TWI466887B - Substituted xanthine derivatives - Google Patents

Description

Substituted xanthine derivative

The present invention relates to novel compounds which are substituted xanthine derivatives and pharmaceutically acceptable salts thereof. The invention also relates to a composition comprising one or more compounds of the invention and a carrier, and the disclosed compounds and compositions, in a method of treating a disease or condition which would benefit from the formulation of pentoxifylline and related compounds the use of.

Formulated with cefolin 1-(5-oxo-oxyhexyl)-3,7-dimethylxanthine under the trademark Trental Sold in the US and Canada. It is currently approved for the treatment of patients with intermittent claudication caused by chronic arteriovenous disease of the extremities. It is also used in clinical trials for glomerulonephritis, renal syndrome, nonalcoholic steatosis hepatitis, Leishmaniasis, cirrhosis, liver failure, Duchenne's muscular dystrophy (Duchenne's) Muscular dystrophy), HIV infection, delayed radiation-induced injury, radiation-induced lymphedema, alcoholic hepatitis, radiation-induced fibrosis, necrotizing enterocolitis in premature infants, chronic kidney disease, pulmonary sarcoidosis, recurrent goose Aphthous stomatitis, chronic breast pain in patients with breast cancer, brain and central nervous system tumors, and malnutrition-inflammation-cachexia syndrome. The combination of cefolin has recently received attention as a potential therapeutic for diabetes and diabetes-related conditions. See Ferrari, E et al, Pharmatherapeutica, 1987, 5(1): 26-39; Raptis, S et al, Acta Diabetol Lat, 1987, 24(3): 181-92; and Rahbar, R et al, Clin Chim Acta, 2000, 301 (1-2): 65-77.

It is known that the combination of cefprolin has activity as an inhibitor of phosphodiesterase (PDE; see Meskini, N et al, Biochem. Pharm. 1994, 47(5): 781-788) and activity against other biological targets, However, the exact mode of action that produces clinical effects is unknown. It has been shown that the compatibility of ciprofloxacin improves blood flow properties by reducing blood viscosity and improving blood rheology of red blood cell flexibility. The combination of cefolin also increases leukocyte deformability and inhibits neutrophil adhesion and activation. (See http://www.fda.gov/cder/foi/nda/99/74-962_Pentoxifylline_prntlbl.pdf for FDA labeling with cefolin). In addition to improving blood rheological properties, Xianxin is also anti-inflammatory and anti-fibrotic.

The clinical pharmacology with cefolin has been attributed to the parent drug and its metabolites, but the sequence of events leading to clinical improvement remains to be defined. The compatibility of cefolin is experiencing rapid first pass metabolism. The peak plasma content of the formulated cefolin and its metabolites was reached within one hour. The structure of the combination of cefolin and its various reported metabolites is shown below.

The main metabolites produced are M-1 and M-5. The plasma levels of these metabolites are five and eight times the parent drug, respectively. (See http://www.fda.gov/cder/foi/nda/99/74-962_Pentoxifylline_prntlbl.pdf for FDA labeling with cefolin). The M-1 metabolite has a palmitic center and forms the ( R )- and ( S )-enantiomers. During the adaptation to the metabolism of ciprofloxacin, a mutual transition occurs between the M-1 enantiomer and the formulated cefolin. The ( S )-enantiomer is the major M-1 species (S:R ratio is reported to be about 90:10 or greater) and is more rapidly converted than the ( R )-enantiomer. The secondary ( R )-M1 metabolite (called lisofylline) has been reported to have novel anti-inflammatory properties.

Although active M1 metabolites appear to play an important role in the clinical activity of cefolin, other metabolites can cause drug toxicity. Especially in patients with renal impairment, the risk of toxicity to cefolin may be greater (http://products.sanofi-aventis.us/trental/trental.pdf). According to the product label, patients with renal impairment who take the drug need to monitor renal function. In addition, at least one product is marked with warning that the combination of cefolin should not be administered to patients with severe renal or hepatic deficits. See Trental Product Monograph, Canada, December 16, 2008. It has been reported that in patients with renal impairment, the plasma levels of prostaglandin and M-1 show a downward trend, while the levels of M-4 and especially M-5 metabolites increase greatly depending on the degree of functional impairment. See Paap, Ann. Pharmacother., 1996, 30: 724. Taken together, these observations suggest that accumulation of M5 metabolites may result in reduced tolerance in patients with renal dysfunction.

Other compounds that are structurally related to the formulation of cefprolin have been reported to be biologically active. Examples of such compounds include albifylline, torbafylline, A-802715 and propentofylline as shown below.

Despite the beneficial activity of the combination of ceflin, there is a continuing need for novel compounds that treat the above-mentioned diseases and conditions in a larger patient population while reducing the risk of toxicity and other adverse effects.

The present invention relates to novel compounds which are substituted xanthine derivatives and pharmaceutically acceptable salts thereof. For example, the present invention relates to novel substituted xanthine derivatives that are structurally related to the formulation of cefolin. The invention also provides the use of a composition comprising one or more compounds of the invention and a carrier, and the disclosed compounds and compositions for the treatment of a disease or condition which would benefit from the formulation of sifillin and related compounds.

The terms "soothing" and "treatment" are used interchangeably and include both therapeutic and prophylactic treatment. Both terms mean reducing, inhibiting, attenuating, attenuating, suppressing, or stabilizing the progression or progression of a disease, such as a disease or condition described herein, reducing the severity of the disease, or ameliorating the symptoms associated with the disease.

"Disease" means any condition or disorder that damages or interferes with the normal function of a cell, tissue or organ.

It will be appreciated that depending on the source of the chemical used in the synthesis, there is some degree of variation in the abundance of natural isotopes in the synthesized compound. Thus, formulations formulated with cefolin will inherently contain small amounts of deuterated isotopic analogs. Despite this change, the concentration of natural abundance stable hydrogen and carbon isotope is low and unimportant compared to the degree of stable isotope substitution of the compounds of the invention. See, for example, Wada E et al, Seikagaku, 1994, 66: 15; Gannes LZ et al, Comp Biochem Physiol Mol Integr Physiol, 1998, 119: 725. In the compounds of the invention, when a particular position is designated as having a enthalpy, it is understood that the abundance of the enthalpy at that position is substantially greater than the natural abundance of 氘 (which is 0.015%). A minimum isotope enrichment factor (50.1% 氘 merging) of at least 3340 is specified for each atom designated as 氘 in the compound, typically designated as having a ruthenium.

The term "isotopic enrichment factor" as used herein means the ratio between the isotope abundance of a given isotope and the natural abundance.

In other embodiments, for each of the specified ruthenium atoms, the compound of the invention has an isotope enrichment factor of at least 3500 (52.5% for each of the specified ruthenium atoms), at least 4000 (60% 氘 merity), at least 4500 (67.5% 氘 consolidation), at least 5000 (75% 氘), at least 5500 (82.5% 氘 consolidation), at least 6000 (90% 氘 consolidation), at least 6333.3 (95% 氘 consolidation), at least 6466.7 ( 97% 氘 merging), at least 6600 (99% 氘 merging) or at least 6633.3 (99.5% 氘 merging).

In the compounds of the invention, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of the other atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", the position is understood to mean hydrogen having a natural abundance of isotopic composition. Again, unless otherwise stated, when a position is specifically designated as "D" or "氘", the position is understood to have a richness of at least 3340 times the natural abundance of 氘 (which is 0.015%) ( That is, at least 50.1% 氘 combined degree).

The term "isotopic analog" refers to a material that differs from the particular compound of the invention only in its isotopic composition.

The term "compound" when referring to a compound of the invention refers to a collection of molecules having the same chemical structure, except for possible isotopic variations between constituent atoms of the molecule. Thus, those skilled in the art will appreciate that compounds represented by a particular chemical structure containing the indicated ruthenium atom also contain minor amounts of isotopic analogs having a hydrogen atom at one or more of the specified oxime positions in the structure. The relative amounts of such isotopic analogs in the compounds of the invention will depend on a number of factors including the isotope purity of the deuteration reagent used to prepare the compound and the rhodium combining efficiency in the various synthetic steps used to prepare the compound. However, as set forth above, the relative amounts of the isotopic analogs are all less than 49.9% of the compound.

The invention also provides salts of the compounds of the invention. Salts of the compounds of the invention are formed between the acid and a basic group of the compound, such as an amine functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.

The term "pharmaceutically acceptable" as used herein refers to the application of contact with tissues of humans and other mammals without proper toxic, irritating, allergic, and the like, within the scope of the correct medical judgment, and A component with a reasonable benefit/risk ratio. "Pharmaceutically acceptable salt" means any non-toxic salt of a compound of the invention which can be provided, directly or indirectly, upon administration to a recipient. A "pharmaceutically acceptable relative ion" is an ionic moiety of a salt that is not toxic when released from a salt after administration to a recipient.

Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen sulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid. , tartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonate Benzenesulfonic acid, lactic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, and related inorganic and organic acids. Accordingly, such pharmaceutically acceptable salts include sulfates, pyrosulfates, hydrogen sulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, cokes Phosphate, chloride, bromide, iodide, acetate, propionate, citrate, octoate, acrylate, formate, isobutyrate, decanoate, heptanoate, propiate , oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-diate, Hexyne-1,6-diacid salt, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate Phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, beta-hydroxybutyrate Acid salts, glycolic acid salts, maleic acid salts, tartrate salts, methanesulfonate salts, propane sulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates and other salts. In one embodiment, the pharmaceutically acceptable acid addition salt comprises an acid addition salt formed with a mineral acid such as hydrochloric acid and hydrobromic acid, and especially with an organic acid such as maleic acid. Acid addition salt.

The invention also includes solvates and hydrates of the compounds of the invention. As used herein, the term "hydrate" means a compound that additionally includes a stoichiometric or non-stoichiometric amount of water joined by non-covalent intermolecular forces. As used herein, the term "solvate" means additionally comprising a stoichiometric or non-stoichiometric amount of a solvent (such as water, acetone, ethanol, methanol, dichloromethane, 2-) linked by non-covalent intermolecular forces. A compound of propanol or an analog thereof.

It should be understood that the carbon atoms bearing the substituents Y ¹ and Y ² in the formulae A, A1, I and B may be palmar in some cases (when Y ¹ , Y ² and R ³ are different from each other) and In other cases it may be non-competitive (when at least two of Y ¹ , Y ² and R ³ are the same). In the formulae A, A1, I and B, this carbon atom (i.e., a carbon atom having Y ¹ and Y ² ) is indicated by "*". Thus, the palmitic compounds of the invention may exist in individual enantiomeric forms, or as racemic or non-racemic mixtures of the enantiomers. Thus, the compounds of the invention include both racemic and non-racemic enantiomeric mixtures as well as individual corresponding stereoisomers that are substantially free of another possible stereoisomer. The term "substantially free of other stereoisomers" as used herein means that less than 25% of other stereoisomers, preferably less than 10% of other stereoisomers, more preferably less than 5% are present. Other stereoisomers and preferably less than 2% of other stereoisomers, or less than "X"% of other stereoisomers (where X is between 0 and 100 and includes values of 0 and 100) . Methods for obtaining or synthesizing individual enantiomers of a given compound are well known in the art and employed when applicable to the final compound or starting material or intermediate.

Unless otherwise indicated, when a disclosed compound is named or described in terms of structure without specifying a stereochemical configuration and having one or more pairs of palmar centers, it should be considered to represent all possible stereoisomers of the compound.

The term "determinate compound" as used herein refers to having sufficient stability to permit manufacture and maintaining the integrity of the compound for a period of time sufficient for the purposes of the detailed description herein (eg, formulation into a therapeutic product for the production of a therapeutic compound) A compound of an intermediate, a detachable or storable intermediate compound, for treating a disease or condition responsive to a therapeutic agent.

"D" means 氘. "Stereoisomer" refers to both enantiomers and diastereomers. "Third", " ^t ", and "t-" each refer to the third. "US" means the United States.

The term "alkylene" as used herein means a straight or branched divalent hydrocarbon group ( _C1-6 alkylene group) preferably having one to six carbon atoms. In some embodiments, an alkylene group has one to four carbon atoms (C _1-4 alkylene). As used herein, the Examples of "Alkylene" to include (without limitation) methylene (-CH ₂ -), extending ethyl (-CH ₂ CH ₂ -), extending propyl (-CH ₂ CH ₂ CH ₂ -), and its branched forms, such as (-CH(CH ₃ )-), -CH ₂ CH(CH ₃ )-, and the like.

"Halo" means chloro, bromo, fluoro or iodo.

"Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and having from 1 to 15 carbon atoms in the chain. Preferred alkyl groups have from 1 to 12 carbon atoms in the chain, and more preferably from 1 to 6 carbon atoms. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. "Lower alkyl" means about 1 to about 4 carbon atoms in the chain which may be straight or branched. Exemplary alkyl groups include methyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, isopropyl, n-butyl, Tributyl, n-pentyl, 3-pentyl, heptyl, octyl, decyl, decyl and dodecyl; preferably methyl, difluoromethyl and isopropyl. The alkyl group may optionally be substituted with one or more groups selected from the group consisting of halo, cyano, hydroxy, carboxy, alkoxy, alkoxycarbonyl, pendant oxy, amine, alkylamino, dioxane Alkyl, cycloheteroalkyl, alkylcycloheteroalkyl, aryl, alkylaryl, heteroaryl and alkylheteroaryl. Typically, any alkyl or alkoxy moiety of the alkyl substituent has from 1 to 6 carbon atoms.

"Aryl" means an aromatic carbocyclic group containing from 6 to 10 carbon atoms. Exemplary aryl groups include phenyl or naphthyl. The aryl group may be optionally substituted with one or more groups which may be the same or different and are selected from the group consisting of alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkyloxy, halo and Nitro.

Typically, any alkyl or alkoxy moiety of the aryl substituent has from 1 to 6 carbon atoms.

"Heteroaryl" means a 5 to 10 membered aromatic monocyclic or polycyclic hydrocarbon ring system wherein one or more carbon atoms in the ring system are elements other than carbon, such as nitrogen, oxygen or sulfur. The heteroaryl group may be optionally substituted with one or more groups which may be the same or different and are selected from the group consisting of alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkyloxy, halo And nitro. Exemplary heteroaryl groups include pyrazinyl, furyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, pyridazinyl, 1,2,4-triazinyl, quinolinyl and iso Quinoline.

"Aralkyl" means an aryl- and alkyl group as defined above for an aryl-alkyl group. Preferred aralkyl groups contain a lower alkyl moiety. Exemplary aralkyl groups include benzyl and 2-phenylethyl.

"Heteroaralkyl" means a heteroaryl and alkyl component as described above for a heteroaryl-alkyl group.

"Cycloalkyl" means a non-aromatic monocyclic, polycyclic or bridged ring system having from 3 to 10 carbon atoms. The cycloalkyl group is optionally substituted with one or more halo or alkyl groups. Exemplary monocyclic cycloalkyl rings include cyclopentyl, fluorocyclopentyl, cyclohexyl and cycloheptyl.

"Heterocycloalkyl" means a non-aromatic monocyclic, bicyclic or tricyclic, or bridged hydrocarbon ring system wherein one or more of the atoms in the ring system are elements other than carbon, such as nitrogen, oxygen or sulfur. Preferred heterocycloalkyl groups contain a ring having a ring size of from 3 to 6 ring atoms. Exemplary heterocycloalkyl groups are pyrrolidine, piperidine, tetrahydropyran, tetrahydrofuran, tetrahydrothiopyran, and tetrahydrothiofuran.

"Cycloalkylalkyl" means a cycloalkyl and alkyl component as previously described.

"Heterocycloalkylalkyl" means a cycloalkyl and alkyl component as previously described.

The term "substituted as appropriate" means that one or more hydrogen atoms of the mentioned moiety or compound may be replaced by a corresponding number of deuterium atoms.

Throughout this specification, the code may be a general reference (e.g., "each R") or may be particularly mentioned (e.g. R ^1, R ^2, R ^3, etc.). Unless otherwise indicated, when a reference is made to the generic term, it is intended to include all the specific embodiments of the particular.

Therapeutic compound

The present invention provides a compound of formula A: (A), or a pharmaceutically acceptable salt thereof, wherein: R ¹ and R ² are each independently selected from hydrogen, -(C ₁ -C ₄ )alkyl, or -(C ₁ -C ₄ ) Alkyl-O-(C ₁ -C ₂ )alkyl, wherein alkyl and alkyl are independently and optionally substituted by deuterium in each case; R ³ is selected from -CH ₃ , -CH ₂ D, - CHD ₂ and -CD ₃ ; R ⁴ is an exo-butyl group optionally substituted by deuterium; R ⁵ is selected from the group consisting of hydrogen, deuterium, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkane Alkyl, aryl and heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl and heteroaryl are each optionally substituted and wherein An alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl or heteroaryl group or one or more of the hydrogen atoms optionally substituted as appropriate a corresponding number of deuterium atoms are substituted; and (a) Y ¹ and Y ² are each fluorine, or together with the carbon to which they are bound, form C=O, or (b) Y ¹ is selected from fluorine and OH; and Y ² is selected from hydrogen, _{deuterium, -CH 3, -CH 2 D,} -CHD 2 , and -CD _3; with the proviso that: when Y ¹ and Y ² in combination with the carbon they When formed from C = O, then ^{R 1, R 2, R 3} , R 4 and R ⁵ having at least one of the at least one deuterium atom; and when Y ¹ is OH and Y ² is hydrogen or CH _3, the Then at least one of R ¹ , R ² , R ³ , R ⁴ and R ⁵ carries at least one deuterium atom.

In another embodiment, the compound of formula A is not the following compound:

In another embodiment of Formula A, when R ¹ and R ² are each methyl optionally substituted by hydrazine and R ⁵ is hydrogen or deuterium, then: (i) Y ¹ is a fluoro group; or (ii) Y ¹ is OH, and Y ² is selected from the group consisting of -CH ₃ , -CH ₂ D, -CHD ₂ and -CD ₃ . In one aspect of this specific example, the compound is not

In a more specific aspect of this specific embodiment, at least one of Y ² , R ¹ , R ² , R ³ and R ⁴ carries at least one deuterium atom.

In another embodiment of Formula A, R ¹ and R ² are each methyl optionally substituted by deuterium; R ⁵ is hydrogen or deuterium; and: (a) Y ¹ and Y ² together with the carbon atom to which they are attached Forming =O, or (b) Y ¹ is -OH and Y ² is selected from the group consisting of hydrogen and helium, with the proviso that when Y ¹ and Y ² together with the carbon to which they are bound form C=O, then R ¹ , At least one of R ² , R ³ , R ⁴ and R ⁵ carries at least one halogen atom; and when Y ¹ is OH, then Y ² , R ¹ , R ² , R ³ , R ⁴ and R ⁵ At least one of them carries at least one helium atom.

In another embodiment of Formula A, R ⁵ is D, and the compound has Formula A1: (A1) or a salt thereof, wherein R ¹ , R ² , R ³ , R ⁴ , Y ¹ and Y ² are as defined for formula A.

In one aspect of Formula A1, R ¹ and R ² are each independently selected from -CH ₃ , -CH ₂ D, -CHD _2, and -CD ₃ ; R ³ is selected from -CH ₃ , -CH ₂ D , -CHD ₂ and -CD ₃ ; R ⁴ is selected from -(CH ₂ ) ₄ -, -(CD ₂ ) ₄ -, -(CD ₂ ) ₃ CH ₂ and -CD ₂ (CH ₂ ) ₃ -, where " "" indicates a portion of the R ⁴ moiety that binds to C(Y ¹ )(Y ² ) in the compound; and (a) Y ¹ is OH and Y ² is selected from hydrogen and hydrazine; or (b) Y ¹ and Y ² Together with the carbon to which it is attached, it forms C=O.

In a more specific aspect of formula A1, R ¹ and R ² are each independently selected from -CH ₃ and -CD ₃ ; R ³ is selected from -CH ₃ and -CD ₃ ; R ⁴ is selected from - ( CH ₂ ) ₄ - and -CD ₂ (CH ₂ ) ₃ -; and (a) Y ¹ is OH and Y ² is selected from hydrogen and hydrazine; or (b) Y ¹ and Y ² together with the carbon to which they are attached form C=O.

In another aspect of Formula A1, R ¹ and R ² are each independently selected from -CH ₃ and -CD ₃ ; R ³ is selected from -CH ₃ and -CD ₃ ; R ⁴ is selected from -(CH ₂ ) ₄ - and -CD ₂ (CH ₂ ) ₃ -; and Y ¹ and Y ² together with the carbon to which they are attached form C=O.

In another embodiment, the present invention provides a compound of formula A, wherein R ⁵ is hydrogen, the compound has the formula I:

R ¹ and R ² are each independently selected from hydrogen, -(C ₁ -C ₄ )alkyl, or -(C ₁ -C ₄ )alkyl-O-(C ₁ -C ₂ )alkyl, wherein Alkyl and alkylene are, in each case, independently and optionally substituted by hydrazine; R ³ is selected from -CH ₃ , -CH ₂ D, -CHD ₂ and -CD ₃ ; R ⁴ is optionally substituted by hydrazine Extending n-butyl; and (a) Y ¹ and Y ² are each fluorine, or together with the carbon to which they are attached, form C=O; or (b) Y ¹ is selected from fluorine and OH; and Y ² is selected from hydrogen,氘, -CH ₃ , -CH ₂ D, -CHD ₂ and -CD ₃ , with the proviso that when Y ¹ and Y ² together with the carbon to which they are attached form C=O, then R ¹ , R ² , R At least one of ³ and R ⁴ carries at least one deuterium atom; and when Y ¹ is OH and Y ² is hydrogen or -CH ₃ , then at least one of R ¹ , R ² , R ³ and R ⁴ With at least one helium atom.

In a more specific embodiment of Formula I, R ¹ and R ² are each independently selected from -CH ₃ , -CH ₂ D, -CHD _2, and -CD ₃ ; R ³ is selected from -CH ₃ , -CH ₂ D, -CHD ₂ and -CD ₃ ; R ⁴ is selected from -(CH ₂ ) ₄ -, -(CD ₂ ) ₄ -, -(CD ₂ ) ₃ CH ₂ and -CD ₂ (CH ₂ ) ₃ -, where " "represents a moiety of the R ⁴ moiety that binds to C(Y ¹ )(Y ² ) in the compound; and Y ¹ is OH and Y ² is selected from hydrogen and hydrazine; or Y ¹ and Y ² together with the carbon to which it is attached Form C=O.

In another aspect of Formula I, R ¹ and R ² are each independently selected from -CH ₃ and -CD ₃ ; R ³ is selected from -CH ₃ and -CD ₃ ; R ⁴ is selected from -(CH ₂ ) ₄ - and -CD ₂ (CH ₂ ) ₃ -; and: Y ¹ is OH and Y ² is selected from hydrogen and hydrazine; or Y ¹ and Y ² together with the carbon to which they are attached form C=O.

In another aspect of Formula I, R ¹ and R ² are each independently selected from -CH ₃ and -CD ₃ ; R ³ is selected from -CH ₃ and -CD ₃ ; R ⁴ is selected from -(CH ₂ ) ₄ - and -CD ₂ (CH ₂ ) ₃ -; and Y ¹ and Y ² together with the carbon to which they are attached form C=O.

In another embodiment, in any of the aspects set forth above, the compound of Formula I is not the following compound:

In another embodiment, in any of the aspects set forth above, the compound of Formula I is not the following compound:

In another embodiment, in any of the aspects set forth above, the compound of Formula I is not the following compound:

Another embodiment of the invention provides a compound of formula II:

R ¹ and R ² are each independently selected from hydrogen, -(C ₁ -C ₄ )alkyl, or -(C ₁ -C ₄ )alkyl-O-(C ₁ -C ₂ )alkyl, wherein Alkyl and alkylene are, in each case, independently and optionally substituted by hydrazine; R ³ is selected from -CH ₃ , -CH ₂ D, -CHD ₂ and -CD ₃ ; R ⁴ is optionally substituted by hydrazine Extending n-butyl; and wherein at least one of R ² , R ³ and R ⁴ carries at least one deuterium atom.

A specific example is a compound of formula A, A1, I or II wherein R ² and R ³ are each independently selected from -CH ₃ , -CH ₂ D, -CHD ₂ and -CD ₃ .

Another specific example is a compound of formula A, A1, I or II wherein R ² and R ³ are each independently selected from -CH ₃ and -CD ₃ .

Another specific example is a compound of formula A, A1, I or II wherein R ¹ is selected from the group consisting of hydrogen, (C ₁ -C ₃ )alkyl and (C ₁ -C ₂ )alkyl-O (C ₁ -C ₂ )alkyl.

Another specific example is a compound of formula A, A1, I or II wherein R ¹ is hydrogen, -CH ₃ , -CD ₃ , -CH ₂ CH ₂ CH ₃ , -CD ₂ CH ₂ CH ₃ , -CD ₂ CD ₂ CH ₃ , -CD ₂ CD ₂ CD ₃ , -CH ₂ OCH ₂ CH ₃ , -CH ₂ OCD ₂ CH ₃ , -CH ₂ OCD ₂ CD ₃ , -CD ₂ OCH ₂ CH ₃ , -CD ₂ OCD ₂ CH ₃ or -CD ₂ OCD ₂ CD ₃ .

Another specific example relates to a compound of formula A, wherein R ⁵ is selected from the group consisting of hydrogen, deuterium, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein alkyl, cyclo Alkyl, heterocycloalkyl, cycloalkylalkyl and heterocycloalkylalkyl groups are each optionally substituted.

In other specific examples of Formula A, AI, or I:

a) each methylene unit in R ⁴ is selected from -CH ₂ - and -CD ₂ -; more specifically R ⁴ is selected from -(CH ₂ ) ₄ -, -(CD ₂ ) ₄ -, ⁺ -CD ₂ (CH ₂ ) ₃ - and ⁺ -(CD ₂ ) ₃ CH ₂ -, wherein " ⁺ " represents the point at which R ^{4 is} attached to C(Y ¹ )(Y ² ) in the compound;

b) when Y ¹ is F, Y ² is selected from the group consisting of hydrogen, -CH ₃ , -CH ₂ D, -CHD ₂ and -CD ₃ ;

c) when Y ¹ is F, Y ² is fluorine; or

d) when Y ¹ and Y ^{2 are} not the same and Y ² and R ^{3 are} not the same and Y ¹ and R _{3 are} not the same, the stereochemical configuration at the “*” is Express; or

e) when Y ¹ and Y ^{2 are} not the same and Y ² and R ^{3 are} not the same and Y ¹ and R ^{3 are} not the same, the stereochemical configuration at the “*” is Said.

In other specific examples of Formula A, A1 or I, R ¹ is -CD ₃ ; R ² and R ³ are -CH ₃ ; Y ¹ and Y ² together form C=O; and R ⁴ is selected from -(CH ₂ ) ₄ -, -(CD ₂ ) ₄ -, ⁺ -CD ₂ (CH ₂ ) ₃ - and ⁺ -(CD ₂ ) ₃ CH ₂ -.

In other specific examples of Formula A, A1 or I, R ¹ is -CD ₃ ; R ² and R ³ are -CH ₃ ; Y ¹ and Y ² together form C=O; and R ⁴ is selected from -(CH ₂ ) ₄ - and - (CD ₂ ) ₄ -.

In other specific examples of Formula A, A1 or I, R ¹ is -CD ₃ ; R ² and R ³ are -CH ₃ ; R ⁴ is -(CH ₂ ) ₄ -; Y ¹ is a fluoro group; and Y ² It is selected from the group consisting of hydrazine, -CH ₂ D, -CHD ₂ and -CD ₃ .

In other specific examples of Formula A, Al or I, R ¹ is -CD ₃ ; R ² and R ³ are -CH ₃ ; R ⁴ is -(CH ₂ ) ₄ -; Y ¹ is a fluoro group; and Y ² It is fluorine.

In other specific examples of Formula A or Al, R ¹ is -CD ₃ ; R ² and R ³ are -CH ₃ ; R ⁴ is -(CH ₂ ) ₄ -; R ⁵ is deuterium; Y ¹ is a fluoro group; And Y ² is selected from the group consisting of hydrazine, -CH ₂ D, -CHD ₂ and -CD ₃ .

In other specific examples of Formula A or Al, R ¹ is -CD ₃ ; R ² and R ³ are -CH ₃ ; R ⁴ is -(CH ₂ ) ₄ -; R ⁵ is deuterium; Y ¹ is a fluoro group; And Y ² is fluorine.

In other specific examples of Formula A, Al or I, Y ¹ is F; Y ² is selected from hydrogen; R ³ is -CH ₃ ; and R ⁴ is -(CH ₂ ) ₄ -.

In other specific examples of Formula A, Al or I, Y ¹ is F; Y ² is fluorine; R ³ is -CH ₃ ; and R ⁴ is -(CH ₂ ) ₄ -.

A specific example provides a compound of formula B: B, or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are each independently selected based -CH _3, and -CD _3; R ⁵ is hydrogen or deuterium; Z ³ are independently hydrogen or deuterium; Z ⁴ each Is hydrogen or deuterium; Z ^{5 is} each hydrogen or deuterium; and (a) Y ¹ is OH, and Y ² is hydrogen or deuterium, or (b) Y ¹ and Y ² together with the carbon to which they are attached form C=O.

Specific examples of a compound of Formula B, where Z ^3, Z ⁴ and Z ⁵ are each hydrogen. In one aspect, R ¹ and R ² are each -CD ₃ . In another aspect, R ⁵ is deuterium. In another aspect, Y ¹ and Y ² together with the carbon to which they are attached form C=O. In another aspect, Y ¹ is OH and Y ² is hydrogen or deuterium.

Another embodiment provides a compound of formula B, wherein each of Z ³ , Z ⁴ and Z ⁵ is deuterium. In one aspect, R ¹ and R ² are each -CD ₃ . In another aspect, R ⁵ is deuterium. In another aspect, Y ¹ and Y ² together with the carbon to which they are attached form C=O. In another aspect, Y ¹ is OH and Y ² is hydrogen or deuterium.

Another embodiment provides a compound of formula B, wherein each of R ¹ and R ² is -CD ₃ . In one aspect, R ⁵ is deuterium. In another aspect, Z ³ , Z ⁴ and Z ⁵ are each hydrogen and R ⁵ is deuterium. In another aspect, each of Z ³ , Z ⁴ and Z ⁵ is deuterium and R ⁵ is deuterium.

Another embodiment provides a compound of formula B wherein Y ¹ and Y ² together with the carbon to which they are attached form C=O. In one aspect, R ⁵ is deuterium. In another aspect, Z ³ , Z ⁴ and Z ⁵ are each hydrogen and R ⁵ is deuterium. In another aspect, each of Z ³ , Z ⁴ and Z ⁵ is deuterium and R ⁵ is deuterium. In another aspect, R ¹ and R ² are each -CD ₃ . In another aspect, R ¹ and R ² are each -CD ₃ and R ⁵ is deuterium. In another aspect, R ¹ and R ² are each -CD ₃ and each of Z ³ , Z ⁴ and Z ⁵ is deuterium. In another aspect, R ¹ and R ² are each -CD ₃ , and Z ³ , Z ⁴ and Z ⁵ are each deuterium and R ⁵ is deuterium. In another aspect, R ¹ and R ² are each -CD ₃ and each of Z ³ , Z ⁴ and Z ⁵ is hydrogen. In another aspect, R ¹ and R ² are each -CD ₃ , and Z ³ , Z ⁴ and Z ⁵ are each hydrogen and R ⁵ is deuterium.

Another embodiment provides a compound of formula B, Y ¹ is OH, and Y ² is hydrogen or deuterium. In one aspect, R ⁵ is deuterium. In another aspect, Z ³ , Z ⁴ and Z ⁵ are each hydrogen and R ⁵ is deuterium. In another aspect, each of Z ³ , Z ⁴ and Z ⁵ is deuterium and R ⁵ is deuterium. In another aspect, R ¹ and R ² are each -CD ₃ . In another aspect, R ¹ and R ² are each -CD ₃ and R ⁵ is deuterium. In another aspect, R ¹ and R ² are each -CD ₃ and each of Z ³ , Z ⁴ and Z ⁵ is deuterium. In another aspect, R ¹ and R ² are each -CD ₃ , and Z ³ , Z ⁴ and Z ⁵ are each deuterium and R ⁵ is deuterium. In another aspect, R ¹ and R ² are each -CD ₃ and each of Z ³ , Z ⁴ and Z ⁵ is hydrogen. In another aspect, R ¹ and R ² are each -CD ₃ , and Z ³ , Z ⁴ and Z ⁵ are each hydrogen and R ⁵ is deuterium.

Another specific example of a compound of Formula B, where R ⁵ is deuterium.

Another specific example of a compound of Formula B, where R ⁵ is deuterium, Z ^3, Z ⁴ and Z ⁵ are hydrogen and R ¹ is -CD _3.

Specific examples of the compound of the formula A, Al, I or II include the compound shown in Table 1-6 (below) or a pharmaceutically acceptable salt thereof, wherein "" indicates the portion of the R ⁴ moiety that binds to C(Y ¹ )(Y ² ) in the compound. In the tables, the compound designated as "( R )" or "( S )" means with Y ¹ The stereochemical configuration of the carbon of the substituent. A compound which is not specified and which contains a palmitic carbon atom in combination with Y ¹ and Y ^{2 is} intended to represent a racemic mixture of enantiomers.

Table 1 above shows examples of specific compounds of formula I. These examples are deuterated and/or fluorinated analogs of neferan and its metabolites.

Table 2 shows the above R ¹ is H and Y ² is the compound of Example I CH ₃ or CD ₃ of a particular type. Such compounds include deuterated and fluorinated analogs of abibutylate (HWA-138). Has been targeted for the use of the relevant Westphetine

Study than theophylline.

Table 3 shows the above R ¹ is optionally substituted by deuterium -CH Examples of specific compounds of Formula I ₂ -O-CH ₂ CH _3's. In these examples, Y ¹ is OH or F and Y ² is CH ₃ or CD ₃ . These compounds include deuterated and fluorinated analogs of toba theophylline (HWA-448). Tobago theophylline has been studied for the treatment of depression, urinary incontinence, large bowel syndrome and multiple sclerosis.

Table 4 shows the above R ¹ is optionally substituted by deuterium -CH Examples of specific compounds of the formula I ₂ CH _{3 2} CH. In these examples, Y ¹ is OH or F and Y ² is CH ₃ or CD ₃ . Such compounds include deuterated and fluorinated analogs of A-802715. A-802715 has been studied for the treatment of septic shock and inhibition of allograft response.

Table 5 shows the above R ¹ is optionally substituted by deuterium -CH Examples of specific compounds of the formula I ₂ CH _{3 2} CH. In these examples, Y ¹ and Y ² together with the carbon between them form a carbonyl group. Such compounds include deuterated analogs of valproline. Valprophylline has been studied for the treatment of Alzheimer's disease, neuropathic pain, traumatic brain injury, dysuria, retinal or optic nerve head damage, and peptic ulcer. It also studies the control of intraocular pressure, the regulation of cerebral blood flow, and the inhibition of allograft response.

Table 6 above shows examples of specific compounds of formula A. Examples of such R ⁵ deuterium lipid lowering its proper allocation of metabolites of deuterated and / or fluorinated analogue is.

In one aspect of the above specific examples, the compound is not any of compounds 100, 116 or 149.

Examples of specific compounds of the invention include the following:

In another set of specific examples, any atomic system not designated as ruthenium in any of the specific examples set forth above is present in its natural isotopic abundance.

The synthesis of the compounds of the invention can be achieved by those skilled in the art of synthetic chemistry. Related procedures and intermediates are disclosed, for example, in Sidzhakova, D et al, Farmatsiya, (Sofia, Bulgaria) 1988, 38(4): 1-5; Davis, PJ et al, Xenobiotica, 1985, 15(12): 1001-10 ;Akgun, H et al, J Pharm Sci, 2001, 26(2): 67-71; German Patent Application DD 274334; Czech Patent No. CS 237719, No. CS201558; PCT Patent Publication WO9531450; No. JP58150594, JP58134092, JP58038284, JP57200391, JP57098284, JP57085387, JP57062278, JP57080385, JP57056481, JP57024385, JP57011981, JP57024386, JP57024382, JP56077279, JP56032477, JP56007785, JP56010188, JP56010187, JP55122779, and JP55076876.

Such methods can be carried out by the use of corresponding deuteration and, optionally, reagents and/or intermediates containing other isotopes to synthesize the compounds described herein, or by employing standard synthetic schemes known in the art to introduce isotope atoms into the chemistry. In the structure.

Exemplary synthesis

The method of synthesizing the compound of formula I is described in the following scheme.

Scheme 1A. Synthesis of a compound of formula I

The deuterated compound 10 is alkylated with deuterated intermediate 11 (wherein X is a chloro, bromo or iodo group) in the presence of potassium carbonate to provide a compound of formula I as described in Scheme 1A. Alternatively, the compound of formula I can be provided using sodium hydroxide in aqueous methanol according to the method of U.S. Patent 4,289,776.

Scheme 1B. Preparation of a compound of Y ¹ =OH from a compound of formula II

As described in Scheme 1B, the compound of Formula II can be prepared using Y ¹ as the OH compound. Thus, according to the general procedure of European Patent Publication No. 0330031, a compound of formula II is reduced with sodium borohydride or sodium borohydride (available at 99 atomic % D) to form a compound wherein Y ¹ is OH and Y ² is hydrogen or hydrazine. The enantiomeric alcohol product can be isolated, for example, by the method of Nicklasson, M et al, Chirality, 2002, 14(8): 643-652. In an alternative method, disclosed in Pekala, E et al, Acta Poloniae Pharmaceutica, 2007, 64(2): 109-113 or Pekala, E et al, Biotech J, 2007, 2(4): 492-496 The method is carried out by enzymatic reduction to provide an enantiomerically enriched alcohol product.

Synthetic compound 10

With reference to Scheme 1A, compounds useful as compounds 10 for the preparation of compounds of formula I are known and include, but are not limited to, the following: commercially available cocoa butter (wherein R ¹ and R ² are CH ₃ ). (a) R ¹ is -CD ₃ and R ² is -CH ₃ ; (b) R ¹ is -CH ₃ and R ² is -CD ₃ ; and (c) R ¹ and R ² are -CD ₃ of 10 Isotopic analogs are known. See Benchekroun, Y et al, J Chromatogr B, 1977, 688: 245; Ribon, B et al, Coll INSERM, 1988, 164: 268; and Horning, MG et al, Proc Int Conf Stable Isot 2nd edition, 1976, 41-54. R ¹ is n-propyl and R ² is -CH ₃ of 3-methyl-7-propyl xanthine commercially available. Compound 10 wherein R ¹ is CH ₂ OCH ₃ and R ² is CH ₃ is also known. See German Patent Application DE 3942872 A1.

Scheme 2. Synthesis of Compound 10

Compound 10 is synthesized in Scheme 2 starting from the commercially available N-nitroso-N-methylurea. Following the method of Boivin, JL et al., Canadian Journal of Chemistry, 1951, 29:478-81, the treatment of the amine 12 for proper deuteration in water provides the N-alkylurea 13 . According to the method of Dubey, PK et al., Indian Journal of Heterocyclic Chemistry, 2005, 14(4): 301-306, urea 13 can be treated with 2-cyanoacetic acid and acetic anhydride to provide a cyanoacetamide derivative 14 Treatment with an aqueous NaOH solution followed by aqueous HCl was followed to provide the cyclized pyrimidinedione 15 . Alternatively, cyanoacetamide 14 can be treated with trimethyl decyl chloride and hexamethyldioxane to provide cyclization via the method of Fulle, F et al, Heterocycles, 2000, 53(2): 347-352. Product 15 .

Following the method of Merlos, M et al, European Journal of Medicinal Chemistry, 1990, 25(8): 653-8, sodium nitrite in acetic acid, and subsequent treatment of pyrimidinedione with ammonium hydroxide and sodium dithionite 15 Compound 16 was obtained which was treated with formic acid to provide the indole derivative 17 . Following the method disclosed in Rybar, A et al., in the Czech patent application CS 263595 B1, in the presence of potassium carbonate and optionally in the presence of an additive such as NaBr, KBr, NaI, KI or iodine, the electrophilic agent is suitably deuterated. 18 (X is a chloro, bromo or iodo group) alkylation of 17 to provide compound 10 .

Reference to Scheme 2, amine reagent 12 suitable deuterated include (but are not limited to) such as n-propyl -d ₇ - amine The commercially available compounds, or 1 such as propan -1,1-d ₂ - a compound known as an amine (Moritz, F et al, Organic Mass Spectrometry, 1993, 28(3): 207-15). Ureas suitable deuterated reagents 13 may include (but are not limited to) such as N- methyl -d ₃ - urea , or methylurea-d ₆ Commercially available compounds.

Suitable deuterated electrophiles 18 may include, but are not limited to, commercially available compounds such as methyl iodide-d ₃ or methyl bromide-d ₃ or 1-bromopropane-d ₇ or 1-bromopropane-1,1-d ₂ , Or such as (chloromethoxy-d ₂ )-ethane (Williams, AG, WO 2002059070A1), or bromomethoxymethane-d ₂ (Van der Veken, BJ et al, Journal of Raman Spectroscopy, 1992, 23 ( 4): 205-23), or (bromomethoxy-d ₂ )-methane-d ₃ (Van der Veken, BJ et al., Journal of Raman Spectroscopy, 1992, 23(4): 205-23) Know the compound. The above commercially available deuterated intermediates 12, 13 and 18 having an isotope purity of at least 98 atom% D can be obtained.

Synthetic intermediate 11a- d ₅ (See Flow 1A)

Scheme 3. Synthesis of intermediates 11a- d ₅

The process for the preparation of compounds 11a- d ₅ (see Scheme 1A) is described in Scheme 3 (wherein R ³ is CD ₃ ; R ⁴ is -CD ₂ (CH ₂ ) ₃ -, and Y ¹ and Y ² together form =O). Thus, methyl lithium was added to commercially available δ-valerolactone 19 according to the procedure of Zhang, Q et al., Tetrahedron, 2006, 62(50): 11627-11634 to provide ketone 20 . The Fodor-Csorba K, Tet Lett, 2002,43: 3789-3792 general procedure of, under microwave conditions, used in the D ₂ O (99 atom% D) TFA- d ₁ (99 atom% D) for 20 Provide decyl ketone 21 . Follow Cl ment, JL, Org Biomol Chem, 2003,1: 1591-1597 general procedure, the following order of triphenylphosphine and carbon tetrachloride treatment, the alcohol moiety of 21 is converted to the chloride to obtain a chloride 11a- d _5.

Scheme 4. Synthesis of intermediates 11a- d ₉ and 11a- d _{1 1}

Scheme 4 describes the synthesis of Compound ₉ and Compound 11a- d 11a- d _{1 1} of. Therefore, commercially available 4-phenylbutyl can be heated in D ₂ O (99 at % D) in the presence of Pd/C and hydrogen according to the general method of Esaki et al., Chem Eur J, 2007, 13: 4052-4063. Acid 22 provides the acidification 23 . According to the general procedure of Porta, A et al, J Org Chem, 2005, 70(12): 4876-4878, the addition of deuterated methyllithium in the presence of trimethylsulfonyl chloride provides the ketone 24 . The ketone 24 was converted to the acetal 25 by treatment with D ₂ SO ₄ (99 at% D) and commercially available ethylene glycol- d ₂ (99 at% D). According to Garnier, JM et al., Tetrahedron: Asymmetry, 2007,18 (12 ): 1434-1442 the general procedure, RuCl ₃ and NaIO ₄ to process 25 provides the carboxylic acid 26. Reduction with LiAlH ₄ or LiAlD ₄ (98 at % D) to provide an alcohol (not shown), followed by chlorination using phosphorus oxychloride or triphenylphosphine and N-chlorobutane diimine (Naidu, SV et al. , Tet Lett, 2007, 48(13): 2279-2282), followed by acetal cleavage with D ₂ SO ₄ (Heathcock, CH et al, J Org Chem, 1995, 60(5): 1120-30) Chlorides 11a- d ₉ and 11a- d _{1 1 are provided} .

Scheme 4a. Synthesis of intermediate 11b-( R )

Scheme 4b. Synthesis of chloride 11b-( S )

4a and 4b described process chlorides particular enantiomer 11b- (R) (wherein Y ¹ is fluorine: Y ² is selected from hydrogen and deuterium; (R & lt) configuration and the compound form) and 11b- (S ) (wherein Y ¹ is fluorine; Y ² is selected from hydrogen and deuterium; and the compound as a (S) configuration) synthesis. In Scheme 4a, a deuterated (or non-deuterated) benzyl protected alcohol 27 system such as known [[[(5R)-5-fluorohexyl]oxy]methyl]-benzene (PCT Publication WO2000031003) Deprotection is provided by hydrogenation in the presence of Pd/C to provide alcohol 28 . According to the general procedure of Lacan, G et al, J Label Compd Radiopharm, 2005, 48(9): 635-643, the alcohol is chlorinated with sulfoxide to provide chloride 11b-( R ) .

In Scheme 4b, deuteration (or non-deuteration) such as known (S)-(+)-5-fluorohexanol (Riswoko, A et al., Enantiomer, 2002, 7(1): 33-39) is made. The alcohol 29 is chlorinated to provide the chloride 11b-( S ) .

Scheme 5. Synthesis of intermediates 11c and 11e

Scheme 5 describes the synthesis of other intermediates 11c and 11e . Therefore, following the method of Kutner, Andrzej et al., Journal of Organic Chemistry, 1988, 53(15): 3450-7 or Larsen, SD et al., Journal of Medicinal Chemistry, 1994, 37(15):2343-51, The Grignard reagent 32 treats compound 30 or 31 (wherein X is a halo group) to provide an intermediate 11c wherein R ³ is the same as Y ² , Y ¹ is OH, and X is a halo group. According to the general procedure of Karst, NA et al, Organic Letters, 2003, 5 (25): 4839-4842 or Kiso, M et al, Carbohydrate Research, 1988, 177: 51-67, in dichloromethane or toluene diethylamino sulfur trifluoride (of DAST) to provide the processing and R ^{3 are} the same Y ^2, Y ¹ is F, and X is a halogen group of the intermediate product 11e.

Commercially available halides can be used to prepare compound 11 as disclosed in Scheme 5. For example, commercially available 5-chloropentanyl chloride, or commercially available 5-bromopentenyl chloride, or commercially available ethyl 5-bromopentanoate may be used as reagent 30 or 31 . Referring again to the process 5, a commercially available methyl iodide - d ₃ - magnesium as the Grignard reagent 32 to provide Y ² and R ³ simultaneously CD ₃ of 11 electrophile.

Scheme 6. Synthesis of intermediate 11e (X=Br)

Scheme 6 describes an alternative synthesis of R ³ and Y ² and an intermediate 11e of X = Br. Therefore, according to the procedure of Hester, JB et al., Journal of Medicinal Chemistry, 2001, 44(7): 1099-1115, via 3,4-dihydro-2H-pyran (DHP) and camphorsulfonic acid (CSA) Treatment to protect commercially available 4-chloro-1-butanol to provide chloride 33 . Alcohol 34 is provided by the formation of the corresponding Grignard reagent with magnesium followed by the addition of acetone (R ³ = Y ² = CH ₃ ) or acetone-d ₆ (Y ² = R ³ = CD ₃ ). Fluoride 35 is provided by fluorination with diethylaminosulfide trifluoride (DAST) in DCM. Deprotection with CSA in MeOH afforded alcohol 36 and treatment with N-bromobutylimine and triphenylphosphine afforded intermediate 11e .

Scheme 7. Alternative synthetic intermediate 11e (X=Br)

Scheme 7 describes the same as R ³ and X = Y ² Synthesis of intermediate 11e Br things. Thus, commercially available 4-hydroxy-butyrate 37 was treated with DHP and CSA or with DHP, TsOH and pyridine to provide ester 38 . Reduction with LiAlD ₄ provides deuterated alcohol 39 which is treated with triphenylphosphine in CCl ₄ (Sabitha, G et al, Tetrahedron Letters, 2006, (volume 2007), 48(2): 313-315 Or treatment with methanesulfonium chloride, lithium chloride and 2,6-lutidine in DMF (Blaszykowski, C et al, Organic Letters, 2004, 6(21): 3771-3774) to provide chloride 40 . Chloride 40 can be converted to 11e following the same procedure as in Scheme 6.

Scheme 8. Synthesis of intermediates 11e- d ₈ (X=Br)

Scheme 8 describes R ³ and Y are the same and X = Br the intermediate ₈ Synthesis of ^{2 11e-} d. Thus, commercially available THF- d ₈ 41 can be treated with DCCl and ZnCl _{2 according} to the general method of Yang, A et al, Huagong Shikan, 2002, 16(3): 37-39 to provide known chloride 42 (Alken, Rudolf-Giesbert, WO 2003080598A1). Chloride 42 can be converted to 11e- d ₈ following the same procedure as in Scheme 6.

Scheme 9. Synthesis of intermediates 11c- d ₈ (X=Br)

Scheme 9 describes R ³ and Y are the same and X = Br the intermediate ₈ Synthesis of ^{2 11c-} d. Thus, the known carboxylic acid 43 (Lompa-Krzymien, L et al., Proc. I nt. Conf. Stable Isot. 2nd edition, 1976, 1975, 574-8) was treated with diazomethane (according to Garrido , NM et al., Molecules, 2006, 11(6): 435-443. General procedure) or treatment with trimethyldecyl chloride and methanol- d ₁ (according to Doussineau, T et al, Synlett, 2004, (10) ): General procedure 1735-1738) to provide methyl ester 44 . As in Scheme 5, the Grignard reagent deuterated treating the ester 45 to provide Intermediate 11c- d _8. For example, using a commercially available methyl iodide -d ₃ - magnesium as the Grignard reagent 45 to provide Y ² and R ³ simultaneously CD ₃ of 11c- d _8.

10. Synthesis process Intermediate 11c- d _2.

Scheme 10 describes the preparation of 11c- d _{2 which} is identical to R ³ and Y ² . Therefore, it is known that deuterated ester 46 (Feldman, KS et al., Journal of Organic Chemistry, 2000, 65(25): 8659-8668) is treated with carbon tetrabromide and triphenylphosphine (Brueckner, AM et al., European Journal) Of Organic Chemistry, 2003, (18): 3555-3561) to provide ester 47 with bromine group X, or with methanesulfonate chloride and triethylamine, followed by lithium chloride and DMF (Sagi, K et al. , Bioorganic & Medicinal Chemistry, 2005,13 ( 5): 1487-1496) to provide the group X is an ester of 47-chloro. As Scheme 5, deuterated Grignard reagent 48 Treatment of ester 47 provides 11c- d _2. For example, using a commercially available methyl iodide -d ₃ - magnesium as the Grignard reagent 48 to provide Y ² and R ³ simultaneously CD ₃ of 11c- d _2.

Other known chlorides that can be used as reagent 11 in Scheme 1A include: 1-chloro-5,5-difluoro-hexane (Rybczynski, PJ et al, J Med Chemistry, 2004, 47(1): 196- 209); 1-chloro-5-fluorohexane (Chambers, RD et al, Tetrahedron, 2006, 62(30): 7162-7167); 6-chloro-2-hexanol (European Patent Publication 0412596); S)-6-chloro-2-hexanol (Keinan, E et al, J Am Chem Soc, 1986, 108(12): 3474-3480); commercially available (R)-6-chloro-2-hexanol; Commercially available 6-chloro-2-hexanone; 6-chloro-2-methylhexan-2-ol is known (Kutner, A et al, Journal of Organic Chemistry, 1988, 53(15): 3450-7); 6-bromo-2-methylhexan-2-ol is known (Kutner, A et al, Journal of Organic Chemistry, 1988, 53(15): 3450-7); 1-bromo-5-fluoro-5 is known. Methyl hexane (Hester, JB et al, Journal of Medicinal Chemistry, 2001, 44(7): 1099-1115).

Scheme 11. Synthesis of a compound of formula A1

Scheme 11 depicts the synthesis of a compound of formula A1. Thus, the compounds of formula I with potassium carbonate in D ₂ O in the process to achieve a hydrogen-deuterium exchange reaction, providing the compounds of Formula A1. Those skilled in the art should be aware that additional hydroquinone exchange reactions can occur elsewhere in the molecule.

Scheme 12. Alternative synthetic Al compounds

An alternative synthesis of one of the compounds of the formula Al is described in Scheme 12. Thus, Intermediate 10 (see process 1A) in order to process the potassium carbonate in D ₂ O to achieve hydrogen-deuterium exchange reaction, providing the form or kind of form ND NH substance compound 50. Alkylation of intermediate 11 in the presence of potassium carbonate provides a compound of formula Al.

Many novel intermediates can be used to prepare the compound of formula A. Accordingly, the present invention also provides such a compound selected from the following:

The above compounds a-d can be prepared using a suitable deuterated starting material as generally described in Org. Lett., 2005, 7: 1427-1429. Compound e-o can be prepared from the appropriate bromides listed above by reference to Scheme 15 shown below.

Certain xanthine intermediates suitable for use in the present invention are also novel. Accordingly, the present invention provides a tritiated scutellaria intermediate III: III, wherein W is hydrogen or deuterium, and R ¹ and R ² are each independently selected from the group consisting of hydrogen, deuterium, optionally substituted C _1-3 alkyl, and optionally substituted C _1-3 alkane Alkoxy group. Examples of the R ¹ and R ² C _1-3 alkyl groups include -CH ₃ , -CD ₃ , -CH ₂ CH ₂ CH ₃ and -CD ₂ CD ₂ CD ₃ . Examples of the C _1-3 alkoxyalkyl group include -CH ₂ OCH ₂ CH ₃ , -CD ₂ OCH ₂ CH ₃ , -CD ₂ OCD ₂ CH ₃ and -CD ₂ OCD ₂ CD ₃ .

Specific examples of Formula III include the following:

In each of the above examples of Formula III, W is hydrogen. In a corresponding set of examples, W is 氘. Salts of the compounds of formula III are also suitable, including those known to be useful in connection with known xanthine. Examples of suitable salts include, but are not limited to, lithium, sodium, potassium and phosphonium salts. An example of a particularly suitable salt is the potassium salt.

The specific methods and compounds shown above are not intended to be limiting. The chemical structure depicted in the Schemes herein is a code that defines the chemical group definition (part, atom, etc.) at the corresponding position in the formula of the formula, regardless of whether the chemical group definition is represented by the same code name (also That is, R ¹ , R ² , R ^{3 ,} etc.) are recognized. One of ordinary skill in the art is fully aware of the suitability of a chemical group in a compound structure for the synthesis of another compound.

Other methods of synthesizing the compounds of the invention and their synthetic precursors, including those within the pathways not explicitly shown herein, are within the skill of those of ordinary skill in the art. Synthetic chemical transformation and protecting group methods (protection and deprotection) suitable for the synthesis of suitable compounds are known in the art and include, for example, the methods described in Larock R, Comprehensive Organic Transformations , VCH Publishers ( 1989); Greene TW et al, Protective Groups in Organic Synthesis , 3rd edition, John Wiley and Sons (1999); Fieser L et al, Fieser and Fieser, s Reagents for Organic Synthesis , John Wiley and Sons (1994); Paquette L, Encyclopedia of Reagents for Organic Synthesis , John Wiley and Sons (1995) and subsequent versions.

Combinations of substituents and symbols contemplated by the present invention are only combinations that result in the formation of stable compounds.

Composition

The invention also provides a non-pyrogenic composition comprising an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof; and an acceptable carrier. Preferably, the compositions of the present invention are formulated for pharmaceutical use ("pharmaceutical compositions") wherein the carrier is a pharmaceutically acceptable carrier. The carrier is "acceptable" in the sense of being compatible with the other ingredients of the formulation, and in the case of a pharmaceutically acceptable carrier, is not deleterious to the recipient in the amounts employed in the medicament.

Pharmaceutically acceptable carriers, adjuvants and vehicles which can be used in the pharmaceutical compositions of the invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as humans Serum albumin, buffer substances such as phosphate, glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate , sodium chloride, zinc salt, colloidal cerium oxide, magnesium tridecanoate, polyvinylpyrrolidone, cellulose-based material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax , polyethylene-polyoxypropylene block polymer, polyethylene glycol and lanolin.

The pharmaceutical composition of the present invention comprises a pharmaceutical composition suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. Things. In certain embodiments, a compound having the formula herein is administered transdermally (e.g., using a transdermal patch or an iontophoresis technique). Other formulations may conveniently be presented in unit dosage form (e.g., lozenges, sustained release capsules) and in the form of liposomes, and may be prepared by any methods known in the pharmaceutical art. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th Ed. 1985).

In certain embodiments, the compounds are administered orally. Compositions of the invention suitable for oral administration can be provided in the form of discrete units (such as capsules, sachets or lozenges) each containing a predetermined amount of active ingredient; powders or granules; aqueous or nonaqueous liquids A solution or suspension; an oil-in-water type liquid emulsion; a water-in-oil type liquid emulsion; a liposome-encapsulated form; or a boluse form. Soft gelatin capsules may be suitable for containing such suspensions, which may advantageously increase the rate of absorption of the compound.

In the case of tablets for oral use, carriers which are usually used include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in a capsule form, suitable diluents include lactose and dried corn starch. When the aqueous suspension is administered orally, the active ingredient is combined with emulsifying and suspending agents. Some sweeteners and/or flavoring and/or coloring agents may be added as needed.

Compositions suitable for oral administration include ingots containing ingredients in a flavoring base (usually sucrose and acacia or tragacanth); and in inert matrices (such as gelatin and glycerin, or sucrose and arabic) A tablet containing the active ingredient in the gum.

Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions which may contain an antioxidant, a buffer, a bacteriostatic agent, and a solute such that the formulation is isotonic with the blood of the intended recipient; and may include a suspending agent And aqueous and non-aqueous sterile suspensions of thickeners. Formulations may be provided in unit or multi-dose containers (eg, sealed ampoules and vials) and may be stored under lyophilization (freeze-drying) conditions, requiring only the addition of a sterile liquid carrier (eg water for injection) immediately prior to use. . Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and lozenges.

The injection solutions can be in the form of, for example, a sterile injectable aqueous or oily suspension. The suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents such as Tween 80 and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-septically acceptable non-toxic diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, conventional sterile, fixed oils are employed as a solvent or suspension medium. For this purpose, any non-irritating, fixed oil may be employed including synthetic monoglycerides or diglycerides. As with pharmaceutically acceptable natural oils such as olive oil or castor oil, especially in the form of polyoxyethylenes, fatty acids such as oleic acid and its glyceride derivatives are also suitable for the preparation of injectables. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

The pharmaceutical composition of the present invention can be administered in the form of a suppository for rectal administration. Such compositions can be prepared by mixing a compound of the invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and thus melts in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

The pharmaceutical composition of the present invention can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may employ benzyl alcohol or other suitable preservatives, absorption enhancers that enhance bioavailability, fluorocarbons, and/or other solubilization or dispersion known in the art. The preparation was prepared as a saline solution. See, for example, Rabinowitz, JD and Zaffaroni, AC US Patent 6,803,031, assigned to Alexza Molecular Delivery Corporation.

Topical administration of the pharmaceutical compositions of the present invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For topical application to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active ingredient suspended or dissolved in the vehicle. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white paraffin, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition may be formulated with a suitable lotion or cream which is suspended or dissolved in the active compound. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, hexadecyl ester wax, cetostearyl alcohol, 2-octyldodecanol, Benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in the form of a suitable enemas formulation. Local transdermal patches and iontophoresis administration are also included in the present invention.

Administration of the subject therapeutic agent can be topical for administration to the site of interest. Various techniques can be used to provide the subject composition to the site of interest, such as injection, use of a catheter, cannula, bombardment particles, pluronic gel, endovascular stent, sustained drug release polymer, or internal access. Other devices.

In another embodiment, the compositions of the present invention additionally comprise a second therapeutic agent. The second therapeutic agent can be selected from any compound or therapeutic agent known to have or exhibit advantageous properties when administered with a compound having the same mechanism of action as the cefolin. Such agents include agents that are indicated for use in combination with a combination of ceflin, including, but not limited to, the agents described in WO 1997019686, EP 0640342, WO 2003013568, WO 2001032156, WO 2006035418, and WO 1996005838.

In the pharmaceutical compositions of the invention, the compounds of the invention are present in an effective amount. The term "effective amount," as used herein, refers to an amount sufficient to treat (therapeutic or prophylactic) a target condition when administered in a suitable dosage regimen. For example, an effective amount is sufficient to reduce or soothe the severity, duration or progression of the condition being treated, to prevent progression of the condition being treated, to improve the condition being treated, or to enhance or ameliorate the prophylactic or therapeutic effect of another therapy.

The intrinsic relationship between the doses used for animals and humans (measured in milligrams per square meter of body surface) is described in Freireich et al., Cancer Chemother. Rep, 1966, 50:219. The body surface area can be approximately determined from the height and weight of the patient. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970, 537.

In one embodiment, an effective amount of a compound of the invention is in the range of from 20 mg to 2000 mg per treatment. In a more specific embodiment, the amount is in the range of 40 mg to 1000 mg per treatment, or in the range of 100 mg to 800 mg, or more specifically in the range of 200 mg to 400 mg. Treatment is typically administered one to three times a day.

As will be recognized by those skilled in the art, the effective dose will also vary depending on the disease being treated, the severity of the disease, the route of administration, the sex of the patient, the age and general health, the use of the excipient, and other therapeutic properties. The likelihood of treatment (such as the use of other agents) and the judgment of the treating physician. For example, a guide to selecting an effective dose can be determined by referring to the information on the location of the Westfield.

For a pharmaceutical composition comprising a second therapeutic agent, the effective amount of the second therapeutic agent is between about 20% and 100% of the dosage normally used in the monotherapy regimen using only the agent. Preferably, the effective amount is between about 70% and 100% of the normal single therapeutic dose. Normal single therapeutic doses of such second therapeutic agents are well known in the art. See, for example, Wells et al, ed., Pharmacotherapy Handbook, 2nd ed., Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), The entire text of each of these references is incorporated herein by reference.

treatment method

In one embodiment, the invention provides a method of inhibiting phosphodiesterase (PDE) activity of a cell comprising contacting a cell with one or more compounds of formula A, A1, I, II or B.

In addition to PDE inhibitory activity, it is known that prostaglandin also inhibits many other biological agents (such as interleukin-1 (IL-1), IL-6, IL-12, TNF-α, fibrinogen, and various growth agents. Factor). Therefore, in another embodiment, the present invention provides a method for inhibiting the production of interleukin-1 (IL-1), IL-6, IL-12, TNF-α, fibrinogen, and various growth factors. , which comprises contacting a cell with one or more compounds of formula A, A1, I, II or B.

According to another embodiment, the invention provides a method of treating a condition in a patient in need thereof which is beneficial for treatment with a sifenlin comprising administering to the patient an effective amount of Formula A, A1, I, II or B A step of a compound or a pharmaceutical composition comprising a compound of formula A, A1, I, II or B and a pharmaceutically acceptable carrier.

Such diseases are well known in the art and are disclosed in, but are not limited to, the following patents and published applications: WO 1988004928, EP 0493682, US 5,112,827, EP 0 484 785, WO 1997 019 686, WO 2003 013 568, WO 2001 032 156, WO 1992007566 WO 1998055110, WO 2005023193, US 4975432, WO 1993018770, EP 0490181 and WO 1996005836. Such diseases include, but are not limited to, peripheral obstructive vascular disease; glomerulonephritis; renal syndrome; nonalcoholic steatosis hepatitis; leishmaniasis; cirrhosis; liver failure; Duchenne muscular dystrophy; Delayed radiation-induced injury; radiation-induced lymphedema; radiation-related necrosis; alcoholic hepatitis; radiation-related fibrosis; necrotizing enterocolitis in premature infants; diabetic nephropathy, hypertension-induced renal failure, and other chronic Nephropathy; focal segmental glomerulosclerosis; pulmonary sarcoidosis; recurrent thrush stomatitis; chronic breast pain in breast cancer patients; brain and central nervous system tumors; malnutrition-inflammation-cachexia syndrome; Disease-mediated disease; graft-versus-host response and other allograft responses; diet-induced fatty liver disease, atheroma, fatty liver degeneration and other diet-induced high fat or alcohol-induced tissue changes Sexually transmitted diseases; type 1 human immunodeficiency virus (HIV-1) and other human retrovirus infections; multiple sclerosis; cancer; fibrosis Disease; fungal infection; drug-induced nephrotoxicity; collagenous colitis and other diseases and/or conditions characterized by elevated levels of platelet-derived growth factor (PDGF) or other inflammatory cytokines; endometriosis; Optic neuropathy and CNS dysfunction associated with acquired immunodeficiency syndrome (AIDS), immune disorder disease or multiple sclerosis; autoimmune disease; upper respiratory tract infection; depression; urinary incontinence; colonic urgency; septic shock Alzheimer's dementia; neuropathic pain; dysuria; retinal or optic nerve damage; peptic ulcer; insulin-dependent diabetes; non-insulin-dependent diabetes mellitus; diabetic nephropathy; metabolic syndrome; obesity; insulin resistance; Lipidemia; pathological glucose tolerance; hypertension; hyperlipidemia; hyperuricemia; gout; hypercoagulability; acute alcoholic hepatitis; olfactory disorders; open arterial catheter; and neutrophil chemotaxis And/or de-inflammation or damage associated with granule action.

Compounds of formula A, A1, I, II or B can also be used to control the intraocular pressure or stabilize the cerebral blood flow of an individual as determined by physical examination.

In a specific embodiment, the method of the invention is used to treat a disease or condition selected from a patient in need thereof: intermittent claudication caused by chronic obstructive arterial disease of the extremities and other peripheral obstructive vascular diseases; Spherical nephritis; focal segmental glomerulosclerosis; renal syndrome; nonalcoholic steatosis hepatitis; leishmaniasis; cirrhosis; liver failure; Duchenne muscular dystrophy; delayed radiation-induced injury; Radiation-induced lymphedema; alcoholic hepatitis; radiation-induced fibrosis; necrotizing enterocolitis in premature infants; diabetic nephropathy, renal failure induced by hypertension, and other chronic kidney disease; pulmonary sarcoidosis; recurrent goose Aphthous stomatitis; chronic breast pain in breast cancer patients; brain and central nervous system tumors; obesity; acute alcoholic hepatitis; olfactory disorders; infertility associated with endometriosis; malnutrition-inflammation-cachexia syndrome; Arterial catheter.

In one embodiment, the methods of the invention are used to treat diabetic nephropathy, hypertensive nephropathy, or intermittent claudication caused by chronic arteriovenous disease of the extremities. In another specific embodiment, the method of the invention is used to treat a disease or condition selected from patients with intermittent claudication caused by chronic arteriovenous disease of the extremities in a patient in need thereof.

In one embodiment, the methods of the invention are used to treat chronic kidney disease. Chronic kidney disease may be selected from glomerulonephritis, focal segmental glomerulosclerosis, renal disease, reflux uropathy, or polycystic kidney disease.

In one embodiment, the methods of the invention are used to treat chronic diseases of the liver. Chronic liver disease can be selected from nonalcoholic steatosis hepatitis, fatty liver degeneration or other diet-induced high fat or alcohol-induced tissue degeneration, cirrhosis, liver failure or alcoholic hepatitis.

In one embodiment, the methods of the invention are used in a diabetes related disease or condition. The disease may be selected from the group consisting of insulin resistance, retinopathy, diabetic ulcer, radiation-related necrosis, acute renal failure, or drug-induced nephrotoxicity.

In one embodiment, the methods of the invention are used to treat patients suffering from cystic fibrosis, including patients suffering from chronic Pseudomonas bronchitis.

In a specific example, the method of the invention is used to aid wound healing. Examples of types of treatable wounds include varicose ulcers, diabetic ulcers, and acne.

In another specific embodiment, the methods of the invention are used to treat a disease or condition selected from a patient in need thereof: insulin-dependent diabetes; non-insulin-dependent diabetes; metabolic syndrome; obesity; insulin resistance; Lipemia; pathological glucose tolerance; hypertension; hyperlipidemia; hyperuricemia; gout; and high coagulability.

The methods described herein also include methods by which a patient is identified as needing the particular treatment. Identifying a patient in need of such treatment can be judged by the patient or health care professional and can be subjective (eg, opinion) or objective (eg, can be measured by test or diagnostic methods).

In another embodiment, any of the above methods of treatment comprises the further step of co-administering one or more second therapeutic agents to the patient. The second therapeutic agent can be selected from any second therapeutic agent known to be suitable for co-administration with the formulated cefolin. The choice of the second therapeutic agent will also depend on the particular disease or condition being treated. An example of a second therapeutic agent that can be used in the methods of the invention is the second therapeutic agent described above for use in a combination composition comprising a compound of the invention and a second therapeutic agent.

In particular, the combination therapies of the invention comprise co-administering a compound of formula A, Al, I, II or B with a second therapeutic agent to treat the following conditions (wherein the particular second therapeutic agent is indicated in parentheses after the indication) ): delayed radiation-induced injury (α-tocopherol), radiation-induced fibrosis (α-tocopherol), radiation-induced lymphedema (α-tocopherol), chronic breast pain in breast cancer patients (α-tocopherol) ), type 2 diabetic nephropathy (captopril), malnutrition-inflammation-cachexia syndrome (oral nutritional supplements such as Nepro; and oral anti-inflammatory modules such as Oxepa); and brain and central nervous system Tumor (radiotherapy and hydroxyurea).

The combination therapies of the invention also include co-administering a compound of formula A, Al, I, II or B with a second therapeutic agent for the treatment of insulin-dependent diabetes; non-insulin dependent diabetes; metabolic syndrome; obesity; insulin resistance; Lipemia; pathological glucose tolerance; hypertension; hyperlipidemia; hyperuricemia; gout; and high coagulability.

The term "co-administered" as used herein means that the second therapeutic agent can be part of a single dosage form, such as a composition of the invention comprising a compound of the invention and a second therapeutic agent as described above, or as a plurality of separate compositions. The dosage form is administered with a compound of the invention. Alternatively, other agents may be administered prior to administration of the compounds of the invention, with other agents being administered continuously with the compounds of the invention or after administration of the compounds of the invention. In the combination therapy, both the compound of the present invention and the second therapeutic agent are administered by a conventional method. Administration of a composition of the invention comprising a compound of the invention and a second therapeutic agent to a patient does not exclude the administration of the same therapeutic agent, any other second therapeutic agent or any compound of the invention to the patient at another time during the course of treatment. .

The effective amount of such second therapeutic agents is well known to those skilled in the art and guidelines for administration can be found in the patents and published patent applications mentioned herein, and in Wells et al., Pharmacotherapy Handbook 2nd Edition, Appleton and Lange , Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000) and other medical textbooks. However, determining the optimal effective amount range for the second therapeutic agent is well within the capabilities of those skilled in the art.

In a specific embodiment of the invention for administering a second therapeutic agent to an individual, the effective amount of the compound of the invention is less than the effective amount thereof when the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is less than the effective amount thereof when the compound of the invention is not administered. In this way, undue side effects associated with high doses of any agent can be minimized. Other potential advantages including, but not limited to, improved dosing regimens and/or reduced drug costs will be apparent to those skilled in the art.

In another aspect, the invention provides the use of a compound of formula A, Al, I, II or B, alone or in combination with one or more of the above second therapeutic agents, for use in the manufacture of a single composition or in separate dosage forms. A medicament for the treatment or prevention of the above-mentioned diseases, conditions or symptoms of a patient. Another aspect of the invention is a compound of formula A, Al, I, II or B for use in the treatment or prevention of a disease, disorder or condition described herein in a patient.

Synthesis example

The following synthetic examples provide detailed procedures for the preparation of certain compounds of the invention. It will be apparent to those skilled in the art that other compounds of the invention can be prepared via the use of other reagents or intermediates with reference to such procedures and procedures described above. The compounds prepared are analyzed by NMR, mass spectrometry and/or elemental analysis as illustrated. ¹ H NMR was performed on a 300 MHz instrument suitable for determining enthalpy of enthalpy. Unless otherwise stated, the absence of an NMR signal as noted in the examples below indicates that the degree of merging is at least 90%.

Example 1 Synthesis of 3-methyl-7- (methyl - d ₃₎ cases. -1- (5-oxo-hexyl) -1 H - purine -2,6 (3 H, 7 H) - dione ( Compound 100 ).

Scheme 13. Preparation of Compounds 100 and 409 .

Step 1.3-methyl-7- (methyl - d ₃₎ -1 H - purine -2,6 (3 H, 7 H) - dione (51). Heating a suspension of 3-methylxanthine 50 (5.0 g, 30.1 mmol, 1 eq.) and powdered K ₂ CO ₃ (5.0 g, 36.0 mmol, 1.2 eq.) in DMF (95 mL) to 60 ° C Methyl iodide-d ₃ (Cambridge Isotopes, 99.5 at% D, 2.2 mL, 36.0 mmol, 1.2 eq.) was added. The resulting mixture was heated at 80 ° C for 5 hours. The reaction mixture was cooled to room temperature (rt) and DMF was evaporated under reduced pressure. The crude residue was dissolved in 5% aqueous NaOH (50 mL). The aqueous solution was washed three times with DCM (500 mL total). The aqueous layer was acidified to pH 5 with acetic acid (6 mL), which afforded a tan precipitate. The mixture was cooled in an ice water bath and the solid was filtered and washed with cold water. The solid was dried in a vacuum oven to give 2.9 g of 51 as a tan solid. The filtrate was concentrated to ca. 25 mL and a second crop (0.70 g) 51 was collected by filtration. The total output of 51 was 3.6 g. The crude material was used without further purification.

Step 2. 3-methyl-7- (methyl - d ₃₎ -1- (5- oxo-hexyl) -1 H - purine -2,6 (3 H, 7 H) - dione (Compound 100). The crude 51 (1.50g, 8.2mmol, 1 equiv) and powdered _{K 2 CO 3 (2.28g, 16.4mmol} , 2 eq.) Was suspended in DMF (30mL) and heated to 50 ℃. To the obtained brown suspension, 6-chloro-2-hexanone ( 52 , 1.2 mL, 9.0 mmol, 1.1 eq.) was added and the reaction temperature was elevated to 130 °C. Heating was continued at 130 ° C for 2 hours during which time the suspension became finer and darker in color. The reaction mixture was cooled to room temperature and DMF was evaporated under reduced pressure. The residual tan paste was suspended in EtOAc (250 mL) and filtered to remove insoluble material. The filtrate was concentrated under reduced pressure to give a yellow oil. The crude product was purified using an Analogix chromatography system eluting with a gradient of 100% EtOAc (10 min) and 0 to 25% MeOH/EtOAc. The product fractions were concentrated under reduced pressure to give a slightly yellow oil which solidified after standing for a few minutes. Solids with heptane (100 mL) triturated and filtered to obtain 2.00g of an off-white solid 100, mp 101.8-103.0 ℃. ¹ H-NMR (300 M Hz, CDCl ₃ ): δ 1.64-1.68 (m, 4H), 2.15 (s, 3H), 2.51 (t, J = 7.0, 2H), 3.57 (s, 3H), 4.01 ( t, J = 7.0, 2H), 7.52 (s, 1H). ¹³ C-NMR (75 MHz, CDCl ₃ ): δ 20.95, 27.41, 29.69, 29.98, 40.80, 43.18, 107.63, 141.41, 148.75, 151.45, 155.26, 208.80. HPLC (method: 20 mm C18-RP column-gradient method 2 to 95% ACN + 0.1% formic acid in 3.3 minutes, and maintained at 95% ACN for 1.7 minutes; wavelength: 254 nm): residence time 2.54 minutes; 98.5% purity . MS (M+H): 282.0. Elemental analysis (C ₁₃ H ₁₅ D ₃ N ₄ O ₃ ): Calculated: C = 55.50, H = 6.45, N = 19.92. Found: C = 55.58, H = 6.48, N = 19.76.

Due to the presence of a triplet at 4.01 ppm in the above ¹ H-NMR spectrum, it is determined whether or not there is a single peak around 3.99 ppm corresponding to the presence or absence of hydrogen on the N-methyl group at the 7-position (R ¹ ) of the anthracene ring. It is impossible.

Example 2. Synthesis of 8- d ₁ -3-methyl-7-(methyl- d ₃ )-1-(6- d ₃ -4- d ₂ -5-oxo-oxyhexyl)-1 H -嘌呤-2,6( 3H ,7H)-dione (compound 409 ).

8- d ₁ -3-methyl-7-(methyl- d ₃ )-1-(6- d ₃ -4- d ₂ -5-oxo-oxyhexyl)-1 H -嘌呤-2,6( 3 H , 7 H )-dione (compound 409 ). A suspension of 100 (1.80 g, 6.4 mmol, 1 eq.) and powdered K ₂ CO ₃ (0.23 g, 1.7 mmol, 0.25 eq.) in D ₂ O (Cambridge Isotope Labs, 99 atom% D) (45 mL) Stir under reflux for 24 hours during which time the suspension turned into a slightly yellow solution. The reaction mixture was cooled to room temperature, saturated with sodium chloride and extracted four times with dichloromethane (400 mL). The combined organic solution was dried over Na ₂ SO _4, filtered, and evaporated under reduced pressure to give 1.7g pale yellow oil which solidified upon standing. The crude material was again subjected to the above hydrogen/deuterium exchange conditions with fresh K ₂ CO ₃ and D ₂ O. After the same treatment with hexane (100 mL) an off-white solid was triturated and filtered to obtain 1.61g of an off-white solid 409, mp 99.6-99.8 ℃. ¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.64-1.69 (m, 4H), 3.57 (s, 3H), 4.01 (t, J = 7.0, 2H). ¹³ C-NMR (75 MHz, CDCl ₃ ): δ 21.05, 27.61, 29.90, 41.02, 107.83, 148.99, 151.69, 155.50, 209.28. HPLC (method: Waters Atlantis T3 2.1 x 50 mm 3 μm C18-RP column-gradient method 5-95% ACN + 0.1% formic acid (1.0 mL/min) in 14 min and held at 95% ACN for 4 min; wavelength : 254 nm): residence time: 3.26 minutes: 98% purity. MS (M+H): 288.3. Elemental analysis (C ₁₃ H ₉ D ₉ N ₄ O ₃ ): Calculated: C = 54.35, H = 6.31, N = 19.50. Found: C = 54.36, H = 6.32, N = 19.10.

It is noteworthy that the following peaks were absent in the above ¹ H-NMR spectrum: a single peak around 2.15 ppm indicating the absence of methylketone hydrogen; a triplet around 2.51 ppm indicating the absence of methylene ketone hydrogen; A single peak around 7.52 ppm indicates that no hydrogen is present at the number 8 position on the anthracene ring. Due to the presence of a triplet at 4.01 ppm in the above ¹ H-NMR spectrum, it is determined whether or not there is a single peak around 3.99 ppm corresponding to the presence or absence of hydrogen on the N-methyl group at the 7-position (R ¹ ) of the anthracene ring. It is impossible.

Example 3. Synthesis of 3,7-bis(methyl- d ₃ )-1-(5-oxo-oxyhexyl)-1 H -indole-2,6(3 H ,7 H )-dione (Compound 101 ).

Scheme 14. Preparation of Compounds 101 and 413 .

Step 1. 3,7-Di(methyl- d ₃ )-1 H -indole-2,6(3 H ,7 H )-dione ( 55 ). A suspension of xanthine 53 (2.00 g, 13.2 mmol, 1.0 eq.) and hexamethyldioxane (32 mL) in toluene (60 mL) was warmed to reflux and stirred for 4 days. The reaction mixture was cooled to room temperature then diluted with toluene (50 mL) and filtered over Celite to remove any unreacted starting material. The filtrate was evaporated to dryness under reduced pressure to yield a white solid of 54 (4.1g). A portion of this material (3.00 g) in a sealed tube placed in a 100mL reaction vessel, followed by addition of toluene (60 mL), and _{CD 3 I (4mL, Cambridge Isotopes} , 99.5 atom% D). The reaction mixture was heated in a 120 ° C oil bath and stirred for 24 hours during which time the reaction mixture became yellow and solid. The reaction mixture was cooled to room temperature, causing the entire reaction mixture to solidify to a yellow solid. The mixture was diluted with acetone (30mL) and MeOH (5mL) and filtered under a stream of N _2. The solid was washed with acetone (100 mL) to remove yellow to afford an off white solid. In the solid was filtered off and dried under a stream of N ₂ to obtain a substantially 1: 7- (methyl - d ₃₎ - 55 and byproduct of monoalkylated 1 mixture ratio of the xanthine. The total mass recovery was 2.6 g (42% crude yield). Due to the poor solubility of this mixture, it was subsequently disposed of without further purification.

Step 2. 3,7-di (methyl - d ₃₎ -1- (5- oxo-hexyl) -1 H - purine -2,6 (3 H, 7 H) - dione (Compound 101). The crude material was heated 55 (2.60g, 13.4mmol, 1.0 equiv) and the powdered _{K 2 CO 3 (2.20g, 16mmol} , 1.2 equiv) in DMF (50mL) to a suspension of 60 ℃. To the resulting tan suspension was added 6-chloro-2-hexanone 52 (2.0 mL, 14.8 mmol, 1.1 eq.) and the mixture was warmed to 140. Heating was continued at 140 °C for 4 hours during which time the suspension became finer and darker in color. The reaction mixture was cooled to room temperature and DMF was evaporated under reduced pressure. The resulting tan paste was suspended in 1:1 dichloromethane / ethyl acetate (200 mL) and filtered to remove insoluble material. The filtrate was concentrated under reduced pressure to give a brown brown oil. The crude reaction product was adsorbed onto silica gel and dry loaded onto a cartridge column packed with 100% dichloromethane. The column was dissolved in a gradient of 0-5% MeOH / dichloromethane. The fractions containing the product were concentrated under reduced pressure to give 0.75 g of a yellow oil. LCMS showed a material purity of about 90%. The yellow oil was further purified using an Analogix chromatography system eluting with 60% EtOAc/Heptane eluting with 20-100% EtOAc/Heptane. The desired product was dissolved for about 20 minutes. The fractions containing the product were concentrated under reduced pressure to give 0.55 g (16%) of compound 101 as a pale yellow oil which solidified after standing. ¹ H-NMR (300MHz, CDCl ₃ ): δ 1.64-1.69 (m, 4H), 2.15 (s, 3H), 2.51 (t, J = 7.0, 2H), 4.02 (t, J = 7.0, 2H) , 7.51 (s, 1H). ¹³ C-NMR (75 MHz, CDCl ₃ ): δ 20.97, 27.43, 29.97, 40.80, 43.19, 107.64, 141.40, 148.78, 151.48, 155.29, 208.77. HPLC (Method: Waters Atlantis T3 2.1 x 50 mm 3 μm C18-RP column-gradient method 5-95% ACN + 0.1% formic acid (1.0 mL/min) in 14 min and maintained at 95% ACN + 0.1% formic acid 4 minutes; wavelength: 305 nm): residence time: 3.24 minutes: 98.6% purity. MS (M+H): 285.3, (M+Na): 307.2. Elemental analysis (C ₁₃ H ₁₂ D ₆ N ₄ O ₃ ): Calculated: C = 54.92, H = 6.38, N = 19.71. Found: C = 54.90, H = 6.40, N = 19.50.

It is noteworthy that there is no single peak around 3.57 ppm in the above ¹ H-NMR spectrum, indicating the absence of N-methyl hydrogen at the 3 position of the anthracene ring. Due to the presence of a triplet at 4.01 ppm in the above ¹ H-NMR spectrum, whether or not there is a single peak around 3.99 ppm is determined by the presence or absence of hydrogen on the N-methyl group at the 7 position (R ¹ ) of the anthracene ring. It is impossible.

Example 4 Synthesis of 8- d ₁ -3,7-bis(methyl- d ₃ )-1-(4,4,6,6,6- d ₅ -5-oxo-oxyhexyl)-1 H - purine -2,6 (3 H, 7 H) - dione (compound 413).

8- d ₁ -3,7-bis(methyl- d ₃ )-1-(4- d ₂ -6- d ₃ -5-oxo-oxyhexyl)-1 H -嘌呤-2,6(3 H , 7 H )-dione (compound 413 ). A mixture of compound 101 (0.60g, 2.1mmol, 1.0 equiv) and powdered _{K 2 CO 3 (0.10g, 0.72mmol} , 0.30 eq.) In _{D 2 O (15mL, Cambridge Isotopes} , 99 atom% D) in the suspension and Stir under reflux for 16 hours during which time the suspension turned into a slightly yellow solution. The reaction mixture was cooled to room temperature, then sat. The combined dried organic extracts were dried over Na ₂ SO _4, filtered, and concentrated to afford 0.53g yellow oil under reduced pressure, which solidified upon standing. The crude reaction product was again subjected to the above reaction conditions with fresh powdered K ₂ CO ₃ and D ₂ O. After the same treatment with hexane (50mL) an off-white solid was triturated and filtered to obtain 0.45g (74%) of an off-white solid compound 413, mp 99.2-99.3 ℃. ¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.64-1.71 (m, 4H), 4.01 (t,J = 7.0, 2H). ¹³ C-NMR (75 MHz, CDCl ₃ ): δ 20.85, 27.41, 40.81, 107.63, 148.80, 151.50, 155.31, 209.09. HPLC (Method: Waters Atlantis T3 2.1 x 50 mm 3 μm C18-RP column-gradient method 5-95% ACN + 0.1% formic acid (1.0 mL/min) in 14 min and maintained at 95% ACN + 0.1% formic acid 4 minutes; wavelength: 254 nm): residence time: 3.25 minutes: 98.7% purity. MS (M+H): 291.3, (M+Na): 313.2. Elemental analysis (C ₁₃ H ₆ D ₁₂ N ₄ O ₃ ): Calculated: C = 53.78, H = 6.25, N = 19.30. Found: C = 53.76, H = 6.39, N = 19.1.

It is noteworthy that the following peaks were absent in the above ¹ H-NMR spectrum: a single peak around 2.15 ppm indicating the absence of methylketone hydrogen; a triplet around 2.51 ppm indicating the absence of methylene ketone hydrogen; A single peak around ppm indicates the absence of N-methylhydrogen at the 3 position on the anthracene ring; and a single peak around 7.51 ppm indicating the absence of hydrogen at the number 8 position on the anthracene ring. Due to the presence of a triplet at 4.01 ppm in the above ¹ H-NMR spectrum, whether or not there is a single peak around 3.99 ppm is determined by the presence or absence of hydrogen on the N-methyl group at the 7 position (R ¹ ) of the anthracene ring. It is impossible.

Example 5. Synthesis of 3-methyl-7-(methyl- d ₃ )-1-(6,6,6- d ₃ -5-oxo-oxyhexyl)-1 H -嘌呤-2,6(3) H ,7 H )-dione (compound 99 ).

Scheme 15. Preparation of Compound 99 .

Step 1. (3-methyl-7- (methyl - d ₃₎ -2,3,6,7- tetrahydro -1 H - purin-1 -yl) -N- methoxy -N- methyl Pentameramine ( 58 ). Heating 51 (1.50 g, 8.. 2 mmol, 1.0 eq. for the preparation of Example 1) and powdered K ₂ CO ₃ (1.80 g, 12.9 mmol, 1.6 eq.) in DMF (40 mL) to 60 ° C . Add 5-bromo-N-methoxy-N-methylpentamidine 57 (2.21 g, 9.8 mmol, 1.2 eq., as outlined in Org. Lett., 2005, 7 : 1427-1429) and at 110 ° C The mixture was heated for 4 hours, during which time the suspended solids became finer and the color turned brown. The reaction mixture was cooled to room temperature and DMF was evaporated under reduced pressure. The resulting tan paste was suspended in 1: 1CH ₂ Cl _2: ethyl acetate (250 mL) and the suspension was filtered to remove insoluble material. The filtrate was concentrated under reduced pressure to a yellow oil. Using an Analogix automated chromatography system, to 100% CH ₂ Cl ₂ over 8 minutes, followed by ₂ Cl ₂ gradient eluting the crude reaction product was purified in 40 minutes 0-5% MeOH / CH. The desired product was dissolved for about 24 minutes. The fractions containing the product were concentrated under reduced pressure to a slightly yellow oil. ¹ H NMR of the oil indicated that it contained about 10% unreacted 5 1 . By Analogix automated chromatography system, to 100% CH ₂ Cl ₂ for 10 minutes, followed by 50 minutes 0-5% MeOH / CH purified by removing impurities second allowable ₂ Cl ₂ gradient of eluting be. The fractions containing the product were concentrated under reduced pressure to a slightly yellow oil which crystallised as an off-white solid upon standing. With heptane (100 mL) and filtered to form a solid triturated obtain 1.29g (49%) of an off-white solid 58.

Step 2. 3-methyl-7- (methyl _{- d 3) -1- (6,6,6- d} 3 -5- oxo-hexyl) -1 H - purine -2,6 (3 H, 7 H )-dione (compound 99 ). Cooling 58 (0.72g, 2.2mmol, 1.0 eq.) In THF (20mL) in the suspension via a syringe to 2 ℃ and a rate to keep the temperature below 5 ℃ of diethyl ether was added dropwise to the 1M CD ₃ MgI (2.4mL , 2.4 mmol, 1.1 equivalents, Aldrich > 99 atom% D). During the addition, the mixture turned into a fine, slightly yellow suspension. When the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 3 h. The mixture was cooled to 2 ° C and a further portion of a CD ₃ MgI solution (0.4 mL, 0.4 mmol) was added. The mixture was allowed to warm to room temperature and stirred for additional 3 hours. In 1N HCl (4mL) quenched and diluted with H ₂ O (10mL), to produce a yellowish solution which is extracted with CH ₂ Cl ₂ (3 ×, 200mL). The dried the combined organic extracts were dried over Na ₂ SO _4, filtered and concentrated to a yellow oil under reduced pressure. Using an Analogix automated chromatography system, to 100% CH ₂ Cl ₂ for 8 minutes and then to 40 minutes 0-5% MeOH / CH ₂ Cl ₂ gradient eluting the crude product was purified. The desired product was first dissolved for about 22 minutes, followed by dissolution of the unreacted starting material. The fractions containing the product were concentrated under reduced pressure to a yellow oil which solidified upon standing. Hexane (25mL) and the solid was triturated to obtain 0.33g collected by vacuum filtration through a white solid of compound (53%) of 99, mp 93.7-94.4 ℃. Also collected solution containing unreacted starting material and the fractions were concentrated to obtain 0.21g as a clear, colorless oil of 58. The recovered material was again subjected to the above alkylation reaction, and after treatment and purification, 0.06 g (33%, total 62% based on total starting material) of compound 99 , mp 93.3 - 94.0 ° C, was obtained. ¹ H-NMR (300MHz, CDCl ₃ ): δ 1.64-1.68 (m, 4H), 2.50 (t, J = 7.0, 2H), 3.58 (s, 3H), 4.02 (t, J = 7.0, 2H), 7.51 (s, 1H). ¹³ C-NMR (75 MHz, CDCl ₃ ): δ 21.16, 27.65, 29.91, 41.03, 43.41, 107.87, 141.62, 149.00, 151.69, 155.50, 209.12. HPLC (Method: Waters Atlantis T3 2.1 x 50 mm 3 μm C18-RP column-gradient method 5-95% ACN + 0.1% formic acid (1.0 mL/min) in 14 min and maintained at 95% ACN + 0.1% formic acid 4 minutes; wavelength: 305 nm): residence time: 3.24 minutes: 99.0% purity. MS (M+H): 285.3, (M+Na): 307.2. Elemental analysis (C ₁₃ H ₁₂ D ₆ N ₄ O ₃ ): Calculated: C = 54.92, H = 6.38, N = 19.71. Found: C = 54.85, H = 6.36, N = 19.49.

It is noteworthy that there was no single peak around 2.15 ppm in the above ¹ H-NMR spectrum, indicating the absence of methyl ketone hydrogen. Due to the presence of a triplet at 4.01 ppm in the above ¹ H-NMR spectrum, whether or not there is a single peak around 3.99 ppm is determined by the presence or absence of hydrogen on the N-methyl group at the 7 position (R ¹ ) of the anthracene ring. It is impossible.

Example 6. Synthesis of (±)8- d ₁ -1-(4,4,6,6,6- d ₅ -5-hydroxyhexyl)-3-methyl-7-(methyl- d ₃ )- 1 H -嘌呤-2,6(3 H ,7 H )-dione (compound 419 ).

16. A process preparing a compound of 419,419 (R) and 419 (S).

(±)8- d ₁ -1-(4,4,6,6,6- d ₅ -5-hydroxyhexyl)-3-methyl-7-(methyl- d ₃ )-1 H -嘌呤- 2,6(3 H ,7 H )-dione (compound 419 ). Compound 409 (0.50g, 1.7mmol, 1.0 eq., See Example 2) was dissolved in EtOD (13mL, Aldrich 99.5 atom% D) was added and the NaBH ₄ (0.07g, 1.9mmol, 1.1 equiv). The temperature was observed to increase from 24 ° C to 28 ° C. The reaction was stirred for 2 hours at room temperature, followed by the addition of _{D 2 O (30mL, Cambridge Isotope} Labs, 99 atom% D) aborted. A white suspension was formed which was extracted with MTBE (4×, a total of 200 mL). The combined the organic extracts were dried Na ₂ SO _4, filtered and concentrated under reduced pressure to a clear, colorless oil (0.45g). By silica gel chromatography, first to _{1% MeOH / CH 2 Cl 2} , followed by 1-5% MeOH / CH ₂ Cl ₂ gradient eluting the crude product was purified. Concentrated under reduced pressure of product containing soluble fractions were obtained (0.41g, 83%) as a clear colorless oil of compound 419, which solidified on standing.

Example 7. Separation of palmar ( R )-8- d ₁ -1-(4,4,6,6,6- d ₅ -5-hydroxyhexyl)-3-methyl-7-(methyl- d ₃ )-1 H -嘌呤-2,6(3 H ,7 H )-dione (compound 419(R) ) and ( S )-8- d ₁ -1-(4,4,6,6, 6- d ₅ -5-hydroxyhexyl)-3-methyl-7-(methyl- d ₃ )-1 H -indole-2,6(3 H ,7 H )-dione (compound 419 ( S ) ).

The enantiomer of compound 419 was isolated. Compound 419 (0.38 g) obtained from Example 6 above was dissolved in a minimum amount of iPrOH (6 mL, HPLC grade, requires heating) and diluted with hexane (4 mL, HPLC grade). Enantiomeric separation was achieved using a Waters HPLC system equipped with a preparative Daicel Chiralpak AD column (20 x 250 mm). During the first minute of operation, the mobile phase was 80% hexane and 20% iPrOH and 0.1% diethylamine. After the first minute, a gradient of 75% hexane and 25% iPrOH and 0.1% diethylamine was used over 15 minutes, followed by maintaining the solvent ratio at a flow rate of 18 mL/min for 17 minutes. This method resulted in a first phase separation of 419( R ) (21.0 minutes) followed by a 419( S ) dissolution (24.1 minutes). Concentrated under reduced pressure enantiomers solution containing isomers from each of the respective parts to obtain 0.16g of an off-white solid of 419 (R) (mp 107.8-108.8 ℃ ) and 419 (S) (mp 108.3-108.4 ℃ ).

A).( R )-8- d ₁ -1-(4,4,6,6,6- d ₅ -5-hydroxyhexyl)-3-methyl-7-(methyl- d ₃ )-1 H -嘌呤-2,6(3 H ,7 H )-dione (compound 419( R ) ). ^{1 H-NMR (300MHz, CDCl} 3): δ1.36-1.50 (m, 2H), 1.60-1.74 (m, 3H), 3.58 (s, 3H), 3.80 (s, 1H), 4.02 (t, J =7.3, 2H). ¹³ C-NMR (75 MHz, CDCl ₃ ): δ 22.70, 27.86, 29.71, 41.14, 67.66, 107.66, 148.78, 151.54, 155.40. HPLC (Method: Waters Atlantis T3 2.1 x 50 mm 3 μm C18-RP column-gradient method 5-95% ACN + 0.1% formic acid (1.0 mL/min) in 14 min and maintained at 95% ACN + 0.1% formic acid 4 minutes; wavelength: 254 nm): residence time: 3.26 minutes: 99.9% purity. For palmar HPLC (method: Chiralpak AD 25 cm column - isocratic method at 1.00 mL/min 78% hexane / 22% isopropanol / 0.01% diethylamine for 40 minutes; wavelength: 254 nm): residence time: 27.51 min (major enantiomer); 31.19 min (expected value of minor enantiomer): >99.9% ee purity. MS (M+H): 290.1, (M+Na): 312.3. Elemental analysis (C ₁₃ H ₁₁ D ₉ N ₄ O ₃ ): Calculated: C = 53.97, H = 6.97, N = 19.36. Found: C = 54.39, H = 7.11, N = 18.89.

It is noteworthy that the following peaks are absent in the above ¹ H-NMR spectrum: a peak around 1.19 ppm indicating that no methyl hydrogen is present in the alpha position relative to the hydroxyl group; and a single peak around 7.51 ppm indicating the anthracene ring No hydrogen is present at the number 8 position. Due to the presence of a multiplet at 1.36 to 1.50 ppm and a triplet at 4.01 ppm in the above ¹ H-NMR spectrum, it is determined whether or not 1.51 ppm exists in the presence of methylene hydrogen relative to the α position of the hydroxyl group. It is impossible to determine whether or not a single peak exists around 3.99 ppm by the peak and whether or not hydrogen is present on the N-methyl group at the 7 position (R ¹ ) of the anthracene ring.

B).( S )-8- d ₁ -1-(4,4,6,6,6- d ₅ -5-hydroxyhexyl)-3-methyl-7-(methyl- d ₃ )-1 H -嘌呤-2,6(3 H ,7 H )-dione (compound 419( S ) ). ¹ H-NMR (300MHz, CDCl ₃ ): δ 1.41-1.48 (m, 2H), 1.64-1.72 (m, 3H), 3.58 (s, 3H), 3.79 (s, 1H), 4.02 (t, J) =7.4, 2H). ¹³ C-NMR (75 MHz, CDCl ₃ ): δ 22.70, 27.86, 29.71, 41.15, 67.66, 107.67, 148.78, 151.54, 155.41. HPLC (Method: Waters Atlantis T3 2.1 x 50 mm 3 μm C18-RP column-gradient method 5-95% ACN + 0.1% formic acid (1.0 mL/min) in 14 min and maintained at 95% ACN + 0.1% formic acid 4 minutes; wavelength: 254 nm): residence time: 3.26 minutes: 99.9% purity. For palmar HPLC (method: Chiralpak AD 25 cm column - isocratic method at 1.00 mL/min 78% hexane / 22% isopropanol / 0.01% diethylamine for 40 minutes; wavelength: 254 nm): residence time: 31.19 min (major enantiomer); 27.51 min (expected value of minor enantiomer): >99.9% ee purity. MS (M+H): 290.1, (M+Na): 312.3. Elemental analysis (C ₁₃ H ₁₁ D ₉ N ₄ O ₃ ): Calculated: C = 53.97, H = 6.97, N = 19.36. Found: C = 54.35, H = 7.28, N = 18.75.

It is noteworthy that the following peaks are absent in the above ¹ H-NMR spectrum: a peak around 1.19 ppm indicating that no methyl hydrogen is present in the alpha position relative to the hydroxyl group; and a single peak around 7.51 ppm indicating the anthracene ring No hydrogen is present at the number 8 position. Due to the presence of a multiplet at 1.36 to 1.50 ppm and a triplet at 4.01 ppm in the above ¹ H-NMR spectrum, it is determined whether or not 1.51 ppm exists in the presence of methylene hydrogen relative to the α position of the hydroxyl group. It is impossible to determine whether or not a single peak exists around 3.99 ppm by the peak and whether or not hydrogen is present on the N-methyl group at the 7 position (R ¹ ) of the anthracene ring.

Example 8. Synthesis of (±)8- d ₁ -1-(4,4,5,6,6,6- d ₆ -5-hydroxyhexyl)-3-methyl-7-(methyl- d ₃ -1 H -嘌呤-2,6(3 H ,7 H )-dione (compound 435 ).

17. A process preparing a compound of 435,435 (R) and 435 (S).

(±)8- d ₁ -1-(4,4,5,6,6,6- d ₆ -5-hydroxyhexyl)-3-methyl-7-(methyl- d ₃ )-1 H - purine -2,6 (3 H, 7 H) - dione (compound 435). (, Aldrich 99.5 atom% D 13mL) was added the NaBD ₄ (0.08g, 1.9mmol, 1.1 equiv, Cambridge Isotope Labs, 99 atom% D) solution of compound 409 (0.50g, 1.7mmol, 1.0 equiv) in EtOD. The temperature was observed to increase from 24 ° C to 27 ° C. The reaction was stirred for 2 hours at room temperature, followed by the addition of _{D 2 O (30mL) (Cambridge} Isotope, 99 atom% D) aborted. A white suspension was formed which was extracted with MTBE (4×, a total of 200 mL). The combined the organic extracts were dried Na ₂ SO _4, filtered and concentrated under reduced pressure to a clear, colorless oil (0.45g). By silica gel chromatography, first to _{1% MeOH / CH 2 Cl 2} , followed by 1-5% MeOH / CH ₂ Cl ₂ gradient eluting the crude product was purified. The product-containing fraction was concentrated under reduced pressure to give 0.40 g (yield: 81%) of compound 435 as a clear colorless oil which solidified upon standing.

Example 9. Separation of palmar ( R )-8- d ₁ -1-(4,4,5,6,6,6- d ₆ -5-hydroxyhexyl)-3-methyl-7-(A Base - d ₃ )-1 H -嘌呤-2,6(3 H ,7 H )-dione (compound 435( R ) ) and ( S )-8- d ₁ -1-(4,4,5, 6,6,6- d ₆ -5-hydroxyhexyl)-3-methyl-7-(methyl- d ₃ )-1 H -indole-2,6(3 H ,7 H )-dione (compound 435( S ) ).

The enantiomer of compound 435 was isolated. Compound 435 (0.32 g) obtained from Example 8 above was dissolved in a minimum amount of iPrOH (5 mL, HPLC grade, heating) and diluted with hexane (4 mL, HPLC grade). Enantiomeric separation was achieved using a Waters HPLC system equipped with a preparative Daicel Chiralpak AD column (20 x 250 mm). During the first minute of operation, the mobile phase was 80% hexane and 20% iPrOH and 0.1% diethylamine. After the first minute, a gradient of 75% hexane and 25% iPrOH and 0.1% diethylamine was used over 15 minutes, followed by maintaining the solvent ratio at a flow rate of 18 mL/min for 17 minutes. This method resulted in the first separation of compound 435( R ) (21.9 minutes) followed by baseline separation of compound 435( S ) dissolved (25.2 minutes). Concentrated under reduced pressure solution containing the individual enantiomers of each isomer is obtained 0.12g of off-white solid of 435 (R) (mp108.0-108.1 ℃) and 435 (S) (mp 107.6-107.7 ℃ ) from the parts.

A).( R )-8- d ₁ -1-(4,4,5,6,6,6- d6 -5-hydroxyhexyl)-3-methyl-7-(methyl- d ₃ )- 1 H -嘌呤-2,6(3 H ,7 H )-dione (compound 435( R ) ).

¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.40-1.48 (m, 3H), 1.66-1.70 (m, 2H), 3.58 (s, 3H), 4.02 (t, J = 7.5, 2H). ¹³ C-NMR (75 MHz, CDCl ₃ ): δ 22.66, 27.86, 29.71, 41.15, 107.67, 148.80, 151.54, 155.41. HPLC (Method: Waters Atlantis T3 2.1 x 50 mm 3 μm C18-RP column-gradient method 5-95% ACN + 0.1% formic acid (1.0 mL/min) in 14 min and maintained at 95% ACN + 0.1% formic acid 4 minutes; wavelength: 254 nm): residence time: 3.25 minutes: 99.8% purity. For palmar HPLC (method: Chiralpak AD 25 cm column - isocratic method at 1.00 mL/min 78% hexane / 22% isopropanol / 0.01% diethylamine for 40 minutes; wavelength: 254 nm): residence time: 27.24 min (major enantiomer); 31.11 min (expected value of minor enantiomer): >99.9% ee purity. MS (M+H): 291.3, (M+Na): 313.2. Elemental analysis (C ₁₃ H ₁₀ D ₁₀ N ₄ O ₃ ): Calculated: C = 53.78, H = 6.94, N = 19.30. Found: C = 54.01, H = 7.07, N = 18.90.

It is noteworthy that the following peaks were absent in the above ¹ H-NMR spectrum: a peak around 1.19 ppm indicating that no methyl hydrogen was present in the alpha position relative to the hydroxyl group; a peak around 3.80 ppm indicating the position of the methine hydroxyl group There is no hydrogen; and a single peak around 7.51 ppm indicating that no hydrogen is present at the number 8 position on the anthracene ring. Due to the presence of a multiplet at 1.36 to 1.50 ppm and a triplet at 4.01 ppm in the above ¹ H-NMR spectrum, it is determined whether or not 1.51 ppm exists in the presence of methylene hydrogen relative to the α position of the hydroxyl group. It is impossible to determine whether or not a single peak exists around 3.99 ppm by the peak and whether or not hydrogen is present on the N-methyl group at the 7 position (R ¹ ) of the anthracene ring.

B).( S )-8- d ₁ -1-(4,4,5,6,6,6- d ₆ -5-hydroxyhexyl)-3-methyl-7-(methyl- d ₃ ) -1 H -嘌呤-2,6(3 H ,7 H )-dione (compound 435( S ) ). _{H-NMR (300MHz, CDCl 3} ): δ1.41-1.48 (m, 3H), 1.62-1.72 (m, 2H), 3.58 (s, 3H), 4.03 (t, J = 7.4,2H). ¹³ C-NMR (75 MHz, CDCl ₃ ): δ 22.69, 27.90, 29.70, 41.17, 107.69, 148.82, 151.58, 155.43. HPLC (Method: Waters Atlantis T3 2.1 x 50 mm 3 μm C18-RP column-gradient method 5-95% ACN + 0.1% formic acid (1.0 mL/min) in 14 min and maintained at 95% ACN + 0.1% formic acid 4 minutes; wavelength: 254 nm): residence time: 3.25 minutes: 99.5% purity. For palmar HPLC (method: Chiralpak AD 25 cm column - isocratic method at 1.00 mL/min 78% hexane / 22% isopropanol / 0.01% diethylamine for 40 minutes; wavelength: 254 nm): residence time: 31.11 min (major enantiomer); 27.24 min (expected value of minor enantiomer): >99.9% ee purity. MS (M+H): 291.3, (M+Na): 313.2. Elemental analysis (C ₁₃ H ₁₀ D ₁₀ N ₄ O ₃ ): Calculated: C = 53.78, H = 6.94, N = 19.30. Experimental values: C = 54.01, H = 7.11, N = 18.78.

It is noteworthy that the following peaks were absent in the above ¹ H-NMR spectrum: a peak around 1.19 ppm indicating that no methyl hydrogen was present in the alpha position relative to the hydroxyl group; a peak around 3.80 ppm indicating the position of the methine hydroxyl group There is no hydrogen; and a single peak around 7.51 ppm indicating that no hydrogen is present at the number 8 position on the anthracene ring. Due to the presence of a multiplet at 1.36 to 1.50 ppm and a triplet at 4.01 ppm in the above ¹ H-NMR spectrum, it is determined whether or not 1.51 ppm exists in the presence of methylene hydrogen relative to the α position of the hydroxyl group. It is impossible to determine whether or not a single peak exists around 3.99 ppm by the peak and whether or not hydrogen is present on the N-methyl group at the 7 position (R ¹ ) of the anthracene ring.

Example 10. Synthesis of 8- d ₁ -3,7-dimethyl-1-(4,4,6,6,6- d ₅ -5-oxo-oxyhexyl)-1 H -嘌呤-2,6 (3 H , 7 H )-dione (compound 407 ).

Scheme 18. Preparation of Compounds 407, 437, 437( R ) and 437( S ) .

8- d ₁ -3,7-dimethyl-1-(4,4,6,6,6- d ₅ -5-oxo-oxyhexyl)-1 H -嘌呤-2,6(3 H ,7 H )-dione (compound 407 ). Heating the commercially available 59 (7.95g, 28.6mmol) and potassium carbonate (990mg, 7.2mmol) in (195mL, Cambridge Isotopes, 99.9 atom% D) in D ₂ O of the mixture to reflux for 24 hours. The suspended solid gradually dissolved to obtain a yellow solution. The solution was cooled to about 40 ° C and concentrated to a tan solid under reduced pressure. The solid was dissolved in D ₂ O (195mL) and the solution was heated to reflux for 24 hours. The solution was cooled to room temperature and concentrated under reduced pressure to a brown solid. Ethyl acetate (200 mL) was added and the mixture was stirred at about 40 ° C for 0.5 h. Insoluble material was filtered off and the filtrate was concentrated under reduced pressure to a pale yellow solid, which was in MTBE (40mL) wet milling to obtain 7.5g (93%) of an off-white solid compound 407.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.64-1.68 (m, 4H), 3.57 (s, 3H), 3.99 (s, 3H), 3.99-4.04 (m, 2H). ¹³ C-NMR (75 MHz, CDCl ₃ ): δ 20.84, 27.40, 29.69, 33.57, 40.81, 107.62, 148.77, 151.48, 155.28, 209.07. HPLC (Method: Waters Atlantis T3 2.1 x 50 mm 3 μm C18-RP column-gradient method 5-95% ACN + 0.1% formic acid (1.0 mL/min) in 14 min and maintained at 95% ACN + 0.1% formic acid 4 minutes; wavelength: 305 nm): residence time: 3.24 minutes: 99.9% purity. MS (M+H): 285.3, (M+Na): 307.2. Elemental analysis (C ₁₃ H ₁₂ D ₆ N ₄ O ₃ ): Calculated: C = 54.92, H = 6.38, N = 19.71. Found: C = 54.89, H = 6.38, N = 19.70.

It is noteworthy that the following peaks were absent in the above ¹ H-NMR spectrum: a single peak around 2.15 ppm indicating the absence of methylketone hydrogen; a triplet around 2.51 ppm indicating the absence of methylene ketone hydrogen; A single peak around 7.52 ppm indicates that no hydrogen is present at the number 8 position on the anthracene ring.

. Synthesis of Example 11 _{(±) 8- d 1 -1- (} 4,4,5,6,6,6- d 6 -5- -hydroxyhexyl) -3,7-dimethyl--1H- purine - 2,6(3H,7H)-dione (compound 437 ). (±)8- d ₁ -1-(4,4,5,6,6,6- d ₆ -5-hydroxyhexyl)-3,7-dimethyl-1H-indole-2,6(3H, 7H)-dione (compound 437 ). Sodium borohydride (1.06 g, 25.3 mmol, Cambridge Isotopes, 99 atomic % D) was added to 407 (6.5 g, 22.9 mmol) in ethanol-d ₁ (65 mL, Aldrich, 99.5 atom% D) at 0 °C. In the suspension. The mixture was allowed to warm to room temperature and stirred until a clear solution had appeared (about 1 hour). Ammonium chloride -d ₄ (Cambridge Isotopes, 98 atom% D) in _{D 2 O (8mL, Cambridge Isotope} , 99.9 atom% D) in the quenched saturated solution, ethanol was evaporated under reduced pressure and extracted with EtOAc -d ₁ The residue was extracted (160 mL). In D ₂ O (20mL) The organic phase was washed, dried over sodium sulfate, filtered and concentrated to obtain 4.8g (73%) of compound as a pale yellow solid 437 under reduced pressure.

Example 12. Separation of ( R )-8- d ₁ -1-(4,4,5,6,6,6- d ₆ -5-hydroxyhexyl)-3,7-dimethyl-1H -嘌呤-2,6(3H,7H)-dione (compound 437( R ) ) and ( S )-8- d ₁ -1-(4,4,5,6,6,6- d ₆ -5 -Hydroxyhexyl)-3,7-dimethyl-1H-indole-2,6(3H,7H)-dione (compound 437( S ) ).

The enantiomer of compound 437 was isolated. Compound 437 (1.60 g) obtained from the above Example 11 was dissolved in iPrOH (20 mL, HPLC grade, heating). Enantiomer separation was achieved using a Waters HPLC system equipped with a preparative Chiralpak AD column (20 x 250 mm Daicel, 10 [mu]M) and a preparative Chiralpak AD front catheter column (20 x 50 mm Daicel, 10 [mu]M). During the first minute of operation, the sample was dissolved in 20% iPrOH/hexane (hereafter 0.1% as the co-dissolving agent diethylamine) while increasing from a flow rate of 15 mL/min to 18 mL/min. Over the next 15 minutes, the sample was dissolved at a flow rate of 20 mL/min of a gradient of 20% to 25% iPrOH/hexane. During the next 19 minutes, the sample was dissolved in 25% iPrOH/hexane at a flow rate of 18 mL/min. Over the next 0.5 minutes, the sample was dissolved at a flow rate of 25% to 20% iPrOH/hexane gradient of 18 mL/min. During the next 4.5 minutes, the sample was dissolved in 20% iPrOH/hexane at a flow rate of 18 mL/min. This dissolution method resulted in a baseline separation of compound 437( R ) first (residence time of about 29 minutes) and compound 437( S ) followed by dissolution (residence time of about 33 minutes). The fractions containing each of the enantiomers were collected and concentrated under reduced pressure to afford 340 mg of 437( R ) (mp 112.0-114.5 ° C) and 375 mg of 437 ( S ) (mp 111.9-112.3 ° C) . [Note: Only 1.0g 437 was injected from the solution prepared above. ]

A.(R)-8- d ₁ -1-(4,4,5,6,6,6- d ₆ -5-hydroxyhexyl)-3,7-dimethyl-1H-indole-2,6 (3H,7H)-dione (compound 437( R ) ). ¹ H-NMR (300MHz, CDCl ₃ ): δ1.36-1.50 (m, 2H), 1.54 (s, 1H), 1.64-1.74 (m, 2H), 3.58 (s, 3H), 3.99 (s, 3H) ), 4.00-4.05 (m, 2H). ¹³ C-NMR (75 MHz, CDCl ₃ ): δ 22.66, 27.86, 29.70, 33.59, 41.14, 107.65, 148.76, 151.52, 155.40. HPLC (Method: Waters Atlantis T3 2.1 x 50 mm 3 μm C18-RP column-gradient method 5-95% ACN + 0.1% formic acid (1.0 mL/min) in 14 min and maintained at 95% ACN + 0.1% formic acid 4 minutes; wavelength: 305 nm): residence time: 3.28 minutes: 99.9% purity. For palmar HPLC (method: Chiralpak AD 25 cm column - isocratic method at 1.00 mL/min 78% hexane / 22% isopropanol / 0.01% diethylamine for 40 minutes; wavelength: 254 nm): residence time: 25.20 minutes (major enantiomer); 28.39 minutes (expected value of minor enantiomer): >99.9% ee purity. MS (M+H): 288.3, (M+Na): 310.2. Elemental analysis (C ₁₃ H ₁₃ D ₇ N ₄ O ₃ ): Calculated: C = 54.34, H = 7.02, N = 19.50. Found: C = 54.32, H = 7.23, N = 19.35.

It is noteworthy that the following peaks were absent in the above ¹ H-NMR spectrum: a peak around 1.19 ppm indicating that no methyl hydrogen was present in the alpha position relative to the hydroxyl group; a peak around 3.80 ppm indicating the position of the methine hydroxyl group There is no hydrogen; and a single peak around 7.51 ppm indicating that no hydrogen is present at the number 8 position on the anthracene ring. Due to the presence of multiple peaks at 1.36 to 1.50 ppm in the above ¹ H-NMR spectrum, it is impossible to determine whether or not a peak is present at 1.51 ppm corresponding to the presence or absence of methylene hydrogen in the α position of the hydroxyl group.

B. ( S )-8- d ₁ -1-(4,4,5,6,6,6- d ₆ -5-hydroxyhexyl)-3,7-dimethyl-1H-indole-2,6 (3H,7H)-dione (compound 437( S ) ). ¹ H-NMR (300MHz, CDCl ₃ ): δ 1.38-1.48 (m, 2H), 1.55 (s, 1H), 1.64-1.72 (m, 2H), 3.58 (s, 3H), 3.99 (s, 3H) , 4.00-4.05 (m, 2H). ¹³ C-NMR (75 MHz, CDCl ₃ ): δ 22.65, 27.84, 29.71, 33.59, 41.13, 107.64, 148.75, 151.52, 155.39. HPLC (Method: Waters Atlantis T3 2.1 x 50 mm 3 μm C18-RP column-gradient method 5-95% ACN + 0.1% formic acid (1.0 mL/min) in 14 min and maintained at 95% ACN + 0.1% formic acid 4 minutes; wavelength: 305 nm): residence time: 3.27 minutes: 99.9% purity. For palmar HPLC (method: Chiralpak AD 25 cm column - isocratic method at 1.00 mL/min 78% hexane / 22% isopropanol / 0.01% diethylamine for 40 minutes; wavelength: 254 nm): residence time: 28.39 min (major enantiomer); 25.20 min (expected value of minor enantiomer): >99.9% ee purity. MS (M+H): 288.3, (M+Na): 310.2. Elemental analysis (C ₁₃ H ₁₃ D ₇ N ₄ O ₃ ): Calculated: C = 54.34, H = 7.02, N = 19.50. Found: C = 54.33, H = 7.30, N = 19.36.

It is noteworthy that the following peaks were absent in the above ¹ H-NMR spectrum: a peak around 1.19 ppm indicating that no methyl hydrogen was present in the alpha position relative to the hydroxyl group; a peak around 3.80 ppm indicating the position of the methine hydroxyl group There is no hydrogen; and a single peak around 7.51 ppm indicating that no hydrogen is present at the number 8 position on the anthracene ring. Due to the presence of multiple peaks at 1.36 to 1.50 ppm in the above ¹ H-NMR spectrum, it is impossible to determine whether or not a peak is present at 1.51 ppm corresponding to the presence or absence of methylene hydrogen in the α position of the hydroxyl group.

Example 13. Synthesis of (±) 1-(5- d ₁ -5-hydroxyhexyl)-3-methyl-7-(methyl- d ₃ )-1H-indole-2,6(3H,7H)- Diketone (Compound 131 ).

Scheme 19. Preparation of Compound 131, 131( R ) and 131( S ) .

(±) 1-(5- d ₁ -5-hydroxyhexyl)-3-methyl-7-(methyl- d ₃ )-1H-indole-2,6(3H,7H)-dione (Compound 131 ). Following the same general procedure as above for the synthesis of compound 437 , compound 100 (see Example 1) was treated with NaBD ₄ in EtOH to afford compound 131 .

Of Example 14. The chiral separation _{(R) -1- (5- d 1} -5- hydroxyhexyl) -3-methyl-7- (methyl - d ₃₎ -1H- purine-2,6 ( 3H,7H)-dione (compound 131( R ) ) and ( S )-1-(5- d ₁ -5-hydroxyhexyl)-3-methyl-7-(methyl- d ₃ )-1H- Indole-2,6(3H,7H)-dione (Compound 131( S ) ).

The enantiomer of compound 131 was isolated. A portion of the racemic compound 131 was obtained from the above Example 13 in the same manner as the above-mentioned racemic compound 437 to afford the isolated enantiomer compound 131( R ) (mp 112.2-112.7 ° C) (210 mg) And compound 131( S ) (mp 112.0-112.1 ° C) (220 mg).

A. ( R )-1-(5- d ₁ -5-Hydroxyhexyl)-3-methyl-7-(methyl- d ₃ )-1H-indole-2,6(3H,7H)-dione (Compound 131( R ) ). ¹ H-NMR (300MHz, CDCl ₃ ): δ 1.19 (s, 3H), 1.39-1.56 (m, 5H), 1.64-1.74 (m, 2H), 3.58 (s, 3H), 4.03 (t, J = 7.3, 2H), 7.51 (s, 1H). ¹³ C-NMR (75 MHz, CDCl ₃ ): δ 22.87, 23.40, 27.89, 29.71, 38.64, 41.13, 107.68, 141.40, 148.76, 151.52, 155.39. HPLC (Method: Waters Atlantis T3 2.1 x 50 mm 3 μm C18-RP column-gradient method 5-95% ACN + 0.1% formic acid (1.0 mL/min) in 14 min and maintained at 95% ACN + 0.1% formic acid 4 minutes; wavelength: 305 nm): residence time: 3.29 minutes: 99.9% purity. For palmar HPLC (method: Chiralpak AD 25 cm column - isocratic method at 1.00 mL/min 78% hexane / 22% isopropanol / 0.01% diethylamine for 40 minutes; wavelength: 254 nm): residence time: 25.14 min (major enantiomer); 28.51 min (expected value of minor enantiomer): >99.9% ee purity. MS (M+H): 285.3, (M+Na): 307.2. Elemental analysis (C ₁₃ H ₁₆ D ₄ N ₄ O ₃ ): Calculated: C = 54.92, H = 7.09, N = 19.71. Found: C = 54.67, H = 7.04, N = 19.35.

It is noteworthy that there is no peak around 3.80 ppm in the above ¹ H-NMR spectrum, indicating the absence of hydrogen at the position of the methine hydroxyl group. Due to the presence of a triplet at 4.01 ppm in the above ¹ H-NMR spectrum, it is determined whether or not there is a single peak around 3.99 ppm corresponding to the presence or absence of hydrogen on the N-methyl group at the 7-position (R ¹ ) of the anthracene ring. impossible.

B.( S )-1-(5- d ₁ -5-Hydroxyhexyl)-3-methyl-7-(methyl- d ₃ )-1H-indole-2,6(3H,7H)-dione (Compound 131( S ) ). ¹ H-NMR (300 MHz, CDCl 3 ): δ 1.18 (s, 3H), 1.39-1.55 (m, 5H), 1.67-1.72 (m, 2H), 3.58 (s, 3H), 4.03 (t, J = 7.3, 2H), 7.51 (s, 1H). ¹³ C-NMR (75 MHz, CDCl ₃ ): δ 23.10, 23.63, 28.12, 29.94, 38.87, 41.36, 107.91, 141.33, 148.99, 151.75, 155.62. HPLC (Method: Waters Atlantis T3 2.1 x 50 mm 3 μm C18-RP column-gradient method 5-95% ACN + 0.1% formic acid (1.0 mL/min) in 14 min and maintained at 95% ACN + 0.1% formic acid 4 minutes; wavelength: 305 nm): residence time: 3.29 minutes: 99.9% purity. For palmar HPLC (method: Chiralpak AD 25 cm column - isocratic method at 1.00 mL/min 78% hexane / 22% isopropanol / 0.01% diethylamine for 40 minutes; wavelength: 254 nm): residence time: 28.51 min (major enantiomer); 25.14 min (expected value of minor enantiomer): >99.9% ee purity. MS (M+H): 285.3, (M+Na): 307.2. Elemental analysis (C ₁₃ H ₁₆ D ₄ N ₄ O ₃ ): Calculated: C = 54.92, H = 7.09, N = 19.71. Found: C = 54.65, H = 7.04, N = 19.32.

It is noteworthy that there is no peak around 3.80 ppm in the above ¹ H-NMR spectrum, indicating the absence of hydrogen at the position of the methine hydroxyl group. Due to the presence of a triplet at 4.01 ppm in the above ¹ H-NMR spectrum, it is determined whether or not there is a single peak around 3.99 ppm corresponding to the presence or absence of hydrogen on the N-methyl group at the 7-position (R ¹ ) of the anthracene ring. impossible.

Biological assessment

Example 15a . Evaluation of pharmacokinetics in dogs after oral administration. Comparative Compound 409 and Teflon

The metabolism of the title compound after oral administration to male beagle dogs was studied. The blood sample is removed from the dog at different times and the plasma is separated therefrom. Plasma samples were used to determine plasma drug content by LC-MS/MS (liquid chromatography tandem mass spectrometry) to estimate pharmacokinetic parameters.

Compound 409 and cefylphene were separately dissolved in saline to a concentration of 4 mg/mL. A 1:1 (v/v) mixture of the two solutions was prepared to obtain a solution having two compounds 409 and a final concentration of 2 mg/mL of cefolin.

Two male Miguel dogs were fasted overnight and then 2.5 mg/kg of Compound 409 and cefylamine were orally administered via tube feeding using the above mixture. At 0 minutes (before administration), 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours after administration Blood samples (1.5-2 mL) were collected via the femoral vein at 24 hours. The blood was stored on ice and then centrifuged to obtain a plasma sample. Centrifugation was performed within 1 hour of blood collection to collect plasma (maximum volume). Plasma was immediately decanted and frozen/stored at -70 °C until analysis.

a) % difference = [(deuterated substance type) - (non-deuterated substance type)] (100) / (non-deuterated substance type)

Table 8 shows the results of the evaluations described in Example 15a. The average _Cmax and mean AUC of Compound 409 (deuterated type of cefolin) were significantly greater than the combination of cefolin. Deuterated compounds exhibit greater exposure in canine plasma compared to the combination of ceflin.

Example 15b. Repeated evaluation of pharmacokinetics in dogs after oral administration. Comparison of Compound 409 with Teflon by Monitoring Metabolites

Example 15a was repeated by additionally monitoring the prostaglandin and compound 409 metabolites. In this experiment, compound 409 and cefylphene were separately dissolved in saline to a concentration of 4.4 mg/mL and 4 mg/mL, respectively. A 1:1 (v/v) mixture of the two solutions was prepared to obtain a solution having a final concentration of 2.2 mg/mL of compound 409 and 2 mg/mL of cefolin. Post-dose data analysis included adjustments to account for 10% difference in dosing concentration between Compound 409 and the formulated cefolin.

Four Miguel dogs (2-3 years old, and weighing 5 to 8 kg) were fasted overnight and then 2.75 mg/kg of Compound 409 and 2.5 mg/kg of Texacillin were orally administered via gavage using the above mixture. Blood samples (about 1 mL) were collected via the femoral vein at 0 minutes (before administration), 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, and 6 hours after administration. ). The blood was stored on ice and then centrifuged to obtain a plasma sample. Centrifugation was performed within 15 minutes of blood collection to collect plasma (maximum volume). Plasma was immediately decanted and frozen/stored at -20 °C until analysis.

The presence or absence of the administered compound and its corresponding M1 metabolite in the plasma sample was analyzed by LC-MS/MS:

The results from each of the four dogs are shown in Figures 1A and 1B. The results from one of the four dogs (Canine H, Figure 1b) were inconsistent with the results of the other three dogs. Five minutes after administration, the dog exhibited a 10-fold higher plasma concentration of each of the administered compounds and their corresponding metabolites. In addition, between 5 minutes and 15 minutes after administration, the dog did not show a characteristic increase in the plasma concentration of the administered compound. It is concluded that the dog is likely to have improper tube feeding and that the compound may be administered via the trachea rather than being administered to the gastrointestinal tract as required. Therefore, the information from this dog is not analyzed. A summary analysis of the remaining three dogs is shown in Table 9.

a) Compound 409 is administered at a concentration that is 10% higher than the concentration of the formulated cefolin and therefore the values reported herein reflect the adjustments made for the 10% increment.

b) % difference = [(deuterated substance type) - (non-deuterated substance type)] (100) / (non-deuterated substance type)

As can be seen in Table 9, compound 409 was observed to have a higher content in terms of _Cmax and AUC when compared to the formulated cefolin co-administered at the same level. Figure 1 shows that Compound 409 was more slowly cleared from plasma in the three dogs that were orally administered, compared to the formulation of ceflin. Figures 1a and 1b show that compound 409 was more slowly cleared from plasma in the three dogs that were orally administered, compared to the formulation of ceflin. Figures 1a and 1b also show that the overall systemic exposure of compound 419 (the morphological M1 metabolite of 409) after compound 409 administration is greater than the exposure of the M1 metabolite after administration of the cefolin.

Example 15c. Evaluation of pharmacokinetics in dogs after oral administration. Compound 413 was compared to the formulation of cefolin.

This study was similar to the studies described in Examples 15a and 15b except that Compound 413 was evaluated. Four male Miguel dogs were orally administered by tube feeding with a mixture containing 2 mg/mL of each of cefylamine and compound 413 in saline. Blood samples were taken as in Example 15b.

Example 10. Plasma content of compound 413 and cefylamine in dogs (Example 15c)

a) % difference = [(deuterated substance type) - (non-deuterated substance type)] (100) / (non-deuterated substance type)

The results of this study are summarized in Table 10 above. This table describes the plasma levels of Compound 413 compared to the formulated sifcillin after oral administration. Compound 413 was observed to have a higher content in terms of _Cmax and AUC when compared to the formulated cefolin co-administered at the same level.

Example 16. Evaluation of the stability of compounds in whole blood of rats. Compounds 409 , 435 ( S ), 435( R ) were compared to the prostaglandin and its M-1 metabolites.

This study was performed to assess the stability of the title compound in rat whole blood. Since the ketone (or keto-compound; the complex of cefolin or 409 ) and its corresponding M-1 alcohol metabolite are converted to each other, these groups are measured after the keto-compound is added to the blood or after the addition of M-1. The content of the portion. In other words, in some tests the keto-compound was the starting test compound, while in other tests the M-1 metabolite was the starting test compound.

Fresh rat whole blood lines were obtained from ViviSource Laboratories, Waltham, MA. A stock solution of the test compound (7.5 millimolar (mM)) was prepared in dimethylhydrazine (DMSO). The 7.5 mM stock solution was diluted in acetonitrile (ACN) to a concentration of 500 micromolar (μM). To 990 microliters (μL) of blood pre-warmed to 37 °C for 7 minutes, 10 μL of 500 μM test compound was added to a final concentration of 5 μM. The test compound was formulated with cefirin, a ( S )-M1 metabolite with cefoline, a ( R )-M1 metabolite with cefoline, a compound 409 , a compound 435 ( S ), and a compound 435 ( R ). The latter two test compounds are the ( S )-M1 and ( R )-M1 metabolites of compound 409 , respectively. The reaction mixture was incubated at 37 °C. An aliquot (50 μL) was removed at 0 min, 5 min, 15 min, 30 min, 1 h and 2 h after addition of the test compound and added to a 96-well plate containing 150 μL of ice-cold acetonitrile and internal standards to stop the reaction. . The plates were stored at -20 °C for 20 minutes, after which 100 μL of 50% acetonitrile/water was added to the wells, followed by centrifugation to pellet the precipitated proteins. Aliquots of 200 μL of each supernatant were transferred to another 96-well plate and the compounds listed in Table 11 below were analyzed by LC-MS/MS using an Applied Bio-System API 4000 mass spectrometer. The amount of a particular metabolite.

a) Quality observed via LC-MS/MS. According to the published profiling of the phenanthrene metabolism, the stereochemical configuration is assumed to be .

The results of this study are depicted in Figures 2 and 3. The time course of metabolite formation is shown in Figure 2. The relative amount of metabolite formed as shown in Figure 3 is based on the earliest time relative to which it was detected in the incubation mixture (5 minutes for A and B and 15 minutes for C) The amount that exists at 2 hours is calculated.

As can be seen in Figure 3, after about 2 hours, the amount of (S)-M1 formed in the whole blood of the rats cultured with the cefolin (Fig. 3, row A) was similar to that of the rats incubated with the compound 409 . The amount of compound 419( S ) formed in whole blood (Fig. 3, row B). Therefore, the substitution of ruthenium in compound 409 for the deuterated ( S )-M1 metabolite (compound 419( S )) compared to the relative content of non-deuterated ( S )-M1 formed from non-deuterated procylin ) does not have a significant impact.

For the reverse reaction of ( S )-M1 to keto-compound, deuteration does have a significant effect. Line C in Figure 3 shows the presence of an appreciable amount of the formulated cefolin after the addition of ( S )-M1. In contrast, compound 409 was not detected 2 hours after the addition of compound 435( S ) (Fig. 3, row D). Under these conditions, the indole substitution in compound 435( S ) hinders the conversion of this compound to the corresponding ketone. This effect is particularly advantageous for enhancing the plasma level of the desired M-1 metabolite.

No metabolic effects of ( R )-M1 to the combination of cefolin were detected in this assay. Similarly, after compound 435( R ) was added to rat blood, compound 409 was not detected. Therefore, no conclusion can be drawn about the effect of deuteration on the conversion of ( R )-M1 to the combination of cefolin. Figure 2 shows the time course for the production of specific metabolites during incubation of the administered compound with rat whole blood.

Example 17. Evaluation of the stability of compounds in human liver microsomes. Compare compounds 409 , 435( S ) , 435( R ) and zephyrin.

Example 17 is similar in design to Example 16 except that human liver microsomes were used in place of rat whole blood to study the metabolic effects of the compounds. Table 11 above shows the pairs of test compounds and metabolites analyzed in this Example 17.

Human liver microsomes (20 mg/mL) were obtained from Xenotech, LLC (Lenexa, KS). Beta-nicotine indoleamine adenine dinucleotide phosphate (reduced form (NADPH)), magnesium chloride (MgCl ₂ ) and dimethyl hydrazine (DMSO) were purchased from Sigma-Aldrich.

A stock solution containing 7.5 mM test compound (formed with cefolin, ( S )-M1 metabolite, ( R )-M1 metabolite, compound 409 , compound 435 ( S ), and compound 435 ( R ) ) was prepared in DMSO. The 7.5 mM stock solution was diluted to 250 [mu]M in acetonitrile (ACN). Human liver microsomes were diluted to 2.5 mg/mL in 0.1 M potassium phosphate buffer (pH 7.4) containing 3 mM MgCl ₂ . The diluted microsomes were added in triplicate to wells of a 96-well deep-well polypropylene plate. 10 μL of 250 μM test compound was added to the microsomes and the mixture was pre-warmed to 37 ° C for 10 minutes. The reaction was initiated by the addition of a pre-warmed NADPH solution. The final reaction volume was 0.5 mL and contained 2.0 mg/mL human liver microsomes, 5 μM test compound and 2 mM NADPH in 0.1 M potassium phosphate buffer (pH 7.4) and 3 mM MgCl ₂ . The reaction mixture was incubated at 37 ° C and 50 μL aliquots were removed at 0, 5, 10, 20 and 30 minutes and added to a shallow well 96-well plate containing 50 μL of ice-cold acetonitrile and internal standards to stop reaction. The plate was stored at 4 ° C for 20 minutes, after which 100 μL of water was added to the wells, followed by centrifugation to make the precipitated protein into a pellet. The supernatant was transferred to another 96-well plate and the amount of compound administered and its specific metabolites (listed in Table 11 above) was analyzed by LC-MS/MS using an Applied Bio-System API 4000 mass spectrometer.

The results of this study are depicted in Figures 4 and 5. The time course of metabolite formation is shown in Figure 4. The relative amount of metabolite formed as shown in Figure 5 is based on the earliest time relative to which it was detected in the incubation mixture (0 minutes for A, B, C, and E, and D for D) Calculated by the amount present at 30 minutes for 5 minutes and for 10 minutes for F. The amount of ( S )-M1 formed in human liver microsomes after 30 minutes of incubation with ceflin (Fig. 5, row A) is similar to compound 419 formed in human liver microsomes incubated with compound 409 ( The amount of S ) (Figure 5, line B). Therefore, compared with the relative content of non-deuterated ( S )-M1 formed from non-deuterated sirfed, the deuteration of Ceflin represented by compound 409 is for deuteration ( S )-M1 The relative amount of metabolite (compound 419( S ) ) did not have a significant effect. These results in human liver microsomes are consistent with those seen with whole blood in rats.

For the reverse reaction of ( S )-M1 to keto-compound, deuteration does have a significant effect. Line C in Figure 5 shows the presence of a large amount of matching cefolin after the addition of ( S )-M1. In contrast, after the addition of compound 435( S ) , the amount of compound 409 detected after 30 minutes was less than the content of ( S )-M1 (Fig. 5, row D). Compared to compound 409 produced from compound 435( S ), the amount of cefolin produced from ( S )-M1 was about 30%. Under these conditions, the indole substitution in compound 435( S ) hinders the conversion of this compound to the corresponding ketone. Although sputum has a greater effect in rat blood, the results are consistent.

The dramatic effect of hydrazine on the metabolism of ( R )-M1 metabolites was observed in human liver microsomes. And from non-deuterated (R) -M1 the non-deuterated form of the proper allocation of the amount of lipid lowering compared to human liver microsomes incubated After 30 minutes, (R) -M1 (Compound 435 (R)) of deuterated The effect was reduced to almost one-fifth of the amount of deuterated cefolin (compound 409 ) formed (compare lines E and F in Figure 5). Figure 4 shows the time course for the production of specific metabolites during incubation of the administered compound with human liver microsomes.

Example 18. Pharmacokinetic study of ( S )-M1 and compound 435( S ) in rats after oral and intravenous administration.

( S )-M1 and compound 435( S ) (( S )-M1 in deuterated form) were dissolved in saline at a concentration of 10 mg/mL, respectively. A 1:1 mixture of the two compounds, each at a final concentration of 5 mg/mL, was then prepared for intravenous administration. For oral administration, the mixture was further diluted in saline to a final concentration of the respective 1 mg/mL compound.

Three male Sprague-Dawley rats were used in each of the oral and intravenous studies. Animals were fasted overnight before administration of the compound. Intravenous administration was achieved by rapid injection of a 1:1 combination of 5 mg/kg single dose into the cannulated jugular vein of the rat. One day prior to dosing, cannulation was performed on rats that had been anesthetized with ketamine (IM 30 mg/kg). Oral administration was achieved by oral gavage of a single dose of 5 mg/kg. At different times (2 minutes, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours) after administration, by anesthesia with isoflurane temporarily Rats were sampled after sputum and blood samples (250 μL) were collected from the rats. Blood samples were placed in the tubes containing K ₂ -EDTA in and stored in ice until centrifugation. Plasma was separated by centrifugation within 30 minutes of collection. A 100 [mu]L aliquot was removed, mixed with 200 [mu]L acetonitrile and stored at -20[deg.] C. until further analysis by LC-MS/MS using an Applied Bio-System API 4000 mass spectrometer.

Samples were analyzed for the presence or absence of the compound administered, the corresponding ketone (formed with cefolin and compound 409 ) and the corresponding M5 metabolite. A sample (10 μL) was injected into a Zorbax SB-C8 (quick split) column (2.1 x 30 mm, 3.5 mm). The initial mobile phase conditions were 100% A (10 mM ammonium acetate in water) and 0% B (methanol) with a flow rate of 0.5 mL/min. The mobile phase B was brought to 55% in 3 minutes and 90% from 55% in 1 minute, and then changed back to 0% in 1 minute. The total operating time is 5 minutes. For the compatibility of cefolin and its M1 and M5 metabolites, the precursor/product ion pair was set to m/z 281/193 (M1), m/z 279/181 (with cefolin) and m/z 267 /221 (M5).

For compounds 435( S ) and 409 , more than one ion pair is set to detect the species resulting from the enthalpy loss. It has been found that a certain degree of enthalpy loss occurs for a compound of the invention (such as compound 409 ) having a hydrazone at a position adjacent to the carbonyl carbon in the side chain. This loss appears to occur in vivo and in vitro via an unknown mechanism. Prior to analysis, acetonitrile was added to the serum samples to prevent any additional in vitro helium loss. Typically, no more than two deuterium atoms are replaced by hydrogen. For compound 435( S ) , after oxidation to keto-compound 409 , the oxime position is depleted. Reversion of 409 to the M1 metabolite introduces a proton at the methine position. When sera from animals administered 435( S ) are analyzed to quantify the administered compound and metabolite, the total amount of the compound substance including one and two side chain oximes is included (hereinafter referred to as "-1D" and "-2D" substance type). Thus, for compounds 435( S ) and compound 409 , the ion pairs are individually set to detect the compound and its corresponding -1D and -2D species. For compound 435( S ) , three ion pairs were detected: m/z 291/197, 290/197, and 189/197. For compound 409 , the ion pairs m/z 288/186, 287/186 and 286/186 were monitored. The inclusion of the -1D and -2D species in the measurement of compound 409 and compound 435( S ) allows for more accurate quantification of the total active species and based on the metabolism and activity of the procylin and its M-1 metabolites. Putting is also reasonable. It is desirable to increase the plasma exposure to any of the M-1 metabolites of Compound 409 or 409 . This includes the -1D and -2D species.

For the corresponding deuterated M5 metabolite ( M5a ): ( M5a ), which has no enthalpy on its acid side chain, and uses only one ion pair m/z 271/225. The standard used for the analysis was indiplon.

a) Quality observed via LC-MS/MS. According to the published profiling of the phenanthrene metabolism, the stereochemical configuration is assumed to be ( S ).

b) % difference = [(deuterated substance type) - (non-deuterated substance type)] (100) / (non-deuterated substance type)

The results of oral administration in rats are shown in Table 12. The deuterated compound 435( S ) showed significantly higher AUC0 _-∞ and _Cmax than its non-deuterated counterpart ( S )-M1. Because there is significant serum interconversion between ( S )-M1 and the combination of cefprolin and both substances have therapeutic activity, the ( S )-M1 and the complexed cefolin, as well as the compound 435( S ) and the compound are also quantified. AUC _0-∞ and C _{max of} 409 . After oral administration of ( S )-M1 and 435( S ) , respectively, compound 435( S ) and compound 409 showed significantly higher AUC0 _-∞ and _Cmax than ( S )-M1 and the combination of cefolin.

AUC _0-∞ of M-5 and M5a metabolites produced by oral administration of ( S )-M1 and 435( S ) , respectively, were also measured. M-5 metabolites may be associated with toxicity in certain patients and are considered undesirable. Table 12 shows that oral administration of Compound 435( S ) provides significantly less M5a compared to the amount of M5 obtained after administration of non-deuterated ( S )-M1. The ratio of the active species of the deuterated compound to the M5 metabolite is much more advantageous than the non-deuterated compound. The ratio of (Compound 435( S ) + Compound 409 ) to M5a was 7.0, which was much better than the ratio of (( S )-M1+ofcephetine) to M5 of 1.6.

a) Quality observed via LC-MS/MS. According to the published profiling of the phenanthrene metabolism, the stereochemical configuration is assumed to be ( S ).

b) % difference = [(deuterated substance type) - (non-deuterated substance type)] (100) / (non-deuterated substance type)

Table 13 shows the results after intravenous administration in rats. The results of intravenous administration are similar to those of oral administration. After intravenous administration, compound 435( S ) has an average AUC0 _{-∞ that is} 110% greater than its non-deuterated counterpart ( S )-M1. After intravenous administration, compound 435( S ) and compound 409 have an average AUC0 _{-∞ which is} 79% greater than ( S )-M1 and neferan. Intravenous administration of Compound 435( S ) provides an amount of M5a metabolite that is 15% less than the amount of M5 metabolite provided by intravenous administration of ( S )-M1. The ratio of the active substance species to the corresponding M5 metabolite in the rats administered the compound 435( S ) intravenously was 7.4, which was in contrast to the 3.5 of the rats administered intravenously ( S )-M1.

Example 19. Pharmacokinetic studies of chimelin and compound 435( S ) in chimpanzees after oral and intravenous administration.

The cefolin and compound 435 ( S ) were dissolved in warm (65 ° C) saline at a concentration of 10 mg/mL. A 1:1 mixture containing the two compounds at a final concentration of 5 mg/mL each was then prepared and the mixture was then sterile filtered through a 0.2 μM filter.

Two chimpanzees (one male and one female) were used in each of the oral and intravenous studies. Animals were fasted overnight before administration of the compound. All animals were sedated with ketamine (about 10 mg/kg) and/or telazol (about 5 mg/kg) prior to dosing. Intravenous administration was achieved by intravenous infusion of 75 mg of each compound (15 mL total administration solution) for 10 minutes. Oral administration was achieved by oral gavage of a single dose of 75 mg of each compound (15 mL of the total administration solution). Blood samples (6 mL) were collected from the drug chimpanzees at different times before and after dosing. For intravenous administration, at 0 minutes (before infusion), 5 minutes, 9.5 minutes (immediately before the end of the infusion), then 6, 15, 30 and 45 minutes after the infusion, and 1, 2, 4, 6 Blood samples were collected at 8, 10 and 12 hours. For oral administration, blood samples were collected at 0 minutes (before administration), 15 and 30 minutes, and 1, 1.5, 2, 4, 6, 8, 10 and 12 hours after administration.

Blood samples were placed in tubes containing sodium heparin, mixed and stored on ice until centrifugation. Plasma was separated by centrifugation of the blood sample within 30 minutes of collection and an aliquot (200 μL) of the resulting plasma was removed. Aliquots of 200 μL of each plasma were mixed with 400 μL of acetonitrile and stored at -70 ° C until further analysis by LC-MS/MS using an Applied Bio-System API 4000 mass spectrometer.

Analysis of all samples was performed by LC-MS/MS as described above for the rat plasma samples in Example 18.

a) Quality observed via LC-MS/MS. According to the published profiling of the phenanthrene metabolism, the stereochemical configuration is assumed to be .

b) % difference = [(deuterated substance type) - (non-deuterated substance type)] (100) / (non-deuterated substance type)

Table 14 shows the results of oral administration of 435( S ) and cefolin in chimpanzees. Orally administered compound 435 (S) and the proper allocation of a lipid lowering: After a composition, compound 435 (S) and its corresponding ketone compound display 409 than the corresponding non-deuterated counterparts (S) -M1 properly and with a lipid lowering Significantly higher average AUC _0-∞ value. Compound 43S (S) with a compound of the mean AUC 409 _0-∞ significantly higher than (S) -M1 duly equipped with a lipid lowering the average AUC _0-∞. Further, undesirable deuterated M-5 metabolite (M5a) of average AUC _0-∞ AUC significantly less than the average non-deuterated M-5 of the _0-∞. Finally, the ratio of the active species of the deuterated compound to the M5 metabolite {( 435( S ) + 409 ): (deuterated M5)} is the corresponding ratio of the non-deuterated species {(( S )-M1+配西西Film): M5} is about 8 times higher.

a) Quality observed via LC-MS/MS. According to the published profiling of the phenanthrene metabolism, the stereochemical configuration is assumed to be ( S ).

b) % difference = [(deuterated substance type) - (non-deuterated substance type)] (100) / (non-deuterated substance type)

Table 15 shows the results of intravenous administration of 435( S ) and cefolin in chimpanzees. The results after intravenous administration showed favorable differences in the sputum compound, but the difference was not as significant as that observed after oral administration. The amount of active substance produced by self-administerment of compound 435( S ) is between 40% and 57% higher than that of administration of cefolin, and the amount of M5 metabolite produced is reduced by 60% and 65%. between. The ratio of the active substance species to the M5 metabolite in the chimpanzee administered intravenously to the compound 435( S ) was about 4 times higher than that of the chimpanzee administered with the siflulin.

The above results show that the compounds of the invention provide greater plasma exposure of the desired active species compared to the corresponding non-deuterated compounds. In addition, the guanidine substitution in the compounds of the invention is shown to reduce the amount of M5 metabolites that may be associated with intolerance in patients with renal impairment.

Without further elaboration, the skilled artisan can make and utilize the compounds of the present invention and practice the claimed methods using the foregoing description and illustrative examples. It will be appreciated that the above discussion and examples are merely illustrative of certain preferred embodiments. It will be apparent to those skilled in the art that various modifications and equivalents may be made without departing from the spirit and scope of the invention.

1A and 1B depict serum levels of a compound of the present invention, a combination of cefirin and certain corresponding metabolites in four individual dogs after oral administration of a combination of ceflin and a compound of the invention.

Figure 2 depicts the time course of the specific metabolites measured in Figure 3 after incubation of different compounds of the invention, cefolin, ( S )-M1 and ( R )-M1 with rat whole blood.

Figure 3 depicts the relative amounts of specific metabolites produced following incubation of different compounds of the invention, cefolin, ( S )-M1 and ( R )-M1 with rat whole blood.

Figure 4 depicts the time course for the production of the specific metabolites measured in Figure 5 after incubation of different compounds of the invention, cefolin, ( S )-M1 and ( R )-M1 with human liver microsomes.

Figure 5 depicts the relative amounts of specific metabolites produced following incubation of different compounds of the invention, cefolin, ( S )-M1 and ( R )-M1 with human liver microsomes.

Claims (28)

a compound of formula B, Or a pharmaceutically acceptable salt thereof, wherein: R ¹ and R ² are each independently selected from -CH ₃ and -CD ₃ ; R ⁵ is hydrogen or deuterium; and (a) Y ¹ is OH, and Y ² is hydrogen or helium, or (b) Y ¹ and Y ² together with the carbon to which they are attached form C=O. A compound of claim 1, wherein R ⁵ is hydrazine. A compound of claim 2, wherein R ¹ is -CD ₃ . The compound of claim 1, wherein each of R ¹ and R ² is -CD ₃ . A compound of claim 1, wherein Y ¹ and Y ² together with the carbon to which they are attached form C=O. A compound of claim 1, wherein Y ¹ is OH and Y ² is hydrogen or deuterium. The compound of claim 1, wherein the compound is a compound of formula I, Or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: Or a pharmaceutically acceptable salt of any of the above; wherein "†" represents a moiety of the compound wherein the R ⁴ moiety is attached to C(Y ¹ )(Y ² ). The compound of claim 1, wherein the compound is a compound of formula A, Or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: Or a pharmaceutically acceptable salt of any of the above; wherein "†" represents a moiety of the compound wherein the R ⁴ moiety is attached to C(Y ¹ )(Y ² ). The compound of claim 1, wherein the compound is selected from any one of the following: Or a pharmaceutically acceptable salt of any of the above. a compound represented by the following structural formula Or a pharmaceutically acceptable salt thereof. For example, the combination of any of items 1 to 10 of the patent application scope Any atomic system in which no yttrium is designated is present in its natural isotopic abundance. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier. The pharmaceutical composition of claim 12, which is for treating a disease or condition of a patient in need thereof, wherein the disease is selected from diabetic nephropathy, hypertensive nephropathy or caused by chronic obstructive arterial disease of the extremities Intermittent limp. For example, the pharmaceutical composition of claim 12 is for the treatment of chronic kidney disease in a patient in need thereof. The pharmaceutical composition of claim 14, wherein the chronic kidney disease is glomerulonephritis, focal segmental glomerulosclerosis, renal syndrome, reflux uropathy, or polycystic kidney disease. For example, the pharmaceutical composition of claim 12 is for the treatment of chronic liver disease in a patient in need thereof. The pharmaceutical composition of claim 16, wherein the chronic liver disease is nonalcoholic steatosis hepatitis, fatty liver degeneration or other diet-induced high fat or alcohol-induced tissue degeneration, liver cirrhosis, liver failure or Alcoholic hepatitis. The pharmaceutical composition of claim 12, which is for treating a diabetes-related disease or condition in a patient in need thereof, wherein the disease or condition is selected from the group consisting of insulin resistance, retinopathy, and diabetic ulcer. Radiation-related necrosis, acute renal failure, or drug-induced nephrotoxicity. For example, the pharmaceutical composition of claim 12 is used for treatment. Intermittent claudication caused by chronic obstructive arterial disease of the extremities in patients in need. The pharmaceutical composition of claim 12, which is for treating a disease or condition of a patient in need thereof, wherein the disease or condition is selected from insulin-dependent diabetes; non-insulin dependent diabetes; metabolic syndrome; Obesity; insulin resistance; abnormal dyslipidemia; pathological glucose tolerance; hypertension; hyperlipidemia; hyperuricemia; gout; A use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for the treatment of a disease or condition in a patient in need thereof, wherein the disease is selected from the group consisting of diabetic nephropathy, Hypertensive nephropathy or intermittent claudication caused by chronic obstructive arterial disease of the extremities. Use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for the treatment of chronic kidney disease in a patient in need thereof. The use of the scope of claim 22, wherein the chronic kidney disease is glomerulonephritis, focal segmental glomerulosclerosis, renal syndrome, reflux uropathy, or polycystic kidney disease. A use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for the treatment of chronic liver disease in a patient in need thereof. The use of claim 24, wherein the chronic liver disease is nonalcoholic steatosis hepatitis, fatty liver degeneration or other diet-induced high fat or alcohol-induced tissue degeneration, liver cirrhosis, liver failure or Alcoholic hepatitis. Use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for treating a diabetes-related disease or condition for a patient in need thereof, wherein the disease or condition It is selected from the group consisting of insulin resistance, retinopathy, diabetic ulcer, radiation-related necrosis, acute renal failure, or drug-induced nephrotoxicity. A use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for the treatment of intermittent claudication caused by chronic obstructive arterial disease of the extremities in a patient in need thereof. Use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for the treatment of a disease or condition in a patient in need thereof, wherein the disease or condition is selected from the group consisting of insulin Dependent diabetes; non-insulin dependent diabetes; metabolic syndrome; obesity; insulin resistance; abnormal dyslipidemia; pathological glucose tolerance; hypertension; hyperlipidemia; hyperuricemia; gout;