(oramid)ate prodrugs can increase the oral bioavailability of the drugs.
Theses aspects are described in greater detail below.
Evidence of the liver specificity can also be shown in vivo after both oral and i.v. administration of the prodrugs as described in Example E.
Drug is also detected in the liver following administration of drugs of formulae VI-VIII, shown below:
Prodrugs of formulae VI, VII, and VIII are particularly preferred.
The mechanism of cleavage could proceed by the following mechanisms. Further evidence for these mechanisms is indicated by analysis of the by-products of cleavage. Prodrugs of formula VI where Y is xe2x80x94Oxe2x80x94 generate phenyl vinyl ketone whereas prodrugs of formula VIII were shown to generate phenol (Example H).
Although the esters in the invention are not limited by the above mechanisms, in general, each ester contains a group or atom susceptible to microsomal oxidation (e.g. alchohol, benzylic methine proton), which in turn generates an intermediate that breaks down to the parent compound in aqueous solution via xcex2-elimination of the phosph(oramid)ate diacid.

Heteroaromatic compounds containing a phosphonate group that are inhibitors of fructose-1,6-bisphosphatase

Abstract: are useful in the treatment of diabetes and other conditions associated with elevated blood glucose or excess glycogen storage.