Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
  • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
  • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
  • C07D235/30—Nitrogen atoms not forming part of a nitro radical
  • C07D235/32—Benzimidazole-2-carbamic acids, unsubstituted or substituted; Esters thereof; Thio-analogues thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline

Definitions

• This invention is in the field of improving the water solubility of benzimidazole derivatives and other weak bases and providing pharmaceutical formulations of the same.
• Benzimidazole derivatives are useful for inhibiting the growth of cancers, tumors and viruses in mammals, particularly in humans and warm-blooded animals (U.S. Patents 6,479,526; 5,880,144; 6,245,789; 5,767,138; 6,265,437).
• Certain benzimidazole derivatives used in combination with other compounds have been reported to be useful as fungicides (U.S. Patents 3,954,993; 4,593,040; 5,756,500; 4,835,169; 4,980,346).
• benzimidazole derivatives including carbendazim
• carbendazim are poorly water soluble.
• the projected oral dose of carbendazim for cancer treatment is up to several hundred mg per day which is far greater than its water solubility.
• Other weak bases suffer from the same poor water solubility.
• 0004 There is a need for improved formulations of benzimidazole derivatives and other weak bases.
• X is hydrogen, halogen, alkyl of less than 7 carbon atoms or alkoxy of less than 7 carbon atoms; n is a positive integer of less than 4; Y is hydrogen, chlorine, nitro, methyl, ethyl or oxychloro; R is hydrogen, alkylaminocarbonyl wherein the alkyl group has from 3 to 6 carbon atoms or an alkyl group having from 1 to 8 carbons, and R 2 is 4-thiazolyl, NHCOORi wherein R 1 is an aliphatic hydrocarbon of less than 7 carbon atoms, or an alkyl group of less than 7 carbon atoms.
• the salt is preferably one or more selected from the group consisting of: chlorides, bromides, phosphates, sulfates, tosylates, benzoylates, nitrates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates and mesylates.
• Each salt comprising a weak base cation and individual anions and all groups and subgroups of anions are particular embodiments of the invention.
• compositions comprising a salt of a weak base compound of formula:
• X is hydrogen, halogen, alkyl of less than 7 carbon atoms or alkoxy of less than 7 carbon atoms; n is a positive integer of less than 4; Y is hydrogen, chlorine, nitro, methyl, ethyl or oxychloro; R is hydrogen, alkylaminocarbonyl wherein the alkyl group has from 3 to 6 carbon atoms or an alkyl group having from 1 to 8 carbons and R 2 is 4-thiazolyl, NHCOORi wherein R1 is aliphatic hydrocarbon of less than 7 carbon atoms, or an alkyl group of less than 7 carbon atoms; one or more free acids; and optional pharmaceutical additives.
• the salt and free acids are present in the composition at a ratio of about 1 :0.5 to about 1 :3 by weight. All individual values and ranges of ratios are included herein, including about 1 :1 and about 1 :2. Also provided are methods of making and using the salts and compositions described herein. Compositions consisting essentially of the components described herein are also included.
• Also provided are methods of treating disease comprising administering to a patient a pharmaceutically effective amount of a pharmaceutical composition comprising a salt of a weak base compound of formula:
• free acid means a composition that ionizes in water to form hydrogen ion and an anion.
• the free acid contains the same anion as the salt.
• the free acid contains one or more anions, one of which can be the same anion as in the salt.
• salt means a composition that ionizes in water to form antician __ ⁇
• the weak base provides the cation in the salt.
• weak base or “weak bases” are those compounds having a pKa below about 7.
• Weak bases include prodrugs of weak bases.
• Preferred weak bases have a pKa below about 5.
• Other preferred weak bases have a pKa below about 4.
• Weak bases having pKa values below about 7 and compounds in all pKa ranges below about 7 are included in the invention.
• Some classes of weak bases include: imidazole derivatives having a pKa below about 7, pyridine derivatives having a pKa below about 7, aniline derivatives having a pKa below about 7 and compounds containing combinations thereof having a pKa below about 7.
• Imidazole derivatives are defined as compounds which include the structure:
• Some preferred imidazole derivatives include the following:
• Some preferred pyridine derivatives include the following:
• R is hydrogen or alkyl having from 1 to 7 carbon atoms.
• the aromatic ring may have other substituents, as known in the art.
• Some preferred aniline derivatives include the following:
• One class of imidazole derivatives include those with the formula:
• benzimidazoles are those having the formula:
• X is hydrogen, halogen, alkyl of less than 7 carbon atoms or alkoxy of less than 7 carbon atoms; n is a positive integer of less than 4; Y is hydrogen, chlorine, nitro, methyl, ethyl or oxychloro; R is hydrogen, alkylaminocarbonyl wherein the alkyl group has from 3 to 6 carbon atoms or an alkyl group having from 1 to 8 carbons and R 2 is 4-thiazolyl, NHCOORi wherein Ri is aliphatic hydrocarbon of less than 7 carbon atoms, or an alkyl group of less than 7 carbon atoms.
• a preferred class of benzimidazoles are those wherein R is hydrogen. Another preferred class of benzimidazoles are:
• benzimidazole derivatives include benzimidazoles as defined above, and prodrugs of benzimidazoles.
• Prodrugs are considered to be any covalently bonded carriers which release the active parent drug (weak base) according to the formula of the parent drug described above in vivo when such prodrug is administered to a mammalian subject.
• Prodrugs of the weak bases are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
• Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively.
• Examples of prodrugs include, but are not limited to, acetate, formate, or benzoate derivatives of alcohol and amine functional groups in the weak bases; phosphate esters, dimethylglycine esters, aminoalkylbenzyl esters, aminoalkyl esters and carboxyalkyl esters of alcohol and phenol functional groups in the weak bases; and the like.
• compositions of the invention are useful for administration to animals, preferably mammals, and preferably humans.
• the compositions of the invention are administered using any form of administration and any suitable dosage that provides a pharmaceutically active dose in an animal, preferably a mammal, as known in the art.
• compositions of the invention are used for oral, slow intravenous injection or infusion administration, as known in the art. Because the compositions are acidic, other forms of administration may be unsuitable. If the compositions are injected, the injection speed should be slow to avoid local irritation, as known in the art.
• compositions of the present invention may be administered in a unit dosage form and may be prepared by any method well known in the art without undue experimentation. Such methods include combining the compositions of the present invention with a carrier or diluent which constitutes one or more pharmaceutically acceptable additives, as known in the art without undue experimentation. Dosages of the compositions of the invention and frequency of adminstration are easily determined by means known in the art without undue experimentation.
• Oral formulations suitable for use in the practice of the present invention include capsules, gels, cachets, tablets, effervescent or non-effervescent powders or tablets, powders or granules; as a solution or suspension in aqueous or non- aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil emulsion.
• the compositions of the present invention may also be presented as a bolus, electuary or paste.
• Capsules or tablets can include suitable additives that provide desired properties, such as binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents and melting agents, as known in the art.
• kits useful in treating disease which comprise one or more compositions of the invention and may include instructions for administration.
• “Pharmaceutically acceptable” and “non-toxic” mean suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation and allergic response) commensurate with a reasonable benefit/risk ratio.
• “Pharmaceutically active” means capable of causing an intended physiological change in an animal, preferably a mammal.
• “Pharmaceutically acceptable additives” include cosolvents, surfactants, complexants, hydrotropes and other components that are desired for pharmaceutical use, as known in the art, such as pharmaceutically acceptable carriers, preservatives, emulsifying agents, diluents, sweeteners, flavorants, viscosity controlling agents, thickeners, colorants and melting agents. Any level of pharmaceutically acceptable additives and any individual pharmaceutically acceptable additive or combination of additives may be used, as long as these additives do not reduce the solubility below a desired level or make the composition toxic, as defined above.
• pharmaceutically acceptable carrier is known in the art, see, for example, U.S. Patent 6,479,526.
• patient means an animal, mammal or human.
• One class of patients is mammals.
• One class of patients is human.
• Figure 2 shows x-ray powder patterns for different salts of carbendazim.
• Figure 4 shows HSM photographs of carbendazim sulfate.
• Figure 5 shows TGA thermograms of carbendazim sulfate and carbendazim hydrochloride.
• Figure 9 shows thermal ellipsoid plot of molecules of different salts of carbendazim in the asymmetric unit at 50% probability, showing atomic numbering scheme: (a) hydrochloride; (b) phosphate; (c) sulfate; (d) mesylate; (e) besylate; and (f) tosylate.
• the guest water molecules in the sulfate salt are located in isolated cavities along the length of the b-axis, forming H-bonds with sulfate, carbendazim and other water molecules. Dehydration of the crystal must therefore involve complete disruption of the crystal structure, as shown in Figure 6, and should occur at a relatively high temperature owing to strong host-guest hydrogen bonding, and location of guest molecules in the isolated cavities.
• the melting enthalpy of the higher melting form B is lower than the melting enthalpy of A. Therefore, the two forms are enantiotropically related, however only form A is stable below the transition temperature.
• the hydrochloride salt was found to undergo dehydration at 66°C, followed by a melting endotherm at 120°C.
• the weight loss of 13.1 % ( Figure 5) over the temperature range 45-86°C agrees with the theoretical value of 13.6%, which was calculated for a solvate containing two molecules of water for each molecule of the hydrochloride salt.
• the hydrochloride salt was found to have three forms, which are also related enantiotropically.
• the carbendazim moiety in all the studied salts was found to be arranged planar, irrespective of the crystal system/space group, and/or the counter-ion present in the crystal lattice. This is not surprising, as the presence of a benzimidazole ring on one end makes the molecule as a whole planar. Interestingly, the carbonyl group next to the oxygen of methoxy group imparts a slight sp 2 character to the oxygen, thereby restricting the free rotation of the methoxy group. This is confirmed by the inability of the oxygen to form a hydrogen bond with any of the available H - donors. None of the salts demonstrated intra or intermolecular hydrogen bonding between the carbendazim molecules, except for the sulfate salt, wherein there existed a weak C-H...O intermolecular hydrogen bond.
• the phosphate salt also forms reinforced hydrogen bonds between the phosphate moieties, however, the carbendazim molecule is only moderately bonded to the phosphate, and therefore has melting point less than sulfonates, but greater than both the hydrochloride and the sulfate.
• both the hydrochloride and the sulfate salt form a number of H-bonds (at least six), which may compete with each other and limit the formation of all bonds. It is very likely that the geometric constraints imposed by some H-bonds may severely inhibit additional bonds, resulting in low melting points. Because of less stringent requirements, both the sulfate and the hydrochloride salts are closely packed.
• incorporation of solvent molecules into the crystal lattice appears to be positively or negatively related to attaining the maximum hydrogen bond number.
• the hydrochloride and sulfate salts are deficient in acceptor and donor atoms.
• the use of water as the solvent in these lattices is analogous to sharing electrons, allowing the hydrochloride and the sulfate to attain stable crystal structures.
• the hydrochloride salt of carbendazim is crystallized in the orthorhombic space group P2 1 2 ⁇ 2- t .
• This space group is chiral, and does not have any symmetry operations associated with inversion or mirror. Thus, it is devoid of a centre of symmetry and aptly defined as non-centrosymmefric.
• the symmetry operation for this space group involves both rotation and translation along a given axis, referred to as the screw axis.
• three two-fold screw axes are present along the a, b, and c directions.
• 2 ⁇ mean that the asymmetric unit moves 14 of a repeat unit along the three axes for each 14 of a revolution about that axis.
• the asymmetric unit of the carbendazim hydrochloride salt contains one molecule each of hydrochloride and carbendazim, along with two water molecules. The presence of two water molecules in the unit pattern illustrates the importance of water during the crystallization process.
• the thermal ellipsoidal diagram of the hydrochloride salt ( Figure 9(a)) includes the atomic labeling scheme, while the stereo packing diagram of its unit cell is shown in Figure 10.
• the chloride anion along with the water molecules act as a cross linker for the carbendazim assemblies.
• the self-assembly patterns of carbendazim molecules (present as cationic species) arrange themselves in infinite helices around a two-fold screw axis, connecting through ⁇ - ⁇ stacking involving imidazole and a phenyl ring ( Figure 10(a)).
• Such assemblies create voids in which chloride ions and water molecules are contained (Figure 10(b)).
• the phosphate salt of carbendazim crystallizes in the triclinic system, having centrosymmetric space group, P ⁇ .
• the triclinic crystal systems have no restrictions regarding cell edges and cell angles.
• the only symmetry operation for the P ⁇ space group is inversion through a point. Since this inversion is along a one-fold axis, it is equivalent to the centre of symmetry. Based on these symmetry operation, we can have two equipoint transformations (x,y,z and -x,-y,-z), yielding the general position multiplicity of 2 in the unit cell.
• This salt adopts a specific molecular conformation, which promotes intermolecular hydrogen bonding.
• this drug molecule is monoprotonated, with a 1 :1 molecular ratio between the drug molecule and the phosphate anion.
• the three N-H donors (N(4), N(7), and N(14)) of the drug molecule and the oxygen acceptor of the phosphate anion participate in the hydrogen bonding.
• the oxygen 0(12) and 0(14) act as acceptors, and each forms two H-bond interactions, one with the protonated drug and the other with the phosphate anion.
• 0(13) acts both as an acceptor (N(7)-H(10A)...O(13)) and a donor (O(13)-H(13B)...O(12)) to form H-bond interactions.
• 0(11) acts as a donor, forming intermolecular H-bonds with the 0(14) of the phosphate anion.
• the strong intermolecular N-H...O bond between the NHs of the cationic drug moiety and the oxygen of the anionic phosphate serve to link neighboring carbendazim molecules into chains.
• the O-H...O hydrogen bonds between the phosphate molecules allows the arrangement of the anion molecules into a line parallel to the b axis ( Figure 11).
• D and A refer to donor and acceptor atoms, respectively.
• the packing arrangement of phosphate salt shows that both carbendazim and phosphate anions are arranged in stacks of parallel molecules, while the molecules in adjacent stacks are arranged in an inverted fashion. Within the stacks, the molecules are all arranged in the same direction.
• the most intense inter-molecular interactions in carbendazim occur among adjacent stacks between the carbon of the carbonyl group and the ⁇ system of the benzene ring.
• the observed bond length (C(3)-C(10)) of 3.261 A is less than the van der Waals value of 3.4A.
• the strong electron acceptor character of the carbonyl oxygen induces the formation of ⁇ - complexes.
• Carbendazim sulfate crystallizes in the monoclinic system, having centrosymmetric space group C2/c.
• monoclinic system there is a "unique" axis - the one which is perpendicular to the other two. This unique axis is normally chosen as the b-axis, and thus, ⁇ ⁇ 90°.
• the crystal pattern for the sulfate salt is centered, unlike the hydrochloride or the phosphate salt that have primitive patterns. In a centered pattern, the grouping of motifs at the center of the rectangular cell is identical with that at the corners.
• the symbol 'C indicates that the lattice is face- centered or end-centered, with a second lattice point lying at the center of the C-face (which is defined by the a- and b- axes).
• the cell volume is double that of the primitive cell.
• the symmetry operation is a 2-fold rotation axis parallel to the b-axis, and a glide plane perpendicular to the b-axis.
• the symbol 'c' indicates that the direction of glide is parallel to the c-axis.
• a glide plane combines the operation of reflection with that of translation, and therefore occurs only in extended arrays.
• the asymmetric unit consists of a single protonated carbendazim molecule, one water molecule, and a half sulfate anion.
• the sulfate salt adopts a molecular conformation which promotes intermolecular hydrogen bonding.
• the three N-H donors of the drug molecule and the sulfate oxygen acceptor of the anion, along with the water molecule participate in hydrogen bonding.
• Strong intermolecular hydrogen bonds between the NHs (both imidazole and carbamate) and the sulfate or water oxygens link the protonated carbendazim, the sulfate anions, and the water molecules into chains, which propogate along the b-axis ( Figure 12).
• the packing diagram of this salt closely resembles that of the phosphate salt, having a column of anion, SO 4 2" in this case, running parallel to the b axis, where the sulfate molecules are hydrogen bonded to the water molecules (O(20)-H(21)...O(10) and O(20)- H(20)...O(11)).
• the drug molecule is again H-bonded to the anion on each side of the molecule, just as they do in the phosphate salt (N(7)- H(7A)...O(10), N(5)- H(5A)...O(11), N(5)-H(5A)...S(1) and N(7)-H(7A)...S(1).
• the drug molecule also forms hydrogen bonds with the water molecule (N(14)- H(14A)...O(20)).
• D and A refer to donor and acceptor atoms, respectively.
• the packing arrangement of the sulfate salt shows the presence of intermolecular hydrogen bonds having carbon as the hydrogen donor.
• an activated C-H group as present in some heterocyclic bases, for example, caffeine, theophylline, uric acid and related compounds, tend to interact with oxygen atoms in the same way as an O-H or N-H group and the short ( ⁇ 3.4A) C--0 contacts observed in the crystals of these molecules were interpreted as C- H...O hydrogen bonds.
• the packing arrangement of the sulfate salt is stabilized by the presence of C-H... ⁇ interactions between the methyl group of one carbendazim and the benzene ring of the other. These interactions are C(11)... H(1C) (2.797A) and C(10)... H(1C) (2.676A).

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• 2004
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