TW201107326A - Substituted xanthine derivatives - Google Patents

Abstract

This invention relates to novel compounds that are substituted xanthine derivatives and pharmaceutically acceptable salts thereof. For example, this invention relates to novel substituted xanthine derivatives that are derivatives of pentoxifylline. This invention also provides compositions comprising one or more compounds of this invention and a carrier and the use of the disclosed compounds and compositions in methods of treating diseases and conditions for which pentoxifylline and related compounds are beneficial.

Description

201107326 VI. Description of the Invention: TECHNICAL FIELD OF THE INVENTION The present invention relates to a novel compound which is a substituted xanthine derivative and a pharmaceutically acceptable salt thereof. The present invention is also directed to a composition comprising one or more of the present sigma sigma and a carrier, and the disclosed compounds and compositions in the treatment of a cup of pentoxify and related compounds and Use in the method of pathology. [Prior Art] The combination of cefolin 1-(5-oxo-oxyhexyl)-3,7-dimethylxanthine is marketed in the United States and Canada under the trademark Trental®. 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 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 thrush stomatitis, chronic breast pain in breast cancer patients, brain and central nervous system tumors, and malnutrition · Inflammation - cachexia syndrome. The compatibility of cefolin has recently received attention as a potential therapeutic for diabetes and diabetes-related conditions. #克Ferrari, E 荨人, Pharmatherapeutica, 1987, 5(1): 26-39 ; Raptis, S et al, Acta Diabetol Lat, 1987, 24(3): 181-92 ' and Rahbar, R_ et al' ciin Chim Acta, 2000, 301 (1-2): 65-77. 201107326 It is known that the combination of cefolin has phosphodiesterase (PDE; see

Meskini, N et al. 'Biochem. Pharm. 1994, 47(5): 781-788) activity of inhibitors and activity against other biological targets, but the exact mode of action for their clinical effects is unknown. It has been shown that the compatibility of ciprofloxacin improves blood flow by reducing blood viscosity and improving blood rheology of red blood cell flexibility. The addition of cefolin also increases leukocyte deformability and inhibits neutrophil adhesion and activation. (See http://www.fda.gov/cder/foi/nda/99/74-962_Pentoxifylline p rntlbl.pdf for FDA labeling with cefolin). In addition to improving the rheological properties of the blood, it 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. Compatible with cefolin experienced rapid first pass metabolism. The peak blood content of the cefolin and its metabolites was reached within - hours. The structure of the combination of ceflin and its various reported metabolites is shown below.

CH3

M-1 is matched with cefolin 4 201107326 0H 〇

Μ-

OH

PH3 I N

The main metabolites produced are Μ-1 and M-5. The blood t content of these metabolites is five and eight times that of the parent drug, respectively. (See http://www.fda.gov/cder/f〇i/nda/99/74.962 Pent〇xifylHne p nulbl.pdf for FDA labeling with cefolin). The μ·丨 metabolite has a palmitic center and forms the (4)- and (7)-enantiomers. During the metabolism of the cefolin, a mutual transition occurs between the Μ·1 enantiomer and the cefolin. The (S)-enantiomer is the main Μ_〗 substance species (s:r ratio reported to be about 90:H) or larger) and is more rapidly converted than the (4)-enantiomer. : owe (/〇-M1 metabolite (called lisofylline) has been reported to have novel anti-inflammatory properties. Although active M1 metabolites appear to be associated with the clinical activity of cefolin 201107326 important role 'but other metabolites It can cause drug toxicity. Especially in patients with renal dysfunction, the risk of toxicity to cefolin may be greater (http://products.sanofi-aventis.us/trental/trental.pdf). It is noted that patients with renal impairment who take the drug need to monitor the renal function. In addition, at least one product is marked with a warning that the application of cefolin should not be given 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 dysfunction b deficiency, the plasma levels of the combination of ceflin and M-1 show a downward trend, while the content of M-4 and especially M-5 metabolites depends on the degree of functional impairment. Greatly increased. See paap, Ann Pharmac〇ther, ι996, 3〇: 724. Comprehensive considerations' These observations indicate 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, t〇rbafyiiine, a_8〇2715 and propentofylline as shown below.

Abiphylline (Rx = Η) levopyl theophylline tobaline (Rx = CH2OCH2CH3) A-80271 5 ( Rx = CH2CH2CH3) 201107326 Despite the beneficial activity of the combination of cefolin, it continues to be needed in larger patients Novel compounds in the population that treat the above-mentioned diseases and reduce the risk of toxicity and other adverse effects. [Invention] The present invention relates to a novel compound which is a substituted xanthine derivative and a pharmaceutically acceptable salt 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 - or a plurality of 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 ceflin and related compounds. [Embodiment] 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. A disease means any condition or disorder that damages or interferes with the normal function of a cell, tissue or organ. It should be recognized that there is some degree of variation in the abundance of natural isotopes in the compounds synthesized by the source of the chemical used in the synthesis. Thus, a formulation formulated with cefolin will inherently contain a small amount of a purine isoform analog. Despite this change, the concentration of the natural abundance-stabilized hydrogen and carbon isotope is lower and less important than the degree of stable isotope substitution of the compounds of the present invention. See, for example, Wada e et al, Seikagaku, 1 994, 66·15, Gannes LZ et al, c; omp Biochem Physiol Mol Integr 201107326

Physiol, 1998, 1 1 9: 725. In the compounds of the present invention, when a particular position is designated as having a hydrazone, it is understood that the abundance of the ruthenium at that position is substantially greater than the natural abundance of ruthenium (which is 0.015%). A minimum isotope enrichment factor (50.1% 氘 merging) of at least 334 Å at each atom designated as 氘 in the compound, 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, the compound of the invention has at least 3500 for each specified deuterium atom. Isotopic enrichment factor (52.5〇/〇 for each specified 氘 atom), at least 4〇〇〇 (60%氘), at least 45〇〇 combined, at least 6000 (90%気 combined Degree), at least 6333 3 (95% gas pooling degree)' at least 6466·7 (97% gas pooling degree), at least 6_(9 state 氘 merging degree) or at least 6633.3 (99 5% 氘 combining degree). In a compound, any atom not specifically designated as a specific isotope is intended to represent any stable isotope of the other atom. Unless otherwise stated, the position is specifically designated as "Η" or "nitrogen," where the position is understood to have a natural abundance isotope The composition of hydrogen. Also, unless otherwise stated, no, the position specified as "D" or "氘", when 誃 has at least A - 〇Λ should be understood as having a natural abundance of up to 4 claws (which is 0.015%) 334 〇 氘 (that is, at least 5· 1 % 氘 merging degree) ^ 素 素 analogs are substances that are characterized by different isotope compositions. The term "compound" f relates to the compound of the invention means that the compound + 201107326: has the same chemical, except for possible isotopic variations between constituent atoms. A collection of knives. Because of this, it is understood by those skilled in the art that a compound represented by a specific chemical structure containing the phase gas + also contains a relatively small amount of an isotope having a hydrogen atom at one or more designated oxime positions in the structure. Things. 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 atmosphere in the various synthetic steps used to prepare the compound, efficiency' However, as noted above, the relative amounts of the isotopic analogs are all less than 49.9% of the compound. Sheming also provides salts of the compounds of the invention. The salt of the compound of the invention is formed between the acid and a basic group of the compound, such as an amine functional group, or between an acidic group of the compound, such as a pendant functional group. According to another specific embodiment, the compound is a pharmaceutically acceptable acid addition salt. The term "pharmaceutically acceptable" as used herein refers to a method suitable for contact with tissues of humans and other mammals, irritating, allergic reactions, and the like, within the scope of correct medical judgment, and 2 The proportion of the benefit/risk ratio is proportional. "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. The "pharmaceutically acceptable relative ion" does not have an ionic portion of the salt when released from the salt after administration to the recipient. - Acids commonly used to form pharmaceutically acceptable salts include inorganic acids, hydrogenated hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, and on-machine 1 such as p-toluene, acid Acid, tartrazine, di-tartaric acid, limonic acid, besysulfonic acid, besyHc acid, anti-butene 201107326 s gluconic acid, glucuronic acid, formic acid, glutamic acid, sulfonic acid, B Physic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-, odorous benzenesulfonic acid, carbonic acid, diacid, citric acid, #carboxylic acid and acetic acid, and related inorganic and organic acids. Accordingly, such medically acceptable salts include sulfur I salts, pyrosulfate salts, hydrogen sulfate salts, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates. , pyrophosphate, chloride, bromide 'iodide, acetate, propionate, citrate, octanoate' acrylate, citrate, isobutyrate, citrate, heptanoate, propyne Acid salts, oxalates, malonates, succinates, suberates, sebacates, fumarates, cis-succinates, butyne-1,4-diacids Salt, hexyne-1,6-diacid salt, benzoate, gas benzoate, methyl benzoate, dinitrophenyl phthalate, hydroxybenzoate, methoxybenzoquinone Acid salt, phthalate, p-dibenzoate, acid salt, diphenyl benzoate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, Hydroxybutyrate, glycolate, maleate, tartrate, sulfonate, propane sulfonate, naphthalene-1 - sulfonate, naphthalene-2 sulfonate, mandelate and others salt. 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 linked by non-covalent intermolecular forces (such as 10 201107326 gas methane, 2-propanol or the like) Water, acetone, ethanol, methanol, compounds. It should be understood that the carbon atoms bearing a substituent in the formula A, Al, u B, and γ2 may be palmar in some cases (when mR3 are different from each other) and in other cases they may be non-pair Palmish (when at least two of γ|, 丫2, and r3 are the same). Α A A, τ 石々日Ν才J. In the formula Α, A1, ϊ and Β, this carbon atom (i.e., a carbon atom having Υ^Υ2) is indicated. Thus, the palmitic compounds of the present invention may exist in individual enantiomeric forms or in the form of 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 which are substantially free of the other possible stereoisomers. The term "substantially free of other stereoisomers" as used herein means that less than 25% of other stereoisomers, preferably less than (10) other stereoisomers, more preferably less than 5% are present. Other stereoisomers and preferably less than 2% of 1 other stereoisomer, or less than "Χ"% of other stereoisomers (where X is between 〇 and 100^ including 0 and 1〇〇) The numerical values obtained. The individual enantiomers of the specified compounds are obtained or synthesized: the methods of the constructs are well known in the art and are employed when applicable to the final compound or starting material or intermediate. Unless otherwise indicated A compound that is not revealed by a person who has not been identified by a name or description and has a stereochemical configuration and has - or more (four) palms should be considered to represent all possible stereoisomers of the compound. As used herein. The term "stabilizing compound" means having sufficient to permit the stability of the material and maintaining the integrity of the compound for a sufficient period of time: for the purpose of the present invention (for example, formulation into a therapeutic product for the production of an intermediate for the treatment of 201107326 therapeutic mouthparts) Separable or A compound that can be stored as an intermediate compound, a disease or condition that responds from a therapeutic agent. ° is a private sputum. "Stereoisomer" refers to both enantiomers and diastereomers. “Third”, ... and “t·” each refer to the third. “us” means the United States. As used herein, "stretching base" means a straight or branched divalent hydrocarbon group (C, -6 alkylene group) preferably having one to six anaerobic atoms. In some specific examples, the excipient has one to four carbon atoms (extension base). As used herein, "alkyl," examples include, but are not limited to, methylene (CH2-), ethyl (_CH2CH2), propyl (_CH2CH2CH2), and its branched forms, such as, _CH2CH (CH+ and the like. "Halo" means a gas group, a bromo group, a fluoro group or an iodine group. The alkyl group means a straight chain or a branched chain and has 1 to 15 stone anti atoms in the chain. An aliphatic hydrocarbon group. Preferably, the alkyl group has from 丨 to 2 carbon atoms in the chain, and more preferably has from 丨 to 6 carbon atoms. Branches mean one or more such as methyl, ethyl or propyl. The lower alkyl group is attached to the linear alkyl chain. "Low-carbon alkyl group means from about 1 to about 4 carbon atoms in the chain which may be straight or branched." Exemplary alkyl groups include methyl, fluoromethyl. Base, difluoromethyl, trifluoromethyl, cyclopropyl decyl, cyclopentyl decyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, 3_ Butyl, heptyl 'octyl, decyl, decyl and dodecyl; preferably methyl, difluoromethyl and isopropyl. The alkyl group may optionally be one or more selected from the group consisting of Substituted: halo, cyano Base group, carboxyl group, alkoxy group, alkoxycarbonyl group, pendant oxy group, amine group, alkyl group 12 201107326 Amino group, dialkylamino group 'cycloheteroalkyl group, alkylcycloheteroalkyl group, aryl group, alkane Alkyl, heteroaryl and alkylheteroaryl. Typically, any alkyl or alkoxy moiety of the alkyl substituent has from 1 to 6 carbon atoms. "Aryl" means 6 to 1 An aromatic carbocyclic group of one carbon atom. 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 groups and aromatic groups. Alkyl, aralkyl, alkoxy, aryloxy, aralkyloxy, halo and nitro. Typically, any alkyl or alkoxy moiety of the aryl substituent has from 6 to 6 carbon atoms 'Heteroaryl" means a 5 to 1 member aromatic monocyclic or polycyclic hydrocarbon ring system in which one or more carbon atoms in the ring system are elements other than carbon, such as nitrogen, oxygen or sulfur. 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, aralkyl Oxyl, functional and nitro. Exemplary heteroaryl groups include, for example, pyrazinyl, furyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isethazolyl, pyridazinyl, anthracene, 2, 4-triazinyl, quinolyl and isoquinolyl. Aralkyl" means an aryl group and an alkyl component. The aryl group as described above preferably has a lower alkyl group. Exemplary aralkyl groups include benzyl and 2-phenylethyl. ''Heteroaralkyl, meaning heteroaryl and alkyl groups are heteroaryl-alkyl groups as previously described. A non-aromatic monocyclic, polycyclic or bridged ring system with 3 to 10 carbon atoms. I have a base- or poly(tetra)-based or no-base substitution. Including cyclopentyl, gas cyclopentyl, cyclohexyl 13 201107326 and phosphinyl. "cake hetero-alkane& is a non-aromatic monocyclic, bicyclic or tricyclic ring, or bridge 熳, wherein - or a plurality of 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 夂"a ring atom. Exemplary heterocycloalkyl groups are pyrrolidine, piperidine tetrahydrofuran, tetrahydrothiopyran and tetrahydrothiofuran. Oxanium cycloalkylane "Base" means a group such as a cycloalkyl group and an alkyl component. The redundant corpse n ''Miscellaneous base') means a group that is more basic than the base group. ^尤月j - The term "replaces by gas, means the part or compound mentioned Or a plurality of hydrogen atoms may be replaced by a corresponding number of deuterium atoms. Throughout this specification, the code number may be referred to generically (eg, ‘‘,,,) ^ special: mention (eg, etc.). Unless otherwise indicated, no heart;:: refers to all special therapeutic compounds that are intended to include a particular code. The present invention provides a compound of formula A:

Or a pharmaceutically acceptable salt thereof, each of R and R is independently selected from hydrogen '-(Ci-cu)morphyl' or _((VC4) 201107326 alkyl-o-(c,-c-decane a base wherein the alkyl group and the alkylene group are substituted in each case in winter and optionally by hydrazine; R3 is selected from the group consisting of -CH3, -CH2D, -CHD2 and -CD3; and R4 is an exo-butyl group which is optionally substituted by hydrazine; K is selected from the group consisting of gas, melon, hydrazine, cycloalkyl, heterocycloalkyl, cycloalkyl: hydrazino, aryl and heteroaryl, wherein aryl, cyclo::, hetero-alkyl , % alkylalkyl, heterocycloalkylalkyl, aryl and heteroaryl; owing: substituted: and wherein alkyl, carbyl, heterobiphenyl, heterocyclic, aryl or heteroaryl Base: - or a plurality of hydrogen atoms in the pit base group are replaced by the number of phase libraries as the case may be; and the carbon of the 邳I number of 氘 atoms is formed together from hydrogen, hydrazine, a) Y and Y Each is fluorine, or is conjugated thereto, or (b) Yi is selected from the group consisting of fluorine and grab and γ2. -CH2D, -CHD2 and -CD3; the restrictions are: at least one of the fields has: When, RI, when Y1 is 〇Η^γ2 is gas or CH3/a scorpion; and At least one of R5 carries at least one deuterium atom / m. In another embodiment, the compound of formula A does not:

15 201107326

H3C

03 PN /N In another specific example of formula A, when R1 and R2 are each methyl optionally substituted by hydrazine and R5 is hydrogen or deuterium, then: (i) Y1 is a fluoro group; or (ii) Y1 is OH, and Y2 is selected from -CH3, -CH2D, -CHD2, and -CD3. In one aspect of this specific example, the compound is not

In a more specific aspect of one of the specific examples, at least one of Y2, R1, R2, R3, and R4 carries at least one germanium atom. In another embodiment of Formula A, R1 and R2 are each an optionally substituted thiol group; R5 is hydrogen or deuterium; and: (a) Y1 and Y2 together with the carbon atom to which they are combined form =0, or (b) Y1 is -OH and Y2 is selected from the group consisting of hydrogen and helium, and the restrictions are as follows: When Y1 and Y2 together with the carbon to which they are combined form C = 0, then at least R1, R2, R3, R4 and R5 One has at least one germanium atom; and when Y1 is OH, at least one of the shells ij Y2, R1, R2, R3, R4 and R5 carries at least one atmosphere atom. In another embodiment of Formula A, R5 is D, and the compound has the formula 16 201107326 X , R1 : a cup R 2 A1 : (A1 ) or a salt thereof, wherein R1, R2, R3, R4, Y, and Y2 are as e is defined by Formula A. In one aspect of Formula A1, ... and R2 are each independently selected from -CH3, -CH2D, _CHD2, and CD3; r3 is selected from the group consisting of even D, _c, and CD3, R # I - (CH2)4. ^ -(CD2)4. , t -(CD2)3CH2 at CD2(CH2)3-, wherein "t, 'is the portion of the r4 moiety that binds to c^KY2 in the compound); a) γ, which is 〇H and γ2 is selected from hydrogen and atmosphere; or (b) γ1 and γ2 are formed by the carbon-bonded thereto (4). In a more specific aspect of formula A1, ^2 is independent Select one (CH:)"ra = ~ connected v-=: freely in another aspect of formula A1, Rl and R2 and even are selected from even. CD^ is independently selected from even-called chuyUy2 is connected to it and is in the other embodiment, the present invention provides c=0. Is hydrogen, the compound has the formula j · ·, eight A compound, of which R5

R3 * R4-N

R1 〆NJ NN R2 (or a salt thereof, wherein R1 and R2 are each independently selected from the group consisting of hydrogen, ~(a 17 201107326 alkyl-OjCi-C^), wherein alkyl and alkyl are in each case Independently and optionally substituted by hydrazine; R3 is selected from the group consisting of _CH3, -CH2D, -CHD2 and -CD3; r4 is an exobutyl group substituted by hydrazine as appropriate; and (a) γ1 and γ2 are each fluorine, or The attached carbons together form C = 〇; or (b) Y1 is selected from the group consisting of fluorine and OH; and Y2 is selected from the group consisting of hydrogen, hydrazine, _CH3, -CH2D, -CHD2, and -CD3, with the following restrictions: When Y1 and When Y2 forms a c = 0 together with the carbon to which it is attached, then at least one of R1, R2, R3 and R4 carries at least one deuterium atom; and when Y1 is OH and Y2 is hydrogen or -CH3, then R1 At least one of R2, R3 and R4 carries at least one gas atom. In a more specific embodiment of Formula I, R1 and R2 are each independently selected from -ch3, -CH2D, -CHD2, and -CD3; It is selected from -CH3, -CH2D ' -CHD2 and -CD3 ; r4 is selected from -(CH2)4·,·((:Ι)2)4-, t _(CD2)3CH2 and t-CD2(CH2) 3_, where "t" represents the part of the R4 moiety that binds to c(y|)(Y2) in the compound And YU 〇H and Y, selected from hydrogen and hydrazine; or γ and γ together with the carbon to which they are attached form c=〇. In the other 'cancer sample of Formula 1, R1 and R2 are each independently selected from - Ch3 and CE>3, R is selected from _Cli3 and 'CD3; R4 is selected from -(CH2)4- and t_C2D2(CH2)3_'a. γ1 is 0H and Y2 is selected from hydrogen and gas; or Y1 And Υ together with the carbon to which it is attached to form c=〇. In another aspect of Formula I and -CD3; R3 is selected from the group consisting of 'R and R2 are each independently selected from -CH3 and -CD3; R4 is selected from _(CH2)4- and t 201107326 -CD2(CH2)3-; and Y1 and Y2 together with the carbon to which they are attached form c = o. In another embodiment, in any of the aspects set forth above, I compounds are not the following compounds:

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:

19 201107326 Another specific example of the present invention provides a < n compound: R3^ r4-n〆 ο

Ν R2 R1

N />

N (II ) or a salt thereof, wherein: R and R are each independently selected from hydrogen, _(Ci_c4)alkyl, or _(Ci_C4) extend m(C|'C2), wherein the base and the extension are burned. The base is independently and optionally substituted by hydrazine in each case; ^ is selected from the group consisting of .CH3, _CH2D ' _ coffee 2 and _CD3; R4 is an exo-butyl hydrazine substituted by hydrazine as appropriate and wherein R, R3 and R4 are At least one of them carries at least one helium atom. A specific example is a compound wherein R2 and R3 are each independently selected from the group consisting of A, Al, I or II, wherein: CH3, -CH2D, -CHD2 and -CD3. Another specific example is a compound of formula A, A, I or II wherein each of the ^ and r3 systems are independently selected from -CH3 and -CD3. Another specific example is a compound of formula A, A1, I or II wherein R is selected from the group consisting of nitrogen, (CrCj alkyl and (C"C2)alkyl-hydrazine-Ci_C2) alkyl. Another specific example is A compound of formula A, A, I or II, wherein R is hydrogen, -CH3, -CD3, -CH2CH2CH3, -CD2CH2CH3, -CD2CD2CH3'-CD2CD2CD3^-CH2OCH2CH3'-CH2OCD2CH3'-CD2OCD2CH3 or -ch2ocd2cd3. -CD2〇 CH2CH3 - cd2ocd2cd3. Another specific example relates to a compound of formula A, wherein R5 is selected from the group consisting of hydrogen, 20 201107326 hydrazine, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl and heterocycloalkylalkyl' Wherein alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl and heterocycloalkylalkyl are each optionally substituted. In other specific examples of formula A, A1 or I: a) each of R4 The methylene unit is selected from the group consisting of _Ch2_&_Cd2_; more specifically, the R4 is selected from the group consisting of -(CH2)4-, -(CD2)4-, f_CD2(CH2)34'-(CD2)3CH2_, which represents r4 Connected to the point of c(yi)(y2) in the compound; b) When Y1 is F, Y2 is selected from hydrogen, _CH3, _CH2D, _CHD2 and -cd3; or c) When Y1 is F, Y2 is fluorine ; or d) when Υ and Υ 2 When γ2 and R3 are different and γ| is the same as R3 and γ1ν, γ2 ′′, “the stereochemical configuration is represented by r3\r4-丨; or e) when Y and Y2 are different and γ2 and R3 are not When the same and γι and R3 are not γΐ γ2 〆, the stereochemical configuration is represented by R3:^R4-丨. 3 In other specific examples of Formula A, A1 or I, Rl is _Cd3 ·, R2 and R3 is -ch3; Y丨 and Y2 together form c=〇; and r4 is selected from (CH2)4_, -(CD2)4-, t-CD2(CH2)3jt.(CD2)3CH2_. In formula A r3 -CH3; and -(cd2)4-. In other specific examples of A1 or I, 'Rl is -CD〆R2 and Y and Y together form C=〇; and R4 is selected from -(CH2)4_3 In other specific examples of Formula A, A1 or I, R| is R2 and is -CH3, R is _(CH2)4-; γ1 is a fluorine group; and γ2 is selected from the group consisting of sinking, -CH2D, _CHd2, and _〇£) 3. 2011 201107326 3 In other specific examples of formula A, A1 or Ϊ, R1 is -Ch; ... and R3 is -CH3; Μ is _(CH2)4-; γ1 is a fluorine group; and 丫2 is a failure. In other specific examples of the formula or A1, Ri is; r2 and y are -CH3; R4 is _(CH2)4_; r5 is 氘; γ丨 is a fluorine group; and γ2 is selected from 氘'-CH2D' - CHD2 and -CD3. In other specific examples of Formula A or A1, R1 is -CD〆R2 and y is -ch3; r, _(CH2)4.; r5u; YU fluoro group; and 丫2 is oxygen. In other specific examples of Formula A, or 1, γΐ is F; γ2 is selected from hydrogen, R is -CH3丨 and r4 is _(CH2)4_. Υ is F; Υ2 is fluorine; in other specific examples of formula A, A 1 or I, r3 is -CH3; and r4 is -((:Η2)4-. A specific example provides a compound of the formula:

^ Υ2 2? Ζ3 25 25 Β, or a pharmaceutically acceptable salt thereof, wherein R and R2 are each independently selected from -CH3 and _ or 氘; Z3 is each hydrogen D gas. 74 々 Δ A,斗, > ^ 马风飞次讥, Z are each hydrogen or helium; Z5 is each hydrogen hamster; and (1) Y丨 is OH, and ¥2 is nitrogen or atmosphere, or (1) ¥丨 and = together with the carbon to which it is attached c = 〇. A specific example is a compound of the formula, u, /, formula B, wherein Z3, Z4 and Z5 are hydrogen. In one aspect, 'RI 3 D 2 is A 11 each is -CD3. In another aspect, 5 is 氘. In another aspect, and Y is taken together with the carbon to which it is attached, c = 0. In another aspect, γ is formed as OH, and Y2 is hydrogen or helium. Another specific example is to extract the Β3 ώ compound, which is Ζ3, Ζ4, and Ζ5 each 22 201107326. In one aspect, R| 2 5 R is each *CD3. In another energy media R5 is 気. In another aspect, ^ n σ γ and γ together with the carbon to which they are attached are a 〇0. In another aspect, a person forms Y as OH and γ2 is chlorine. Another specific example provides a compound of the formula ψ, ψ ρ ΐ 2~ -CD3. In one aspect, R5 〃 R and R are each a horse rat. In another aspect, ^4 Ώ s is each hydrogen and V is gas. In the sample: 'z, z, and Z5 and R5 is 氘. And ζ each provides a compound of formula B for another specific example, wherein the γ1 2 attached carbons together form C; In one aspect, R5 is the sample, and each of Z3, z4, and Z5 is a claw. In the other state 3 is 虱 and R5 is 氘. In the other four pens A z4 and Z5 are each uR5 clever claws in another state, z3, ^ horse rat 0 in another state, R1 and R2夂έ are -cd3. In another aspect, each of R and the ruler l and R are each -CD, and R5 or the bird is in another aspect, R丨 and Λ Α and R is a claw (. is 氖. in another aspect) Wherein, R1 is from: wide 3: and Z and z5 are each said and R5 is 氖. In each of -CD3, Z3, Z4 and z5 and 23, 24 and 25, R1 and R2 are each In another aspect, each of R1 and R2 is self-hydrogen and R5 is an atmosphere. Another specific example is 佴 or 氖. In one aspect, R51 Oral substance, γ is 0H, and γ2 is hydrogen and each is chlorine and ~. In the other atmosphere = -25 and R5 is 氖. In the other 4 pain samples, ζ, ζ4 and Ζ5 are each in the atmosphere In another aspect, each of R and R of RI and r2 is -CD3. In another R and R2, each is ·c〇3, and 4勹汛 is in another sample, like _, R1 and r2 Each, Z and Z5 are each 氘. In another state

For, ~ and f are each 氖 and RU 23 201107326 氘. In another aspect, each of R1 and R2 is -CD3, and each of Z3, Z4 and Z5 is hydrogen. In another aspect, R1 and R2 are each -CD3, and Z3, Z4 and Z5 are each hydrogen and R5 is deuterium. Another embodiment provides a compound of formula B, wherein R5 is deuterium. Another embodiment provides a compound of formula B wherein R5 is deuterium, Z3, Z4 and Z5 are hydrogen and R1 is -CD3. 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 "t" represents the R^ moiety and the C^Y1 in the compound. "2) A combination of components. In these tables, a compound designated as "" or "(S)" refers to a stereochemical configuration of a carbon with a substituent of Υ1. No designation is given and Compounds of 1 and Υ2 in combination with a palmitic carbon atom are intended to represent racemic mixtures of enantiomers. Table 1: Examples of specific compounds of formula I. Deuteration and/or fluorine of the combination of ceflin and its metabolites Compound R1 R2 R3 R4 Y1 Y2 100 cd3 ch3 ch3 (CH2)4 together form =0 101 cd3 cd3 ch3 (CH2)4 together form =0 102 ch3 cd3 ch3 (CH2)4 together form =0 103 cd3 cd3 cd3 (CD2)4 together formed as =0 104 ch3 ch3 cd3 (CD2)4 together formed as =0 105 cd3 ch3 cd3 (CD2)4 together formed as =0 106 ch3 cd3 cd3 (CD2)4 together form =0 107 ch3 ch3 cd3 tCD/CHA are formed together as =0 108 ch3 ch3 cd3 kCD+CHs are formed together as =0 109 cd3 ch3 cd3 tCD/CHA It is formed as = 0 110 cd3 ch3 cd3 t (CD2) 3CH2 taken together as = 024201107326

Compound R1 R2 R3 R4 Y' Y2 111 ch3 cd3 cd3 together form = 112 112 ch3 cd3 cd3 卞 (032) 3012 together form = 〇 113 cd3 cd3 cd3 tCD2(CH2)3 together form = 114 cd3 cd3 cd3 卞(cd2)3ch2 is formed together as =0 115 cd3 cd3 ch3 (CH2)4 OH Η 116 cd3 ch3 ch3 (CH2)4 OH Η 117 ch3 cd3 ch3 (CH2)4 OH Η 118 cd3 cd3 cd3 fCD2(CH2)3 OH Η 119 cd3 ch3 cd3 fCD2(CH2)3 OH Η 119(Λ) cd3 ch3 cd3 fCD2(CH2)3 (8)OH Η 120 ch3 cd3 cd3 tCD2(CH2)3 OH Η 121 ch3 ch3 CDs tCD2(CH2)3 OH Η 122 cd3 cd3 CDs (CD2)4 OH Η 123 cd3 ch3 cd3 (CD2)4 OH Η 124 ch3 cd3 cd3 (CD2)4 OH Η 125 ch3 CH cd3 (CD2)4 OH Η 126 cd3 cd3 cd3 f(CD2)3CH2 OH Η 127 cd3 Ch3 cd3 f(CD2)3CH2 OH Η 128 ch3 cd3 cd3 ^ϋ2)3(:Η2 OH Η 129 ch3 ch3 cd3 f(CD2)3CH2 OH Η 130 cd3 cd3 ch3 (CH2)4 OH D 131 cd3 ch3 ch3 (CH2) 4 OH D 131(i?) cd3 ch3 ch3 (CH2)4 (8)OH D 131(5) cd3 ch3 ch3 (CH2)4 (5)OH D 132 ch3 cd3 ch3 (CH2)4 OH D 133 ch3 ch3 ch3 (CH2)4 OH D 133(i ?) ch3 ch3 ch3 (CH2)4 (8)OH D 133C5T) ch3 ch3 ch3 (CH2)4 GS0OH D 134 cd3 Cd3 cd3 also 2 up 2) 3 OH D 135 cd3 ch3 cd3 ^〇2(〇Η2)3 OH D 135(H) CDs ch3 cd3 tCD2(CH2)3 (8)OH D 136 ch3 cd3 cd3 fCD2(CH2)3 OH D 137 Ch3 ch3 cd3 +CD2(CH2)3 OH D 138 cd3 cd3 cd3 (CD2)4 OH D 139 cd3 ch3 cd3 (CD2)4 OH D 140 ch3 cd3 cd3 (CD2)4 OH D 141 ch3 ch3 cd3 (CD2)4 OH D 25 201107326

Compound R1 R2 R3 R4 Y1 Y2 142 cd3 cd3 cd3 t(CD2)3CH2 OH D 143 cd3 ch3 cd3 Hco2)2Cu2 OH D 144 ch3 cd3 cd3 kCDACHz OH D 145 ch3 ch3 cd3 elevation 2) 3 (: than OH D 146 CD3 Cd3 ch3 (CH2)4 FH 147 cd3 ch3 ch3 (CH2)4 FH 148 ch3 cd3 ch3 (ch2)4 FH 149 ch3 ch3 ch3 (CH2)4 FH 150 CD3 cd3 ch3 (CH2)4 FF 151 cd3 ch3 ch3 (CH2) 4 FF 152 ch3 cd3 ch3 (CH2)4 FF 153 ch3 ch3 ch3 (CH2)4 FF Table 1 above shows examples of compounds of the specific formula i. These examples are deuterated and/or metabolites of sirphilin and/or metabolites thereof. Fluorinated analogs. Table 2: Examples of specific compounds of formula I wherein R1 is deuterium and Y2 is CH3 or CD3. Compound R1 R2 R3 R4 Y1 Y2 200 H cd3 ch3 (CH2)4 OH ch3 201 H cd3 cd3 (CH2)4 OH cd3 202 H ch3 cd3 (CH2)4 OH cd3 203 H cd3 cd3 ^ϋ2(ΟΗ2)3 OH cd3 204 H ch3 cd3 ^Ο2(0Η2)3 OH cd3 205 H cd3 cd3 (CD2)4 OH cd3 206 H ch3 cd3 (CD2)4 OH cd3 207 H cd3 ch3 (CH2)4 F ch3 208 H ch3 ch3 (CH2)4 F ch3 209 H cd3 cd3 (CD2)4 F cd3 210 H ch3 cd3 (CD2)4 F cd3 Table 2 above A compound of the formula I wherein R1 is deuterium and Y2 is CH3 or CD3 Examples of such compounds include the deuterated and fluorinated analogs of abibutylate (HWA-1 38). The study of A 26 201107326 compared to theophylline has been studied for the use associated with the formulation of cefolin. Table 3: R1 is A specific example of the formula I of -CH2-0-CH2CH3, which is optionally substituted by hydrazine. Compound R1 R2 R3 R4 Y' Y2 250 CD2OCD2CD3 cd3 ch3 (CH2)4 OH ch3 251 cd2och2ch3 cd3 ch3 (CH2)4 OH ch3 252 CH2OCH2CH3 cd3 Ch3 (CH2)4 OH ch3 253 CD20CD2CD3 ch3 ch3 (CH2)4 OH ch3 254 CD2OCH2CH3 ch3 ch3 (CH2)4 OH ch3 255 cd2ocd2cd3 cd3 cd3 (CH2)4 OH cd3 256 CD20CH2CH3 cd3 cd3 (CH2)4 OH cd3 257 CH20CH2CH3 cd3 Cd3 (CH2)4 OH cd3 258 CD2OCD2CD3 ch3 cd3 (CH2)4 OH cd3 259 CD20CH2CH3 ch3 cd3 (CH2)4 OH cd3 260 CH2OCH2CH3 ch3 cd3 (CH2)4 OH cd3 261 CD20CD2CD3 cd3 cd3 tCD2(CH2)3 OH cd3 262 CD20CH2CH3 Cd3 cd3 tCD2(CH2)3 OH cd3 263 CH2OCH2CH3 cd3 CDs ^ϋ2(ΟΗ2)3 OH cd3 264 cd2ocd2cd3 ch3 cd3 fCD2(CH2)3 OH cd3 265 CD20CH2CH3 ch3 cd3 cd2(ch2)3 OH cd3 266 CH20CH2CH3 ch3 cd3 tCD/ CHA OH cd3 267 CD20CD2CD3 cd3 cd3 (CD2)4 OH cd3 268 CD20CH2CH 3 cd3 cd3 (CD2)4 OH cd3 269 CH20CH2CH3 cd3 cd3 (CD2)4 OH cd3 270 CD2OCD2CD3 ch3 CD3 (CD2)4 OH cd3 271 cd2och2ch3 ch3 cd3 (CD2)4 OH cd3 272 CH20CH2CH3 ch3 cd3 (CD2)4 OH cd3 273 CD20CD2CD3 cd3 ch3 (CH2)4 F ch3 274 CD20CH2CH3 cd3 ch3 (CH2)4 F ch3 275 CH2OCH2CH3 cd3 ch3 (CH2)4 F ch3 276 CD20CD2CD3 ch3 ch3 (CH2)4 F ch3 277 CD20CH2CH3 ch3 ch3 (CH2)4 F ch3 278 CH20CH2CH3 ch3 ch3 (CH2)4 F ch3 279 CD2OCD2CD3 cd3 cd3 (CD2)4 F cd3 280 CD20CH2CH3 cd3 cd3 (CD2)4 F cd3 281 CH20CH2CH3 cd3 cd3 (CD2)4 F cd3 282 CD20CD2CD3 ch3 cd3 (CD2)4 F cd3 283 CD2OCH2CH3 ch3 cd3 (CD2)4 F cd3 284 CH20CH2CH3 ch3 cd3 (CD2)4 F cd3 27 201107326 Table 3 above shows an example of a specific compound of formula I wherein R1 is optionally substituted with -CH2-0-CH2CH3. In these examples, Y1 is OH or F and Y2 is CH3 or CD3. These compounds include deuterated and fluorinated analogs of toba theophylline (HWA-448). Tobagoline has been studied for the treatment of depression, urinary incontinence, colonic irritability and multiple sclerosis. Table 4: R1 is a specific example of Formula I in which -CH2CH2CH3 is optionally substituted by hydrazine and Y1 is OH or F. Compound R1 R2 R3 R4 Y1 Y2 300 cd2cd2cd3 cd3 ch3 (CH2)4 OH ch3 301 CD2CH2CH3 cd3 ch3 (CH2)4 OH ch3 302 CH2CH2CH3 cd3 ch3 (CH2)4 OH ch3 303 CD2CD2CD3 ch3 ch3 (CH2)4 OH ch3 304 CD2CH2CH3 ch3 Ch3 (CH2)4 OH ch3 305 CD2CD2CD3 cd3 CDs (CH2)4 OH cd3 306 CD2CH2CH3 cd3 cd3 (CH2)4 OH cd3 307 CH2CH2CH3 cd3 cd3 (CH2)4 OH cd3 308 cd2cd2cd3 ch3 cd3 (CH2)4 OH cd3 309 CD2CH2CH3 ch3 Cd3 (CH2)4 OH cd3 310 CH2CH2CH3 ch3 cd3 (CH2)4 OH cd3 311 CD2CD2CD3 cd3 cd3 tCD2(CH2:h OH cd3 312 CD2CH2CH3 cd3 cd3 tCD/CHA OH cd3 313 CH2CH2CH3 cd3 cd3 ^ϋ2(ΟΗ2)3 OH CDs 314 CD2CD2CD3 ch3 cd3 fCD2(CH2)3 OH cd3 315 CD2CH2CH3 ch3 cd3 tcd2(ch2)3 OH cd3 316 CH2CH2CH3 ch3 cd3 tCD2(CH2)3 OH cd3 317 CD2CD2CD3 cd3 cd3 (CD2)4 OH cd3 318 CD2CH2CH3 cd3 cd3 (CD2)4 OH cd3 319 ch2ch2ch3 cd3 cd3 (CD2)4 OH cd3 320 cd2cd2cd3 ch3 cd3 (CD2)4 OH cd3 321 CD2CH2CH3 ch3 cd3 (CD2)4 OH cd3 322 CH2CH2CH3 ch3 cd3 (CD2)4 OH cd3 28 201107326 Compound R1 R2 R3 R4 Yl Y2 323 cd2cd2cd3 CDs ch3 (CH2)4 F ch3 324 cd2ch2ch3 cd3 Ch3 (CH2)4 F ch3 325 ch2ch2ch3 cd3 ch3 (CH2)4 F ch3 326 cd2cd2cd3 ch3 ch3 (CH2)4 F ch3 327 CD2CH2CH3 ch3 ch3 (CH2)4 F ch3 328 ch2ch2ch3 ch3 ch3 (CH2)4 F ch3 329 CD2CD2CD3 cd3 Cd3 (CD2)4 F cd3 330 CD2CH2CH3 cd3 cd3 (CD2)4 F cd3 331 ch2ch2ch3 cd3 cd3 (CD2)4 F cd3 332 CD2CD2CD3 ch3 cd3 (CD2)4 F cd3 333 CD2CH2CH3 ch3 cd3 (CD2)4 F cd3 334 CH2CH2CH3 ch3 Cd3 (CD2)4 F cd3 Table 4 above shows an example of a specific compound of formula I wherein R1 is optionally substituted with -CH2CH2CH3. In these examples, Y1 is OH or F and Y2 is CH3 or CD3. These compounds include the deuterated and fluorinated analogs of A-8027 15 . A-802715 has been studied for the treatment of septic shock and inhibition of allograft response. Table 5: R1 is a specific example of the formula I which is substituted with -CH2CH2CH3 and Y1 and Y2 are formed as =0. R1 R2 R3 R4 Y' Y2 350 cd2cd2cd3 cd3 ch3 (CH2)4 are formed together as 0 351 CD2CH2CH3 CD3 ch3 (CH2)4 together formed as = 0 352 ch2ch2ch3 cd3 ch3 (CH2)4 together formed as = 0 353 cd2cd2cd3 ch3 ch3 (CH2)4 together formed as = 0 354 CD2CH2CH3 ch3 ch3 (CH2)4 together formed =0 355 cd2cd2cd3 cd3 cd3 (CH2)4 together formed as =〇356 CD2CH2CH3 cd3 cd3 (CH2)4 together formed as =0 357 ch2ch2ch3 cd3 cd3 (CH2)4 together formed as =0 29 201107326 Compound R1 R2 R3 R4 Y1 Y2 358 CD2CD2CD3 ch3 cd3 (CH2)4 together form = 359 cd2ch2ch3 ch3 cd3 (CH2)4 together form =0 360 CH2CH2CH3 ch3 cd3 (CH2)4 together form = 361 CD2CD2CD3 cd3 cd3 tCD2(CH2)3 together =0 362 CD2CH2CH3 cd3 cd3 tCDWCHA together formed as =0 363 CH2CH2CH3 cd3 cd3 卞 cd2(ch2)3 together formed as 〇364 CD2CD2CD3 ch3 cd3 tCD/CHA together formed as =0 365 CD2CH2CH3 ch3 cd3 tCD/CHA together form = 0 366 CH2CH2CH3 ch3 cd3 also 2(012)3 together formed as =0 367 CD2CD2CD3 cd3 cd3 (CD2)4 together form = 368 cd2ch2ch3 cd3 cd3 (CD2)4 together form = 369 CH2CH2CH3 cd3 cd3 (CD2)4 together form = 370 370 CD2CD2CD3 ch3 cd3 (CD2)4 together Formed as = 0 371 CD2CH2CH3 ch3 cd3 (CD2)4 together formed as = 〇 372 ch2ch2ch3 ch3 cd3 (CD2) 4 together formed as =0. Table 5 shows that R1 is a specific compound of formula I which is optionally substituted with hydrazine -CH2CH2CH3 Example. In these examples, Y1 and Y2 together with the carbon between them form a Wei group. These compounds include the analogs of the acetophenone tea assay. Valprophylline has been studied for the treatment of Alzheimer's disease, neuropathic pain, traumatic brain injury, dysuria, retinal or optic nerve head injury, and peptic ulcer. It is also studied to control intraocular pressure, stabilize cerebral blood flow, and inhibit the response of allografts. 30 201107326 Table 6: Examples of specific compounds of formula A. R5 is a deuterated and/or fluorinated analog of D.

Compound R1 R2 R3 R4 R5 Y1 Y2 400 cd3 ch3 ch3 (ch2)4 D is formed together as =0 401 cd3 CDs ch3 (CH2)4 D is formed together as =0 402 ch3 cd3 ch3 (CH2)4 D is formed together as =0 403 cd3 cd3 cd3 (CD2)4 D is formed together as =0 404 ch3 ch3 CDs (CD2)4 D is formed together as =0 405 cd3 ch3 cd3 (CD2)4 D is formed together as =0 406 ch3 cd3 cd3 (CD2)4 D is formed together as = 0 407 ch3 ch3 cd3 ^CO2(CU2)3 D is formed together as = 0 408 ch3 ch3 cd3 % ϋ 2) 3 (: Η 2 D * - is formed as = 0 409 cd3 ch3 cd3 tCDKCHA D is formed together =0 410 cd3 ch3 cd3 coffee 2) 3〇12 D together form = 411 411 ch3 cd3 cd3 fCD2(CH2)3 D together form = 0 412 ch3 CDs cd3 shirt 2) 3〇12 D together form = 413 Cd3 cd3 CDs tCD2(CH2)3 D together form = 414 cd3 cd3 cd3 YCDACHz D together form = 415 CDs cd3 ch3 (CH2)4 D OH H 416 cd3 ch3 ch3 (CH2)4 D OH H 417 ch3 CDs Ch3 (CH2)4 D OH H 418 cd3 cd3 cd3 ^Ο2(0Η2)3 D OH H 419 cd3 ch3 cd3 fCD2(CH2)3 D OH H 419(/?) cd3 ch3 cd3 tCD/CHA D (8)OH H 419(5 Cd3 ch3 cd3 +cd2(ch2)3 D (5)OH H 420 ch3 cd3 cd3 fCD2(CH2)3 D OH H 421 ch3 ch3 cd3 tD2(CH2)3 D OH H 422 cd3 CDs cd3 (CD2)4 D OH H 423 cd3 ch3 cd3 (CD2)4 D OH H 424 ch3 cd3 cd3 (CD2)4 D OH H 425 ch3 ch3 CDj (CD2)4 D OH H 426 cd3 cd3 CDs t(CD2)3CH2 D OH H 427 cd3 ch3 cd3 as 02) 3012 D OH H 428 ch3 cd3 cd3 々CDACHz D OH H 429 ch3 ch3 cd3 \CO2hCH2 D OH H 31 201107326

Compound r| R2 R3 R4 R5 Y1 Y2 430 cd3 cd3 ch3 (CH2)4 D OH D 431 cd3 ch3 ch3 (CH2)4 D OH D 432 ch3 cd3 ch3 (CH2)4 D OH D 433 ch3 ch3 ch3 (ch2)4 D OH D 434 cd3 cd3 cd3 ^β2(〇η2)3 D OH D 435 cd3 ch3 cd3 fCD2(CH2)3 D OH D 435(i?) cd3 ch3 cd3 tCD/CHA D (8)OH D 435(5) cd3 ch3 cd3 fCD2(CH2)3 D (5)OH D 436 ch3 cd3 cd3 ^ϋ2(εΗ2)3 D OH D 437(7?) ch3 ch3 cd3 fCD2(CH2)3 D (8)OH D 437(5) ch3 ch3 cd3 tC:D2 (CH2)3 D (S)OH D 437 ch3 ch3 cd3 +CD2(CH2)3 D OH D 438 cd3 cd3 cd3 (CD2)4 D OH D 439 cd3 ch3 cd3 (CD2)4 D OH D 440 ch3 cd3 cd3 ( CD2)4 D OH D 441 ch3 ch3 cd3 (CD2)4 D OH D 442 cd3 cd3 cd3 'CDACHz D OH D 443 cd3 ch3 cd3 HCO2hCK2 D OH D 444 ch3 cd3 cd3 VCDACHz D OH D 445 ch3 ch3 cd3 卞(〇) 2)3〇12 D OH D 446 cd3 cd3 ch3 (ch2)4 DFH 447 ch3 ch3 ch3 (CH2)4 DFH 448 cd3 ch3 ch3 (CH2)4 DFH 449 ch3 cd3 ch3 (CH2)4 DFH 450 cd3 cd3 ch3 (CH2 ) 4 DFF 451 cd3 ch3 ch3 (CH2)4 DFF 452 ch3 cd3 ch3 (CH2)4 DFF 453 ch3 ch3 ch3 (CH2)4 DFF Table 6 above shows the specific formula A compound An example of something. These examples are the deuterated and/or fluorinated analogs of Rifampin with its metabolites. In one aspect of the above specific examples, the compound is not any of Compounds 1, 00, 116 or 149. 32 201107326 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 present invention can be carried out by those skilled in the art of synthetic chemistry up to 33 201107326. 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 W0953 1450; and Japanese Patent Publication No. JP58150594, No. JP58134092, JP58038284, JP57200391, JP57098284, JP57085387, JP57062278, No. JP57080385, JP57056481, JP57024385, JP57011981, JP57024386, No. JP57024382, JP56077279, JP56032477, JP56007785, JP56010188, JP56010187, Jp55122779, and JP55076876. Such methods can be carried out using the 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 a compound of formula I is described in the following scheme. Scheme 1A. Synthesis of a compound of formula I 34 201107326

The deuterated compound is deuterated and pitted to provide a compound of formula I as described in Scheme 1 A in the presence of potassium carbonate using a deuterated intermediate (where X is a gas group, a bromo group or a mercapto group). Alternatively, the compound of formula I can be provided in accordance with U.S. Patent No. 4,289, 776, the use of sodium hydroxide in aqueous decyl alcohol. Scheme 1B. Preparation of a compound of formula Y1 = 〇H from a compound of formula II R3 text R4

NaB(Y2)4

R2 Formula II or Enzyme Reduction HV2 1 R3 Person R4—N Person j 0 and N〆 R2

R1 N As described in Scheme 1B, a compound of the formula γH can be prepared using a hydrazine compound. Therefore, according to the general method of European Patent Publication No. 33〇〇3, sodium borohydride or sodium borohydride (available at 99 atom% D) can be used to reduce the compound of formula II to form Y1 as 0H and γ2 as hydrogen or hydrazine. Compound. The enantiomeric alcohol product can be isolated, for example, by the method of Nicklasson, Μ, et al., Chiraiity, 2002, 14(8): 643-652. In an alternative method, use Pekala, E et al. 'Acta P〇l〇niae Pharmaceutica, 2007: 64(2). 109-1 13 or Pekala, E et al.' Biotech J, 2007, 2(4): 492 The method disclosed in -496 is subjected to enzymatic reduction to provide enantiomeric 35 201107326 although the alcohol product is concentrated. Synthesis of Compound 1 〇 can be used as Compound 10 to prepare a compound of Formula I, but is not limited to the following: Commercially available cocoa beans Reference Scheme 1 A ' can be used as Compound 10 is known and includes (but not limited to) the following & C (where R and R2 are CH3). (a) R1 is -CD3 and R2 is -CH3; (b) R1 is -CH3 and R2 is ; and (c) ri and r2 are -Cd3

The isotopic analogs are all known. Shenke Benchekroun, Y et al., J

Chromatogr B, 1 977, 688: 245; Ribon, B et al, Coll INSERM, 1988, 1 64: 268; and Horning, MG et al., Proc Int Conf Stable Isot 2nd edition, 1976, 41-54. 3-mercapto-7-propylxanthine wherein R1 is n-propyl and R2 is _CH3 is commercially available. Compound 10 wherein R1 is CH2OCH3 and R2 is Ch3 is also known. #名德国专利申请 DE 3942872A1. Scheme 2. Synthesis of Compound 10

-^ , N Ac2〇 Η

1. NaOH, H20 HN 2. HCI, H20

36 16 201107326

HCOOH

R1X (18)

K2CO〇 DMF

Compound 10 is synthesized in Scheme 2 starting from the commercially available N-nitroso-N-carbazine. Following the method of Boivin, JL et al., Canadian J〇urnai 0f Chemistry, 195 1, 29: 478-81, for the appropriate sinking of water in the month of the female 1 2 treatment provides N-calcining gland 13. According to Dubey, PK, etc., in(jian

Journal of Heterocyclic Chemistry, 2005, 14(4): 301-306 Method 'Can treat gland 13 with 2-cyanoacetic acid and acetic anhydride to provide cyanoacetamide derivative 14' which is first treated with aqueous NaOH and then with HCl The aqueous solution is treated to provide a cyclized pyrimidinedione 15. Or, via Ful丨e, F et al,

Heterocycles, 2000, 53(2): 347_352 The process of treating cyanoacetamide 14 with trimethylsulfanyl and hexamethyldioxane to provide a cyclized product of 15 °. Follow Merlos, Μ et al., European Journal Of Medicinal emistry, 1990' 25(8): 653-8, in which sodium nitrite in acetic acid is used, and then pyrimidinedione 15 is treated with ammonium hydroxide and sodium dithionite to obtain compound 16, which is a citric acid Treatment to provide an anthracene derivative 17. According to the rule disclosed in the Czech patent application CS 263595B1, in the presence of anti-know potassium and optionally in the presence of additives such as NaBr, KBr, Nal, KI or iodine, The electronic agent 丨8 (X is a gas group, a bromo group or an iodine group) is alkylated to provide a compound 10. Reference Scheme 2 'Applicable Amine Chemical Reagent 12 includes, but is not limited to, 37 201107326 commercially available compounds such as n-propyl-dr amine or known compounds such as 丨-propyl, υ-amine (Moritz, F, etc.) Human, 〇rganic Mass Spectrometry, 1993. 2 8(3): 207-1 5 ). Suitable for urea chemical reagent 13 may include, but is not limited to, such as N-mercapto-d3-urea

Or thiourea-d6

Commercially available compounds.

Suitable deuterated electrophiles 18 may include, but are not limited to, commercially available compounds such as hexane-ch or methyl bromide-d3 or 1-bromopropane-d7 or hydrazine-bromopropane- hydrazine, or such as (gas)曱oxy_d2)_ethane (Williams, AG, WO 2002059070A1) ' or bromomethoxy 曱' (Van der Veken, BJ et al, Journal of Raman spectroscopy, 1992, 23(4): 205-23 A known compound of ' or (> skoxoxy_d2)_metholone_d3 (Van der Veken, BJ et al., Journal of Raman Spectroscopy, 1992, 23(4): 205-23). 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 lla-rfs (see Scheme ία) Scheme 3. Synthesis intermediate iia-^/s

38 201107326

11a-c/5 PPh3, CCI4

~~ 〇3C DD The method for preparing compound jj a_^5 is described in Scheme 3 (see Scheme 1A) (wherein R3 is CD3; R4 is f-CD2(CH2)3-, and γ1 and γ2 are formed = 〇) . Therefore, according to the procedure of Zhang, Q et al., Tetrahedron, 2006, 62(50): 1 1627-1 1634, methyllithium was added to commercially available azlactone 19 to provide 嗣20. Treatment of TFA-A (99 atomic % / 〇 D) in 〇 2 〇 (99 atom % D) under microwave conditions according to the general method of Fodor-Csorba K, Tet Lett, 2002, 43: 3789-3792 20 provides decyl ketone 21 . Following the general procedure of Cldment, JL, Org Biomol Chem, 2003, 1: 1591-1 597, after treatment with triphenylphosphine and tetra-carbonated carbon, the alcohol portion of 21 is converted to a vapor to obtain chloride 11 a- Seven.

HO

H2, Pd/C D20, heating

TMSCI CD3Li D DD D 23 THF, Et20 22 d3c

Do^od D〗S〇4

Nal04, RuCI3 Ca4, CH3CN, D20 39 25 24 201107326 1. LiA old 4 2. POCI3, pyr tender PPh3, NCS, CH2CI2 3. D2SO4, D20, THF D3C"W^( 0 oPd / — D DD D 11a-d9 a pX^C/COOH °3C ΑΧ D DD D 1. L1AID4 lyy 26 2. POCI3, pyr (or) d3c^vvs PPh3, NCS, CH2CI2 3. D2S04i D20, THF D DD D 11 ac/i 1 Description of Process 4 Synthesis of compound 11a-heart and compound. Therefore, it can be heated in DzO (99 atom% 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. 4-phenylbutyric acid 22 is commercially available to provide deuterated acid 23. According to the general method of P〇rta, A et al. 'J Org Chem, 2005, 70(12): 4876-4878, in dimethyl-based Adding a chaotic methyl group in the presence of gas provides a ketone 24. The ketone 24 is converted to a condensed sugar 25 by treatment with D2S〇4 (99 atom% D) and a commercially available ethylene glycol-heart (99 atom% d). Garnier, JM, etc.,

Tetrahedron: Asymmetry, 2007, 18(12): General Method for 1434-1442 'Protein 26 is provided by treatment with NaI〇4 and R11CI3. Reduction with LiAlH4 or UAID4 (98 at% D) provides alcohol (not shown), which is then gasified using oxygenated phosphorus or triphenylphosphine and N-chlorobutaneimine (Naidu, SV et al., Tet Lett , 2007, 48(13): 2279-2282), followed by acetal cleavage with D2S04 (Heathcock, CH et al, J 〇rg Chem, 丨995, 60(5): 1 120-30) to provide vaporization, respectively Lla_rf9 and. Scheme 4a. Synthesis intermediate llb_(^) 40 201107326 rAr4—OBn

H2l Pd/C

R3 human R4—OH S〇CI〇27 28 R3^Lc, 11b-(R) Scheme 4 b. Synthesis of chloride 11 b - (Fantasy > γ2 soci2 r3 r4-oh - R3^R4_c 29 u 11b·(5) 4a and 4b describe the specific enantiomer of the vaporization i b_ (/? 乂 where Y1 is fluorine; Y2 is selected from hydrogen and hydrazine; and the compound is in a (hole) configuration) and llb-(S) ( Wherein γ1 is fluorine; γ2 is selected from the group consisting of hydrogen and hydrazine; and the compound is synthesized in the (S) configuration. In Scheme 4a, such as known [[[(5R)_5_fluorohexyl]oxy]methyl] The deuterated (or non-deuterated) benzyl protected alcohol 27 of benzene (PCT Publication W02000031003) is deprotected by hydrogenation in the presence of Pd/C to provide alcohol 28. According to Lacan, G et al, j Label c 〇mpd Radiophann, 2005, 48(9): General procedure of 635-643, gasification of alcohol with sulphur sulphur to provide vapor 1丨b_(/j). In Scheme 4b, such as known (S )-( + )_5_Fluorohexanol (Risw〇k〇, A et al, Enantiomer, 2〇〇2, 7(1): 33_39) deuteration (or non-deuterated) alcohol 29 gasification to provide vaporization nb_( Magic. Process 5. Synthesis of intermediates 11 c and 11 e 41 201107326

Cl

EtO

THF R3MgX (32) HO, /Y2 DAST Fwy2 R3X^-^x 11c Aben He R3=Y2 R3=y2 Scheme 5 describes the synthesis of other intermediates 11 c and 11 e. Therefore, follow Kutner, Andrzej et al, Journal of Organic Chemistry, 1988, 53(1 5): 3450-7 or Larsen, SD et al, Journal of Medicinal Chemistry, 1994, 3 7(15): 2343-5 1 Alternatively, compound 30 or 31 (wherein X is a halo group) can be treated with Grignard reagent 32 to provide an intermediate, LLC, wherein R3 is the same as Y2, Y1 is OH, and X is a halo group. According to Karst, NA et al, Organic Letters, 2003, 5(25): 4839-4842 or Kiso, Μ et al. 'Carbohydrate Research, 1988, 177: 51-67, in a general procedure for dioxane or toluene The triethylammonium disulfide (DAST) treatment provides the intermediate lie where R3 is the same as gamma 2, gamma is F, and X is a halo group. A commercially available compound can be used to prepare the compound π as disclosed in Scheme 5. For example, a commercially available 5-methoxypentanyl group gas, or commercially available 5·bromopentenyl chloride, or commercially available 5-bromopentanoic acid ethyl acetate may be used as the reagent 3〇 or 3ι. Referring again to Scheme 5, commercially available methyl iodide-magnesium is used as the Grignard reagent 32 to provide both R3 and Y2 as CD; the electrophile j i. Scheme 6. Synthesis of intermediates lu ( χ=Β〇 42 201107326

DHP CSA

Et20 CI\^v^〇THp 33

34

OTHP 35

1. Mg, THF 2. Acetone or propionan ~ d6 CSA MeOH

DAST OTHP DCM Y2

11e (X = Br) Scheme 6 describes an alternative synthesis of R3 and Y2 which is the same as X2 and an intermediate 11e of Br. Thus, according to the procedure of Hester, JB et al, Journal of Medicinal Chemistry, 2001, 44(7): 1099-1 1 15 , via 3,4-dihydro-2H-pyran (DHP) and camphorsulfonic acid ( CSA) treatment to protect commercially available 4-chloro-; 1-butanol to provide vapor 33. Alcohol 34 is provided by the formation of the corresponding Grena reagent in magnesium followed by the addition of acetone (R3 = Y2 = CH3) or acetone-d6 (Y2 = R3 = CD3). Fluoride 35 is provided by fluorination with diethylaminosulfide trifluoride (DAST) in DCM. The alcohol 36 is deprotected with CSA in MeOH and treated with N-bromosuccinimide and triphenylphosphine to provide intermediate 11 e. Cheng 7. Alternative synthetic intermediate lie ( X = Br)

EtO'

,〇H DHP, CSA, Et2〇 Et〇'

LiAID4 HO. 〇 37 CCI4, pph3 or DHP, TsOH, pyr, CH2CI2 〇 〇D>C^

OTHP 38 39

Cl> or MeS02CI, LiCI, 2,6·dimercaptopyridine, dmf

OTHP

D OTHP Et2〇

D D 11e (X = Br) Scheme 7 describes the synthesis of the intermediate 11 e of R3 and Y2 and X = Br. Therefore treated with DHP and CSA, or treated with DHP, TsOH and pyridine 43 201107326

Ethyl 4-hydroxy-butyrate 37 was sold to provide ester 38. Reduction with LiA1D4 to provide deuterated alcohol 39' for triphenylphosphine treatment in CCU (sabitha, G et al, Tetrahedron Letters, 2006, (volume 2007), 48(2): 3 1 3-3 1 5 ) or in the DMF, sulfonium, gas, lithium and 2,6-dimethyl. Bisidine treatment (Blaszykowski, C et al, 〇rganic Letters, 2004, 6(2 1): 3 77 1 -3774 ) to provide a vapor 40. Following the same method as in Process 6, the vapor 40 can be converted to 11 e. Scheme 8. Synthesis intermediate lle-rf8 ( X=Br) D, (T〇, nn„ DCI'ZnCI2 〇2〇—GD2 d2 d2 cl, crc, cx, 〇H — D2 D2 p Y d2 d2 —r3乂Crc, c, c, D2 D2 41 42 11e-d8

Br Flow 8 describes the synthesis of the same lie and heart of R3 and Y2 and X=Br. Thus, the commercially available THF-heart 41 can be treated with DC1 and ZnCl2 according to the general method of Yang, A et al., Huagong Shikan, 2002, 16(3): 37-39 to provide a known gasification 42 (Alken, Rudolf- Giesbert, WO 2003080598 A1). Gasification 42 can be converted to 11 e-rf8 following the same procedure as in Scheme 6. Scheme 9. Synthesis of intermediates llc-rf8 (X=Br) 43

^ 〇2 CH2N2, Et:0 HO human CTC, (TC'Br v, TMCri ..' D2 D2 or TMSCI. MeOD

R3 MgX (45) 44

THF Y2 HOUR3 person S; D2 D2b2

Br 11c-ds 44 201107326 Scheme 9 describes the synthesis of the intermediate 11 c_d8 where R3 is the same as γ2 and X=Br. Thus, the known carboxylic acid 43 (Lompa-Krzymien, L. et al., Proc. Int. Conf. Stable Isot. 2nd edition, 1976, session 1975, 574-8) was treated with diazomethane (according to Garrido , et al., Molecules, 2006, 1 1(6): 435-443. General method) or treated with trimethylsulfanyl and methanol (according to Doussineau, Τ et al.' Synlett, 2004, (10): 1 7 3 5 -17 3 8 general method) to provide methyl vinegar 4 4 . As in Scheme 5, the ester is treated with deuterated Grignard reagent 45 to provide intermediate 11 c-8. For example, commercially available deuterated fluorenyl-d3-magnesium is used as a Grignard reagent 45 to provide an inter-rf8 in which R3 and Y2 are both CD3. Scheme 10. Synthesis of the intermediate llc-rf2.

R3 MgX (48)

Scheme 10 describes the preparation of the same llc-rf2 as R3 and Y2. Therefore, it is known that murine Sa 46 (Feldman, KS et al., Journai 〇f 〇rganic 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, or treatment with sulfonium sulfonate and triethylamine, followed by treatment with lithium hydride and DMF (Sagi, K Et al., Bioorganic & Medicinal Chemistry, 2005, 13(5): 1487-1496) to provide ester 47 wherein X is a chloro group. As in Scheme 5, 45 201107326 treatment of ester 47 with deuterated Grignard reagent 48 provides 11 c-rf2. For example, commercially available decyl-d3-magnesium is used as a Grignard reagent 48 to provide a vector-rf2 in which R3 and Y2 are simultaneously CD3. Other known vapors that can be used as reagent 11 in Scheme 1A include: Bugas-5,5-difluoro-hexane (Rybczynski, PJ et al, J Med Chemistry, 2004, 47(1): 196-209 1- gas-5-fluorohexane (Chambers, RD et al, Tetrahedron, 2006, 62(30): 7162-7167); 6-gas-2-hexanol (European Patent Publication 0412596); (S -6-Ga-2-hexanol (Keinan, E et al, J Am Chem Soc, 1986, 108(12): 3474-3480); commercially available (R)-6-gas-2-hexanol; 6-Gas-2-hexanone is sold; 6·Ga-2-mercaptohexan-2-ol is known (Kutner, Α et al, Journal of Organic Chemistry, 1988, 5 3(15): 3450-7); 6-bromo-2-methylhexan-2-ol is known (Kutner, A et al, Journal of Organic Chemistry, 1988, 53(1 5): 3450-7); 1-di--5-fluorine is known -5-mercaptohexanone (Hester, JB et al, Journal of Medicinal Chemistry, 2001, 44(7): 1099-1 1 15 ) 0 Scheme 11. Synthesis of a compound of formula A1

Scheme 1 1 describes the synthesis of a compound of formula A1. Thus, the compound of formula I is treated with potassium carbonate in DaO to effect a hydroquinone exchange reaction, providing a compound of formula A i 46 201107326. Those skilled in the art should be aware that additional hydroquinone exchange reactions can also occur elsewhere on the Φ v, τ. Scheme 1 2. Alternative synthetic formula A 1 compound

K2C〇3 d2o

R1 N /^D R2 (11) K2C03 R2 Formula A1 50 An alternative synthesis of a compound of formula A1 is depicted in Scheme 12. Therefore, the intermediate: ΠΚ see Scheme 1A) is used to exchange the reaction in the potassium carbonate in 〇2〇 to provide the form of the substance N...H. An intermediate u ° compound in the presence of potassium carbonate. The invention can also be used to provide a compound which is a diterpene compound. therefore,

47 201107326

48 201107326 The above compound a_d can be prepared by the general description of the use of a suitable deuterated starting material as described in 〇rg. Lett., 2005, 7: 1427_1429. Compounds can be prepared from the appropriate deserts listed above by the procedure 15' shown below. Certain xanthine intermediates suitable for use in the present invention are also novel. Therefore, the present invention provides an intermediate of samarium sulphate: 0 R1 wAv〇

〇ϊ N r2 111 'wherein W is hydrogen or 氘' and R1 and R2 are each independently selected from the group consisting of hydrogen, sinking, optionally substituted by gas, CI, 3 alkyl, and optionally substituted by C, -3 Alkoxyalkyl. Examples of the R1 and R2 Ci.3 alkyl groups include -CH3, -CD3, -CH2CH2CH3, and -CD2CD2CD3. Examples of the Cu alkoxyalkyl group include -CH2OCH2CH3, -CD2OCH2CH3, -CD20CD2CH3, and -cd2ocd2cd3.

C D2CD 2〇 D 3 III-a III-b III-c ,

pH2CH2CH3

Ill-e cr H,

Ch2ch2ch3 III-: III-d 49 201107326

HiS cd2cd2cd3 -N , />*D , N ch3 ch2och2ch3

Ill-g o H'

0, 'N N I CD-,

N />~D

Ill-j

GD2OCD2CD3 CH2OCH2CH3 and

CD, CD2〇CD2CD3 N L DΝ',

In the case of each of the above formulas, III-l f, w is hydrogen. In a corresponding set of examples, W is 氘. Salts of the compounds in the formula are also suitable, including the salts which are known to be relevant to known 嘌呤. Examples of suitable salts include, but are not limited to, lithium salts, sodium salts, potassium salts and barium 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. This: The chemical structure depicted in the scheme matches the definition of the corresponding group in the formula (partial 'atoms, etc.) in this formula, and the code is defined accordingly, regardless of whether the chemical group definition is represented by the same code name ( That is, R1 R2: R3, etc.) to identify. The general practitioner is fully aware of the structure of the compound: the suitability of the chemical group for the synthesis of another compound. Other methods of synthesizing the compounds of the invention and their synthetic precursors (including methods within the pathways not explicitly shown herein) are within the skill of those of ordinary skill in the art. It is used to synthesize synthetic chemical transformations of suitable chelates. The protecting group method (protection and deprotection) is known in the art and includes, for example, the methods described in the following literature: ^〇仏ι Comprehensive Organic Transformations, yCH PubUshe; 50 201107326 (1989), Greene TW et al., Growps 3rd edition, John Wiley and Sons (1999); Fieser L et al. 'Fieser and Fieser' s Reagents for Organic Synthesis, John Wiley and Sons ( 1994); and Paquette L, less c/opei/k of Reagents for Organic Synthesis, John Wiley and Sons (1 995) 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

I 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. ~ σ pharmaceutically acceptable carriers, adjuvants and vehicles for use in the pharmaceutical compositions of the invention include, but are not limited to, ion exchangers, oxidized sulphate, stearic acid I, lipids, serum proteins such as Human serum albumin, slow sputum such as sulphate, glycine, sorbic acid, potassium sorbate, saturated plant sulphuric acid, partial glycerin, and daily fighting. From U, water, salt or Electrolytes, such as protamine sulfate, dihydrogen phosphate, potassium hydrogen citrate, gasified sodium, zinc salt, waist energy-oxygen cutting, three-material magnesium, various phases, mainly cellulose 51 201107326 Substance, Poly B 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 well known in the pharmaceutical art. See for example Remingt〇n, s

Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, pa (17th ed. 1 985). ^ In certain embodiments, the compounds are administered orally. Compositions of the invention suitable for oral administration can be provided as follows: I from discrete units (such as capsules, sachets or elixirs) containing a predetermined amount of active ingredient; powders or granules, aqueous or non-aqueous liquids a solution or suspension; water. Oil-in-oil type liquid emulsion; % water-in-water type liquid emulsion; liposome encapsulated form. : bolster form and the like. Soft gelatin capsules may be adapted to contain such suspensions, 'which may advantageously increase the rate of absorption of the compound. In the case of a sugar and a key for use in the mouth, a carrier which is usually used includes a milk in a capsule type, such as stearic acid. For the Jade Hall: 1σ & and 5 ‘applicable diluents include lactose and dry suspension combinations. If desired, fB f can be 6 with emulsifying and or coloring agents. It is necessary to add certain sweeteners and/or flavoring agents to the Japanese temple and/or it. 52 201107326 Compositions suitable for oral administration are included in the flavoring base (usually in sugar and acacia or tragacanth). The mouth of the ingredient contains a tablet containing the active ingredient in an inert matrix such as gelatin and glycerin, or sucrose and arabic. Compositions for enteral administration and enteral administration include aqueous and non-aqueous sterile injectable solutions which may contain antioxidants, buffers, bacteriostatic agents, and a substance which renders the formulation isotonic with the blood of the intended recipient; and may include Aqueous and non-aqueous sterile suspensions of suspending and thickening agents. Formulations can be supplied in unit-dose or multi-dose containers (eg, sealed ampoules and vials) and can be stored in cold; bundle-dried (Donggan) conditions, requiring only 2 liquid carriers to be added immediately prior to use ( For example, water for injection). Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and lozenges. Such injection solutions may 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 or humectants such as Tween 8(R) and suspending agents. The injectable preparation may also be a parenterally-incorporated, non-toxic diluent or a solution, an injectable solution or suspension, for example, in the form of a solution in 1,3-butanediol. . It can also be used as MA ^ 砰r (the acceptable media and solvent used are mannitol, water, : osmotic solution. Another use, non-volatile oil is used as solvent or suspension medium. a non-irritating, non-volatile oil, including synthetic glycerol-receiving sputum ^ (4) medicinally-oil (such as eucalyptus oil or woven), especially glycerol, and its glycerin Ester derivatives, mediators, and cyanobacteria are also suitable for the preparation of injectables. These oil solutions 53 201107326 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 the compound of the present 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, bioavailability absorption enhancers 'fluorocarbons and/or other solubilization or dispersion known in the art. The preparation is a saline solution. See, for example, Rabin 〇witz, JD and 2 Pooled 1 ac US Patent 6,803,03 1 assigned to Alexza Delivery Corp〇rati〇n. The desired treatment involves a region or organ that is readily accessible by topical application. The pharmaceutical composition of the present invention is especially suitable for topical administration. For topical application to topical application to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active ingredient in suspension or dissolution. Carriers for topical administration of the compounds of the invention include, but are not limited to, oils, liquid petroleum, paraffin, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying waxes, and water. The pharmaceutical composition may contain an active substance suspended or dissolved in a carrier. Formulated with a lotion or cream. Suitable carrier package Shaw (but not limited to i minerals > 去, sorbitan monostearic acid vinegar ' $ sorbic acid 酉 60, ::, base: wax, hexadecanol octanol, 2· xin The base drug and the product may also be topically applied to the lower intestinal tract by a rectal suppository formulation or in the form of a suitable enema 54 201107326. The topical percutaneous patch is also included in the present invention. Tablets and iontophoresis can be administered. The application of the therapeutic agent can be applied topically for administration to the site of interest. Various techniques can be used to provide the target composition to the site of interest, such as injection, use of catheters, sleeves. Tubes, bombardment particles, Phonic gels, endovascular stents, sustained drug release polymers, or other devices that provide internal access. 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 be administered with or with the same bioavailability as the compound having the same mechanism of action as the cefolin. The agents include those indicated to be suitable for use. West film combination Agents, including (but not limited) WO 1997019686, EP 0640342,

Agents described in WO 2003013568, WO 2001032156, WO 200603541 8 and WO 1996005838. In the pharmaceutical compositions of the present invention, the compound of the present invention is present in an effective amount, as used herein, and the term effective amount means an amount sufficient to treat (therapeutic or prophylactic) a target condition when administered in an appropriate 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 dose of 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 measured from the patient's body and body weight. See, for example, Scientific Tables, Geigy 55 201107326

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 human, or from wo mg to 8 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 Westin. For a pharmaceutical composition comprising a second therapeutic agent, the effective amount of the second therapeutic agent is about 20% and 100% of the amount normally used in a single-therapy 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, WeUs et al., ed.,

Phar嶋cotherapy Handbook, 2nd edition, Appleton and Lange,

Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarasc〇n PubHshing,

Loma Unda, Calif. (2000), the entire contents of each of which are incorporated herein by reference. Method of treatment 56 201107326 Phosphodiesterase Formula A, A1 In one embodiment, the invention provides a method of inhibiting cell (DE)/linguality comprising contacting a cell with a compound of one or more, hydrazine or B . In addition to PDE inhibitory activity, it is known that the combination of cefprolin also inhibits many other biological agents (such as interleukin " (IL-D, IL-6, IL-12, TNF.a, fibrinogen and various growth factors) Thus, in another embodiment, the invention provides a method of inhibiting the production of interleukin-1 (IL_n, il_6, IL-12, TNF_a, fibrinogen, and various growth factors) comprising The cells are contacted with one or more compounds of formula A, A1, 丨, π or B. According to another embodiment, the invention provides a method of treating a condition in which a patient in need thereof is benefiting from treatment with sirfeline, It comprises the step of administering to the patient an effective amount of a pharmaceutical composition of formula A, hydrazone 1, hydrazine, π or hydrazine or a pharmaceutical composition comprising a hydrazine, hydrazine, hydrazine, II or hydrazine compound 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, ΕΡ 0493682, US 5 1 12827, ΕΡ 0484785, WO 1997019686, WO 2003013568, WO 2001032156, WO 1992007566, WO 1998055 1 10, WO 2005023 193, US 4975432, WO 1993018770, ΕΡ 0490181 and WO 1996005 836. 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; 57 201107326 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 kidney disease; 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; Interleukin 丨-mediated disease; graft versus host response and other allograft responses; diet-induced fatty liver disease atherosclerotic lesions, fatty liver degeneration and other diet-induced high fat or alcohol induced Tissue degenerative conditions; fi human immunodeficiency virus (HIV-Ι) and other human retrovirus infections; multiple Cancer; fibroproliferative disease; fungal infection; drug-induced nephrotoxicity; collagenous colitis and other diseases and/or diseases characterized by elevated levels of platelet-derived growth factor (pDGF) or other inflammatory cytokines Endometriosis · 'associated with acquired acquired immunodeficiency syndrome (Ams), immune disorder disease or multiple sclerosis optic neuropathy and CNS functional impairment; autoimmune disease; upper respiratory tract virus infection; depression; urine Incontinence; large bowel dysfunction; septic shock; Alzheimer's dementia; neuropathic pain; dysuria; retinal or optic nerve damage; peptic ulcer; insulin-dependent diabetes; non-insulin-dependent diabetes; diabetic nephropathy; '·obesity; 姨 素 resistance; abnormal dyslipidemia; pathological glucose tolerance; hypertension; hyperlipidemia; hyperuricemia; gout 'high glucency' · acute alcoholic hepatitis; Open arterial catheter; and inflammatory injury associated with chemotaxis and/or degranulation of neutrophilsCapsules 58 201107326 Compounds of formula A A1, i, η or B can also be used to control the intraocular pressure or turbulent blood flow of an individual as determined by physical examination. * In the specific example of y, the method of the present invention is used to treat a disease or condition selected from the group consisting of chronic obstructive arterial disease of the extremities and other peripheral obstructive ▲ tube diseases. Claudication; glomerular nephritis; focal segmental glomerulosclerosis; renal syndrome; nonalcoholic steatosis hepatitis; leishmaniasis; cirrhosis; liver failure; Duchenne muscular dystrophy; Radiation-induced injury; radiation-induced lymphedema; alcoholic hepatitis; & evoked fibrosis; necrotizing enterocolitis in premature infants; diabetic nephropathy, renal failure induced by hypertension, and other chronic kidney disease; Tumor disease; recurrent thrush stomatitis; breast cancer, chronic breast pain; brain and central nervous system tumors; obesity, acute/sickness and hepatitis, olfactory disorders; infertility associated with endometriosis Malnutrition - inflammatory - cachexia syndrome; and open 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. The nephropathy may be selected from glomerulonephritis, focal segmental glomerulosclerosis, renal syndrome, reflux uropathy, or polycystic kidney disease. In one embodiment, the method of the invention is used to treat chronic diseases of the liver 59 201107326. Chronic liver disease can be selected from non-alcoholic 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 adenosine resistance 'retinopathy' diabetic ulceration, radiation-related necrosis, acute renal failure or drug-induced nephrotoxicity. In a specific example, the method of the invention is used to treat a patient suffering from cystic fibrosis, including a patient suffering from chronic Pseudomonas bronchitis: In a specific example, the method of the invention is used to aid wound healing. Examples of types of wounds that can be treated include venous cancer and acne. Zhang H Guang, Diabetic Crush: Another - specific specific example of 'the patient of the invention's # ό, ν mouth W $ for the non-Island...: 姨 素 Dependent Diabetes; Non-魄 素 dependence dependent , Zhuang. # W > 卜内' Sex. Heterosexual blood 0 group; Obesity, · 姨岛辛抗, 异*血月曰症; pathological glucose', disease resistance, · hyperuricemia; gout And high coagulability and disease 1 blood plant Jian, · high blood lipids The methods described in this article also include methods of patient treatment. Identifying the need for the treatment is determined by the particular professional and can be subjective (eg, measured by a patient or health care by a test or diagnostic method). ") or objective (for example, in another specific example, any of the above-described steps of treating a total of eight or more second therapeutic agents to be administered to the patient. Another - will be known to be compatible with the formulation of the Ceffifine $-therapeutic agent Self-selection. The selection of the second therapeutic agent is also carried out in the therapeutic agent. The disease or condition of the temple is determined by the method of the present invention. The second therapeutic agent which can be used in the method of the present invention is the compound of the present invention. And a second therapeutic agent for use in a combination composition of the second therapeutic agent. In particular, the combination therapy of the present invention comprises co-administering a compound of formula A, A1, I II or B with a second therapeutic agent to treat the following conditions (The specific second therapeutic agent is indicated in parentheses after the indication): delayed radiation-induced injury (α-tocopherol), radiation-induced fiber ° and bauxite, Q:-shengyue g), radiation Induced lymphedema (α_ fertility), chronic breast pain in breast cancer patients), type 2 diabetic nephropathy (catoxin (-Π)), malnutrition and cachexia syndrome (oral: supplements, such as I and oral anti-inflammatory module For example, 0xepa) 1 brain and central nervous system tumors (radiotherapy and transurea) and the combination therapy of the present invention also include co-administered formula a, Ab compound and second therapeutic agent to treat 姨2 dependence Diabetes; metabolic syndrome: disease 'non-姨 吊 吊 吊 ' · · · 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 The shoot "" is a single-sword type (such as a composition of the invention comprising a second therapeutic residue as a therapeutic agent) and a second therapeutic compound of the invention as described above. In part or as a plurality of separate dosage forms and pre-administered to other medicine swords, and the present invention can be administered to other compounds or in the course of administration of the compound of the present invention. The compound of the invention is further administered with other agents. The combination therapy treatment system and the therapeutic agent are all granted by the method of f. The administration of the composition of the present invention comprising the compound of the present invention and the second therapeutic agent to a patient at 61 201107326 is not excluded. Another during the treatment The patient is administered the same > therapeutic agent, any other second therapeutic agent or any of the compounds of the invention separately.

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 WeUs et al., Pharmacotherapy Handbook 2nd Edition, Appleton and Lange , Stamford, Conn. (2000) ; PDR

Pharmacopoeia, Ding arasc〇n p〇cket 2_, Deluxe Edition ' Taiascon Publishing, Loma Linda, Calif (2000) and other sauces in thousands of textbooks. However, it is determined that the optimal effective amount range of the second therapeutic agent is within the capabilities of those skilled in the art. In one embodiment of the administration of a second therapeutic agent to an individual, the effective amount of the present compound 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 it is forked to the compound of the invention. With this #, the undue side effects associated with high doses of any of the agents 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 Formula A, A1, Bu or B alone or in combination with one or more of the above second therapeutic agents, either in the form of a mono-component or in a separate dosage form. A medicament for treating the above-mentioned disease 35, disorder or symptom of a patient I. The L sample of the present invention is a compound of formula A, A1, I, I having ten η ^, or B, which is used for treating a patient The disease's condition or symptom described herein. 62 201107326 Synthetic Examples The following synthetic examples provide detailed procedures for the preparation of certain compounds of this % d. Those skilled in the art will readily appreciate this. Other procedures for the preparation of the present invention are carried out by using other reagents or intermediates, etc. The prepared compounds are analyzed by NMR, mass spectrometry and elemental analysis of the + 明 ° 兄 兄The IHNMR system is performed on a 30 丨 MHz instrument suitable for determining the enthalpy of enthalpy. Unless otherwise stated, the NMR signal is indicated as indicated in the following examples; Is at least 9〇0/.. Example 1. Synthesis of 3-methyl·7_(methyl τ 基--heart)-1-(5-sided oxyhexyl)-ιη-π 吟-2,6(3//,7//)-dione (Compound ι〇〇). Scheme 1 3 · Preparation of Compound 1 〇〇 and 4 〇 9

...1· 3-methyl-7-(methyl On 呤_2,6 (present (9) 丨51). Heating 3_f base 嗓 嗓^s〇 (5.〇g, 3〇.imm〇i,^ 4 63 201107326 and powdered K2C03 (5.0 g, 36.0 mm 〇b 12 equivalent) in DMF (95 mL) in suspension of liquid i 6 (TC and added 峨甲烧_d3 via syringe

Isotopes, 99.5 atoms %D ' 2·2 mL, 36 〇 followed by 1, l 2 equivalents). The resulting mixture was heated at 8 (TC) 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% Na?H aqueous solution (50 mL) Solution. The aqueous solution was washed three times with DCM (50 mL). The aqueous layer was acidified to pH 5 with acetic acid (6 mL) to give 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 about 25 mL and the second crop was obtained by filtration. The total yield of 51 was 51 g. The crude material was used without further purification. Step 2 '3_Mercapto-7((fluorenyl-heart)-1-(5-oxo-oxyhexylindole-2,6(3//,7//) )-Dione (Compound 1〇〇) β Suspension of crude 51 ( } 5〇g, 8 2 (1) and 1 equivalent) and powdered K2C03 ( 2.28 g, 16.4 mmo丨, 2 equivalents) in DMF (3〇mL) And heated to the thief. Add 6-milo-2-hexanone (52, 1.2 mL, 9.0 mmol, 1.1 eq.) to the resulting brown suspension and raise the reaction temperature to 13 〇t. Succession The mixture was heated for 2 hours, during which time the suspension became finer and the color was darker. The reaction mixture was cooled to room temperature and DMF was evaporated under reduced pressure. The residual brown broth was suspended in EtOAc (250 mL) Filtration to remove insoluble material. Concentration of the filtrate under reduced pressure afforded a yellow oil. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The crude product was purified by dissolving for 50 minutes. The product was concentrated under reduced pressure to dissolve a mixture of &lt;RTI ID=0.0&gt;&&&&&&&&&&&&&&&&&&&&& g, 100, mp 101.8-103. CTC. W-NMR (3 〇〇 MHz, CDC 13): 5 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). l3C-NMR (75 MHz, CDC13): δ 20.95, 27.41, 29.69, 29.98, 40.80 , 43.1 8, 107.63, 141.41, 148.75, 151.45, 155.26, 208.80. HPLC (Method: 20 mm Cl 8-RP column-gradient method 2 to 95 Torr in 3.3 minutes. ACN + 0.1% citric acid' 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 (C13H15D3N403): Calculated: c = 55.50, H = 6.45 Ν = 19.92. Found: C = 55.58, H = 6.48, N = 19.76. Due to the presence of the triple bee at 4.01 ppm in the above iH-NMR spectrum, it is determined whether or not there is a single bee around 3.99 ppm corresponding to the presence or absence of hydrogen on the N-methyl group at the 7th position (R1) of the anthracene ring. possible. Example 2·Synthesis of 8-A-3-methyl-7-(methyl-cardiyloxyhexyl)-1//-嘌呤-2,6(3//,7//)-dione (compound) 4〇9). 8-ί/,-3-mercapto-7-(fluorenyl-heart)-1-(6-(/3-4-heart-5-sideoxyhexyl)-1//-° ticket - 2 , 6(3F,7//)-dione (compound 409). ι〇〇( ^ g, 6.4 mmol ' 1 eq.) and powdered K2C03 (0.23 g, 1.7 mm 〇1, 0.25 eq.) in D2 〇 (Cambridge Isotope Labs, 99 Atom.) The suspension in (45 mL) was stirred under reflux for 24 hours, during which time the suspension became a slightly yellow solution. The reaction mixture was cooled to room temperature, 65 201107326 Saturated and extracted four times with dioxane (400 mL). The combined organic solution was dried over Na 2 EtOAc, filtered, and evaporated under reduced pressure to afford 1.7 g of a yellow oil which solidified upon standing. The crude material was again subjected to the above hydrogen/hydrazine exchange conditions with fresh K2C03 and DjO. After the same treatment, the ash solid was wet-purified with hexane (1 〇〇mL) and filtered to obtain 1.61 g of 409 as an off-white solid. Mp 99.6-99.8. (:. i-NMR (300 MHz, CDC13): δ 1.64-1.69 (m, 4 Η), 3_57 (s, 3 Η), 4.01 (t, J = 7.0, 2H). l3C-NMR ( 75 MHz, CDC13): (5 21.05, 27.61, 29.90, 41.02, 1 07.83, 148.99, 151.69, 155.50, 209.28. HPLC (Method. Waters Atlantis T3 2_lx50 mm 3 μηι C18-RP column-gradient method 5_95% ACN + 〇.1〇/o citrate in 14 minutes (! 〇mL/ Min), and maintained at 95% ACN for 4 minutes; wavelength: 254 nm): residence time: 3.26 minutes: 98% purity. MS (M + H): 288_3. Elemental analysis (Cl3H9D9N4〇3): Calculated value: C = 54 35, h = 6.31, N = 19 5 〇. Experimental values: C = 54.36, H = 6.32, N = 19.1 〇. Value / main thinking 疋, the following peaks are absent in the above ijj-NMR spectrum: 2.15 A single peak around Ppm indicates the absence of mercapto ketone hydrogen; the peak around the 5 卯 卯 , , , , , , , , , , , , — — — — — — — — — — — 不 不 不 不 不 不 不 不 不 不 不 不 不 不 不There is no argon at the number 8 position above. Due to the presence of a triplet at 4. 〇 1 ppm in the above 1H-NMR spectrum, it corresponds to the N_ fluorene at 7 (R) of $? It is impossible to determine whether or not there is a single peak around 3 99 ppm by the presence of hydrogen. Example 3. Synthesis of 3,7-di(indolyl 1 (5-sideoxyhexyl) (8) 66 201107326 嘌呤-2,6(3//,7//)-dione (compound 101). Preparation of Compounds 1 and 1 and 413.

1. CD3I 2. MeOH

Ο

Η

N HMDS N 甲笨 Η Reflow 53

Ο

Cd3 Ν Κ2〇〇3

... ^ ^ S DMF iD3 reflux 101 Step 1. 3,7-Di(indolyl-4)-1//-嘌呤-2,6(3//,7//)-dione (55). A suspension of xanthine 53 (2.00 g, 13.2 mmol, 1. 当量 equivalent) and hexamethylene diazane (32 mL) in decylbenzene (60 mL) was heated to reflux and stirred for 4 days. The reaction mixture was cooled to room temperature, diluted with hydrazine (50 mL) and passed through a celite to remove any unreacted starting material. The mash was evaporated to dryness under reduced pressure to yield 54 (4.1 g). A portion of this material (3.〇〇g) was placed in a 1 〇〇 mL sealed tube reaction vessel followed by the addition of toluene (60 mL) and CD3I (4 mL, Cambridge Isotopes, 99·5 atom% D). The reaction mixture was heated in an oil bath at 120 ° C and stirred for 24 hours. During this time the reaction mixture turned 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 (30 mL) and MeOH (5 mL). The solid was washed with acetone (1 〇 〇 m L ) to remove yellow 67 201107326 to provide an off-white solid. The dried solid was filtered under a stream of N2 to afford a mixture of &lt;RTI ID=0.0&gt;&gt; The total mass recovery was 2.6 g (42% crude yield). Due to the poor solubility of this mixture, it was subsequently treated without further purification. Step 2. 3,7-Di(methyl-4)-1-(5-sided oxyhexyl hydrazone-2,6(3//,7//) diketone (compound). Heating crude material η (2.6 〇g, 13·4 mm〇hu equivalent) and a suspension of powdered K2C〇3 (2 2〇g, 16 claws, 1.2 equivalents) in DMF (50 mL) to 60t: to the resulting tan Add 6-gas-2-hexanone 52 (2.0 mL·, 14.8 mmol, 1.1 when 2) to the suspension and heat the mixture to i for 4 hours at i 4 (rc), during which time the suspension becomes Finer and darker in color. Cool the reaction mixture to room temperature and evaporate DMFe under reduced pressure to obtain a brown paste suspension, 1:1 gas methane / ethyl acetate (200 mL) and filter to remove insoluble The material was concentrated under reduced pressure to give a yellow-brown oil (3. g). The crude reaction product was adsorbed on a silica gel and dry-loaded on a stone-filled tube filled with 丨〇〇% 二气曱院. On the column, the column 卩〇·5% Me〇H/the gradient of the two gas enthalpies is separated. The dissolved fraction containing the product is concentrated under reduced pressure to obtain a yttrium-yellow yellow oil. 9〇%. Use Α-χ layer The system was further purified by a 6 ()% Et 〇 Ae / hexane over 20 min, followed by a gradient of 6 〇 _ _ EtOAc / heptane to further purify the yellow oil. The desired product was dissolved for about 20 minutes. The product-containing fraction was concentrated under reduced pressure to give a compound m of y·55 g (16%) as a slightly yellow oil, which was allowed to stand after standing to stand for 'H-NMRCBOOMHz^DC,): 1.64-1.69 (ms4H)52.15 68 201107326 (s,3H),2.51 (t,J = 7.0, 2H),4.02 (t,J = 7.0, 2H), 7.51 (s, 1H) 〇,3C-NMR (75 MHz, CDC13 ): 5 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 1χ5〇3 μηΊ C18-RP column-gradient method within 14 minutes) 5_95% ACN + 〇丨% decanoic acid (1 _0 mL/min) and maintained at 95% ACN + 〇·1% formic acid for 4 minutes; Wavelength: 305 nm): Residence time: 3.24 minutes: 98.6% purity. Ms (Μ + Η): 285.3, (M+Na): 307.2. Elemental analysis (c, 3H, 2D6N4〇3): Calculated: C = 54_92, Η = 6.38, N = 19.71. Experimental values: C = 54_9 〇, H = 6.4 〇, Ν = 19.50. It is worth noting that there is no single peak around 3 57 in the above iH_nmr spectrum, indicating that N_mercaptohydrogen is not present at the 3 position of the anthracene ring. Due to the presence of a triplet at 4·01 ppm in the above 1H-NMR spectrum, whether or not there is hydrogen on the N_thiol group at the 7 position (Ri) of the anthracene ring is judged whether there is a single around 3.99 ppm. The peak is impossible. Example 4. Synthesis of 8_'3,7-di(methylamyl) small (44,6,6,6 is ·5· oxohexyl)-1//-嘌呤_2 6 (3 ugly, 7/ /)_dione (compound 413). Di(methyl-4)-1-(4-heart-6-4-5-sided oxyhexyl)_]&quot; 嘌呤-2,6(3//,7/〇-dione (compound 413 Heating compound 1〇1 (g of g, 2.1 mmo1, h0 equivalent) and powdery K2C03 (0.10 g, 0.72 mm〇1 0.30 field) in d2〇 (15, Cambridge Isotopes, 99 original %D) The suspension was stirred and refluxed for 6 hours, and the suspension liquid turned into a yellowish solution during j. The reaction mixture was cooled to room temperature, saturated with sodium carbonate 69 201107326, and extracted with dioxane (200 mL). The combined organic extracts were dried with EtOAc EtOAc (EtOAc m. The crude reaction product was again subjected to the above reaction conditions. After the same treatment, the off-white solid was wet-purified with hexane (50 mL) and filtered to give 〇45 g (74%)

Compound 413, mp 99.2-99.3, as a white solid. (:. j. NMR (300 MHz, CDC13): δ 1.64-1.71 (m, 4 Η), 4.01 (tj = 7 0 2H). nC-NMR (75 MHz, CDC13): 5 20.85, 27-41, 40.81 , 107.63, 148.80, 151.50, 155.31, 209.09° HPLC (method: Waters

Atlantis T3 2.1x5 0 mm 3 μηι Cl 8-RP Column-gradient method 5-95% ACN + 0.1 % decanoic acid (1.〇mL/min) in 14 minutes, and at 95〇/〇acn + 〇· Hold for 1 minute under 1% formic acid; Wavelength: 254 nm): Residence time: 3 25 minutes: 98.7% purity. MS (M + H): 291.3, (M + Na): 3132. Elemental analysis (Ci3H6D12N4〇3): Calculated: c = 53.78, H = 6 25 N = 19.30. Experimental values: C = 5 3.76, H = 6.3 9, N = 19.11. It is noteworthy that the following peaks are absent in the above iH_NMR spectrum: 2.15 single peak around Ppm indicating the absence of methylketone hydrogen; 2.5i p (four) surrounding triplet ' indicates the absence of methylene_hydrogen; 3.57 ppm around The single peak ' indicates that there is no N_f base nitrogen at the 3 position on the t ring; and a single peak around 75 ippm indicates that hydrogen is not present at the (4) 8 position on the anthracene ring. Due to the above, there is a triplet at 4.01 ppm in the H_NMR spectrum. Therefore, 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 (Rl) of the anthracene ring. possible. 70 201107326 Example 5. Synthesis of 3·mercapto_7_(fluorenyl-cardiac dry hexyl)-1//-嘌呤-2,6(3孖,7//)-dione (compound 99). Flowing spear i 1 5 · Preparation of compound 9 9 .

Step 1. 5-(3-indolyl·7·(fluorenyl-heart)_2,3,6,7-tetrazo-1//-mercapto)-N-methoxy-N-mercapto pentylene Amine (58). Heat 51 (1.50 g, 82 mmol '1.0 equivalents for the preparation see example 丨) and powder I &lt;: 2C 〇 3 (18 〇g, 12.9 mmol '1.6 eq.) in DMF (40 mL) to 60 ° C. Add 5-bromo-N-decyloxy-N-mercaptopurine 57 (2.11 g, 9 8 mmol, 1.2 eq., as outlined in 〇rg. Lett., 2005, 7: 1427-1429) and The mixture was heated at 〇 ° C 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 is suspended in! : i CH2C12. Ethyl acetate (25 〇 mL) and the suspension was filtered to remove insoluble materials. The filtrate was concentrated under reduced pressure to a yellow oil. This crude reaction product was purified using an Anai〇gix automated chromatography system eluting with 100% CH2C12 over 8 min then followed by a gradient of 0-5% MeOH/CHzCl2 over 40 min. The desired product was dissolved for about 24 minutes. The fractions containing the product were concentrated under reduced pressure to a slightly yellow oil. The iH NMR of the oil indicated that it contained about 1% unreacted 51. The second purification was carried out via an Analogix automated chromatography system with 1% CH2Cl2 for 10 minutes followed by a gradient of 〇_5% MeOH/CH2Cl2 over 50 minutes to allow for the removal of impurities. The fractions containing the product were concentrated under reduced pressure to a slightly yellow oil which crystallised as an off-white solid upon standing. The solid was triturated with heptane (EtOAc (EtOAc) EtOAc (EtOAc) Step 2. 3-Methyl-7-(indolyl-(5) small ^/^ core + pendant oxyhexyl oxime 2,6 (3//, 7//&gt; diketone (compound 99). Cooling 58 (〇72 g '2.2 mm〇l 'u equivalent) in THF (2〇社) suspension to 2 C and via syringe to keep the temperature below 5. The rate of 〇 is added dropwise to the 1M CD3MgI in E-turn (2.4 mL, 2.4 mmol, 1.1 eq., Aldrich &gt; 99 atom% D) ^ During the addition, the mixture became a fine, slightly yellow suspension. When the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 3 hours. ~ Part of the compound to 2 C and add a portion of CD3MgI solution (〇.4 mL, 0.4 mmol). Warm the mixture to room temperature and stir for another 3 hours. Stop the reaction with Μhci (4 mL) and Η&quot (1 〇 mL) was diluted to give a yellow-yellow solution which was extracted with CH.sub.sub.3 (3 EtOAc, EtOAc). Anal 〇g x autochromatography system, 1 〇〇% CH2Ci2 over 8 minutes, and then the crude product was purified by gradient elution with 〇·5% MeOH/CHKh over 40 min. Dissolution for about 22 minutes' followed by dissolution of unreacted 72 201107326 starting material. The fractions containing the product were concentrated under reduced pressure to a yellow oil which solidified after standing. The solid was wet-dried with hexane (25 mL) 0.33 g (53%) of Compound 99, mp 93.7-94.4, as a white solid, was obtained by vacuum filtration. (:: The fractions containing the unreacted starting material were also collected and concentrated to give 0.21 g of clarified, colorless. Oily 58. The recovered material was 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 X: was obtained. H-NMR (300 MHz, CDC13): (5 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, lH) 〇13C-NMR (75 MHz, CDC13): δ 21.16, 27.65, 29.91, 41.03, 43.41, 107.87, 141.62, 149.00, 151.69,1 55.50, 209.12. HPLC (method: Waters Atlantis T3 2.1 X50 mm 3 μηι C 1 8-RP column-gradient method 5_95〇/〇acn + 〇. 1 % formic acid (1.〇mL/min) in μmin, and under 95% ACN + 0.1% formic acid maintain 4 minutes; Wavelength: 305 nm): Residence time: 3.24 minutes: 99 〇0/〇 purity. Ms (M + H): 285.3, (M+Na): 307.2. Elemental analysis (C^ 3:H丨2〇6&gt;^〇3): Calculated value · C-54.92, H=6.38, N=19.71. Experimental values: c = 54.85, H = 6.36, N = 19_49. It is worth noting that there is no 2丨5 _ in the above lH_NMR spectrum.

The monosynthesis on the second day indicates the absence of decyl ketone hydrogen. Due to the presence of a doublet at 4 _ 〇 1 ppm in the above lH-NMR, it is determined whether or not there is a single peak corresponding to the presence or absence of hydrogen on the N. methyl group at the 7-position (R) of the anthracene ring. possible. 73 201107326 Example 6. Synthesis (±) 8-4_1_(4,4,6,6,6-heart-5-hydroxyhexyl) fluorenyl-7-(fluorenyl-c/3)-1//-嘌呤-2,6(3//,7//)-dione (Compound 419: Scheme 1 6. Preparation of Compounds 419, 419 (Λ) and 419(S). η

NaBH4

EtOD

Cd3 N /&gt;-〇 N to palmity HPLC separation

419(S)

(soil) 8-β^-1-(4,4,6,6,6-ί/5-5-hydroxyhexyl)-3-indolyl-7-(mercaptopurine-1 good-. 2,6(3//,7//)-dione (compound 419). Compound 4〇9 (0.50 g' 1.7 mmol' 1.0 eq., see Example 2) was dissolved in Et 〇D (13 mL, Aldrich 99.5 atomic % D) and NaBH4 (〇〇7 g, 1.9 mmol, 1.1 eq.) was added. The temperature was observed to increase from 24t to mi. The reaction was stirred at room temperature for 2 hours, then by adding 〇2〇 (3〇) mL ,

Cambridge Isotope Labs, 99 Atomic D) discontinued. A white suspension was formed which was extracted with MTBE (4 Torr, 200 mL total). The combined organic extracts were dried with EtOAc EtOAc m. The crude product was purified by silica gel chromatography, first eluting with 1% <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; Concentration of the product-containing fractions under reduced pressure afforded (0.41 g, 83%) of compound 419, which was obtained as a colorless oil, and was solidified in the form of a solid oil. ,4,6,6,6_heart_5 hydroxyhexyl)-3 -mercapto-7-(methyl 0-1-purine-2,6(3//,7//)-dione (compound) 419(i?)) and (7) small (4,4,6,6,6n via hexyl)_3 methyl-7-(methyl-heart)-1仏嘌呤_2,6(3//,7 Diketone (Compound 419(^). The enantiomer of compound 419 was isolated. Compound 419 (0.38 g) from Example 6 above was dissolved in a minimum amount of iPr〇H (6 mL, HPLC grade It was heated and diluted with hexane (4 mL, HPLC grade). Enantiomeric separation was achieved using a Waters HPLC system equipped with a preparative Daicd Chiralpak ad column (20 x 250 mm). In the first minute of operation 'The mobile phase is 80% hexane and 2% iPr〇H and 〇丨% diethylamine. After the first minute, the gradient of hexane and 25% hydrazine and 0.1% diethylamine is reached in 15 minutes. This solvent ratio was then maintained at a flow rate of 18 mL/min for π minutes. The baseline of 419 (magic first dissolving (21.0 min), followed by 419 〇y) dissolving (μ" min) was separated. The fractions containing the respective enantiomers were concentrated under reduced pressure to obtain the respective 〇.16 g of grayish white. Solid 419 (/?) ((7) 〇 〇 7 81 〇 8 8 〇 c) and 419 (51) (mp l 〇 8.3-l 〇 8.4 ° C). A) · (/?)-8-4 1-(4,4,6,6,6-4-5-hydroxyhexyl)_3-indolyl-7-(methylindole-2,6(3//,7//)-dione ( Compound 419W).Ιη·νμιι (300 MHz, CDCI3): (5 1.36-1.50 (m, 2H), 1.60-1.74 (m, 3H), 3.58 (s, 3H), 3.80 (s, 1H), 4.02 ( t, J = 7.3, 2H) 13C-NMR (75 MHz, CDC13): d 22.70, 2 7.86, 29.7 1,41.14, 75 201107326

67.66, 107.66, 148.78, 15 1.54, 155.40. HPLC (Method: Waters Atlantis T3 2.1x5 0 mm 3 μηι Cl 8-RP column-gradient method 5-95% ACN + 0.1% decanoic acid (1. 〇mL/min) in 14 minutes, and at 95% ACN + 0.1% niobic acid for 4 minutes; wavelength: 254 nm): residence time: 3 26 minutes: 99.9% purity. For palmar HPLC (method: Chiralpak AD 25 cm official column - temple method at 1 · 〇〇 mL / min 78% hexane / 22% isopropyl alcohol / 0. 01% - ethylamine for 40 minutes; wavelength: 254 nm): residence time: 27.51 minutes (main enantiomer); 3119 minutes (expected value of minor enantiomer) ·· &gt; 99.9% ee purity. MS (M + H): 290 1 (M + Na): 312.3. Elemental analysis (Cl3HuD9N4〇3): Calculated: 053.97, Η = 6.97, N = 19.36. Found: 〇54.39, H = 7.11, N=1 8.98. It is worth noting that there is no peak around 1.19 ppm in the above ih_nmr spectrum, indicating that there is no thiol hydrogen and a single peak around 7.51 ppm relative to the alpha position of the hydroxyl group, indicating the number on the ring (a) standing ? There is hydrogen. Due to the presence of a multiple peak of 136_15() shoulder and a triplet at 4.01 ppm in the above lH_NMR spectrum, it is determined whether or not 151 is present at 151, corresponding to the presence or absence of methylene hydrogen in the α position of (4). It is impossible to determine whether a single peak exists around 3.99 Ppm at the 7 position of the 嗓呤 ring and whether it exists on the N-methyl group at 1). B) _ (5)-8-4-1-(4,4,6,6,6-〇f5-5-ylhexyl)-3-methyl_7_(methyl-can! //-嗓吟-2,6 (wind 7//)·dione (compound 41). 1h_nmr (3〇〇MHz, GDC,): , 1.4m.48 (m? 2H)&gt; t 64-1 ?2 ( Mj 3H), 3.58 (s, 3H), 3.79 (s, 1H), 4 〇 2 (t, = 7 4, 2h). 76 201107326 l3C-NMR (75 MHz, CDC13): (5 22.70, 27.86, 29.71, 41.1 5, 67.66, 107.67, 148.78, 15 1.54, 155.41. HPLC (Method: Waters Atlantis T3 2.1x50 mm 3 μη Cl 8-RP column-gradient method 5-95% ACN + 0.1% in 14 minutes Formic acid (1.0 rnL/min) and maintained at 95% ACN + 0.1% formic acid for 4 minutes; wavelength: 254 nm): residence time: 3.26 minutes: 99.9% purity. For palmity ^^1^ (method: (:1^31?31&lt;eight 〇25 (^ tube column - isocratic method at 1·〇〇mL/min 78% hexane / 22% isopropanol / 0.0 1% diethylamine for 40 minutes; Wavelength: 2 5 4 nm ) ··Retention time: 31.19 minutes (main enantiomer); 27.51 minutes (expected value of minor enantiomer): &gt;99.9% ee Purity. MS (M + H ): 290.1, (M+Na): 312.3. Elemental analysis (Ci3HmD9N4〇3): calculation Value: C = 53,97, Η = 6.97, N = i9.36. Experimental values: c = 54 35, h = 7 28, N = 1.75. ' The value is noted above, above H. There are no peaks in the NMR spectrum. 1.19 Peak around the peak, refers to (4) for the presence of silk: 单 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 There are multiple peaks in the spectrum and 4 m test + _ PPm... Is there a sub-two: the weight: and corresponding to the 7 position of the ticket ring (Rl;:.51PPm since there is a peak) It is impossible to determine whether or not the surrounding =) single = base is in the early peak. Example 8. Synthesis (±) 8 base) _3_methyl ~ 7 · (曱基1-(4,4,5, 6,6,6-heart-5 呤-2,6(3//,7//)-dioxatong••hydroxyl (compound 77 201107326 435 ). Scheme 17. Preparation of Compounds 435, 435 (/〇 and 435 (51) »

(±)8-«^/-1-(4,4,5,6,6,6-heart-5-ylhexyl)-3-mercapto-7-(methyl〇1 //-嘌呤- 2,6 (3 //,7 //)-dione (compound 4 3 5 ). To compound 4 〇9 (0.50 g' 1.7 mmol' 1.0 eq) in EtOD (13 mL, Aldrich 99.5 atom% 〇) NaBD4 (0.08 g, 1.9 mmol, Μ equivalent 'Cambridge Isotope Labs, 99 atomic % D) was added to the solution. The temperature was observed to increase from 24 ° C to 27 ° C. The reaction was stirred at room temperature for 2 hours, followed by addition. D20 (30 mL) (Cambridge Isotope, 99 Atomic % d) was discontinued. A white suspension was formed which was extracted with MTBE (4×, a total of 200 mL). The combined organic extracts were dried over Na 2 〇 4, filtered and reduced The pressure was reduced to a clear, colorless oil (0.45 g). The crude product was purified by silica gel chromatography eluting with i% MeOH/CH2Cl2 followed by i-5% MeOH/CH2Cl2i gradient. Concentration of the product-containing fractions gave 435.4〇g (8 1 °/Q) as a clear, colorless oil of compound 435 which solidified upon standing. 78 201107326 Example 9. Separation of palms (and) 5 hydroxyl groups Hexyl)-3-methyl-7·(曱嘌呤_2,6(3孖,7 ugly)_dione (compound 435(/〇) and (5)-8-4-1-(4,4,5,6,6,6-^-5- Hydroxyhexyl)-3-mercapto-7-(indolyl-heart)-1仏嘌呤_2,6(37/,7 ugly)-dione (compound 435(51)). Separation of the dimerization of compound 435 The compound 435 (0.32 g) obtained from Example 8 above was dissolved in a minimum amount of iPr〇H (5 mL, HPLC grade required heating) and diluted with hexane (4 red, HPLC grade). Enantiomer separation was achieved with a Waters HPLC system equipped with a preparative Daicel Chiralpak AD column (20 x 250 mm). The mobile phase was 80% hexane and 20% iPr〇H and 0.1% in the first minute of operation. Ethylamine. After the first minute 'Use 75% hexane and 25% iPrOH and 梯度. 1 〇 / 〇 monoethylamine gradient' then maintain this solvent at a flow rate of 18 mL / min The ratio lasted for 17 minutes. This method resulted in the first dissolution of compound 435 (i?) (21.9 minutes) followed by baseline separation of compound 435 (5&quot;) dissolution (25.2 minutes). The aliquots containing the respective enantiomers were concentrated under reduced pressure to give each of 0.12 g of 435 (7?) (mp 1 〇 8.0-1 〇8·Γ(:) and 435 〇S) as an off-white solid ( Mp 107.6-107.7.(:). Α) . (Λ)-8-heart-1-(4,4,5,6,6,6-^-5-hydroxyhexyl)-3-indolyl-7- (曱基嘌呤·2,6(3/7,7//)-dione (compound 435(/?)). 'H-NMR (3〇〇MHz, CDC13): (5 1.40-1.48 (m, 3H), 1-66-1.70 (m, 2H), 3.58 (s, 3H), 4.02 (t, J = 7.5, 2H). 13C-NMR (75 MHz, CDC13): 5 22.66, 27.86, 29.71, 41.15 , 107.67, 148.80, 151.54, 155.41. HPLC (Method: Waters 79 201107326

Atlantis Τ3 2·1χ50 mm 3gmC18-RP Column-gradient method 5-95% ACN + 0.1 % decanoic acid (1.〇mL/min) in μ minutes and kept for 4 minutes under 95% ACN + 0.1 % formic acid ; Wavelength: 254 nm): Residence time: 3.25 minutes: 99.8% purity. For palmar HPLC (method: Chiralpak AE > 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 minutes (major enantiomer); 31. n minutes (expected value of minor enantiomer): &gt; 99.9% purity. MS (M + H): 291 3 (M+Na): 313.2. Elemental analysis (Cl3Hi()Di() N4〇3): Calculated: C = 53.78, Η = 6.94, Ν = 19.30. Experimental values: 〇54〇1, h = 7〇7, N = 1 8 · 9 0 〇 It is worth noting that the following peaks are absent in the above 丨H_NMR spectrum. The peak around 19 ppm indicates the relative basis There is no methyl nitrogen 3.8 in the alpha position. A peak around PPm indicating that there is no single peak indication around the hydrogen dihydrazide PPm at the methine radical position. The number on the ticket ring is "stand-up... in hydrogen. Due to the above-mentioned 丨H-NMR hitting the left*!, the eve of each of the eves is K. There is +?1 in the 1111) 111;; And the triplet at 4.01 ppm, thus corresponding to the presence or absence of methylene fish in the alpha group: the presence of methylene fish 丨#, sz υ.51 卿 是否 是否 51 51 51 51 51 51 51 51 51 51 51 51 51 51 51 51 51 51 51 51 Whether nitrogen is present on the N-methyl group: It is impossible to determine whether there is a single peak around 3_99Ppm. &quot; B ). (夕) U/-1 - (4 : ·*» V, '5,6' 6,6-〇^-5-hydroxyhexyl)·3· -7-(methyl-嘌呤·2,6(3i/,7//)-dione (compound 43Sm) Ή-NMR (300 MHz, CDC1 V ^ (

,62, Cl3)· &quot; (m, 3H ^62-172 ^ (s, 3H), 4,3 (t, ,.7,5 2H)e 80 201107326 13C-NMR (75 MHz, CDC13): &lt;;5 22.69, 27.90, 29.70, 41.17, 107.69,148.82,151.58,1 55.43. HPLC (Method: Waters Atlantis T3 2.1x50 mm 3 μιη C18-RP tube-gradient method 5-95% ACN + 0.1 in 14 minutes % decanoic acid (lo mL/min) and maintained at 95% ACN + 0.1% citric acid for 4 minutes; wavelength: 254 nm): residence time · 3.25 minutes: 99.5% purity. Palmitic 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): retention time: 31.11 minutes (mainly mapped Isomer); 27.24 minutes (expected value of minor enantiomer): &gt; 99.9% ee Purity. MS (M + H) · 291.3, (M + Na): 313.2. Elemental analysis: Calculated value: C = 53·78' H=6·94, N=19.3〇. Experimental values: C = 54.01, H = 7.H, N = 18.78. It is worthwhile to think that 'does not exist in the above 1H-NMR spectrum The following peaks: (3) The peak of Ah Guan, refers to (9) the presence of sulfhydryl hydrogen for «αα ;; 3.8〇PPm the peak of stomach circumference, Indicates that no nitrogen is present at the position of the methine sulfhydryl group; and a single peak around 7.5 1 ppm means that there is no 虱 at the number 8 position on the ^ ° 虱 归因 归因 虱 虱 虱 虱 虱 虱 虱 虱 虱 虱 虱 虱 虱 虱 虱 虱 虱 虱 虱 虱 虱 虱 虱 虱There is a 1.6-1.50 ppm imaginary multiple peak in the spectrum and a heavy peak at the PPm at 4.01 ppm'. Therefore, it corresponds to the relative &AA position of the presence of methylene hydrogen to the base of ^^ 疋1,51 Whether there is 嵝 at the PPm and whether it corresponds to the 7-position Γp丨, Shangrenfeng, and the N-methyl group at the 嘌呤 ring, whether it is a farmer or a bird. 3.&quot;Ah week ^No existence is the existence of Ke Neng Example 10. Synthesis of rf/·3,7-dimethyl_1_(4,4,6,6,6-i/s-5 side 81 201107326 oxyhexyl)-1//-嘌呤-2, 6 (3 ugly, 7//)-dione (compound 407). » Scheme 1 8. Preparation of Compounds 407, 437, 437 (and) and 437 (51).

Palm separation

8-Heart-3,7-dimercapto-1-(4,4,6,6,6-c?5-5-oxooxyhexyl)-1//-嘌呤-2,6(3// , 7//)-dione (compound 407). Commercially available 59 ( 7.95 g, 28.6 mmol) and potassium carbonate (990 mg, 7.2 mmol) in d20 (195 mL,

The mixture in Cambridge Isotopes' 99.9 atomic 〇) was refluxed 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 waste. The solid was dissolved in (1 95 mL) and the solution was reheated to reflux for 24 hours. Cool the solution. Ethyl acetate (200 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The mixture was stirred at about 4 ° C for 5 ,, and the filtrate was concentrated to a pale yellow solid under reduced pressure. </ RTI> 7.5 g (93%) was obtained as a white ash solid 82 201107326 'H-NMR (300 MHz, CDC13 ): (5 1.64-1.68 (m, 4H), 3.57 (s 3H), 3.99 (s, 3H), 3_99·4·04 (m, 2H). 13C-NMR (75 MHz, CDC13): (5 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 2·1χ50 mm 3 μηι C18-RP column-gradient method at 14 points

5-95% ACN + 0.1% citric acid (io mL/min) in the clock and kept at 95% ACN + 0.1% citric acid for 4 minutes; wavelength: 3 0 5 nm ): residence time: 3 2 4 minutes: 99.9% purity. MS (M + H): 285.3, (M + Na): 307.2. Elemental analysis (C13H12D6N403): Calculated: C = 54.92, H = 6.38, Ν = 19.71. Found: 054.89, Η = 6.38, N = 19.70. It is noteworthy that the following peaks were absent in the above 1H-NMR spectrum: a single peak around 2.15 ppm indicating the absence of mercapto ketone hydrogen; a triplet around 2.51 ppm indicating the absence of hydrazinone hydrogen; And a single peak around 7.52 pprn' indicates that no hydrogen is present at the number 8 position on the ankle ring. Example 11. Synthesis of (±)8-c//-l-(4,4,5,6-ylhexyl)-3,7-didecyl-1Η-嘌呤-2,6(3Η,7Η)- Diketone (compound 437). (±) 8-3/-1-(4,4,5,6,6,6-^-5-ylhexyl)-3,7-didecyl-1^^- ° 呤-2, 6(311,71^-dione (compound 437). Add borohydride (1.06 g' 25.3 mmol, Cambridge Isotopes, 99 atom. / 〇D) to 407 (6.5 g, at 0:(:) 22.9 mmol) in a suspension of ethanol-di (65 mL, Aldrich, 9 Q c atom / 〇D). The mixture was allowed to warm to room temperature and stirred until a clear solution (about 1 hour) appeared. Ammonium-d4 (Cambridge Is〇t〇pes, 98 atomic % 〇) was quenched in a saturated solution of D20 (8 mL, Cambridge Isotope, 83 201107326 99.9 atom% 〇), and ethanol-d was evaporated under reduced pressure, and The residue was extracted with EtOAc (EtOAc EtOAc EtOAc. Example 12. Separation of bismuth (and)-8-Mountain_;1_(4,4,5,6,6,6-£/6-5-hydroxyhexyl)-3,7-dimethyl-1Η - ° 吟-2,6(3H,7H)-dione (compound 437(i?)) and (5)-8-3/-1-(4,4,5,6,6,6-heart -5-ylhexyl)-3,7-dimercapto-1H- Indole-2,6(3H,7H)-dione (Compound 437(51)). The enantiomer of compound 437 was isolated. Compound 437 ( 1.60 g) obtained from the above Example was dissolved in iPrOH ( 20 mL, HPLC grade, required to be heated. Use a preparative Chiralpak AD column (20x 25 0 mm Daicel ' 10 #Μ) and a pre-made Chiralpak AD front catheter column (20x50 mm Daice Bu 10 / / Μ) Waters HPLC system to achieve enantiomeric separation. In the first minute of operation, the sample was dissolved in 20% iPrOH / hexane (here 0.1% as the co-dissolving agent of diethylamine), while from 1 The flow rate of 5 mL/min was raised to 18 mL/min. During the next 15 minutes, the sample was dissolved at a flow rate of 18 mL/min with a gradient of 20% to 25% iPrOH/hexane. The sample was dissolved in 25% iPrOH/hexane at a flow rate of 18 mL/min. The sample was dissolved in a gradient of 25% to 20% iPrOH/hexane at a flow rate of 18 mL/min over the next 0.5 minutes. The sample was dissolved in 20% iPrOH/hexane at a flow rate of 18 mL/min over the next 4.5 minutes. This dissolution method resulted in the first dissolution of compound 437 (7?) (residence time of about 29 minutes) and the baseline separation of compound 437 (5*) followed by 84 201107326 dissolution (residence time of about 33 minutes). The fractions containing the respective enantiomers were collected and concentrated under reduced pressure to give 340 mg of 437 (i?) (mp 112.0-114.5 〇C) and 375 mg of 43 7 (51) (mp) 111.9-112.3 ° C). [It should be noted that only 1.0 g 437 was injected from the solution prepared above. ] A. (and)-8-^?/-1-(4,4,5,6,6,6-heart-5-transhexyl)-3,7-dimercapto-111-° -2,6(311,711)-dione (compound 437 (and)). 4^]\41^(3〇〇MHz, CDC13): δ 1.36-1.50 (m, 2Η), 1.54 (s, 1H), 1.64-1.74 (m, 2H), 3.58 (s, 3H), 3.99 ( s, 3H)S 4.00-4.05 (m, 2H). UC-NMR (75 MHz, CDC13): δ 22.66, 27.86, 29.70, 33.5 9, 41.14, 107.65, 148.76, 15 1.5 2,15 5.40. HPLC (Method: Waters Atlantis T3 2.1x50 mm 3 μπι C18-RP column-gradient method 5-95% ACN + 0.1% decanoic acid (lo mL/min) in 14 minutes, and under 953⁄4 ACN + 0.1% formic acid Hold for 4 minutes; Wavelength: 3 〇 5 nm): Residence time: 3 · 2 8 minutes: 9 9 · 9 % purity. For palmity η PLC (method: Chiralpak AD 25 cm column - isocratic method at 〗. 〇〇mL/min 78% hexane / 22% isopropanol / 0.01% diethylamine for 4 minutes; Wavelength: 254 nm). Residence time: 25.20 minutes (major enantiomer); 28 39 minutes (expected value of minor enantiomer): &gt; 99.9% in purity. Ms (M + H): 288·3, (M+Na): 310.2. Elemental analysis (c13h13d7n4o3): Calculated value: c=54.34, H=7 02, N=19 5〇. Found: 054.32, H = 7.23, N = 19.35. It is worth noting that there are no peaks in the above ih_nmr spectrum: peaks around Wppm, indicating that no sulfhydryl gas is present relative to the base; 85 201107326 3.80 peak around 'ppm' indicates the position of the methine hydroxyl group There is hydrogen; and a single peak around 7.5 1 ppm indicating the absence of hydrogen at the number 8 position on the anthracene ring. It is attributed to the presence of multiple peaks at 1.36 to 1.50 ppm in the above j-NMR spectrum. Therefore, it is impossible to determine whether or not there is a peak at 1 · 5 1 ppm corresponding to the presence or absence of methylene gas in the hydroxy group. of. B. (5)-8-3/-1-(4,4,5,6,6,6-4-5-transhexyl)_3,7-dimethyl-lH-°^^-2, 6(3H,7H)-monoketone (compound 437(5)) eiH-NMRQOO MHz, CDC13): δ 1.38-1.48 (m,2Η), 1.55 (s,1Η) 1.64-1.72 (m,2H),3.58 (s, 3H), 3.99 (s, 3H), 4.00-4.05 (m, 2H) 〇l3C-NMR (75 MHz, CDC13): 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_ 1x50 mm 3 μιη Cl 8-RP column-gradient method 5-95% ACN + 〇.i〇/0 decanoic acid (1() mL/min) in 14 minutes, and 95% ACN + 0.1〇/o acid for 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 uo mL/min 78% hexane/22./〇 isopropanol/0.01% _ethylamine for 40 minutes; wavelength: 254 nm): Retention time: 28.39 minutes (major enantiomer); 25 2 〇 minutes (expected value of minor enantiomer): &gt; 99 9% ee purity. (M + H): 288.3, (M + Na): 310.2. Elemental analysis (Ci3H|3D7N4〇3): Calculated value: c = 54.34, Η = 7·02, Ν = 19.50. Experimental values: C = 54.33, H = 7_30, n = 19.36. It is noteworthy that the following peaks are absent in the above iH-NMR spectrum: a peak around L19 ppm indicating the absence of methyl hydrogen relative to the alpha position of the hydroxyl group; 86 201107326 indicating the position of the methine hydroxyl group

It is not possible to determine if a peak is present at 1.5 1 ppm. The peak around 3.80 ppm, only: 7.51 ppm in hydrogen. Due to the above multiple bees, there is no gas corresponding to the position of the crucible; and there is no presence of methylene hydrogen in the alpha position at 1.3 6-1.5 〇ppm at the number 8 position. Example 13 Synthesis ) 1_(5_(_5_hydroxyhexyl)_3·decyl·?_(fluorenyl-heart)-1Η-嗓吟- 2,6(3H,7H)-diindole (Compound 131). Scheme 1 9 Preparation Compounds 131, 131 (7Ϊ) and 1 3 1 (S).

Palm separation

(±) 1-(5-4-5-hydroxyhexyl)-3-indenyl-7-(indolyl-indole-2,6(3H,7H)-dione (Compound 131). Follow the above synthetic compounds The same general procedure as in 437 'Compound 1 处理 was treated with NaBD4 in EtOH (see Example 1) to provide compound 131. Example 14. Separation of palms (/〇-1-(5-heart-5-hydroxyhexyl) )-3-mercapto_7_(methyl_Α)·1Η-嘌呤-2,6(3H,7H)-dione (Compound 131(^0) and 87 201107326 (5)-1-(5-4 -5-Hydroxyhexyl)-3-indolyl-7-(methylindole-2,6(3H,7H)-dione (Compound 131(^). The enantiomer of Compound 131 was isolated. The racemic compound 437 was isolated in the same manner as in the above Example 13 to obtain a portion of the racemic compound 131 to provide the isolated enantiomer compound 131(1?) (mp 112.2-112.7 ° C ) ( 210 Mg ) and compound 131 (»S) ( mp 1 12.0-1 12.1 ° C ) ( 220 mg ) A. Hydroxyhexyl)-3-mercapto-7-(mercaptopurine-2,6(3H,7H) -dione (Compound 131 (i〇). iH-NMR (300 MHz, CDC13): 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). l3C-NMR (75 MHz, CDCI3): δ 22.87, 23.40, 27.89, 29.71, 38.64, 4 1.13, 107.68, 141.40, 148.76, 15 1.52, 155.39. HPLC (method: Waters Atlantis T3 2.1x50 mm 3 μηι Cl 8-RP column-gradient method 5-95% ACN + 0.1 〇/〇 formic acid (1.0 mL/min) in 14 minutes and maintained at 95% ACN + 0.1% citric acid 4 min; wavelength: 305 nm): residence time: 3.29 minutes: 99.9% purity. For palmar HPLC (method · Chiralpak AD 25 cm tube 枉 - isocratic method at 1 · 〇〇 mL / min 78% hexane / 22% isopropanol / 0.01% diethylamine for 40 minutes; wavelength: 254 nm): residence time: 25.1 4 minutes (main enantiomer); 2 8.5 1 minute (expiration of minor enantiomers) Value): &gt;99.9% ee purity. MS (M + H): 285.3, (M + Na): 307.2. Elemental analysis (C|3Hl6D4N4〇3): Calculated value: C = 54.92, Η = 7_09, Ν = 19.71. Experimental values: C = 54.67, Η = 7.04, Ν = 19.35. 88 201107326 It is worth noting that there is no peak around 3 8 〇 ppm in the above iH NMR spectrum, indicating that no hydrogen is present at the position of the decyl hydroxy group. Due to the presence of a triplet at 4.01 ppm in the above W-NMR spectrum, it is impossible to determine whether a single peak exists around 3 99 corresponding to the presence or absence of hydrogen on the N_fluorene group at the 7th position (R1) of 嘌呤%. of. B. (5)-1-(5-heart-5-hydroxyhexyl)-3-indenyl-7-(fluorenyl-heart)-1 H-indole-2,6(3H,7H)-dione ( Compound 131 (5)). 'H-NMR (300 MHz, CDC13): 5 !-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). 13C-NMR (75 MHz, CDCh): (5 23.10, 23.63, 28.12, 29.94, 38.87, 41.36, 107.91, 141.63, 148.99, 15 1.75, 1 55.62 » HPLC (method: Waters Atlantis T3 2.1x50 mm 3 μτη C18- RP column _ gradient method 5 - 9 5 % ACN + 〇 · 1 % decanoic acid (1. 〇mL / min) in 14 minutes and maintained at 95% ACN + 0.1% citric acid for 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 loo mL/min 78% hexane / 22% isopropanol / 0.01% two Ethylamine for 40 minutes; wavelength: 254 nm): residence time: 28.51 minutes (major enantiomer); 25.14 minutes (expected value of minor enantiomer): &gt; 99.9% ee purity. MS ( M+H): 285.3, (M+Na): 307.2. Elemental analysis (C|3Hi6D4N4〇3): Calculated: C = 54.92, H=7.09, N = 19.71. Experimental value: C = 54.65, Η=7 · 04, N = 19.32. It is worth noting that there is no peak around 3.80 ppm in the above 1H-NMR spectrum, indicating the absence of hydrogen at the position of the hydroxyl group at the secondary thiol group. Due to the above 89 201107326, there is a 4.01 ppm Triple peak, so phase ring It is impossible to determine whether there is a nitrogen on the N-methyl group at the sputum to determine whether there is a single peak around the guangxi. &amp;Do not PPm biological evaluation Example 15a. Evaluation of the compound 409 in dogs after oral administration The metabolism of the title compound after the injection of the male phenanthrene to the male beagle dog. The blood sample was removed from the dog at different times and the blood was separated from the blood sample. The plasma drug content was determined by LC_MS/MS (liquid chromatography tandem mass spectrometry) to estimate the pharmacokinetic parameters. Compound 409 and cefoline were separately dissolved in saline to a concentration of 4 mg/mL. A solution of the solution: a mixture of strontium (Wv) to obtain a solution having a final concentration of 2 mg/mL of the two compounds 409 and the formulated cefolin. Two male Miguel dogs were fasted overnight and then using the above mixture via Tube feeding was orally administered with 2.5 mg/kg of Compound 409 and cefolin. In 〇 minutes (before administration), 15 minutes after administration, 3 〇 minutes '45 minutes' i hours, 1.5 hours, 2 hours, 3 hours , 4 hours ' 6 hours, 8 Blood samples (1.5 - 2 mL) were collected via the femoral vein at hour, 1 hour, 12 hours, 16 hours, and 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 _7 ° C until analysis. 90 201107326 Table 8. Plasma content of compound 409 and terfenphyrin in dogs (Example 15a) _Compound _ cefylamine-average Cmx (ng/mL) 784 Π average AUC (hr*ng/mL) 448 Compound 409 1230 811 difference %a +57% +80% a) difference %=[(chemical substance type)_(non-deuterated substance type)](1 00)/(non-degenerated substance type) Table 8 shows implementation The results of the evaluation described in Example I5a. The average c_ and average enthalpy of the compound 4〇9 (gasification type of cefolin). Significantly greater than the matching of cefraline. 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 4〇9 with Prostaglandin by Monitoring Metabolites Example 15a was repeated by additionally monitoring the prostaglandin and Compound 4〇9 metabolites. In this experiment, compound 4〇9 and cefene were separately dissolved in saline to a concentration of 4_4/red 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 22 mg/mL of compound 4〇9 and 2 mg/mL of cefolin. Post-dose data Knife analysis included adjustments to account for the 1% difference in the concentration of compound 409 and the dose of the cefolin. Four Miguel dogs (2-3 years old, weighing 5 to 8 kg) were fasted and then used to feed mg/kg via &lt; Toxafilin. In the sputum minute (before administration), 91 201107326 5 minutes, 15 minutes, 30 minutes, 45 minutes after administration '!&quot; 夺, ι 5 hours, 2 丨, 3 hours, 4 hours and 6 hours via the femoral vein Blood samples (approximately 1 mL) were collected. 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). Blood t was immediately decanted and frozen/stored at _2 〇 1 until analysis. The presence of the administered compound and its corresponding Μ1 metabolite in the blood sample was analyzed by LC-MS/MS:

H3C

Π3 /Ν with female Westfield

H3C

Η3 C/ Ν /Ν Ml

Compound 409 (to be administered)

Ch3 Compound 419 (M1 metabolite) = The results from each of the four dogs are shown in Figures 1A &amp; 1B. The result from one of the four dogs (Canine H, Figure lb) and the other three dogs. If not. Five minutes after administration, the dog exhibited a blood concentration of 1% of the administered substance and its corresponding metabolite. In addition, between 5 minutes after the administration and 5 minutes after the administration, the dog did not show a characteristic increase in the blood table concentration of the administered compound. It was concluded that this canine may be inappropriate and that compound 92 t 201107326 may be administered via tracheal administration instead of 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. Table 9. Plasma content of compound 4〇9 and cefylamine in dogs (Example 15b) Compound formulation - average Cmax (ng/mL) 166 ~ average AUC (hr*ng/mL) 69 ^ Compound 409a 299 136 difference ' +80% +97% a ) Compound 409 is administered at a concentration 1 〇 / 高 higher than the dose of cefolin and therefore the values reported herein reflect the 10% increments Adjustment. b) Differences. /. = [(deuterated substance type (non-deuterated substance type)] (100) / (non-deuterated substance type) As can be seen in Table 9, when compared with the same amount of co-administered cefolin Compound 409 was observed to be more accommodating in terms of Cmax and AUC. Figure 1 shows that compound 409 was slowly cleared from plasma in the three dogs administered orally. a and ]b showed that compound 409 was more slowly cleared from plasma than the prostaglandin in the three dogs administered with wrinkles. Figures 1 a and 1 b also show compound 419 after administration of compound 4〇9. The overall systemic violent stimuli (diluted M1 metabolites at 409) were greater than the exposure to metabolites after administration of cefolin. Example 15c. Evaluation of pharmacokinetics in dogs after oral administration 93. Comparing compound 413 with cefylphenin. In addition to evaluating compound 413, 'this study is similar to the study described in Examples 15a and 15b. Oral administration to four male Migru dogs by tube feeding in saline 2 mg/mL of a mixture of cevirin and compound 413. As in Example 1 5 b Blood samples were taken. Example 10. Plasma content of compound 413 and cefylamine in dogs (Example 1 5 c ) Average Cmax (ng/mL) of compound Average AUC (hr*n2/mL) 369 ----——_〇 238 Compound 413 542 415 Difference %3 +47% +74% a ) Difference % = = [(chemical substance type) _ (non-deuterated substance type)] (1〇〇 ) / (non-deuterated species) 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 sifcillin co-administered in the same amount. Example 16. Evaluation of the stability of compounds in whole blood of rats. Comparison of compounds 4〇9, 435W, 43 is called and the combination of ceflin and its cardiac metabolites. This study was performed to assess the stability of the title compound in rat whole blood. Because ketone (or keto-based compound; with cefylamine or 4 and its corresponding M-1 alcohol metabolites are converted to each other, after adding keto-based compound to 2 blood 94 201107326 or adding force... In these tests, I 仍 1 I still &lt; 3 in 5, in a m-ι metabolite as the starting test compound, and in other tests 'the starting test compound. ♦ Rat whole blood Obtained from ViviSource Laboratories, Walthim 爹. 爹m, vvaitham, !-methane sulfoxide (Qing 0) prepared test compound reserves; · House Moer concentration (Fu). Dilute in acetonitrile (ACN) to a micromolar concentration (aM). Add 丨 to the blood of 99 〇 microliters, “) pre-warmed to 3 rc for 7 minutes. “L5〇〇&quot; “J-form. The final concentration of the substance to 5 # M. The test compound is matched with cefolin. Xifeilin (7)·Μ1 metabolite, metabolite of cefolin, compound 409, compound 435 (A and compound 435 (/?). The latter two test compounds are compound 409 (7)_M1 and (8)·generation Incubate the reaction mixture at 3 7 c. Remove the aliquot (50 #L) at 5 minutes, 15 minutes, 3 minutes, 2 hours, and 2 hours after the addition of the test: and add to the containing The reaction was stopped in a 96-well plate of ice-cold acetonitrile and hydrazine. The plate was stored at _2 Torr (&gt;c for 2 minutes, then 1 〇〇# L 50% acetonitrile/water was added to the well. This was followed by centrifugation to pellet the precipitated protein. An aliquot of each of the supernatants was transferred to another 96-well plate and analyzed by LC_MS/MS using an Appiied Bi0-System API 4000 mass spectrometer. The amount of the compound administered and its specific metabolites listed in table n below. 95 201107326 and Table π. Analysis of the compound - A metabolite of a compound of the blood incubated with (Experiment 17) 6 Experiment ^ -Mir- a t, |, compound 409

Compound 435 (and) with cefylamine / kg analysis of metabolism &amp; compound 419 CSV with cevirin compound 409 with cefolin compound 409 The results of the study 9 are described in Figures 2 and 3.祌&amp; displayed at the time of m^ metabolite formation... 'relative amount of metabolites formed as shown in Figure 3

It is calculated relative to the amount at which the earliest time point (5 minutes for A and i5 minutes for c) measured at 2 hours in the incubation mixture. * As can be seen in Figure 3, after about 2 hours, the amount of W-M1 (Fig. 3, row A) was formed in the blood of the rat king (see Figure 3, row A) similar to that of 曰. The amount of compound 419 (*S) formed in whole blood of rats (Fig. 3, 4 dry R, -") Therefore, it is a non-deuterated (·5)-Μ 1 formed from non-deuterated matching of cefolin. Compared with the relative content, the hydrazine substitution in the compound does not have a significant effect on the cleavage (the phantom Μ1 metabolite (compound 419(5)). 96 201107326 For the reverse reaction of 〇S)-Ml to keto-compound In other words, the deuteration does have a significant effect. Line C in Figure 3 shows the presence of an appreciable amount of Teflon after the addition of 1. In contrast, compound 409 was not detected 2 hours after compound 435 was added (Figure 3 , line D). Under these conditions, the substitution of hydrazine in compound 435 (51) prevents the conversion of this compound to the corresponding ketone. This effect is especially beneficial for enhancing the plasma content of the desired M-1 metabolite. The metabolism of (7?)·Μ1 to the prosofin was detected. Similarly, compound 435 (and) was added to the rat. After the blood, compound 409 was not detected. Therefore, no conclusion can be drawn about the effect of deuteration on the conversion of (Λ)-Μ 1 to the complexed siphyrin. Figure 2 shows the total compound and rat administered. The time course of the production of specific metabolites during the incubation of blood.Example 17. Evaluation of the stability of compounds in human liver microsomes.Comparative compounds 409, 435(51), 435 (i〇 and cefionin. Example 7 is similar to Example 丨6 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. Liver microsomes (20 mg/mL) were obtained from Xenotech, LLC (Lenexa, KS). Nicotinamide adenine dinucleotide phosphate (reduced form (NADPH)), magnesium (MgCl2) and diterpenes The sulphate (DMSO) system was purchased from Sigma-Aldrich. Prepared in DMSO containing 7.5 mM test compound (with saffron 97 201107326 lin, (&gt;S)-M1 metabolite, metabolite, compound 409, compound 435 (5) and compound 435 (/〇) stock solution The 7.5 mM stock solution was diluted to 250 μL in acetonitrile (ACN). Human liver microsomes were diluted to 2.5 mg/mL in 0.1 Μ potassium phosphate buffer (pH 7.4) containing 3 mM MgCh. Microsomes were added in triplicate to wells of a 96-well deep-well polypropylene plate. 10 /i L 250 &quot; Μ test compound was added to the microsomes and the mixture was pre-warmed to 37 ° C for 1 〇 minutes. The reaction was initiated by the addition of a pre-warmed NADPH solution. The final reaction volume was mL 5 mL and contained 2.0 mg/mL human liver microsomes, 5 # Μ test compound and 2 mM NADPH in 1 μ potassium acetate buffer (pH 7.4) and 3 mM MgCl2. Incubate the reaction mixture at 37 °C and remove 50 eL aliquots at 0, 5, 1 〇, 2 〇 and 3 〇 minutes and add to 5 〇&quot;l ice-cold acetonitrile and internal standards The shallow wells were placed in a 96-well plate to stop the reaction. The plate was stored at 4 ° C for 2 , minutes, after which 100 / 8 L of water was added to the wells, followed by centrifugation to make the precipitated protein into a centrifuge block. The supernatant was transferred to another 96-well plate and the amount of the administered compound and its specific metabolite (listed in Table n 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 formed in human liver microsomes after 30 minutes of incubation with cefolin (Fig. 5 'row A) is similar to compound 409. 人类 乂 乂 θ 人类 human liver micro 98 201107326 granule formation Compound 419 (magic amount (Fig. 5, row B). Therefore, the relative content of non-deuterated (5&gt;)_Μ1 formed from non-deuterated cefolin is 2, as represented by compound 409 The deuteration of toxifene has no significant effect on the relative content of deuterated metabolites (compound 419(iS)). These results in human liver microsomes are consistent with the results seen with whole blood in rats. The gasification does have a significant effect on the reverse reaction of S)-M 1 to the keto-compound. Line C in Figure 5 shows the presence of a large amount of prostaglandin after the addition of β)_Μι. In contrast, compound 43s was added (after phantom, the amount of compound 409 detected after 3 minutes was less than (Q-M1 content (Fig. 5 'row D). Compounds derived from compound 435 (ty) 4〇9, compared with about 3% by weight of (1S1) Μ1, under these conditions, compound 435 (the phantom substitution effect hinders the conversion of this compound to the corresponding ketone. Although the gas is There is a greater influence in the blood of rats, but the results are consistent. The striking effect of strontium on the metabolism of metabolites is observed in human liver microsomes and non-deuterated with non-deuterated (Λ)_Μ i Compared with the amount of toffeeline, after 3 minutes of incubation with human liver microsomes, the deuteration of (Λ)-Μ1 (compound 435(7?)) was reduced to the formed deuterated cefolin (compound) The amount of 409) is almost 1 /5 (compare the Ε 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. Pharmacokinetic studies after oral and intravenous administration and Compound 435(5) in rats. 99 201107326 (lS)_M1 and compound 43咐) (the disordered form of (8)-Ml) were dissolved in saline at a concentration of 1 〇mg/mL, respectively, and then two compounds having a final concentration of the compound of $5 mg/site were prepared. The mixture of ι:ι, which is used intravenously, is administered orally, and the mixture is further diluted in saline to the final concentration of each 丨mg/mL compound. Three males are used in oral and intravenous studies. Sprague-Dawley rats. Animals were fasted overnight before administration of the compound by rapid injection of a 1:1 combination of 5 mg/kg in a single dose to the neck of the rat. Intravenous administration was achieved in the vein. On the day before the administration, the rats who had been anesthetized with acetaminophen (IM 30 mg/kg) were subjected to cannulation. By oral gavage 5 mg/kg The second dose is used for oral administration. Different times after administration (2 minutes, 5 minutes, 丨〇 minutes, 2 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours) Self-medicated rats by post-sampling for rats temporarily anesthetized with isoflurane Blood samples were collected (250 in L). Blood samples were placed in tubes containing K^EDTA and stored on ice until centrifugation. Plasma was separated by centrifugation within 3 minutes of collection. Remove 1 〇〇# L Aliquots, mixed with 200 &quot; L acetonitrile and stored at -20 °C until further analysis by LC-MS/MS using an Applied Bio-System API 4000 mass spectrometer. Samples were analyzed by the corresponding ketones (with cefolin and compound 409) and the corresponding M5 metabolites. The sample (1〇 &quot; L) was injected into the Zorbax SB-C8 (quick split) column (2·1χ3〇 mm, 3.5 mm). The initial mobile phase conditions were 100% A (10 mM acetic acid in water) and 〇% B (methanol) with a flow rate of 0.5 mL/min. The mobile phase b is 55% in the 3 100 201107326 clock and 9% from 55% in 1 minute, and then back to 0% in j minutes. The total operating time is 5 minutes. For the compatibility of cefolin and its Μ1 and M5 metabolites, the precursor/product ion pair was set to m/z 281/193 (Ml), m/z 279/181 (with cefolin) and m/z 267/221 (M5) 〇 For compounds 435 (51) and 409, more than one ion pair is set to detect the material due to enthalpy loss. It has been found that a certain degree of enthalpy loss occurs for a compound of the invention having a hydrazine at a position adjacent to a few base carbons in the side chain, such as compound 409. This loss appears to occur in vivo and in vitro through unknown mechanisms. Prior to analysis, acetonitrile was added to the serum samples to prevent any additional in vitro deuterium loss. Typically, no more than two helium atoms are replaced by hydrogen. For compound 435 (α, the 曱 位置 位置 在 ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' The serum of the animal of (5), when the compound and the metabolite are administered in a quantitative manner, includes a compound substance species having a total of one and two side chain oximes (hereinafter referred to as -1 D and "-2D" substance species). Therefore, for compounds 435(5) and 409, the ion pairs are set separately to detect the compound and its corresponding -1D and -2D species. For compound 435 (magic, three ion pairs are detected: m/ z 291/197, 290/197 and 189/197. For compounds 4〇9, 'monitoring ion pairs m/z 288/1 86, 287/186 and 286/1 86. In compound 409 and compound 4 3 5 ( 51) The measurement includes -1 D and -2 D species to more accurately quantify the total active species and is also reasonable based on the understanding of the metabolism and activity of the pros and its metabolites. 101 201107326 Increased plasma exposure to any Μ-1 metabolite of Compound 409 or 409 . This material comprises -1 D and -2D species respective deuterated M5 metabolite (M5a) in terms of:

0 Ρ〇3 Ν (M5a), which has no enthalpy on its acid side chain, using only one ion pair m/z 271/225. The standard used in the analysis was indiplon. Table 12. Pharmacokinetic results after oral administration of 435(S) and (S)-Ml in rats. The measured compound a AUC0-a (hr*ng/mL) Cmax(ng/mL) 435(5) 4507± 1015 4105 ±964 (5&gt;Μ1 1628 ±272 1570 ±249 difference %13 + 177% + 162 % 435(5) + 409 13464 ± 3502 15647 ±7421 〇S&gt;Ml+ with cefolin 4632 ±437 5032 ±630 difference %b +191% +212% 氘化M5(M5a) 1924土183 M5 2985 ±601 difference %b -36% a ) The mass observed via LC-MS/MS. According to the published metaphyseal metabolite report, the stereochemical configuration is assumed to be 2 95% (magic. b) difference % = [(deuterated species) - (non-deuterated species)] (1〇〇) / (Non-deuterated substance type) 102 201107326 The results of oral administration in rats are shown in Table 12. Gasification compound 435 (51) showed significantly higher AUCq m and Cmax than its non-deuterated counterpart (5 &gt; 。 1 because there was significant serum interconversion between (iS)-Μ 1 and the formulated cefolin and two All of the substances have therapeutic activity', so also quantify 1 and the combination of ceflin, and the Cmax of compound 435 (51) and compound 409. After oral administration (5 &gt; Μ 1 and 435 (*y), respectively, compound 435 ( 51) The ratio of (*S)-M 1 to compound 409 showed significantly higher AUCo.c^ Cmax. The measurements were also produced by oral administration (iS^-Ml and 435(5), respectively. The AUC〇-~M-5 metabolites of the M-5 and M5a metabolites may be associated with toxicity in some patients and are considered undesirable. Table 1 2 shows M5 obtained after administration of non-deuterated Oral administration of Compound 435 (^ provides significantly less M5a compared to the content of the compound.) The ratio of the active species of the gasified compound to the ratio of the y[5 metabolite is much more favorable than the non-deuterated compound. The ratio of 435 (sentence + compound 409) to M5a is 7.0, which is much better than the ratio of (6 &gt; M1 + with female West African forest) to M5. 103 201107326 Table 1 3 · Pharmacokinetic results after intravenous administration in rats. Measured compound 3 AUC〇.〇j(hr*ng/mL) 435(5) 7127±816 3390 ±302 difference %b +110% 435( 5) + 409 11247±1326 (5)-Μ1+ with cefolin 6280 ± 460 difference %b +79% 氘化M5(M5a) 1522 ±530 M5 1795 ±521 difference%15 -15% a ) via LC-MS /MS observed quality. According to the published profiling of the phenanthrene metabolism, the stereochemical configuration is assumed to be 2 95% (*S). b) Difference % = [(deuterated species) - (non-deuterated matter) Species)] (100) / (non-deuterated substance type) Table 1 3 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 ( 51) has an average AUCo greater than 110% of its non-deuterated counterpart (magic-Ml--. After intravenous administration, compound 435(5) and compound 409 have an average AUC of 79% greater than the matching of cefolin. Intravenous administration of Compound 435 (5) provides an amount of M5a metabolite that is 15% less than the amount of M5 metabolite provided by the phantom-Ml. Intravenous administration. Ratio in vivo activity of compound 435 (5) of rats substance classes of the corresponding metabolite M5 was 7.4, and administered intravenously (5.3) of the rats of 3.5 -Μ1 contrast. 104 201107326 Example 19. Oral and intravenous administration ^ ^ ^ ^ ^ \ Stupid female West African forest and compound 43 5 (*S) pharmacokinetic study in chimpanzees. The phenanthrene and compound 435C5VtV Sii I; 1 λ , w:h 屻 knife will be dissolved in warm (65 ° C) saline at a concentration of 1 〇 mg / mL. The on-demand donors then prepared a mixture of the two compounds with a final concentration of 5 mg/mL each of the compounds and then sterilized the mixture via a 0.2 μ Μ filter. Two chimpanzees (one male and one female) were used in each of the oral and intravenous studies. Animals were fasted = before the compound was administered. All animals were sedated with acetaminophen (about 1 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) over a period of 1 minute. Oral administration was achieved by oral gavage of a single dose of 75 mg of each compound (a total of Η(7) 给药 administration solution). Blood samples (6 mL) were collected from the drug black (4) at different times before and after administration. For intravenous administration 'in sputum minutes (before infusion), 5 minutes, 9.5 minutes (immediately before the end of the infusion), then 6, 5, 3 and 45 minutes after stopping the infusion' and 1 2 4 6 Blood samples were collected at 8, 1 and 12 hours. For oral administration, blood samples were collected at 0 minutes (before administration), 15 and 3 minutes, and at 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 3 minutes of collection and an aliquot (2 〇〇 # L ) of the resulting plasma was removed. An aliquot of each #L plasma was mixed with 4 〇〇# L acetonitrile and stored at _7 〇 (&gt;c until further analysis by LC_MS/MS using the Applied Bio-System API 4000 mass spectrometer 105 201107326. Analysis of all samples was performed by LC-MS/MS as described for the rat plasma samples in Example 18. Table 1 4. Pharmacokinetic results after oral administration in chimpanzees. AUC〇.〇〇( Hr*ng/mL) Compound 3 measured male ltt隹 435(5) 829 672 (S)-M\ 300 301 difference %13 + 176% +123% 435(5) + 409 1097 1277 〇S&gt;Ml+ fitted Siphyrin 414 525 difference %13 + 165% +143% deuterated M5 (M5a) 462 606 M5 1456 1868 difference %b -68% -68% a ) The mass observed via LC-MS/MS. The stereochemical configuration is assumed to be 2 95% (&lt;S) according to the published profilinglin metabolism report. b) difference % = [(deuterated species) - (non-deuterated species)] (1〇〇) / (non-deuterated species) Table 1 4 shows oral administration of 435 (51) in chimpanzees and Match the results of cefolin. Compound 435 (51) and its corresponding ketone compound 409 showed a significantly higher average than the corresponding non-deuterated counterpart and the combination of cefolin after oral administration of Compound 435 (5) and a 1:1 combination of cefolin. AUC〇_〇〇 value. The average AUCo.co of compound 435(51) and compound 409 was significantly higher than the average AUCo-co of (*S)-M1 106 201107326 and the formulated cefolin. In addition, the average AUCo-co of the undesired M-5 metabolite (M5a) was significantly lower than the average AUC〇- of the non-deuterated M-5. Finally, the ratio of the active species of the gasification compound to the Μ5 metabolite { ( 435(5) + 409 ): (氘 Μ 5 ) } is the corresponding ratio of the non-deuterated species {((幻-Ml + matching) West phenanthrene): Μ5} is about 8 times higher. Table 1 5. Pharmacokinetic results after intravenous administration in chimpanzees AUC〇.=° (hr*ng/mL) Compound a measured male 435 (5) 2522 1213 (3)-Ml 1559 657 difference %15 +61% +84% 435(5) + 409 3219 1607 (6)-Ml + with cefolin 2285 1018 difference %b +40% +57% 氘化M5 428 632 M5 1195 1560 difference %b -65% -60% a ) Quality observed via LC-MS/MS. The stereochemical configuration is assumed to be 2 95% (61) according to the published metaphyseal metabolism. b) difference % = [(deuterated substance type) - (non-deuterated substance type)] 〇〇〇) / (non-deuterated substance type) Table 1 5 shows intravenous administration of 435(5) and distribution in chimpanzees The result of torfield. The results after intravenous administration showed a favorable difference 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-administration of compound 435 (iS) was between 40% and 57% higher than that of the compounded West 107 201107326 film, and the amount of M5 metabolite produced was reduced by 6%. Between 65 / 〇. The ratio of the negative species of the active substance to the Μ5 metabolite in the black obtained by intravenous administration of the compound 435 (51) was about 4 times that of the black administered with the cefolin. 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 present invention is shown to reduce the amount of Μ5 metabolites that may be associated with intolerance in patients with renal impairment. No need for further description. The prior art and the illustrative embodiments can be used to make and utilize the compounds of the present invention and to implement the claimed methods. It should be understood that the above discussion and examples provide only certain preferred embodiments. Detailed description. Different modifications and equivalents may be obtained without departing from the spirit and scope of the invention. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 Α and 1 β describe the compound of the present invention, the combination of ceflin and a corresponding metabolite thereof, which are administered orally in the mouth? Soap and 4 #办 a丄, ‘ ^ 杈 配 配 配 配 西 西 西 与 与 与 与 与 与 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 And, in the case of different compounds of the present invention, the combination of cefolin, (7)· and (Λ)-Μ1 together with atmospheric whole blood, you will 洚 4 times, 丄 t. The time course of the metabolites measured in Figure 3 was generated after the month. Figure 3 and W-M1 for the amount. Specific metabolites produced after the different compounds of the invention are formulated to be incubated with rat whole blood 108 201107326 Figure 4 depicts the different compounds of the invention, formulated with cefolin, (ι5)·Μ1 and (i〇- Ml and human liver microsomes produce the time course of the specific metabolites measured in Figure $. (7)-Ml Metabolites Figure 5 depicts the different compounds of the invention, the combination of cefolin, and W-M1 with humans. Liver microsomes - the relative amount produced after cultivation" [Main component symbol description] No 109

Claims (1)

201107326 VII. Patent application scope: 1 · A compound of formula B B' or a pharmaceutically acceptable salt thereof, wherein: R and the pedigree are each independently selected from -ch3 and -CD3; R is hydrogen or deuterium; Z3 is each hydrogen or deuterium; z is each hydrogen or deuterium; Z5 Each is hydrogen or helium; and (a) Y1 is OH, and Y2 is hydrogen, which is connected to the sputum, or (b) γ ΐ and γ2 together with the enthalpy that it is transported to form c=o. 2. For example, the compound of claim 1 is R, gas. 3. The compound of claim 2, wherein Z3, 5 are each hydrogen and R1 is _CD3. Z4:7: The compound of the first or second item of the Shenqing patent range, wherein z3, z. and Z5 are each hydrogen. 5) The compound of claim 2 or 2, wherein each of A z and Z is 氖. A compound according to any one of claims 1, 2, 4, or 5, wherein each of ... 2 is -CD3. / 7. 7. For the compound of the scope of claim 1, item 2 or item 4 to item 6, the mY2 together with the carbon to which it is attached forms 110 201107326 c=o. The compound of any one of claims 1, 2, or 4 to 6, wherein Y1 is OH and Y2 is hydrogen or hydrazine. 9. A compound of formula I, R1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: Compound R1 R2 R3 R4 Y1 Y2 101 cd3 cd3 ch3 (CH2)4 together formed = =0 102 ch3 cd3 ch3 (CH2)4 together form = =0 103 cd3 CD3 cd3 (cd2)4 are formed together = =0 104 ch3 ch3 CD3 (CD2)4 are formed together = =0 105 cd3 ch3 CD3 (CD2)4 are formed together = =0 106 ch3 cd3 cd3 (CD2 ) 4 is formed together = =0 107 ch3 ch3 cd3 tCD^CHA is formed together = =0 108 ch3 ch3 cd3 _2) 3 (: Η 2 is formed together = =0 109 CD3 ch3 CD3 tCD2(CH2)3 together form = =0 110 cd3 ch3 CD3 t(CD2)3CH2 are formed together = =0 111 ch3 cd3 CD3 cd2(ch2)3 are formed together = =0 112 ch3 cd3 cd3 卞(cd2)3ch2 are formed together as =0 113 CD3 cd3 Cd3 卞cd2(ch2)3 is formed together as =0 114 CD3 cd3 cd3 \〇Ό2)3αι2 is formed together as: =0 115 CD3 cd3 ch3 (CH2)4 OH Η 117 ch3 cd3 ch3 (CH2)4 OH Η 118 CD3 cd3 Cd3也2(卿3 OH Η 119 cd3 ch3 cd3 tCD2(CH2)3 OH Η 120 ch3 cd3 cd3 tCD2(CH2)3 OH Η 121 ch3 CH3 CD3 ^ϋ2(ΟΗ2)3 OH Η 122 cd3 CDs cd3 (CD2)4 OH Η 123 cd3 ch3 CD3 (CD2)4 OH Η 124 ch3 cd3 cd3 (CD2)4 OH Η 125 ch3 ch3 cd3 (CD2)4 OH Η 126 CD3 cd3 CD3 卞 批 OH Η 111 201107326 Compound R1 R2 R3 R4 Y1 Y2 127 cd3 ch3 cd3 ^CD^CHi OH H 128 ch3 cd3 cd3 OH H 129 ch3 ch3 cd3 ten (.〇2)3〇12 OH H 130 cd3 cd3 ch3 (ch2)4 OH D 131 cd3 ch3 ch3 (CH2)4 OH D 132 ch3 cd3 ch3 (CH2)4 OH D 133 ch3 ch3 ch3 (CH2)4 OH D 134 cd3 cd3 cd3 also 2 (Qing 3 OH D 135 cd3 ch3 cd3 tCD2(CH2)3 OH D 136 ch3 cd3 cd3 fCD2(CH2)3 OH D 137 ch3 ch3 cd3 also 2 (»)3 OH D 138 cd3 cd3 cd3 (CD2)4 OH D 139 cd3 ch3 cd3 (CD2)4 OH D 140 ch3 cd3 cd3 (CD2)4 OH D 141 ch3 ch3 cd3 (CD2)4 OH D 142 cd3 cd3 cd3卞_3〇12 OH D 143 cd3 ch3 cd3 OH D 144 ch3 cd3 cd3 吆02)3〇12 OH D and 145 ch3 ch3 cd3 \CO2hcH2 OH D. 10. - a compound of formula A, R2, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: Compound R1 R2 R3 R4 Rs Y1 Y2 400 cd3 ch3 ch3 (CH2)4 D together formed as: =0 401 cd3 cd3 ch3 (ch2)4 D Together they are formed as: =0 402 ch3 cd3 ch3 (CH2)4 D are formed together as: =0 403 cd3 cd3 cd3 (CD2)4 D are formed together as: =0 404 ch3 ch3 cd3 (CD2)4 D are formed together == 0 405 cd3 ch3 cd3 (CD2)4 D is formed together = =0 406 ch3 cd3 cd3 (CD2)4 D is formed together = =0 407 CHj ch3 cd3 ^ό2(0Η2)3 D is formed together = =0 408 ch3 Ch3 cd3 f(CD2)3CH2 D is formed together = =0 112 201107326 Compound R1 R2 R3 R4 R5 Y1 Y2 409 cd3 ch3 cd3 tCD2(CH2)3 D Together form = =0 410 cd3 ch3 cd3 %ο2)3〇η2 D is formed together = =0 411 ch3 CDs cd3 D are formed together as: =0 412 ch3 cd3 CDs 2) 3〇12 D are formed together = =0 413 cd3 cd3 cd3 Yd2(ch2)3 D together form: 0 414 cd3 CD3 cd3 'CDACH〗 D is formed together as: =0 415 cd3 cd3 ch3 (CH2)4 D OH Η 416 cd3 ch3 ch3 (CH2)4 D OH Η 417 ch3 cd3 ch3 (CH2)4 D OH Η 418 cd3 CD3 cd3 ^ο2(〇η2)3 D OH Η 419 Cd3 ch3 cd3 ^CO2(CH2h D OH Η 420 ch3 cd3 cd3 tCD^CHA D OH Η 421 CH3 ch3 cd3 tCD2(CH2)3 D OH Η 422 cd3 cd3 cd3 (CD2)4 D OH Η 423 CDs ch3 cd3 (CD2) 4 D OH Η 424 ch3 cd3 cd3 (CD2)4 D OH Η 425 ch3 ch3 cd3 (CD2)4 D OH Η 426 CD3 cd3 CDs D OH Η 427 cd3 ch3 cd3 !(〇〇2)3〇Η2 D OH Η 428 Ch3 cd3 cd3 t(CD2)3CH2 D OH Η 429 ch3 ch3 cd3 'CDACH: D OH Η 430 CD3 cd3 ch3 (CH2)4 D OH D 431 cd3 ch3 ch3 (CH2)4 D OH D 432 ch3 cd3 ch3 (CH2) 4 D OH D 433 ch3 ch3 ch3 (CH2)4 D OH D 434 cd3 cd3 cd3 fCD2(CH2)3 D OH D 435 cd3 ch3 cd3 coffee (〇12)3 D OH D 436 ch3 cd3 cd3 fCD2(CH2)3 D OH D 437 ch3 ch3 cd3 ^ϋ2(ΟΗ2)3 D OH D 438 cd3 cd3 cd3 (CD2)4 D OH D 439 cd3 ch3 cd3 (CD2)4 D OH D 440 ch3 cd3 cd3 (CD2)4 D OH D 441 ch3 Ch3 cd3 (CD2)4 D OH D 442 cd3 cd3 cd3 #ϋ2)3(:Η2 D OH D 443 cd3 ch3 cd3 qing 2)3012 D OH D 444 ch3 cd3 cd3 #02)3Οί2 D OH D 445 ch3 ch3 cd3 t (CD2) 3CH2 D OH D or a pharmaceutically acceptable salt of any of the above. 113 201107326 11.-A compound ' is selected from any one of the following , ch3 437 (R) ^ 437 (S) or a pharmaceutically acceptable salt of any of the above. 12. For example, the scope of the patent application is: Any of the atomic systems in which the glycine a is in any one of the eleventh items. Dan's natural abundance is a 13_-medicine composition containing 如 a compound and a pharmaceutically acceptable carrier. Shen ... _ 丨 丨 种 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 _ _ _ _ _ _ _ _ _ _ _ _ Diabetic nephropathy, hypertensive softness: 绂成物' Chronic occlusive arterial disease her intermittent break. Or by limbs 114 201107326 15. A method for treating chronic kidney disease in a patient in need thereof. The patient is administered an effective amount of the composition of claim 13 of claim IE, B, .... 16. For example, the patent scope of the § § 甘山-κα $町万法' wherein the chronic kidney disease is glomerulonephritis, focal segmental glomerulosclerosis is fluid urinary tract disease or polycystic kidney disease . , '正|,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, The composition of item 13 of the encirclement. 1 8 · Such as the patent range of the application of the 1st non-alcoholic steatosis liver *,> 'The chronic liver disease is I earth month f χ, fatty liver fat or alcohol induced tissue changes 3, induced high alcoholic hepatitis . ...'...C-like, cirrhosis, liver dysfunction or 19' A method of treatment with a lemma that contains _: "diabetes-related diseases or components of disease η, :;:: = effective amount For example, the patented range of retinopathy m is selected from the group consisting of 姨 素 抗性 、 视 视 视 病 病 病 病 病 病 病 病 病 病 病 病 病 病 病 病 病 病 病 病 病 病 病 病 病 病 病 病 病 病 病 病 病 病 病 病蝎 or 2〇· A patient in need of treatment, comprising an effective amount of the patient, as in the application 跛7 method, a package 21. A composition for treating a person in need of U. The method of chronic kidney disease, which comprises administering to the patient an effective amount of 如 申请 申请 四 四 四 22 在 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ The disease or condition is selected from insulin dependence: two (four) diabetes mellitus '·metabolic syndrome; obesity; Tengdao: insulin dependence, · pathological glucose ^, a few, abnormal blood lipids J and disease, back blood wish And macro asked blood syndrome; high uric acid blood stasis 5 201107326 disease; pain Wind; and high coagulability, which comprises administering to the patient an effective amount of the composition of claim 13 of the patent scope. VIII. Schema: as the next page.