CONTRAST AGENTS FOR ENHANCED MAGNETIC RESONANCE IMAGING

Abstract

The disclosure relates to compounds of the formula (Ia), (Ib), (IIa), and (IIb) and the use of the compounds of the formula (IIa) and (IIb) in method for imaging (e.g., magnetic resonance imaging) a subject in need thereof.

Claims

1. A compound of the formula (IIa), (IIb), (Ia) or (Ib): ##STR00040## or a salt thereof, wherein: R.sup.1 and R.sup.2 are each independently alkyl, arylalkyl or aryl; R.sup.11-R.sup.13 are each independently H, alkyl, a monosaccharide, a polysaccharide (e.g., a disaccharide, trisaccharide, and the like) or a polypeptide; R.sup.14-R.sup.16 are each independently H, alkyl or R.sup.14 and R.sup.15 or R.sup.15 and R.sup.16, together with the oxygen atoms to which they are attached, form a heterocyclyl group; and X.sup.2 is OH or NHR.sup.10, wherein R.sup.10 is H or acyl; or ##STR00041## or a salt thereof, wherein: R.sup.1 and R.sup.2 are each independently alkyl, arylalkyl or aryl; R.sup.3, R.sup.4, and R.sup.6 are each independently alkyl, a protecting group, a monosaccharide, a polysaccharide (e.g., a disaccharide, trisaccharide, and the like) or a polypeptide; R.sup.7, R.sup.8, and R.sup.9 are each independently alkyl or R.sup.7 and R.sup.8 or R.sup.8 and R.sup.9, together with the oxygen atoms to which they are attached, form a heterocyclyl group; and X.sup.1 is OR.sup.5, wherein R.sup.5 is H, a protecting group, a monosaccharide, a polysaccharide (e.g., a disaccharide, trisaccharide, and the like), a polypeptide or NHR.sup.10, wherein R.sup.10 is H or acyl;

2. The compound of claim 1, wherein R.sup.1 and R.sup.2 are each independently (C.sub.1-C.sub.6)alkyl.

3. The compound of claim 1, wherein R.sup.1 and R.sup.2 are each isopropyl.

4. The compound of claim 1, wherein X.sup.1 is OR.sup.5 or NHR.sup.10.

5. The compound of claim 4, wherein R.sup.10 is alkylacyl or arylacyl.

6. The compound of claim 1, wherein R.sup.6 is alkyl.

7. The compound of claim 6, wherein R.sup.6 is methyl.

8. The compound of claim 1, wherein R.sup.7 and R.sup.8 or R.sup.8 and R.sup.9, together with the oxygen atoms to which they are attached, form an acetonide of the formula: ##STR00042##

9. The compound of claim 1, wherein X.sup.2 is OH or NHR.sup.10.

10. The compound of claim 9, wherein R.sup.10 is alkylacyl or arylalkylacyl.

11. The compound of claim 1, wherein R.sup.13 is alkyl.

12. The compound of claim 1, wherein R.sup.13 is H.

13. The compound of claim 1, wherein R.sup.14 and R.sup.15 or R.sup.15 and R.sup.16, together with the oxygen atoms to which they are attached form an acetonide of the formula: ##STR00043##

14. The compound of claim 1, wherein the compounds are of the formula: ##STR00044## or a salt thereof and diastereomers thereof.

15. The compound of claim 1, wherein the compounds are of the formula: ##STR00045## ##STR00046## ##STR00047## or a salt thereof and diastereomers thereof.

16. The compound of claim 1, wherein the compounds of the formula: ##STR00048## or a salt thereof and diastereomers thereof.

17. The compound of claim 1, wherein the compounds of the formula: ##STR00049## or a salt thereof and diastereomers thereof.

18. A pharmaceutical composition comprising at least one compound of claim 1 and a pharmaceutically acceptable excipient.

19. A method for magnetic resonance imaging, the method comprising: administering at least one compound of claim 1 to a subject; and imaging the subject.

20. The method of claim 19, wherein the subject is a human subject or a veterinary subject.

Description

DESCRIPTION

[0005] Reference will now be made in detail to certain embodiments of the disclosed subject matter. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter.

[0006] The disclosure relates to compounds of the formula (Ia) or (Ib):

##STR00001##

or a salt thereof,
wherein: [0007] R.sup.1 and R.sup.2 are each independently alkyl, arylalkyl or aryl; [0008] R.sup.3, R.sup.4, and R.sup.6 are each independently alkyl, a protecting group, a monosaccharide, a polysaccharide (e.g., a disaccharide, trisaccharide, and the like) or a polypeptide; [0009] R.sup.7, R.sup.8, and R.sup.9 are each independently alkyl or R.sup.7 and R.sup.8 or R.sup.8 and R.sup.9, together with the oxygen atoms to which they are attached, form a heterocyclyl group; and [0010] X.sup.1 is OR.sup.5, wherein R.sup.5 is H, a protecting group, a monosaccharide, a polysaccharide (e.g., a disaccharide, trisaccharide, and the like), a polypeptide or NHR.sup.10, wherein R.sup.10 is H or acyl.

[0011] The disclosure also relates to stable free radicals/paramagnetic compounds such as compounds of the formula (IIa) or (IIb):

##STR00002##

or a salt thereof,
wherein: [0012] R.sup.1 and R.sup.2 are each independently alkyl, arylalkyl or aryl; [0013] R.sup.11R.sup.13 are each independently H, alkyl, a monosaccharide, a polysaccharide (e.g., a disaccharide, trisaccharide, and the like) or a polypeptide; [0014] R.sup.14-R.sup.16 are each independently H, alkyl or R.sup.14 and R.sup.15 or R.sup.15 and R.sup.16, together with the oxygen atoms to which they are attached, form a heterocyclyl group; and [0015] X.sup.2 is OH or NHR.sup.10, wherein R.sup.10 is H or acyl.

[0016] In the compounds of the formula (Ia), R.sup.3 can be a protecting group. In embodiments, in the compounds of the formula (Ia), R.sup.4 can be a protecting group. In embodiments, in the compounds of the formula (Ia), R.sup.5 can be a protecting group. In embodiments, in the compounds of the formula (Ia), R.sup.6 can be a protecting group. In embodiments, in the compounds of the formula (Ib), R.sup.7 can be a protecting group. In embodiments, in the compounds of the formula (Ib), R.sup.8 can be a protecting group. In embodiments, in the compounds of the formula (Ib), R.sup.9 can be a protecting group. In embodiments, in the compounds of the formula (Ia), R.sup.3 and R.sup.4; R.sup.3 and R.sup.5; R.sup.3 and R.sup.6; R.sup.4 and R.sup.5; R.sup.4 and R.sup.6; R.sup.5 and R.sup.6; R.sup.3-R.sup.5; R.sup.3, R.sup.4, and R.sup.6; R.sup.4-R.sup.6; R.sup.3, R.sup.5, and R.sup.6; or R.sup.3-R.sup.6 can each independently be a protecting group. In embodiments, in the compounds of the formula (Ib), R.sup.7 and R.sup.8; R.sup.8 and R.sup.9; R.sup.7 and R.sup.9; or R.sup.7-R.sup.9 can each independently be a protecting group. In any of the foregoing, R.sup.3-R.sup.9 or R.sup.11-R.sup.16 together with the oxygen atom to which each is attached can independently form a methoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ether, benzyl ether, p-methoxybenzyl ether, trimethylsilyl ether, triethylsilyl ether, triisopropyl silyl ether, t-butyldimethyl silyl ether, triphenylmethyl silyl ether, acetate ester, substituted acetate esters, pivaloate, benzoate, methanesulfonate and p-toluenesulfonate. In one embodiment, R.sup.3-R.sup.9 or R.sup.11-R.sup.16 together with the oxygen atom to which each is attached can independently form a silyl ether, such as a trimethylsilyl ether.

[0017] In the compounds of the formula (Ia), (Ib), (IIa), and (IIb), R.sup.1 and R.sup.2 can each independently be (C.sub.1-C.sub.6)alkyl, such as (C.sub.2-C.sub.5)alkyl. In one example, R.sup.1 or R.sup.2 can be isopropyl. In another example, R.sup.1 and R.sup.2 are each isopropyl.

[0018] Additionally, or alternatively, X.sup.1 can be OR.sup.5 in the compounds of the formula (Ia). Alternatively, in the compounds of the formula (Ia), X.sup.1 can be NHR.sup.10, wherein R.sup.10 is acyl, such as alkylacyl (e.g., acetyl) or arylalkylacyl (e.g., benzoyl).

[0019] In the compounds of the formula (Ia), R.sup.6 can be alkyl, such as (C.sub.1-C.sub.6)alkyl or (C.sub.2-C.sub.5)alkyl. In one example, R.sup.6 can be methyl. Alternatively, R.sup.6 can be H.

[0020] In the compounds of the formula (Ib), R.sup.7 and R.sup.8 or R.sup.8 and R.sup.9, together with the oxygen atoms to which they are attached, form a heterocyclyl group. Thus, for example, in the compounds of the formula (Ib), R.sup.7 and R.sup.8 or R.sup.8 and R.sup.9, together with the oxygen atoms to which they are attached, form an acetonide of the formula:

##STR00003##

[0021] In the compounds of the formula (IIa), X.sup.2 can be OH. Alternatively, X.sup.2 can be NHR.sup.10, wherein R.sup.10 is acyl, such as alkylacyl (e.g., acetyl) or arylalkylacyl (e.g., benzoyl). Additionally, or alternatively, R.sup.13 can be alkyl in the compounds of the formula (IIa), such as (C.sub.1-C.sub.6)alkyl or (C.sub.2-C.sub.5)alkyl. In one example, R.sup.13 can be methyl. Alternatively, R.sup.13 can be H.

[0022] In the compounds of the formula (IIb), R.sup.14 and R.sup.15 or R.sup.15 and R.sup.16, together with the oxygen atoms to which they are attached, form a heterocyclyl group. Thus, for example, in the compounds of the formula (IIb), R.sup.14 and R.sup.15 or R.sup.15 and R.sup.16, together with the oxygen atoms to which they are attached, form an acetonide of the formula:

##STR00004##

[0023] Examples of the compounds of the formula (Ia) and (IIa) include compounds of the formula:

##STR00005##

or a salt thereof and diastereomers thereof.

[0024] Examples of the compounds of the formula (Ia) and (IIa) include compounds of the formula:

##STR00006##

or salts thereof.

[0025] Examples of compounds of the formula (Ib) and (IIb) include compounds of the formula:

##STR00007##

or a salt thereof and diastereomers thereof.

[0026] Examples of the compounds of the formula (Ib) and (IIb) include compounds of the formula:

##STR00008##

or salts thereof.

[0027] The disclosure also includes a method for magnetic resonance imaging, the method comprising: [0028] administering at least one compound of the formula (IIa) and/or (IIb) to a subject; and [0029] imaging the subject.

[0030] The subject can be any subject, such as a human subject or a veterinary subject (e.g., a canine or a feline). The at least one compound can be a compound of the formula:

##STR00009##

or a salt thereof; such as a compound of the formula:

##STR00010##

a salt thereof.

[0031] Any suitable route of administration can be used in the above methods, such as intravenous. An effective amount for, e.g., MRI, can be determined by one of ordinary skill in the art using dosage range determining methods known in the art. Typically, a physician (or veterinarian for non-human subjects) will determine the actual dosage, which will be most suitable for an individual subject. The specific dose level for an individual may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, gender, diet, mode and time of administration, rate of excretion, and other administered drugs.

[0032] The compounds of the formula (II) can be formulated as pharmaceutical compositions comprising a pharmaceutically acceptable carrier using methods well-known in the art. Carrier is used generically herein to refer to pharmaceutically acceptable carriers, diluents, adjuvants, and excipients. See, e.g., Remington: The Science and Practice of Pharmacy, 23rd edition, Oct. 30, 2020, Adeboye Adejare, ed. Accordingly, further provided is a pharmaceutical composition comprising the compound of formula (II) and a pharmaceutically acceptable carrier.

[0033] For oral administration, the compounds of the formula (II) can be formulated readily by combining them with pharmaceutically acceptable carriers well-known in the art. Such carriers enable the compounds to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Optionally the oral formulations can also be formulated in saline or buffers, e.g., EDTA for neutralizing internal acid conditions, or can be administered without any carriers.

[0034] The terms substituted, substituent, and functional group refer to a group that can be or is substituted onto a molecule or onto another group (e.g., on an aryl or an alkyl group). Examples of substituents include, but are not limited to, a halogen (e.g., F, Cl, Br, and I), OR, OC(O)N(R).sub.2, CN, NO, NO.sub.2, ONO.sub.2, azido, CF.sub.3, OCF.sub.3, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R).sub.2, SR, SOR, SO.sub.2R, SO.sub.2N(R).sub.2, SO.sub.3R, (CH.sub.2).sub.0-2P(O)(OR).sub.2, C(O)R, C(O)C(O)R, C(O)CH.sub.2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R).sub.2, OC(O)N(R).sub.2, C(S)N(R).sub.2, (CH.sub.2).sub.0-2N(R)C(O)R, (CH.sub.2).sub.0-2N(R)C(O)OR, (CH.sub.2).sub.0-2N(R)N(R).sub.2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R).sub.2, N(R)SO.sub.2R, N(R)SO.sub.2N(R).sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R).sub.2, N(R)C(S)N(R).sub.2, N(COR)COR, N(OR)R, C(NH)N(R).sub.2, C(O)N(OR)R, or C(NOR)R wherein each R can be, independently, hydrogen, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, wherein any alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl or two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can together with the nitrogen atom or atoms form a heterocyclyl, which can be mono- or independently multi-substituted.

[0035] As used herein, the term protecting group refers to a group that, together with the oxygen atom to which it is attached (e.g., the oxygen atom to which each of R.sup.3-R.sup.9, and R.sup.11-R.sup.16 is attached), forms a methoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ether, benzyl ether, p-methoxybenzyl ether, trimethylsilyl ether, triethylsilyl ether, triisopropyl silyl ether, t-butyldimethyl silyl ether, triphenylmethyl silyl ether, acetate ester, substituted acetate esters, pivaloate, benzoate, methanesulfonate and p-toluenesulfonate.

[0036] The term alkyl as used herein refers to substituted or unsubstituted straight chain and branched mono- or divalent alkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms (C.sub.1-C.sub.40), 1 to 6 carbon atoms (C.sub.1-C.sub.6). 2 to 5 carbon atoms (C.sub.2-C.sub.5), 3 to 6 carbon atoms (C.sub.3-C.sub.6), 1 to about 20 carbon atoms (C.sub.1-C.sub.20), 1 to 12 carbons (C.sub.1-C.sub.12), 1 to 8 carbon atoms (C.sub.1-C.sub.5), or, in some embodiments, from 1 to 6 carbon atoms (C.sub.1-C.sub.6). Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. As used herein, the term alkyl encompasses n-alkyl, isoalkyl, and ante-isoalkyl groups as well as other branched chain forms of alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0037] The term alkenyl as used herein refers to substituted or unsubstituted straight chain and branched mono- or divalent alkenyl groups and cycloalkenyl groups having at least one double bond and having from 1 to 40 carbon atoms (C.sub.1-C.sub.40), 1 to about 20 carbon atoms (C.sub.1-C.sub.20), 1 to 12 carbons (C.sub.1-C.sub.12), 1 to 8 carbon atoms (C.sub.1-C.sub.8), or, in some embodiments, from 1 to 6 carbon atoms (C.sub.1-C.sub.6). Examples of straight chain alkenyl groups include those with from 1 to 8 carbon atoms such as CHCH, CHCHCH.sub.3, and CH.sub.2CHCHCH.sub.2 groups, wherein the double bonds can have an E- or Z-configuration. And when there are multiple bonds, each double bond can, independently, have an E- or a Z-configuration. Examples of branched alkenyl groups include, but are not limited to, CHC(CH.sub.3) and CH.sub.2CCH(CH.sub.3) groups. Representative substituted alkenyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0038] The term cycloalkyl as used herein refers to substituted or unsubstituted cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7. Cycloalkyl groups can have any number of carbon atoms, e.g., 3 to 8 carbon atoms (C.sub.3-C.sub.8), 3 to 6 carbon atoms (C.sub.3-C.sub.6), and 4 to 8 carbon atoms (C.sub.4-C.sub.8). Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like.

[0039] The term cycloalkylalkyl as used herein refers to substituted or unsubstituted alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bond to a cycloalkyl group as defined herein. Representative cycloalkylalkyl groups include, but are not limited to, cyclopentylalkyl.

[0040] The term alkylcycloalkyl as used herein refers to substituted or unsubstituted cycloalkyl groups as defined herein in which a hydrogen of a cycloalkyl group as defined herein is replaced with a bond to an alkyl group as defined herein. Representative alkylcycloalkyl groups include, but are not limited to, alkylcyclopropyl.

[0041] The term acyl as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to another carbon atom, which can be part of a substituted or unsubstituted alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. In the special case wherein the carbonyl carbon atom is bonded to a hydrogen, the group is a formyl group, an acyl group as the term is defined herein. An acyl group can include 0 to about 12-40, 6-10, 1-5 or 2-5 additional carbon atoms bonded to the carbonyl group. An acryloyl group is an example of an acyl group. An acyl group can also include heteroatoms within the meaning here. A nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a haloacyl group. An example is a trifluoroacetyl group.

[0042] The term heterocyclylcarbonyl is an example of an acyl group that is bonded to a substituted or unsubstituted heterocyclyl group, as the term heterocyclyl is defined herein. An example of a heterocyclylcarbonyl group is a prolyl group, wherein the prolyl group can be a D- or an L-prolyl group.

[0043] The term aryl as used herein refers to substituted or unsubstituted cyclic aromatic hydrocarbons that do not contain heteroatoms in the ring. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbons (C.sub.6-C.sub.14) or from 6 to 10 carbon atoms (C.sub.6-C.sub.10) in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined herein. Aryl and the phrase aryl group includes fused ring species including those that include fused aromatic and non-aromatic groups. Accordingly, aryl and the phrase aryl group include groups of the formula:

##STR00011##

each of which can be substituted or unsubstituted, such as hydroxy substituted.

[0044] Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups such as those listed herein.

[0045] The terms aralkyl and arylalkyl refer to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.

[0046] The term heterocyclyl or heterocyclo refers to substituted or unsubstituted aromatic and non-aromatic ring compounds containing 3 or more ring members, of which one or more (e.g., 1, 2 or 3) is a heteroatom such as, but not limited to, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl or a heteroaryl or, if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. In some embodiments, heterocyclyl groups include heterocyclyl groups that include 3 to 8 carbon atoms (C.sub.3-C.sub.8), 3 to 6 carbon atoms (C.sub.3-C.sub.6), 3 to 5 carbon atoms (C.sub.3-C.sub.5) or 6 to 8 carbon atoms (C.sub.6-C.sub.8). A heterocyclyl group designated as a C.sub.2-heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise, a C.sub.4-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds, such as in the group 3,6-dihydro-2H-pyran and 3,4-dihydro-2H-pyran, having the formula:

##STR00012##

respectively, each of which can be substituted.

[0047] A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase heterocyclyl group includes fused ring species including those that include fused aromatic and non-aromatic groups. Representative heterocyclyl groups include, but are not limited to tetrahydro-2H-thiopyran-1,1-dioxide, having the formula:

##STR00013##

which can be substituted, 4a,5,6,7-tetrahydro-4H-pyrrolo[1,2-d][1,3,4]oxadiazinyl, having the formula:

##STR00014##

which can be substituted, pyrrolidinyl, pyrrolidinone (e.g., pyrrolidin-2-one), azetidinyl, piperidynyl, piperazinyl, morpholinyl, chromanyl, indolinonyl, isoindolinonyl, furanyl, pyrrolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, thiophenyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, imidazo[1,2-a]pyridinyl, having the formula:

##STR00015##

which can be substituted, triazyolyl, tetrazolyl, benzoxazolinyl, thiazolyl, benzthiazolinyl, and benzimidazolinyl groups. Examples of indolinonyl groups include groups having the general formula:

##STR00016##

wherein R is as defined herein.

[0048] Examples of isoindolinonyl groups include groups having the general formula:

##STR00017##

wherein R is as defined herein.

[0049] Examples of benzoxazolinyl groups include groups having the general formula:

##STR00018##

wherein R is as defined herein.

[0050] Examples of benzthiazolinyl groups include groups having the general formula:

##STR00019##

wherein R is as defined herein.

[0051] In some embodiments, the group R in benzoxazolinyl and benzthiazolinyl groups is an N(R).sub.2 group. In some embodiments, each R is hydrogen or alkyl, wherein the alkyl group is substituted or unsubstituted. In some embodiments, the alkyl group is substituted with a heterocyclyl group (e.g., with a pyrrolidinyl group).

[0052] The term heterocyclylalkyl refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bond to a heterocyclyl group as defined herein. Representative heterocyclylalkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl methyl, and indol-2-yl propyl.

[0053] The term heterocyclylalkoxy refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bond to a heterocyclyl group as defined herein and the alkyl group is attached to an oxygen. Representative heterocyclylalkoxy groups include, but are not limited to, O(CH.sub.2).sub.q heterocyclyl, wherein q is an integer from 1 to 5. In some embodiments, heterocyclylalkoxy groups include O(CH.sub.2).sub.q morpholinyl such as OCH.sub.2CH.sub.2-morpholine.

[0054] The term heteroarylalkyl refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined herein.

[0055] The term alkoxy refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include one to about 12-20 or about 12-40 carbon atoms bonded to the oxygen atom, can further include double or triple bonds, and can also include heteroatoms. For example, an allyloxy group is an alkoxy group within the meaning herein. A methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith.

[0056] The terms amine, amine group, amino, and amino group refer to a substituent of the form NH.sub.2, NHR, NR.sub.2, or NR.sub.3.sup.+, wherein each R is defined herein, and protonated forms of each, except for NR.sub.3.sup.+, which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An amino group within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group.

[0057] An alkylamino group includes a monoalkylamino, dialkylamino, and trialkylamino group. An example of a alkylamino is NH-alkyl and N(alkyl).sub.2.

[0058] An example of a cycloalkylamino group is NH-cycloalkyl and N(cycloalkyl).sub.2.

[0059] An example of a cycloalkyl heterocycloamino group is NH-(heterocyclo cycloalkyl), wherein the heterocyclo group is attached to the nitrogen and the cycloalkyl group is attached to the heterocyclo group.

[0060] An example of a heterocyclo cycloamino group is NH-(cycloalkyl heterocycle), wherein the cycloalkyl group is attached to the nitrogen and the heterocyclo group is attached to the cycloalkyl group.

[0061] The term amido refers to a group of the formula C(O)NR.sub.2, wherein R is defined herein.

[0062] The terms halo, halogen, and halide group, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0063] The term haloalkyl group includes mono-halo alkyl groups, poly-halo alkyl groups, wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, CF(CH.sub.3).sub.2 and the like.

[0064] Values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range were explicitly recited. For example, a range of about 0.1% to about 5% or about 0.1% to 5% should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement about X to Y has the same meaning as about X to about Y, unless indicated otherwise. Likewise, the statement about X, Y, or about Z has the same meaning as about X, about Y, or about Z, unless indicated otherwise.

[0065] In this document, the terms a, an, or the are used to include one or more than one unless the context clearly dictates otherwise. The term or is used to refer to a nonexclusive or unless otherwise indicated. In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting. Further, information that is relevant to a section heading can occur within or outside of that particular section. Furthermore, all publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference.

[0066] In the event of inconsistent usages between this document and those documents so incorporated by reference, the usage in the incorporated reference should be considered supplementary to that of this document; for irreconcilable inconsistencies, the usage in this document controls.

[0067] In the methods described herein, the steps can be carried out in any order without departing from the principles of the invention, except when a temporal or operational sequence is explicitly recited. Furthermore, specified steps can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed step of doing X and a claimed step of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.

[0068] The term about as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range.

[0069] The term substantially as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more.

[0070] The term substantially no as used herein refers to less than about 30%, 25%, 20%, 15%, 10%, 5%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.001%, or at less than about 0.0005% or less or about 0% or 0%.

[0071] Those skilled in the art will appreciate that many modifications to the embodiments described herein are possible without departing from the spirit and scope of the present disclosure. Thus, the description is not intended and should not be construed to be limited to the examples given but should be granted the full breadth of protection afforded by the appended claims and equivalents thereto. In addition, it is possible to use some of the features of the present disclosure without the corresponding use of other features. Accordingly, the foregoing description of or illustrative embodiments is provided for the purpose of illustrating the principles of the present disclosure and not in limitation thereof and can include modification thereto and permutations thereof.

[0072] The disclosure also includes the following numbered Embodiments listed in no particular order of importance:

1. A compound of the formula (Ia) or (Ib):

##STR00020##

or a salt thereof,
wherein: [0073] R.sup.1 and R.sup.2 are each independently alkyl, arylalkyl or aryl; [0074] R.sup.3, R.sup.4, and R.sup.6 are each independently alkyl, a protecting group, a monosaccharide, a polysaccharide (e.g., a disaccharide, trisaccharide, and the like) or a polypeptide; [0075] R.sup.7, R.sup.8, and R.sup.9 are each independently alkyl or R.sup.7 and R.sup.8 or R.sup.8 and R.sup.9, together with the oxygen atoms to which they are attached, form a heterocyclyl group; and [0076] X.sup.1 is OR.sup.5, wherein R.sup.5 is H, a protecting group, a monosaccharide, a polysaccharide (e.g., a disaccharide, trisaccharide, and the like), a polypeptide or NHR.sup.10, wherein [0077] R.sup.10 is H or acyl.
2. A compound of the formula (IIa) or (IIb):

##STR00021##

or a salt thereof,
wherein: [0078] R.sup.1 and R.sup.2 are each independently alkyl, arylalkyl or aryl; [0079] R.sup.11R.sup.13 are each independently H, alkyl, a monosaccharide, a polysaccharide (e.g., a disaccharide, trisaccharide, and the like) or a polypeptide; [0080] R.sup.14-R.sup.16 are each independently H, alkyl or R.sup.14 and R.sup.15 or R.sup.15 and R.sup.16, together with the oxygen atoms to which they are attached, form a heterocyclyl group; and [0081] X.sup.2 is OH or NHR.sup.10, wherein R.sup.10 is H or acyl.
3. The compound of Embodiment 1 or 2, wherein R.sup.1 and R.sup.2 are each independently (C.sub.1-C.sub.6)alkyl.
4. The compound of Embodiment 1 or 2, wherein R.sup.1 and R.sup.2 are each independently (C.sub.2-C.sub.5)alkyl.
5. The compound of any preceding Embodiment, wherein R.sup.1 or R.sup.2 is isopropyl.
6. The compound of any preceding Embodiment, wherein R.sup.1 and R.sup.2 are each isopropyl.
7. The compound of any of Embodiments 1 and 3-6, wherein X.sup.1 is OR.sup.5.
8. The compound of any of Embodiments 1 and 3-6, wherein X.sup.1 is NHR.sup.10.
9. The compound of Embodiment 8, wherein R.sup.10 is alkylacyl or arylacyl.
10. The compound of any of Embodiments 1 and 3-9, wherein R.sup.6 is alkyl.
11. The compound of Embodiment 10, wherein R.sup.6 is (C.sub.1-C.sub.6)alkyl or (C.sub.2-C.sub.5)alkyl.
12. The compound of Embodiment 10 or 11, wherein R.sup.6 is methyl.
13. The compound of any of Embodiments 1 and 3-6, wherein R.sup.7 and R.sup.8 or R.sup.8 and R.sup.9, together with the oxygen atoms to which they are attached, form an acetonide of the formula:

##STR00022##

14. The compound of any of Embodiments 2-6, wherein X.sup.2 is OH.
15. The compound of any of Embodiments 2-6, wherein X.sup.2 is NHR.sup.10.
16. The compound of Embodiment 15, wherein R.sup.10 is alkylacyl or arylalkylacyl.
17. The compound of any of Embodiments 2-6, 14, and 15, wherein R.sup.13 is alkyl.
18. The compound of Embodiment 17, wherein R.sup.13 is (C.sub.1-C.sub.6)alkyl or (C.sub.2-C.sub.5)alkyl.
19. The compound of any of Embodiments 2-6, 14, and 15, wherein R.sup.13 is H.
20. The compound of any of Embodiments 2-6 and 14-19, wherein R.sup.14 and R.sup.15 or R.sup.15 and R.sup.16, together with the oxygen atoms to which they are attached form an acetonide of the formula:

##STR00023##

21. The compound of any of Embodiments 1-13, wherein the compounds are of the formula:

##STR00024##

or a salt thereof and diastereomers thereof.
22. The compound of any of Embodiments 1-13 and 21, wherein the compounds are of the formula:

##STR00025## ##STR00026##

or salts thereof.
23. The compounds of any of Embodiments 2 and 14-20, wherein the compounds of the formula:

##STR00027##

or a salt thereof and diastereomers thereof.
24. The compounds of any of Embodiments 2, 14-20, and 23, wherein the compounds of the formula:

##STR00028##

or salts thereof.
25. A pharmaceutical composition comprising at least one compound of any of Embodiments 1-24 and a pharmaceutically acceptable excipient.
26. A method for magnetic resonance imaging, the method comprising: administering at least one compound of any of Embodiments 1-24 or a pharmaceutical composition of Embodiment 25 to a subject; and imaging the subject.
27. The method of Embodiment 26, wherein the subject is a human subject or a veterinary subject.

Examples

[0082] The disclosure can be better understood by reference to the following examples which are offered by way of illustration. The disclosure is not limited to the examples given herein.

Experimental

General Experimental

[0083] 1D and 2D NMR spectra (.sup.1H, .sup.13C, COSY, DQCOSY, HSQC, HMBC) were recorded in deuterated solvents (CDCl.sub.3 or D.sub.2O) at 300 K using a Varian 400 MHz MR spectrometer. Chemical shifts are reported in parts per million (ppm, 5) NMR relative to residual CHCl.sub.3 (7.26 ppm) for organic soluble compounds or 3-(trimethylsilyl)-1-propanesulfonic acid sodium salt (0.00 ppm) for aqueous soluble compounds. .sup.1H NMR splitting patterns are designated as singlet (s), doublet (d), triplet (t), doublet of doublets (dd), doublet of triplets (dt), multiplet (m), or broad (br). Coupling constants (J) are reported in Hertz (Hz). Signals caused by rotational hindrance are indicated by a star (*). All reactions were conducted in oven-dried glassware. Reactions were monitored by thin layer chromatography (TLC) on glass-backed plates (60 porosity silica gel, 250 m thickness, with a 254 nm fluorescent indicator). Thin layer chromatography (TLC) plates were run using ratios of hexanes/ethyl acetate or dichloromethane/methanol as eluent and visualized using orcinol or potassium permanganate stains, or UV light. Isolation of compounds was carried out using flash chromatography (Biotage Isolera automated system visualizing at all wavelengths, 10 g silica gel cartridges100 pore size, 60 m). Chromatography methods are reported in column volumes (CVs). High-resolution mass spectrometry (HRMS) was obtained using an Agilent-6500 ESI TOF spectrometer with samples dissolved in CH.sub.3CN. CDCl.sub.3 was purchased from Cambridge Isotope Laboratories and stored over 4 molecular sieves. Solvents were purchased and used as received except where noted (companies in parentheses): Pentane (Acros Organics), hexanes (Pharmco), ethyl acetate (Pharmco), dichloromethane (VWR Chemicals), pyridine (Fisher Chemical) distilled over CaH.sub.2 and stored over 4 molecular sieves, Dess Martin periodinane (Chem Scene), Poly(4-vinylpyridine), 25% crosslinked with divinylbenzene, ca. 18 mesh (Acros Organics).

General Procedure for the Synthesis of C-6 Tetrazane TMS-Carbohydrates

[0084] To an oven-dried flask was charged the per-TMS-carbohydrate (1 equiv., 2 mmol), CH.sub.2Cl.sub.2 (10 mL), and pyridine (2 equiv., 4 mmol). With vigorous stirring, Dess-Martin periodinane (1.5 equiv., 3 mmol) was added in portions and the solution stirred for a further 1.5-2 hours during which time the solution goes from clear to opaque with the formation of a precipitate. [Analysis by TLC is challenging due to the sensitivity of the aldehyde. However, progress can be monitored via .sup.1H NMR spectroscopy using a small aliquot of the reaction. Completion of the oxidative deprotection is demonstrated by the complete disappearance of the anomeric hydrogen atom of the starting material, the appearance of a new anomeric hydrogen atom signal and an aldehyde signal.] After 1.5-2 hours, pentane (50 mL) is added to precipitate out the periodinane by-products. The organic layer is washed with water (350 mL) then dried with MgSO.sub.4, filtered, and concentrated in vacuo to yield the crude aldehyde as a colorless oil.

[0085] Concurrently with the oxidative deprotection, 2,4-diisopropylcarbonohydrazide bis-hydrochloride (1.1 equiv., 2.2 mmol) is added to CH.sub.2Cl.sub.2 (10 mL). Poly(4-vinylpyridine) (mass=3the mass of the hydrazide) and a small amount of MgSO.sub.4 to remove residual water is added and this mixture is stirred for 1-2 hours. The crude aldehyde is dissolved in CH.sub.2Cl.sub.2 (5 mL), and the free hydrazide is filtered into the flask containing the aldehyde, with the PVP resin being washed with CH.sub.2Cl.sub.2 (10 mL). Stirring is continued for 1 h with the reaction typically turning a pale yellow during that time. The reaction is concentrated and chromatographed using a pentane/ethyl acetate gradient.

General Procedure for the Deprotection and Formation of the 6-Oxoverdazyl Radical of C-6 Tetrazane TMS-Carbohydrates

[0086] Methyl glycosides (C-6 tetrazane TMS-OMe-carbohydrates) are dissolved in MeOH (10 mL) and Amberlyst-15 (two times the mass of the tetrazane) is added. The solution is stirred for 30 minutes, after which time the Amberlyst-15 is filtered off, washed with MeOH (10 mL), and the resulting solution concentrated to give the deprotected C-6 tetrazane carbohydrate in quantitative or near quantitative yield. For C-6 tetrazane TMS-OMe-carbohydrates that are not glycosides, the compound is dissolved in a 1:1 solvent mixture of water:acetontrile and the reaction is stirred for 12 hours. The deprotected C-6 tetrazane carbohydrate is dissolved in the minimum amount of water or water:MeOH for methyl glycosides (or less polar) derivatives. A second solution of K.sub.3[Fe(CN).sub.6](3.1 equiv.) in H.sub.2O (2 mL) with 2M Na.sub.2CO.sub.3 (15 drops) is prepared and stirred to ensure that the K.sub.3[Fe(CN).sub.6] is fully dissolved. This is then added dropwise to the tetrazane solution. A small amount of effervescence occurs, and the solution turns a dark yellow or yellow/green. After 1 hour the solution is concentrated. The resulting solid/oil is vigorously stirred with CH.sub.3CN (20-30 mL), a small amount of MgSO.sub.4 is added, the solution is filtered and concentrated. The product is purified using column chromatography using a CH.sub.2Cl.sub.2/MeOH gradient to yield a yellow solid.

Data Using General Procedure 1

6-[(2R,3R,4S,5R,6S)-6-methoxy-3,4,5-tris[(trimethylsilyl)oxy]oxan-2-yl]-2,4-bis(propan-2-yl)-1,2,4,5-tetrazinan-3-one (from TMS-methyl -D-glucopyranoside) (1a)

##STR00029##

[0087] General Procedure 1. Chromatography conditions: [100:0 pentane (2 CV); 100:0 pentane/EtOAc to 90:10 pentane/EtOAc (15 CV); 90:10 pentane/EtOAc (15 CV)]. The product was recovered as a colorless solid (720 mg, 64%); Rf=0.39 (2:1 Hex/EtOAc). .sup.1H NMR (400 MHz, CDCl.sub.3) 4.71 (septet, J=6.7 Hz, 1H), 4.63 (d, J=6.7 Hz, 1H), 4.60 (septet, J=6.7 Hz, 1H), 4.09-3.70 (m, 5H), 3.63 (m, 1H), 3.46 (dd, J=9.2, 3.5 Hz, 1H), 3.36 (s, 3H), 1.18 (d, J=6.7 Hz, 3H), 1.15 (d, J=6.7 Hz), 1.07 (d, J=6.7 Hz), 1.04 (d, J=6.7 Hz, 3H), 0.18 (s, 9H), 0.17 (s, 18H). .sup.13C NMR (101 MHz, CDCl.sub.3) 153.25, 99.78, 75.73, 73.52, 72.93, 70.46, 66.61, 54.98, 47.64, 47.15, 19.61, 19.55, 19.40, 18.32, 1.41 (3C), 1.11 (3C), 0.71 (3C). HRMS [M+H] Calc. 565.3267 Found. 565.3281.

6-[(2R,3R,4S,5S,6S)-6-methoxy-3,4,5-tris[(trimethylsilyl)oxy]oxan-2-yl]-2,4-bis(propan-2-yl)-1,2,4,5-tetrazinan-3-one (from TMS-methyl -D-mannopyranoside) (1b)

##STR00030##

[0088] General Procedure 1. Chromatography conditions: [100:0 pentane (2 CV); 100:0 pentane/EtOAc to 90:10 pentane/EtOAc (15 CV); 90:10 pentane/EtOAc (15 CV)]. The product was recovered as a colorless solid (568 mg, 50%); Rf=0.43 (2:1 Hex/EtOAc).

[0089] .sup.1H NMR (400 MHz, CDCl.sub.3) 4.69 (septet, J=6.7 Hz, 1H), 4.62 (septet, J=6.7 Hz, 1H), 4.47 (s, 1H), 4.21 (d, J=12.3 Hz, 1H), 4.10 (t, J=9.1 Hz, 1H) 4.00 (br, 1H), 3.80-3.71 (m, 4H), 3.34 (s, 3H), 1.18 (d, J=6.7 Hz, 3H), 1.14 (d, J=6.7 Hz, 3H), 1.08 (d, J=6.7 Hz, 3H), 1.04 (d, J=6.7 Hz, 3H), 0.17 (s, 9H), 0.14 (s, 9H), 0.12 (s, 9H). .sup.13C NMR (101 MHz, CDCl.sub.3) 153.42, 101.71, 72.81, 72.57, 72.22, 69.09, 66.83, 54.90, 47.50, 47.15, 19.57, 19.50, 19.22, 18.31, 0.89 (3C), 0.54 (3C), 0.51 (3C). HRMS [M+H] Calc. 565.3267 Found. 565.3271.

2,4-bis(propan-2-yl)-6-[(2R,3R,4S,5R,6S)-3,4,5,6-tetrakis[(trimethylsilyl)oxy]oxan-2-yl]-1,2,4,5-tetrazinan-3-one (from -TMS-glucopyranoside) (1d)

##STR00031##

[0090] General Procedure 1. Chromatography conditions: [100:0 pentane (2 CV); 100:0 pentane/EtOAc to 90:10 pentane/EtOAc (15 CV); 90:10 pentane/EtOAc (15 CV)]. The product was recovered as a colorless solid (435 mg, 35%); Rf=0.59 (2:1 Hex/EtOAc). NMR appears to show hindered rotation and two conformations for one of the isopropyl groups. There looks to be a multiplet (probably septet) around 4.5 ppm (hidden beneath the doublet) that integrates to 0.5 ppm. This correlates by HSQC to the doublet at 1.5 ppm which integrates to 3. So, this would match one isopropyl group that has hindered rotation on the NMR timescale. These signals are labeled with a star below.

[0091] .sup.1H NMR (400 MHz, CDCl.sub.3) 4.68 (septet, J=6.7 Hz, 1H), 4.62 (septet, J=6.7 Hz, 1H), 4.49 (t, J=7.2 Hz, 1H), 4.47 (septet, J=6.7 Hz, 1H)*, 4.01-3.90 (m, 1H), 3.87-3.75 (m, 2H), 3.71-3.51 (m, 2H), 3.44 (t, J=8.4 Hz, 1H), 3.26 (t, J=8.0 Hz, 1H), 1.49 (d, J=7.0 Hz, 1H)*, 1.17 (d, J=6.7 Hz, 3H), 1.15 (d, J=6.7 Hz, 3H), 1.07 (d, J=6.7 Hz, 3H), 1.05 (d, J=6.7 Hz, 3H), 0.18 (d, J=1.0 Hz, 18H), 0.17 (s, 9H), 0.16 (s, 9H). .sup.13C NMR (101 MHz, CDCl.sub.3) 153.08, 98.45, 79.09, 77.34, 77.12, 77.02, 76.70, 75.25, 72.40, 66.38, 47.97*, 47.32, 47.22, 21.21*, 19.62, 19.55, 19.32, 18.37, 1.48 (3C), 1.43 (3C), 1.18 (3C), 0.58 (3C).

[0092] HRMS [M+H] Calc. 623.3506 Found. 623.3520.

2,4-bis(propan-2-yl)-6-[(2R,3S,4S,5R,6R)-3,4,5,6-tetrakis[(trimethylsilyl)oxy]oxan-2-yl]-1,2,4,5-tetrazinan-3-one (1e)

##STR00032##

[0093] General Procedure 1. Chromatography conditions: [100:0 pentane (2 CV); 100:0 pentane/EtOAc to 90:10 pentane/EtOAc (15 CV); 90:10 pentane/EtOAc (15 CV)]. The product was recovered as a colorless solid (650 mg, 52%); Rf=0.52 (2:1 Hex/EtOAc). .sup.1H NMR (400 MHz, CDCl.sub.3) 5.09 (d, J=3.1 Hz, 1H), 4.48 (septet, J=6.8 Hz, 1H), 4.46 (septet, J=6.8 Hz, 1H), 4.11-4.02 (m, 2H), 3.90-3.73 (m, 3H), 3.73 (br, 1H), 1.48 (d, J=6.7 Hz, 1H)*, 1.16-1.07 (m, 12H), 0.16 (s, 9H), 0.14 (s, 18H), 0.11 (s, 9H) [other NH not observed due to broadening].sup.13C NMR (101 MHz, CDCl.sub.3) 153.31, 94.67, 72.66, 70.44, 70.04*, 70.00, 69.46, 47.10, 47.08, * 46.56, 46.54, * 21.21, 19.90, 19.37, 19.22, 18.98, 0.90 (3C), 0.35 (3C), 0.33 (3C), 0.31 (3C). HRMS [M+H] Calc. 623.3506 Found. 623.3513.

2,4-bis(propan-2-yl)-6-[(2R,3R,4S,5S,6S)-3,4,5,6-tetrakis[(trimethylsilyl)oxy]oxan-2-yl]-1,2,4,5-tetrazinan-3-one (from TMS-mannopyranoside) (1f)

##STR00033##

[0094] General Procedure 1. Chromatography conditions: [100:0 pentane (2 CV); 100:0 pentane/EtOAc to 90:10 pentane/EtOAc (15 CV); 90:10 pentane/EtOAc (15 CV)]. The product was recovered as a colorless solid (643 mg, 50%)

[0095] .sup.1H NMR (400 MHz, CDCl.sub.3) 4.88 (s, 1H), 4.68 (septet, J=6.6 Hz, 1H), 4.60 (septet, J=6.6 Hz, 1H), 4.18-4.07 (m, 2H), 3.90 (br, 1H), 3.87 (d, J=2.8 Hz, 2H), 3.73 (t, J=11.8 Hz, 1H), 3.65 (s, 1H), 1.17 (d, J=6.6 Hz, 3H), 1.14 (d, J=6.6 Hz, 3H), 1.06 (d, J=6.6 Hz, 3H), 1.03 (d, J=6.6 Hz, 3H), 0.18 (s, 9H), 0.17 (s, 9H), 0.15 (s, 9H), 0.12 (s, 9H). .sup.13C NMR (101 MHz, CDCl.sub.3) 153.26, 95.42, 74.36, 72.86, 71.64, 69.08, 66.68, 47.39, 47.11, 19.59, 19.48, 19.23, 18.31, 0.92 (3C), 0.53 (3C), 0.48 (3C), 0.10 (3C).

N-[(2R,3R,4R,5R,6R)-6-[6-oxo-1,5-bis(propan-2-yl)-1,2,4,5-tetrazinan-3-yl]-2,4,5-tris[(trimethylsilyl)oxy]oxan-3-yl]acetamide (1 g)

##STR00034##

[0096] General Procedure 1. Chromatography conditions: [100:0 pentane (2 CV); 100:0 pentane/EtOAc to 60:40 pentane/EtOAc (15 CV); 60:40 pentane/EtOAc (15 CV)]. The product was recovered as a colorless solid (352 mg, 30%); Rf=0.29 (2:1 Hex/EtOAc). .sup.1HNMR (400 MHz, CDCl.sub.3) 5.34-5.21 (m, 1H), 5.07 (d, J=3.3 Hz, 1H), 4.70 (septet, J=6.7 Hz, 1H), 4.61 (septet, J=6.7 Hz, 1H), 4.07-3.88 (m, 3H), 3.75 (m, 4H), 2.02 (s, 3H), 1.17 (d, J=6.7 Hz, 3H), 1.15 (d, J=6.7 Hz, 3H), 1.05 (d, J=6.7 Hz, 3H), 1.03 (d, J=6.7 Hz, 3H), 0.19 (s, 9H), 0.18 (s, 9H), 0.16 (s, 9H). .sup.13C NMR (101 MHz, CDCl.sub.3) 170.03, 152.99, 92.44, 73.74, 73.02, 70.98, 66.49, 54.17, 47.47, 47.15, 23.71, 19.68, 19.50, 19.46, 18.32, 1.24 (3C), 1.06 (3C), 0.09 (3C). HRMS [M+H] Calc. 592.3376 Found. 592.3385

Data Using General Procedure 2

3-oxo-2,4-bis(propan-2-yl)-6-[(2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl]-3,4-dihydro-1,2,4,5-tetraazin-1 (2H)-yl (2a)

##STR00035##

[0097] General Procedure 2 and 3. TMS-tetrazane (720 mg, 1.274 mmol). Radical chromatography conditions: [100:0 CH.sub.2Cl.sub.2 (2 CV); 100:0 CH.sub.2Cl.sub.2/MeOH to 60:40 CH.sub.2Cl.sub.2/MeOH (15 CV); 60:40 CH.sub.2Cl.sub.2/MeOH (15 CV)]. The product was recovered as a yellow solid (133 mg, 30%); Rf=0.34 (9:1 CH.sub.2Cl.sub.2/MeOH). HRMS [M] Calc. 345.1774 Found. 345.1775.

3-oxo-2,4-bis(propan-2-yl)-6-[(2R,3S,4S,5S,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl]-3,4-dihydro-1,2,4,5-tetraazin-1 (2H)-yl (2b)

##STR00036##

[0098] General Procedure 2 and 3. TMS-tetrazane (568 mg, 1.005 mmol). Radical chromatography conditions: [100:0 CH.sub.2Cl.sub.2 (2 CV); 100:0 CH.sub.2Cl.sub.2/MeOH to 60:40 CH.sub.2Cl.sub.2/MeOH (15 CV); 60:40 CH.sub.2Cl.sub.2/MeOH (15 CV)]. The product was recovered as a yellow solid (147 mg, 41%); Rf=0.31 (9:1 CH.sub.2Cl.sub.2/MeOH). HRMS [M] Calc. 345.1774 Found. 345.1773.

3-oxo-2,4-bis(propan-2-yl)-6-[(2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl]-3,4-dihydro-1,2,4,5-tetraazin-1 (2H)-yl (2c)

##STR00037##

[0099] General Procedure 2. TMS-tetrazane (435 mg, 0.698 mmol). Chromatography conditions: [100:0 CH.sub.2Cl.sub.2 (2 CV); 100:0 CH.sub.2Cl.sub.2/MeOH to 60:40 CH.sub.2Cl.sub.2/MeOH (15 CV); 60:40 CH.sub.2Cl.sub.2/MeOH (15 CV)]. The product was recovered as a yellow solid (80 mg, 35%); Rf=0.20 (9:1 CH.sub.2Cl.sub.2/MeOH). HRMS [M] Calc. 331.1618 Found. 331.1636.

3-oxo-2,4-bis(propan-2-yl)-6-[(2R,3R,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl]-3,4-dihydro-1,2,4,5-tetraazin-1 (2H)-yl (2d)

##STR00038##

[0100] General Procedure 2. TMS-tetrazane (650 mg, 1.043 mmol). Chromatography conditions: [100:0 CH.sub.2Cl.sub.2 (2 CV); 100:0 CH.sub.2Cl.sub.2/MeOH to 50:50 CH.sub.2Cl.sub.2/MeOH (15 CV); 50:50 CH.sub.2Cl.sub.2/MeOH (15 CV)]. The product was recovered as a yellow solid (72 mg, 21%); Rf=0.63 (4:1 CH.sub.2Cl.sub.2/MeOH). HRMS [M] Calc. 331.1618 Found. 331.1628.

3-oxo-2,4-bis(propan-2-yl)-6-[(2R,3S,4R,5R)-3,4,6-trihydroxy-5-(methylcarbonylamino)tetrahydro-2H-pyran-2-yl]-3,4-dihydro-1,2,4,5-tetraazin-1 (2H)-yl (2e)

##STR00039##

[0101] General Procedure 2. TMS-tetrazane (353 mg, 0.596 mmol). Chromatography conditions: [100:0 CH.sub.2Cl.sub.2 (2 CV); 100:0 CH.sub.2Cl.sub.2/MeOH to 50:50 CH.sub.2Cl.sub.2/MeOH (15 CV); 50:50 CH.sub.2Cl.sub.2/MeOH (15 CV)]. The product was recovered as a yellow solid (135 mg, 60%); Rf=0.45 (4:1 CH.sub.2Cl.sub.2/MeOH). HRMS [M+H] Calc. 373.1956 Found. 373.1982.