TW203008B - - Google Patents

Description

203008 A6 _ B6 _ V. Description of the invention (1) The present invention relates to a novel phosphorus derivative, its preparation method and its medical use. Specifically ,; $: the invention is about its use as an enzyme inhibitor of the collagenase family of neutral metalloproteinases to treat arthritis and other diseases. The Qinin family of mammalian collagenases includes a variety of protein enzymes, examples of which are interstitial (.1) collagenases themselves, matrix lysins (also known as proteolytic enzymes or transforming enzymes), connective tissue cells and polymorphonuclear leukocytes Gelatinase (also known as collagen IV—enzyme), and 'pump—〃 (hypothetical type gold fermented protein enzyme 1, uterine metalloproteinase) C Goldberg et al., J. Biol. Chem. 2610, 6600, 1986;

r r »< I f I < I

Whitham et al., Biochem. J. 240, 913, 1986; Breathnach et al., Nucleic Acids Rea., 15, 1139, 1987; Muller et al., Biochem. J., 253, 187, 1988; Collier et al ., J. Biol. Chem., 263, 6579, 1988; Murphy et al., Biochem. J., 258, 463, 1989; Quantin et al., Biochem. (NY), 28, 5327, 1989; B i rkedal-Hans en, J. Oral Pathol., 17, 445, 1988]. The family qualification of mammalian collagenase of protease is easy to confirm, because it has a variety of high characteristics and experimentally identifiable properties. These properties can be used as a benchmark for identifying this enzyme family, selected from the following properties: Economic Printed and burned by the Ministry of Central Affairs (please read the precautions on the back and then fill in this book) ⑻Optimal proteolytic activity at neutral pH. ⑹Enzyme activity depends on the presence of zinc. It can be seen from the passivation caused by the treatment of ion chelating agents, such as 1,10 phenanthroline (1,10 phenanthroline) (especially the chelation of zinc) A 4 (210X 297 public) 4 203008 A6 B6 V. Description of the invention (2), or EDTA (lower chelating properties); both EDTA and EGTA cause enzyme inactivation, which is caused by chelating calcium ions needed to stabilize the enzyme.) (C) TIMP (Tissue inhibitor of metalloproteinase / Tissue

Inhibitor of Metalloproteases), TIMP is a protease inhibitor, which plays an important role in the physiological control of the collagenase family. Other families of metalloproteinases are not inhibited by TIMP. At least so far, the results of related studies have been the same. ⑹ For other neutral zinc-containing metal protein enzymes, such as pyrolysin, angiotensin-converting enzymes and enkephalinase (enkephalinase) (EC 3 · 4 · 24 · η) inhibitors, etc., there is no obvious inhibition phenomenon. One of the most commonly used inhibitors is phosphatidylamide, which inhibits pyrolysin and Ankerase *. ⑼In biosynthesis and secretion in the form of latent precursor. (Proenzyme), extracellular activation is required. A variety of endogenous protein enzymes, organic mercury compounds and Chao tropic agent can achieve the activation effect. Printed by the Central Standards Bureau of the Ministry of Economic Affairs ^ (please read the precautions on the back before filling in this 11) neutral metalloproteinase Members of the collagenase family have different matrix properties. Therefore, type I collagenase itself has the special ability to split the specific winning bonds of natural fibrils in interstitial collagen (for example, type Ϊ, II, or III). Gelatinase has only a very low activity on these collagens, but it is sufficient to degrade the interstitial collagen, and it can also degrade non-fibrillar collagen such as type IV collagen that can be found in the basement membrane. According to reports, pump -1 is particularly suitable for acting on the degraded collagen (gelatins), although its A 4 (210X 297 male larvae) ~ 5 ~ 203008 A6 B6 Ministry of Economic Affairs Central Standards Bureau printed-V. Description of the invention (3) It is different from matrix lysin or type IV collagenase. Both stromelysin and gelatinase can break down non-collagenous structured proteins, such as the protein nucleus of protein () and elastin (elastin). Macromolecules involved in cell-glycolysis and cell-cell interactions, such as laminin and fibronectin, can also be degraded by several of the metalloproteinases described. The range of medical applications of the inhibitors of the collagenase family described below reflects these. The basic role of various protein matrices in the enzymes in the connective tissues of the entire body. Its use is not only for the treatment of many diseases and phenomena due to the net destruction of collagen and other connective tissues, but also for the lesions of normal or abnormal tissues. Collagen enzymes are produced by synovial and skin connective tissue cells, chondrocytes, peripheral mononuclear cells, keratinocytes, and gingival tissue. , And in the granular storage sacs of polymorphonuclear leukocytes (PMNLs / polymorphonuclear leucocytes). Inhibitors of the collagenase family containing various enzymes are considered effective for the treatment of the following diseases: (i) Arthritis diseases, such as rheumatic and osteoarthritis, soft tissue rheumatism, polychondritis, and tendinitis Etc .; (ii) Bone depletion diseases, such as osteoporosis, Bechtel's disease, hyperparathyroidism and cholesteatoma, etc .; (Πί) promote collagen destruction, which occurs in association with diabetes Disease; {Please read the precautions on the back before filling in this page) • Installed • • Ordered • • Line · A 4 (210X297 public) 6 203008

AB Printed by the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (4) (iv) Hidden diseases of dystrophic epidermal blister; (V) Peripheral diseases and: the related effects of collagenase in the production of gums The effect of PMNL collagenase release after the cells infiltrate into the inflamed gingiva. This symptom is caused when susceptible diabetic patients resist diseases around the teeth; (vi) corneal ulcers, for example, due to Corneal ulcers caused by metal or other burns, radiation, vitamin E or retinal defects; (vii) ulcers of the skin and gastrointestinal tract, and ulcers of abnormal wound healing; (vi ii) symptoms after surgery, including anastomosis of the colon Among them, the level of collagenase will be increased; (ix) Cancer, the enzyme group in the collagenase family containing various enzymes, is hidden in the formation of new vessels that must support tumor growth and survival. During the process of tissue reorganization of the primary and secondary tumor growth, and hidden during the penetration of tumor cells through the basement membrane of the vessel wall during metastasis; (X) Central and peripheral nervous system Traditional demyelinating diseases include the following syndromes: loss of myelin in basic pathology, and axonal dystrophy. The degeneration of myelin in these diseases, exemplified by multiple sclerosis, is mediated by the enzyme group in the swelling proenzyme family that contains various enzymes. Inhibitors of the collagenase family containing various enzymes, such as the inhibitors disclosed in the present invention—a particular example is the expansion of cartilage, bone and tendon at the joints, protein and elastin Arthritis diseases with extensive loss of ingredients should be treated with collagenase inhibitors; protein (please read the precautions on the back and then fill out this page)-Pack · • Hit ·. Line · A4 (210X297 public) 7 203008 A6 B6 V. Description of the invention (5) (Please read the notes on the back before filling in this page) The lysozyme (matrix lysin) and the gelatinase are considered to be the most important enzymes nowadays. These enzymes have been detected by the inventors in the state of being in the leaching fluid of synovial membrane and cartilage tissue, and have also been extensively investigated by the inventors in the state of being in the tissue culture fluid of many related tissues. Unlike the biochemical synthesis control method, the secretion and activation of enzymes, under normal and diseased conditions, the most important natural regulation of these enzymes is considered to be, for example, gold® protease tissue inhibitors and alpha-2 Endogenous manufacture of inhibitors of globulin tissue inhibitors. The local imbalance of proteolytic enzymes and natural inhibitors will cause the destruction of connective tissue components. The compound described in the present invention is synthetic and a low molecular weight inhibitor of the above-mentioned enzyme family, which can provide a restoration that can restore the more normal or non-pathological balance between inhibitory and enzyme activity Effective therapy; these compounds can be used as a supplemental source of endogenous enzyme inhibitors. In detail, because these enzymes appear in the most inflamed exudate before they are reduced in function by inhibitors circulating in the blood Previously, it usually only acts in the surrounding environment of restricted cells. Therefore, the low molecular weight inhibitors disclosed in the present invention can be more effective than endogenous protease inhibitors; these protease inhibitors are due to their Because of the size, it is excluded from the local area where the connective tissue is destroyed. European Patent No. 0554862 has disclosed a substituted two-category class having an effective inhibitory activity of Ankerase. The present invention discloses 7F—a related compound system with a novel structure, which can be used as a swelling enzyme inhibitor, which involves collagen dissolution in the treatment of 4C210X 297 g) 203008 A6 B6 5. Description of the invention (6) Diseases with active and tissue disease have potential. According to the present invention, a compound having the following general formula (I), or a salt, solvate or hydrate thereof is provided:

0 Η R. (I) where B is hydrogen, h-6 alkyl or optionally substituted benzyl; Εχ is hydrogen or CVe alkyl; heart is C 3-6 halo; & is hydrogen , Alkyl, mono-CH2_Z (Z is optionally substituted phenyl or heteroaryl); R3 may be a group with the formula -CH-0-R7 I r8 (please read the precautions on the back before filling in (This page is printed by the Central Business Administration of the Ministry of Economic Affairs. Among them, it is hydrogen, alkyl or -CH2 — Ph (Ph is a selectively substituted base), Re is a gas or burned group; it is a CH2 — (CHt) η 〇β 5 or a C — (CH2) η 〇C〇R6 or

Rr

R 10 A 4 (210X 297 public) 9 ^ 203008 A6 B6 Printed by the Central Bureau of Standards of the Ministry of Economy ¾ V. Description of invention (7) Among them, η is an integer from 1 to 6, and xin, R6 and β9 are hydrogen or Qe group , K. It is a hydroxy group, a 〇- 仏 -6 alkyl group or a NR5 R6 (R5 and R6 can be combined or heterocyclic ring); In addition, Rs and R4 can be combined to form an integer m. 4 ~ 12. One (CH2)-. Unless otherwise mentioned, each alkyl group described above is preferably a G-β alkyl group, preferably a hexa-6 alkyl group, which may be linear or branched. The selective substituents of phenyl and heteroaryl can be selected from OH, 1-6 alkyl, Ch alkoxy, halogen, a NHOOCh alkyl, —NHOOPh and a CONEsE6; wherein, Ph, R5, R6 are As defined above. The selective substituted benzyl group referred to herein refers to the selective substituted Z benzyl group in the phenyl group. Optional substituents include those mentioned in the above description of the phenyl and heteroaryl groups of variable r3. When Z is a heteroaryl group, it includes a monocyclic heteroaryl group having five or six ring elements, and a bicyclic heteroaryl group having nine or ten ring elements. In addition, the above-mentioned heterocyclic heteroaryl groups with five or six ring members and bicyclic heteroaryl groups with nine or ten ring members preferably contain one or two selected nitrogen, oxygen and sulfur Of heteroatoms. When Z is a bicyclic heteroaryl group consisting of nine or ten ring elements, one of the two bonded rings has a ring of five or six ring elements, preferably containing a single heteroatom; for example, z An example is indolyl. β is preferably 舆 i, methyl or ethyl 'is preferably hydrogen ° d series may be hydrogen, methyl, ethyl, isopropyl and n-butyl. As the alkyl group, I is preferably methyl or ethyl. r2 should be a 〇4 alkyl group such as n-butyl, isobutyl or second butyl, the most (please read the precautions on the back and then fill out this page)-installed. • fight ·-margin. A 4 (21 〇X 297 public) 10 A6 B6 203008 V. Description of the invention (8) Good is isobutyl. (Please read the precautions on the back before filling this page) R3 is preferably benzyl, 4-hydroxybenzyl, or such as C1H! Alkoxybenzyl, or such as 3-indolyl A condensed (condensed) bicyclic heteroarylmethyl group with nine or ten ring elements in methyl. R3 and R * are preferably combined to form a (CH,) "-, especially advantageous is the situation of m = 丨 0, so that it will form-an internal amide structure composed of a ring with thirteen elements. Compounds of formula (I) can form compounds with e.g. sodium hydroxide gaseous compounds. In addition, the compounds of formula (I) have a compound nitrogen atom that can form acid addition compounds with compounds such as carboxylic acids. These compounds also As part of the present invention, when the compound of formula (I) or its compounds are formed as solvates or hydrates, such solvates and hydrates are also one of the characteristics of the present invention. The compound of formula (I) has at least one , May have two, three or more asymmetric centers, therefore, can exist in more than one form of stereoisomers. The scope of the present invention extends to all such forms and mixtures thereof, including racemates , As well as diastereoisomeric mixtures. The more isomers are, when e3 is not a hydrogen atom, in the compound of formula (I) is marked with a star-shaped asymmetric center with an S configuration isomer Printed by the Central Bureau of Standards of the Ministry of Economic Affairs (Form I) Compound or its classes, solvates or hydrates, preferably formed into a form that is pharmaceutically acceptable. The so-called "acceptable form" refers to the unacceptable form such as dilution Commonly used pharmaceutical additives such as agents and carriers, but excluding toxic A4 (210X 297 public) at normal dosage levels 11 A6 B6 203008 V. Description of invention (9) The degree of purity of the substance. (Please read first Note on the back and then fill in this page) The compound of formula (I) or its compound, solvate or hydrate is preferably presented in a substantially pure form. The substantially pure form generally contains about 50% by weight, Preferably 75% by weight, more preferably 90% by weight, and most preferably 95% by weight or more than 99% by weight of the compound of formula (I) or its compounds or solvates. The compound of formula (I) or its compounds or solvates Or a hydrate, which can be separated as a crystalline solid, foam or gel. The preferred pharmaceutically acceptable form is a crystalline solid. The present invention provides a formula (I) that can be used as an active therapeutic agent Change Compound, or a pharmaceutically acceptable compound; this active therapeutic agent is especially used to treat the symptoms of connective tissue degradation or other proteinase-related components in the human body; this symptom is caused by collagen decomposition activity, for example Muscle structural disorders caused, especially rheumatism and / or arthritis diseases and tissue lesions. Compounds of formula (I), when treating cancer, prevent myelin degeneration in the central and peripheral nervous system, and include Enzymes in the collagenase family of sex-protease enzymes have the potential to respond when they have pathological significance or play other roles. Printed by the Central Business Administration of the Ministry of Economic Affairs The present invention provides a method for preparation (I) The method of the compound, this method includes: the compound of formula (I): A 4 (210X297 public) 12 203008 A6 B6 V. Description of the invention (10)

R. (II) Printed by the Central Bureau of Standards of the Ministry of Economy ¾ In the dagger type, R2e is alkyl or optionally substituted benzyl, hydrogen, alkyl or optionally substituted benzyl, I, e2, shame And e4 are as defined in formula (ϊ)) the step of converting R * 〇 into hydrogen by cracking its group Rw, and the step of converting R «into hydrogen if necessary. The cracking of R2〇, and the cracking of R21, if necessary, can be achieved in an acid or an aqueous solution of chamois, or using a trimethylsilyl halide, preferably bromotrimethylsilane. For example, in an inert solvent of methylene chloride. The benzyl ester is alternatively removed by hydrogenolysis or other standard debenzylation processes. When both Rio and R »are alkyl, and only want to cleave r2 (> to make it in formula (I) is hydrogen and r21 is alkyl, it also makes the compound (I) an R-based alkyl The compound of formula (I) can be achieved by treating the compound (I) with an excessive amount of emu under mild conditions, for example, an aqueous solution of sodium hydroxide in an alcoholic solvent at room temperature. Similarly, When Rm is an optionally substituted benzyl group and an alkyl group, the benzyl group can be cracked by hydrogenation to form a compound of formula (I) in which R 2 is hydrogen and Eu is an alkyl group. The cracking of the alkyl group can be cracked by the above method to form the compound of formula (I) where R is hydrogen. (Please read the precautions on the back before filling this page) A4 (210X297 public) 13 203008 A6 B6 Printed by the Central Bureau of Standards of the Ministry of Economic Affairs V. Description of the Invention (11) When E in the compound of formula (I) is hydrogen and the compound in formula (I) is not hydrogen, R «and its cracking can be simply Achieved by a single reaction. The team ❶ and R2i are both alkyl, such as methyl or ethyl, or benzyl. The best compound of formula (Ϊ) Where is hydrogen, making it itself a compound of formula (Ο compound of the present invention. The compound of formula (I) can be obtained by combining the compound of formula (I) · ° >? 20 〇 / r21 (wherein, Ri, E *, R2 () and Ra are as defined in formula (H), but R21 is not Η) Prepared by treatment with compound of formula (IV): nhr4 (IV) In formula C, R3 and B4 are as in formula ( I)) The reaction is preferably in the presence of a coupling agent, such as in dicyclohexylcarbodiimide or 1-ethyl-3- (3- (dimethylamino) propyl] carbodiimide In the presence of hydrochloride, supplement it with 1 monohydroxybenzotriazole, or use 1, carboxydiimidazole, such as dichloromethane or

(Please read the precautions on the back before filling ^ this page) • Install · (1111. Order · • Line. A 4 (210X 297 public) 14 203008 A6 B6 V. Description of the invention (12) in acetonitrile inert solvent Then, the selective cracking can use the above process for preparing the compound of formula (I) to obtain the compound of formula (] [) where R21 is hydrogen. The intermediate compound of formula (] 1) can be obtained by using the formula (V) Compound or its class:

NH

OR 2 21 (V) (In the formula, R:, R2〇 and R21 are as defined in the formula (certification)) The steps of the following formula (VIA) or (VIB) compound or its class: R2 R2 (please Read the precautions on the back first and then fill out this page). Pack .. Order. R11 C02r12 Ο C02r12 (VIB) (VIA) (where R2 is as defined in formula (I), such as halogen, methanesulfonamide Oxy or trifluorosulfonyloxy and other leaving groups, ei2 is a hydrogen or carboxy protecting group) and the subsequent steps to remove R12 to obtain c When using the compound of formula (VI8), reductive amination reaction It can be achieved by a hydrogenation reaction using precious gold, such as palladium, attached to carbon as a catalyst, or by reaction with sodium borohydride under pH = 6 ~ 7. Zhuzhong 4 (210X297 public). Line. Printed by the Central Bureau of Standards of the Ministry of Economic Affairs 15 203008 A6 _ B6 V. Description of the invention (13) Lower alkanol solvents such as methanol and ethanol are suitable for the above-mentioned second reaction. These reactions can be carried out in the presence of molecular drops. Although the hydrogenation reaction is preferred, the use of any compound of formula (V) and (VIB) where R2 «or R12 is benzyl is excluded from this reaction. The carboxyl protecting group is preferably a methyl or ethyl ester group. The ester protecting group can be removed by standard hydrolysis conditions using diluted emu, such as 1N aqueous sodium hydroxide solution in methanol. When the compound of formula (V) is in the form of a free emperor, the compound of formula (VIB) is preferably an α-keto ester (R12 = alkyl). When the compound of formula (v) is a salt, such as hydrochloride salt, the compound of formula (VIB) is preferably a salt of α-keto acid (Rl2 = H.), such as sodium salt. The preparation of compounds of formula (ϊ II) using compounds of formula (VIA) can be achieved under standard alkylation conditions. The halogen leaving group is preferably desert, and the leaving group based on oxygen is preferably trifluoromethane extended oxy group. In addition, the compound of formula (JI) can also be represented by the formula (νι) or its class, and Ri As defined in the formula (!) Aldehydes _ £: 110 condensation steps: R2 (please read the precautions on the back before filling in this page) • Install · · hit ... green. Printed by the Central Bureau of Economic Affairs ¾ h2n CO2R12 (VII) (where R2 is as defined in formula (I) 'R12 is a carboxy protecting group) A 4 (210X 297 male ⑷! 6 A6 B6 203008 V. Description of the invention (14) and subsequent condensation The product is prepared with the appropriate dialkyl phosphite or trialkyl phosphite, for example, the treatment step with dimethyl phosphite, and the last step to remove the carboxyl protecting group. The carboxyl group can be conveniently in the form of alkyl ester or benzyl ester The ground is protected, and these ester groups can be removed by using standard hydrolysis or hydrogenation conditions. As described in the reductive amination reaction of the compound of formula _ (VIB) above, when the benzyl protecting group R12 is removed by hydrogenation Later, Rw and R2l can be limited to alkyl. And R21 is alkyl or optionally substituted The compound of the formula (mutual) of methyl group can be obtained by using the compound of formula (VIII) ... Ο Ο ................................. ........... ...........! st (Please read the precautions on the back before filling in this page) Order (VIII) (where r2, 1 ^ and 1 ^ 4 is as defined in formula (I) and compound of formula (IX): line

OR 20 P

OR Printed by the Central Bureau of Standards of the Ministry of Economic Affairs '11 21 (IX) (where Ri is as defined in formula (I), E2. And R21 is alkyl or A4 (210X297)) ~ 17

Printed by the Central Bureau of Standards of the Ministry of Economic Affairs U 203008 A6 ____ B6 _ V. Description of the invention (15) Selectively substituted benzyl., R11. Leaving group as defined in the formula (VIA)) In such as triethylamine or Proton Sponge (1,8-bis (dimethylamino) -naphthalene) is reacted in the presence of or reacted in the presence of anhydrous potassium carbonate in an alcoholic solvent. When Rn is an oxygen-based leaving group, such as the trifluoromethanesulfonyloxy group, the replacement of the leaving group is conveniently Pro ton Sponge in an inert solvent such as methanol. In the presence of, in the absence of light, after a few days to reach "another preparation method of the compound of formula (I), by using the formula as defined above. (IX) compound, and the formula for the carboxyl protecting group (vi I ) The compound is reacted under the conditions for the reaction of the compound of formula (VIII) and (IX) above, and then deprotected. Suitable carboxy protecting groups include alkyl, benzyl and trialkylsilyl. A trialkylsilyl protecting group, such as trimethylsilyl, is particularly suitable as a carboxyl protecting group; this is because the trialkylsilyl group can appear by adding, for example, hexamethylsilazane There is triethylamine in the reactant in the acetyl alkene, and it is easily used as a protective group in the in-situ compound, and because it can be selectively removed in the methanol aqueous solution without any restrictions on r2〇 and e21 Reason. Other silylating agents include trimethylsilyl chloride and N, N-diethyltrimethylsilylamine. The R12 alkyl group as a carboxyl protecting group can be hydrolyzed by alkali, for example, it can be removed by using sodium hydroxide in an aqueous methanol solution. When the carboxyl protecting group is an alkyl group, β2β and r21 are preferably alkyl groups (please read the precautions on the back before filling out this page) • Pack. • Order • • Line 4 (210X 297 public) 18 A6 B6 203008 V. Description of the invention (16) or benzyl derivatives, but when R12 is benzyl, Ra〇 and Κί1 are restricted to alkyl groups. When the compound of formula (H) is prepared by this route, R2 in the compound of formula (IX). Rn is preferably benzyl, and Ru is preferably trifluoromethanesulfonyloxy; in addition, R12 in the compound of formula (VII) is preferably trimethylsilyl or methyl. The compound of formula (VIII) can be treated by using the compound of formula (Iv) above in the presence of a coupling agent such as that described above for preparing the compound of formula (I) from compounds of formula (I) and (IV) VII) ί dagger compound is prepared: (Please read the precautions on the back before filling in this page) Η2Ν C02r12 (VII) Printed by the Central Standards Bureau of the Ministry of Economic Affairs ¾ (In the formula, R2 is as defined in formula (I), r12 is hydrogen, in which the amine group is selectively protected) The compound of formula (IX) can be made from a hydroxyalkylphosphonate derivative by converting a hydroxyl group to a leaving group Ru by a conventional method. For example, when Ru is trifluoromethanesulfonyloxy, it can be added according to the general method shown in Journal of Organ ic Chemistry 50, 2165, (1985) by E. Vedejs et al. The compound of formula (IX) is prepared in a hydroxyalkylphosphonate in an inert solvent such as dichloromethane, under low temperature in an inert atmosphere. A 4 (210X297 public) 19 203008

AB V. Description of the invention (Γ7) Hydroxyalkylphosphonates can be obtained by making related phosphites, such as diphenyl phosphite and —C00 (Ri is as defined in the compound of formula (I)) This reaction is made according to the general method disclosed in F. Texi 61: -8〇111161 and A. Foucaud et al. In Synthesis, 916 (1982). Benzyl phosphite and alkyl phosphite are commercially available compounds that can be made from commercially available starting materials by standard methods. The intermediate compound of formula (V) may be a conventional compound, or standard methods may be used, and if necessary, lead to R2 «) and r21, which are made of conventional amine alkylphosphonic acid derivatives. In these reactions, it may be necessary to protect the function of the amine. When R2n or e21 is methyl, its lead X can be achieved by reacting with diazomethane in a suitable inert solvent. The compound of formula (V) with a fixed configuration can be prepared by the method shown by R. Jacquier et al. In Phosphorns and Sulfur 36, 73, (1 988).

The compounds of formula (IV) and (VII) are both conventional amino acid derivatives and can also be prepared from related derivatives according to conventional methods. The compounds of formula (VIA) and (VIB) are also known compounds and can be prepared from conventional compounds according to conventional methods. The Central Bureau of Standards of the Ministry of Economic Affairs printed this article; the intermediates of the formula (] [), (] | [) of 3ρς, and some intermediates of the formula (v) are novel compounds that constitute the features of the present invention; In addition, the preparation method of these intermediates is also one of the characteristics of the present invention. When preparing a pharmaceutically acceptable compound of the formula (I), the compound can be reacted with an appropriate acid or base according to conventional methods, and 20 (please read the precautions on the back before filling this page) A 4 (210X297 public issue) 203008 A6 B6 V. Description of the invention (18). In addition, the solvate of the compound (I) can be formed by crystallization from an appropriate solvent. As mentioned above, the compound of formula (I) may exist in the form of more than one diastereomer. When the mixture prepared by the present invention is a mixture of the compounds, individual isomers can be separated from other isomers by colored layer separation, for example, by HPLC. In addition, the isolated diastereomers of the compound of formula (I) can also be used by using pure starting materials in stereoisomerism, or by changing the desired difference at any stage of the reaction process The intermediates of the structure are separated, and then these intermediates are converted into compounds of formula (I) to obtain. Preferably, a single diastereomer of the compound of formula (I) can be made by more than one of the above methods. Each method can define a different asymmetric center; when a special method is used, it can be deduced An unmeasurable configuration at the asymmetric center occurs at the asymmetric center. Although the decisive configuration at a particular asymmetric center cannot be understood, it is gratifying to refer to the direction of polarized light deflection, and the relative epimer makes a definite diastereomer Be characterized. The present invention further provides a chemical composition consisting of: a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. The composition system of the present invention can be effectively used for the treatment of muscular structural disorders, especially rheumatism and / or arthritis diseases, and can also be effectively used for regulating tissue diseases. The father of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before writing this page) The composition of the present invention, when treating cancer, prevents myelin degeneration in the central and peripheral nervous systems, and contains neutral gold The enzymes in the collagenase family of pride proteases have the potential to respond when they have pathological or other roles. The composition of the present invention can be prepared by mixing, and can contain diluents, binders, fillers, disintegrating agents, fragrances, coloring agents, moisturizers according to the customary method. 21 203008 A6 B6 Printed by the Central Bureau of Standards of the Ministry of Economy V. Description of Invention (19) Slipper or preservative. These conventional excipients can be used in a conventional manner, for example, according to the manner adopted in the preparation of the relevant enzyme inhibitors, such as the preparation of the ACE inhibitor enalapr il. The composition of the present invention can be made suitable for oral administration, local administration, rectal administration, or parenteral administration, but oral administration is more effective. The non-normally administered composition / system can be administered into the body via intravenous administration, intramuscular administration, or intra-articular administration. The pharmaceutical composition of the present invention is preferably formed in a unit dosage form, and is preferably formed in a form suitable for medical or veterinary use. For example, the preparation of the present invention may be packaged in a state of being recorded or printed with instructions for use as a medicine for treating or preventing any of the above-mentioned conditions. The proper use range of the compound of the present invention varies with the compound, and may also vary according to the symptoms to be treated. In addition, the amount of use is also related to the relationship between the absorption capacity and the chosen delivery method. The compound or composition of the present invention can be formulated into a form that can be administered by any route. The preferred route depends on the disease to be treated; in addition, it is preferably formed into a unit dose form or available The patient administers it in a single-dose state. In addition, the composition of the present invention may be formed into tablets, capsules, sachets, vials, powders, granules, tablets, reconstituted powders, or liquid preparations; examples of liquid preparations are Solution or suspension, or suppository. The composition of the present invention, for example, a composition suitable for oral administration, may contain conventional excipients; examples of excipients include: such as syrup, acacia gum, gelatin, sorbitol, gum tragacanth , Or Polyvinylpyrrolidone-please read the precautions on the back before filling in this tribute). ¾. • Hit. • Color · A 4 (210X297 Public Issue) 22 ~ A6 B6 203008 V. Description of the invention (20) etc. Binders such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine acid filler; tablet lubricants such as magnesium stearate; such as starch, polyvinylpyrrolidone, sodium starch ethylenedioxide Alcohol., Or microcrystalline disintegrant of vitamins; such as sodium lauryl sulfate pharmaceutically acceptable wetting agent. The solid composition can be mixed, filled, ingots, etc.

V is obtained by method. Repeated mixing operations can be used to disperse the active ingredient in compositions using large amounts of fillers. When the composition is formed into tablets, powders or tablets, any carrier suitable for preparing a solid pharmaceutical composition can be used; examples of carriers include magnesium stearate, starch, glucose, lactose, sucrose, rice Fine powder, and chalk '. The tablets can be applied according to methods conventionally known in general pharmaceutical practice, and especially coated with an enteric coating. In addition, if a carrier or other plutonium is required, the composition of the present invention may be formed into a capsule that can be ingested. For example, it may be gelatin containing the compound of the present invention. For example, in a hard gelatin capsule, in addition to containing the necessary amount of the compound of the present invention formed into powder or granules, it also contains a lubricant such as magnesium stearate intimately mixed with the compound, such as microcrystalline Cellulose fillers, and such as sodium starch glycolate. The composition for oral administration in liquid form may be in the form of, for example, an emulsion, syrup, or liqueur, or it may be presented as a dry product reconstituted with water or other suitable carrier before use. These liquid compositions may contain conventional additives; examples of additives include: such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel 3. Hydrogenated edible oils such as lecithin and sorbitol (please read the precautions on the back before filling the nest page) • Pack. • Line · Central Purple Bureau of the Ministry of Economic Affairs, Printing Zijia 4 (210X297) 23 ~ 203008 A6 B6 Printed by the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (21) Emulsifiers of oleate and acacia gum, such as edible oils including almond oil, fractionated coconut oil, and oily esters including glycerides , Propylene glycol, ethanol, glycerin, water or physiological food water and other aqueous or non-aqueous carriers, such as preservatives of methyl or propyl anhydrobenzoate, or sorbic acid. If necessary, customary fragrances or colorants can be used in the additives. The compounds of the present invention can also be administered via parenteral routes. According to routine pharmaceutical practice, the composition of the present invention can be formulated, for example, as a suppository for rectal administration or as an injectable parenteral administration. For injection, for example, by intra-articular injection, intra-cerebrospinal fluid injection, or other routes that allow the compound of the present invention to approach the site of myelination, due to free soluble solutions or poorly dispersed substances. Therefore, the compound of the present invention can be mixed with a pharmaceutically acceptable liquid in the state of an aqueous or non-aqueous solution, suspension or emulsion, for example, mixed with sterile non-pyrogenic water or non-enteric acceptable oil Class liquids or liquid mixtures, which may contain bacteriostatic agents, antioxidants or other preservatives, buffers or solutes that make the solution isotonic with blood, thickeners, suspending agents or other pharmaceuticals Acceptable additives. These systems for injection can be formed into sterile unit dosage forms housed in vials or in discarded containers, or multi-dose forms where appropriate doses contained in large bottles can be withdrawn In addition, the substance for injection can be formed into a solid or a concentrate to prepare a preparation for injection. For topical and transdermal administration, the preparation can also be in the state of ointment, cream, emulsion, gel, spray, aerosol, lotion, skin coating, or patch. Render. (Please read the precautions on the back before filling out this page)-¾. A4 (210X 297W issued) 24 203008 A6 B6 Printed by the Central Standards Bureau of the Ministry of Economic Affairs V. Description of Invention (22) Unit dose for inflammatory diseases, usually Containing 10 to 1 000 mg of the molybdenum compound of the present invention, preferably containing 10 to 5,000 mg of the compound of the present invention, the specific case of the content is 10, 50, 100, 150, 200, 250, 300, 350, 400, 4 50 or 5 00 mg. The molybdenum compound can be administered more than once a day, for example, two, three or four times a day, so that the total daily dose of an adult with a body weight of 70 Kg / falls within the range of 10 to 3000 mg. This dose is approximately at a level of about 0.15 to 50 mg / Kg · day. In addition, in particular, there is a concern that the unit dose contains about 2 to 200 mg of the compound of the present invention and is administered as many times as necessary to obtain the necessary daily dose. The present invention further provides a method for treating symptoms of connective molybdenum degradation or other protein enzyme related components in the body. Examples of such symptoms (disorders) occur in breastfeeding, such as rheumatism in humans And / or arthritis; this method includes the step of administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable compound to mammals who must undergo treatment. The present invention further provides a compound of formula (I) or a pharmaceutically acceptable compound thereof for the preparation of a medicament; this medicament is used to treat the degradation of connective molybdenum and other protein enzyme-related components in the body , For example, to treat symptoms of rheumatism and / or arthritis. The following description and examples exemplify the preparation process of the present invention, and the subsequent biological data exemplify its pharmaceutical activity. All temperatures are expressed in ° (: said. (Please read the precautions on the back before filling in this page) • Install · · Order · · Line · A 4 (210X297 public) 25 203008 A6 B6 V. Description of the invention (23 ) Descriptive Example 1 N — (1 phosphorous carboxyethyl) 1-ethyl leucine triethyl (D 1) ch3

I Η5 <: 2〇 \ 丄 a 〇 ^ \ HC〇2C2H5 OC2H5 First, diethyl [1-[(phenylmethyl) amino] ethyl] phosphonate (2.76 g) [by hE Atherton et al. Shown in 1986, Issue 29, J_. Med. Chem · P: 29)] dissolved in ethanol (100 ml), and hydrogenated at atmospheric pressure using 10% shavings attached to charcoal as a catalyst . Then, (4-methyl-2-oxo) ethyl valerate (1.58 g) and molecular sieve were added to it, and hydrogenation was continued for 48 hours. Next, the catalyst was filtered out by filtration, and the filtrate was evaporated to obtain a colorless oily product; the product was chromatographed on a silica gel column (eluent: ethyl acetate) To obtain the title compound (0.83g) as a mixture of isomers. Descriptive Example 2 N — (1 -diethoxyphosphorylethyl) monoleucine (D2) (please read the precautions on the back before filling out this page) • Install · • Hit · * Line. Ministry of Economic Affairs Printed by the Central Bureau of Standards ^ A4 (210X297 public) 26 203008 A6 B6 V. Description of the invention (24)

〇C2H5 The Ministry of Economic Affairs Central Standards Bureau said Method A. First, dissolve N- (1-phosphoranylocarboxyethyl) triethyl leucine (D 1) (t.Sl g) in methanol (30 ml) , And treated with sodium hydroxide (b. 2 g) dissolved in water (15 ml). After 24 hours, the resulting solution was acidified with 4 N HC1 and extracted with dichloromethane. Next, the organic extract was dried over anhydrous sodium sulfate, and the solvent contained in it was removed in the air to obtain the title compound (0.66 g). Method 8 First, a solution obtained by dissolving the acid salt of diethyl [1- (phenylmethyl) amino] ethyl] phosphonate (15 g) in ethanol (400 ml) was used at 10% of the charcoal is absolutely hydrogenated as a catalyst until it is completely converted into a primary amine. Then, sodium 4-methyl-2-oxopentanoate was added to it in a state of being dissolved in a minimum volume of water, and hydrogenation was continued for 3 days. Then, the catalyst was removed by filtration, and the filtrate was evaporated to obtain a colorless oily product. After that, the product was mixed with chloroform, followed by water (30 ml) and dilute citric acid. Wash with aqueous solution (2X30ml) and water. After drying (Na2S〇4), evaporate the chloroform layer to dryness to obtain a sticky white solid (please read the precautions on the back before filling this page) 甲 '4 (210X297 public) 27 A6 B6 203008 V. Description of the invention (25) (please read the precautions on the back and then fill in " this page) the title compound whose spectral properties are the same as those obtained in Method A. Narrative Example 3 N — [N —— [N— (i — diethoxyphosphorylethyl) _ leukoamino] one (S) — tryptophanyl] one (s) — methyl alanine (D3)

The Central Bureau of Standards of the Ministry of Economic Affairs first cracked, first of all, N — (1 — diethoxyphosphorylethyl) monoleucine (D.2) (1.0 g) dissolved in dichloromethane (50 ml) Cool to 0 ° C. Then, 1-hydroxybenzotriazole (0.6 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.88 g) were added to it, The resulting solution was stirred at 0 ° C for 2 hours. Next, H-Trp-Ala-OMe trigas acetate (1.5 g) and diisopropylethylamine (2 ml) were added thereto, and the resulting solution was stirred at 0 t for 1 hour. Thereafter, it was stirred at room temperature for 24 hours, and the resulting solution was filtered, then washed with water, saturated sodium bicarbonate, and a% citric acid aqueous solution, and then dried over anhydrous sodium sulfate. Then, the resulting solution was filtered, and the solution was steamed 4 (210X 297 Gongfa) 28 A6 B6 2〇3〇〇8 Fifth, the invention description (26) was removed to obtain a yellow oily product . The product was purified by silica gel column chromatography (eluent: 3% methanol / ethyl acetate) to obtain the title compound (0.45 g) as a colorless oil.

Observed El M + 566. Narrative Example 4 N — [N — [N — (1-Diethoxyphosphorylethyl)-Leucamide] Monooxymethyl [S]-Tyramine base 〕 One (S) —Alanine formaldehyde (D 4) (Please read the precautions on the back and then fill out this page). Install · Ο CH 3 H5C2〇

• Order · The title compound (0.45 g) printed by the Central Bureau of Standards of the Ministry of Economic Affairs was borrowed from N — (1 —diethoxyscale ’acetylethyl) leucine (D2) (0_5g) and H — Tyr (Me) — Ala — OMe trifluoroacetic acid (0.84g), prepared according to the process described in Example 3. Observed El M + 557. Narrative example 5 A 4 (210X 297 male) 29 • Line · 203008 A6 B6 5. Description of the invention (27) .N— ((S) — 1 diethoxy magnetic acetyl group) One (R)-methyl leucine and N-((S)-1-diethoxyphosphoryl propyl one (S)-methyl leucine (D5) CH. H5c2 0 0

、 CH 3 八八 广 C〇2CH3 OC2H5 {Please read the precautions on the back before filling out this page) Purpose, first (S) — 1, 1, ((iS, 2S, 5S) 2 — hydroxy one 2, 6, 6-trimethylbicyclo [3,1,1] hepta-3-dihexylamino] propylphosphonic acid diethyl ester (12g) [showed by E. JwquUr et al. In 1988, Issue 73 Phosphorus and Sulfur P · Prepared by the method in 36], placed in a solution consisting of 15% citric acid aqueous solution (210 ml) and tetrahydrofuran (2M ml), and stirred at room temperature for 72 hours. Then, the resulting solution was concentrated, washed with benzene (150 ml), then alkalized with sodium carbonate, and extracted with chloroform (4 × 200 ml). Next, the combined extract was dried over anhydrous sodium sulfate, and the solvent was distilled off in vacuo to obtain (S) -1-aminopropylphosphonic acid diethyl ester (5.63g) as an unstable oil. After the Central Bureau of Standards of the Ministry of Economic Affairs printed it, (S) — 1_ amino propylphosphonic acid diethyl ester (5.63 g) and (4-methyl-2-oxo) valeric acid methyl ester (12.47 g) It was dissolved in ethanol (200 ml) and hydrogenated for 72 hours at atmospheric pressure using -10% palladium attached to charcoal as a catalyst. Then, filter to remove the reminder f 4 (210X 297 public fund) 30 08%%

A B Printed by the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (28) Chemical agent, and the filtrate is evaporated to obtain a colorless oily product. Next, the product was dissolved in dichloromethane (50 ml) and washed with saturated aqueous sodium bicarbonate solution (50 ml) and 5% aqueous citric acid solution (50 ml), and then it was dried over anhydrous sodium sulfate After drying◊removing the solvent, the title compound is obtained in the form of a mixture of two diastereoisomers; the silica gel column is used for color-layer separation (eluent: ether) to obtain a single diastereomer Isomers. Isomer D5A (1.72 g) = + 27.32 ° (c = l% in methanol) 5 (CDCI3): 0.94 (6H, t), 1.06 (3H, t), 1.34 (6H, dt), 1.40-2.00 (5H, m), 2.68 (1H, m), 3.70 (3H, s), 3.78 (1H, t), 4.13 (4H, m). Further elution to obtain a single diastereomer with slower flow. isomer D5B (1.26 g) [a] D2〇 »+ 1.04〇 (Cel% in methanol) 5 (CDCI3): 0.90 (6H, dd), 1.05 (3H, t), 1.45 (6H, dt), 1.42-1.95 (5H, m), 2.76 (1H, m), 3.48 (1H, t), 3.72 (3H, S), 4.12 (4H, m). Descriptive example 6 N — ((S) — i — diethoxy Phosphatylpropyl)-(r) monoleucine and N — ((S) — i —diethoxyphosphorylpropyl) _ (S) -leucine (D 6) (please listen first Read the precautions on the back and then fill out this page) • Installed • • Played--Green • A 4 (210Χ 297 public) 31 Printed and printed by the Central Bureau of Economic Affairs of the Ministry of Economic Affairs 2〇3〇〇8 A6 B6 V. Invention description (29 ) CH3 | C2H5 H5C2〇I [H3

〇 ^ \ H C02H ° C2H5 (D6) First, N — ((S) —1—diethoxyphosphoryl propyl) — (E or S) —methyl leucine (isomer D5 A ) (1.71g) dissolved in ethanol (30 ml) and treated with sodium hydroxide (< 23 g) dissolved in water (20 ml). After 24 hours, the resulting solution was acidified with 5 N HC1 and extracted with dichloromethane. Next, the obtained organic extract was dried with anhydrous sodium sulfate, and the solvent therein was evaporated to obtain a single diastereomer (D6 A) (1.49 g). [a] D20 = + 23.7 ° (c = l% in methanol) δ (CDC13): 〇.97 (6H, d), 1.08 (3H, t), 1.36 (6H, dt), 1.44-1.99 (5H, m), 2.80 (lH, m), 3.78 (lH, t), 4.17 (4H, m). Observed M + 309. C13H28N05P requires M 309. Similarly, with N — ((S) —1—diethoxy Phosphatylpropyl) — (R or S) —Methyl leucine (isomer D5B) (iMg), the title compound (D 6 B) can be obtained as a single diastereomer (D 6 B) ; 1.05 g). A4 (210X297 public) 32 (please read the precautions on the back before filling in this page) • Install · • Line · A6 B6 2〇3〇〇8 5. Description of the invention (30) [α] 〇20 = + 4.07 ° (c = 0.984% in methanol) 5 (CDC13): 0.96 (6H, dd), 1.05 (3H, t), 1.34 (6H, dt), 1.43-1.98 (5H, n〇, 2.78 (lH, dt ), 3.42 (lH, dd), 4.16 (4H, m). Observed M + 309. C13H28NO5P requires M 309. Descriptive Example 7 3_ [N — [N_ (S) — 1 phosphoramidocarboxypropyl) one (R) —White Amino Acetyl]] mono (_) monoaminoazacyclotridecane-2-ketodiethyl ester and 3- [N — [N — (S) _1-phosphoramidocarboxypropyl) one (S ) —White Amino Acetyl]] One (one) monoamino azatridecane-1 2 one ketone diethyl ester (D 7) (Please read the precautions on the back before filling this page}

Printed by the Central Bureau of Standards of the Ministry of Economic Affairs (D7) First, dissolve N— ((S) — 1 — bis-ethoxy-terminated _propyl) one (R or S) —leucine (D6 A) ( 〇.68g) of dichloromethane (25 1111) cooled to 0 ° (:. Then, 1-hydroxybenzotriazole (〇.41g) and 1-ethyl mono 3 (3-dimethylaminopropyl ) Carbodiimide hydrochloride (0.58 g) was added to it, and the resulting solution was stirred at 〇 • C for i / 2 hours. Then, the (—)-3-aminoamino heterocyclic thirteen will be dissolved焼 -2-keto （〇 · 52 ^） (〔α〕 # = — 63.6 ° (C = 1% A 4 (210X 2971 'hair) 33 a〇3〇〇8 Fifth, invention description (31), in methanol )) Of dichloromethane (25 ml), added dropwise. Then, the resulting solution was stirred at room temperature for 24 hours, and then washed with water, saturated sodium bicarbonate and 5% citric acid aqueous solution Then, the resulting solution was dried over anhydrous sodium sulfate and evaporated in vacuo to obtain a colorless oily product. The color layer was separated using a sand column (eluent: 2-10% methanol / ether gradient) Liquid) for purification, to obtain a single A diastereomer.

Isomer D7A (0.83 g) [α] 〇20 = -6.23 ° (c = l% in methanol) mp 146-147 ° C. Δ (CDCI3): 0.94 (6H, t), 1.12 (3H, t), 1.26 -1.97 (30H, m), 2.68 (lH, m), 2.87 (lH, m), 3.68 (2H, m), 4.13 (4H, m), 4.40 6.47 (lH, broad s), 7.62 (lH, d ).

Analysis: C25H50N3O5P requires C, 59.6.2; H, 10.01; N, 8.34%. Found C, 59.78; H, 10.24; N, 8.38%. Further elution, to obtain a single non-non-purified as a small amount of impurities Enantiomers. isomer D7B (0.20 g) [a] D20 = -82.11 ° (c = l% in methanol) mp 142-144 ° c. Printed by the Central Bureau of Economic Affairs of the Ministry of Economy ¾ (please read the precautions on the back before filling this page ) δ (CDC13): 0.88 (6H, dd), 1.04 (3H, t), 1.14-1.91 (30H, m), 2.68 (2H, m), 3.55 (lH, m), 3.70 (lH, m >, 4.06 (4Η, Π〇, 4.43 (lH, m), 6.97 (lH, broad s), 7.69 (lH, dd).

Analysis: C25H50N3O5P requires, C, 59.62; H, 10.01; N, 8.34%. Found: C, 59.61; H, 10.06; N, 8.10%. A 4 (210 father 297 public) 34 ~ A6 B6 203008 V. Description of the invention (32) (Please read the precautions on the back before filling in this book) Similarly, take N — ((S) —1—diethoxyphosphoryl propyl) — (R or S) —leucine Acid (D 6 β) (0.64 g), the title compound (D 7 C) (0.39 g) presented as a single diastereomer can be obtained 〇 [α] 〇20 = -33.99 ° (c = l% in methanol) δ (CDCI3): 〇.96 (6H, d), 1.03 (3H, t), 1.20-1.92 (30H, m), 2.75 (lH, dt), 2.93 (lH, m), 3.32 (lH , m), 3.54 (lH, m), 4.17 (4H, m), 4.47 (lH, dt), 7.74 (lH, broads), 8.11 (lH, d). Observed M + 503. C25H50N3O5P requires M 503 . Description Example 8 (1-Hydroxypropyl) phosphonic acid bis # methyl ester 0 (PhCH2〇) 2P C2H5 〇H (D8) In this example, F. Texier-Boullet and A.

The general method shown by Foucaud [Synthes is, 198 2, 916] is printed by the Central Bureau of Standards of the Ministry of Economic Affairs. First, stir dibenzoyl phosphite (3 1.1 3 ml, 0 · 14 mole) and propionaldehyde (10.21 ml, 1 equiv ·) at room temperature, and mix the aluminum oxide (70 g) added to it. Then, after being left at room temperature overnight, chloroform was added thereto, and then the alumina therein was filtered off, and the alumina was washed with chloroform. Then, the obtained filtrate was evaporated to dryness, and the resulting clear oily product was separated by silica gel (600g) column chromatography, during which gradient elution (diethyl ether-5% A 4 (210X297) ) 35 A6 B6 2〇3〇〇8 Fifth, the description of the invention (33) (please read the precautions on the back before filling this page) methanol-ethyl ether). Finally, the title compound was obtained as a clear oil, which solidified on standing (2 ^ 82 g, 64%). Recrystallized with ether / pentane system to obtain a white crystalline solid (melting point 81-82 t) sample.

Found: C, 64.09; H, 6.71. Ci7H2i〇4pl requires C, 63.74; H, 6.61%. 5 (CDC13) 1.04 (3H, t, J »7H2), 1.6-1.95 (2H, m), 2.27 (1H , brs), 3.8 (1H, 2 overlapping triplets, J => 5 and 10Hz), 4.97-5.18 (4H, m), 7.34 (10H, S). Descriptive Example 9 ((1-Trifluoromethanesulfonamide) ) Propyl) phosphonic acid dipyridamole (D 9) 0

(PhCH2〇) 2P τ? Ο-S-CF,

II O (D9) The title compound of the Central Standards Bureau of the Ministry of Economic Affairs was prepared by the general method shown by E. Vedejs et al. [J. Org. Chem. 1985, 50 (丨 2), 2165]. First, dichloromethane (180 ml) solution of (1 monohydroxypropyl) phosphonic acid divolume (D8) (24.97 g, 0.078 mole) was dissolved under N2 to a temperature of 50 t. Then, while maintaining a temperature of 50 ° C, 2,6-dimethylpyridine (11.12 ml, 0.095 mole) and trifluoromethanesulfonate (15.1 ml, 0.0898 mole) were sequentially added thereto. . Secondly, the resulting mixture is slowly warmed to 0t, and then 4 (210X297 public splash) 36 A6 B6 V. Description of the invention (34) is placed in cold ether. Then, the organic layer in the resulting solution was quickly washed with ice water, dilute acid (secondary) and final water (operation involving water). Afterwards, the washed organic layer was dried (anhydrous MgS04) and evaporated to dryness to obtain the title compound (33.77 g, 96%) as a pinkish orange oil, which was provided without further purification. use. 6 (CDC13) 1.08 (3H, t, J = 7H2), 1.88 (2H, m) / 4.94 (1H, 2 overlapping triplets, J = 5.5 and 7Hz), 4.88-5.22 (4H, m) and 7.35 (l〇 H, m). (Please read the precautions on the back before filling in this page) • Install · Descriptive Example 10 (S) —White amine awakening group— (1) —3-Aminoazacyclotridecane-1 — Ketone (D 10)

• Hit. (D10) First, cool a solution of N-Cetylmethoxy hinge- (S) leucine (I · 87 g) in dichloromethane (130 ml) to 〇 »c, then 1-Hydroxybenzotriazole (1.25g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (fl.88g) were added to it, and this The solution was stirred at 0 ° C for I / 2 hours. Then, dissolve (―) _ 3 monoaminoazacyclotridecane-2-one (15 g) (〔a〕 g ° = — 63.6. (C = l% in methanol) bis Chloromethane (50 • Line · Central Bureau of Economic Standards, Ministry of Economic Affairs, India 4 (210X297 father not) 37 A6 B6 2〇3〇 ^ 8 V. Description of invention (35) ml). After adding, add at room temperature The resulting solution was shaken for 24 hours, and then washed with water and saturated aqueous sodium bicarbonate solution, and then dried over anhydrous sodium sulfate. Next, the resulting solution was filtered, and the solvent was evaporated to obtain a white color. A solid product. Next, dissolve this product in ethanol (shed ml) and hydrogenate it at atmospheric pressure using 10% palladium attached to charcoal as a catalyst. Finally, the resulting solution is filtered and the solvent therein Distillation to obtain the title compound (DIO) (1.1 g). Δ (CDC13): 0.95 (6H, t), 1.20-2.10 (23H, m), 2.83 (lH, m), 3.40 (lH, m ), 3.73 (lH, m), 4.45 (lH, m), 6.68 (1H, broad s) and 7.96 (1H, broad d).

Observed M + 325 · C18H35N3O2 requires M 325. Descriptive Example 11 3_ [N — [N — (1-phosphonocarboxypropyl)-(S) -White Amino Acetyl]] One (one) monoamino nitrogen heterocyclic deca Trioxane 2 — gi Division Diphenyl Methyl Ester (D 11) (Please read the precautions on the back before filling this page) (PhCH, 0), P 2 ΊΙ 0

(Dll) Printed by the Central Bureau of Standards of the Ministry of Economic Affairs. First of all, 1 1- (trifluoromethanesulfonamide hydropropyl) propylphosphine_diphenylmethyl ester (D9) (1.4g) and. (S) — white amine acetyl (―) _ 3 — Aminoazacyclotridecane-2-one (Dio) (1.0 g) was dissolved in methanol (6 ml). Then, 1,8-bis (dimethylamino) -naphthalene (a 4 (210X29)) 38 A6 B6 2〇3〇〇8 V. Description of the invention (36) 0.66 g) was added to the methanol solution , And the resulting reaction mixture was stirred at room temperature in a dark state on the 0th day ❶ followed by distilling off the solvent, and dissolving the resulting residue in chloroform (50 ml), and then Wash it with water and dilute citric acid aqueous solution, and then dry it with anhydrous sodium sulfate. The solvent was removed to obtain the product as an orange oil, which was separated by silica gel column chromatography (eluent: ethyl acetate) to obtain the title compound as a mixture of two diastereomers (D 11) (〇.73 g).

Observed FAB (M + H) + 628. 〇3,5H54N3 ° 5p requires M 627. Descriptive example 12 N — (1-(R) -diphenylmethoxyphosphorylpropyl S) monoleucine (D12A ) And N— (1— (S) -Di-extracted methoxyphosphoramidopropyl)-(S) -leucine (D 丨 2B) (please read the precautions on the back and then fill this page)

Yin Zi, Central Bureau of Standards, Ministry of Economic Affairs

Method A According to the general method disclosed in US 48 08 — 741 A for the preparation of trimethylsilyl leucine, firstly, (s) -leucine (1> 15 g, 0.00 8 8 mole), Acrylonitrile (13.5 ml) solution of a mixture of hexamethyldisilazane (1.75 ml) and triethylamine (1.38 ml) was heated under reflux for a total of 4 hours. A 4 (210X 297 public) 39

〇〇〇〇〇〇8 Fifth, the description of the invention (37) (please read the precautions on the back before filling in this page), then, ((1 trifluoromethanesulfonyloxy) propyl) phosphonic acid dimethyl ester ( D9) (4.5 g, 0.01 mole) was added thereto, and the resulting mixture was kept at 40 ~ 42 ° C for 48 hours. This reaction can also be carried out at room temperature. After cooling the mixture, it was filtered and washed with methanol, and then the filtrate was evaporated to dryness. Following this, the residue was placed in chloroform and washed with dilute HC1 (secondary) and then with water. Then, the chloroform layer was dried (anhydrous Na 2 SO 4), filtered, and evaporated to dryness to obtain an orange gel-like solid (3.67 g). Then, the crude product was milled with a minimum volume of ether / pentane to obtain a white solid product. After being collected, washed with a small amount of cold ether / pentane and dried, the title compound K, S was obtained. Isomer (D 丨 2 A) (0.47 g, 11%), melting point is 112 ~ 115 ° C.

Observed Desorption Cl (NH3) MH + 434. C23H32NO5P requires M 433.

[a] D20 = -23.09 ° (C = 0.97 MeOH).

Found: C, 63.73; H, 7.42; N, 3.23. C23H32NO5P requires C, 63.73; H, 7.44; N, 3.23%. 5 (CDCI3) 0.89 (6H, t), 1.03 (3H, t) / 1.25-2.0 (5H, m), 2.74 (lH, m), 3.28 (2H, brs), 3.73 (1H, brt), 4.9-5.15 (4H, m), 7.35 (10H, S): Printed by the Central Standards Bureau of the Ministry of Economic Affairs ¾ Another-isomer N — (1 — (S) -dibenzyloxyphosphorylpropyl)-(S) -leucine (D12 8), which can be used by using Harailt〇n PRP — 1 Column (300 X 7.0 '264 R) preparative HPLC' 40: 60 acetonitrile: water as eluent, 4.0m1 · / min flow rate 40 A 4C10X 297 public) 2〇3〇οδ Central Standard of the Ministry of Economic Affairs Printed by the Bureau 5. The description of the invention (38) Obtained. Under these conditions, the R and S isomers (D12A) were first eluted at a retention time of 34.6 minutes, while the s, S isomers (D 〖28) were well separated at 4; 2.7 minutes . For isomers (D | 2 β): Observed FAB (M + H) + 434. C23H32NO5P requires Μ 433. δ < CDC13) 0.85 (6H, t), 0.92 (3H, t), 2.62 (lH , m), 3.26 (lH, m), 4.8-5.1 (4H, m), 7.28 (10H, S). There is an additional signal at 1.5 5 which is covered by an overlapping water signal. When S, S isomer (.D12B) is coupled to (S) -amino acid derivative, S, S and S series are generated. Method β First, dissolve (S) -methyl leucine hydrochloride (0.543 g; 〇_〇〇3 mole) and (1-trifluoromethane phosphorus oxyinyl) dissolved in methanol (2 ml) A mixture of dibenzyl phosphonate (D 9) (1:35 g; 0.003 mole) and anhydrous potassium carbonate (1.0 g), heated at 50 ° C for 4 hours while stirring, and then left in Overnight at room temperature. -Next, the reaction was evaporated to dryness, and the resulting residue was dissolved in chloroform (5 ml) and filtered. After that, the filtrate and the washing liquid were combined, and the color layer was separated on a silica gel 60 (50 g) column (eluent: ethyl acetate-pentane (1: 1) mixture) to obtain N— (1_ (R) One-di-extracted methoxyphosphoramidylpropyl)-(S) -methyl leucine and N_ (1 one (s) -difan methoxycarbon_ylpropyl)-(s) -leucine (Please read the precautions on the back before filling in this page) • Pack · • Order · • Line. A 4 (210X297 public) 41 A6 B6 203008 V. Description of the invention (39) Oily mixture of methyl ester ({〇 · 55 g). Next, the resulting ester mixture (1.1 g, 0.025 mole) was dissolved in methanol (4.0 ml), and sodium hydroxide (ϋ. 11 g; (〇.〇〇275 mole)) Water (Ι · 5 ml) solution to treat it, and then the resulting solution was stirred at room temperature overnight. Next, evaporate it to 1/3 volume, and deplete it in water, and then Extract it with diethyl ether. Then, acidify the aqueous layer with citric acid to a pH of 3 ~ 4, and extract it with chloroform (5 times). After that, extract the chloroform part Dry refining (Na * S04) and evaporate to dryness to obtain an oily mixture of the title compounds (D12A) and (D12B), which will slowly solidify. The above product is triturated with ether to obtain N_ (1 as a white solid — (R) ~ Disaimethoxyphosphoramidylpropyl) — (S) -leucine (D12 A) (0.34g), which is the same as the technetium product obtained by Method A. Descriptive Example 13 (please first Read the precautions on the back and fill out this page) • Pack ·. Order. (PhCH-0), Ρ 2 2 \\ 0 Printed by the Central Bureau of Standards of the Ministry of Economic Affairs N — [N— (i_ (R) A submagnetic carboxyl group Propyl) — (3) A white amine group] a 0 -methyl mono (S)-tyrosine _N_ (2-hydroxymethyl) amine dioxonate (D 13) 〒2H5

OH First, dissolve N— (i— (E) _dimethoxymethoxyphosphorylpropyl— (s) —leucine (D12A) (0.89 g, 0.00 21 mole. Thread · A4 (210X297 Public eaves) ~ 42 203008 5. Description of the invention (40)) The stirred acetonitrile (9 ml) solution was placed in an ice bath and cooled to 〇t under a blanket of nitrogen, and then 1, 1, bispyridyl (0 · 37 recovered, L. 1 equ iv.)-Added to it once. After 15 minutes, let the mixture warm to room temperature within 30 minutes, and then cooled to 0 ° C again. After another 15 minutes, the 0-methyl- (S) -tyrosine (2-hydroxymethyl) amide 1 [according to the standard coupling method and deprotected by TFA / CHaCl2, and then by 8〇C-0 -Methyl mono (S) -tyrosine acid] (b. 49 g, 1 equiv) was added, and the resulting mixture was stirred at room temperature overnight. Then, the resulting reaction mixture was evaporated to dryness, and The resulting residue was dispersed in EtOAc and water. Next, the organic layer therein was washed successively with saturated NaHCO 3, citric acid, water, and water. After that, the organic layer Dry (anhydrous Na2S04) and evaporate to dryness to obtain a pale yellow gum product (1.16g). The product was chromatographed on a silica gel column (gradient elution, increased from EtOAc to 10% MeOH / Et OAc) to obtain a colorless colloidal product (0.43 g, 32%).

Observed FAB (M + H) + 654. 〇35Η48Ν3 ° 7ρ requires 653.5 (CDC13) 0.8 (6Η, 2 overlapping d), 〇.96 (3H, t), 1.05-1.35 (2H, m), 1.35- 1.65 (2H, m), 1.65-1.9 (lH, m), 2.4 (1H, brs), 2.68 (lH, m), 2.9 (1H, 2 overlapping d), 3.07 (1H, 2 overlapping d), 3.2- 3.45 (2Hrm), 3.5-3.8 (total 6H, m; including singlet at 3.2 (3H)), 4.72 (lH, dd), 4.83-5.1 6.75 (2H, d), 7.08 (2H, d), 7.2 Ministry of Economic Affairs Printed by the Central Bureau of Standards (please read the precautions on the back before filling in this page) (1H, brt), 7.3 (10H, S), 7.5 (lH, d). A 4 (210X297 public) 43 1. US 2,833,764 203 ° 08 as B6 V. Description of the invention (41) Description example 14 (1-hydroxypentyl) phosphonic acid dimethyl ester (D 14) 〇 (PhCH2〇, 2 ^^ 〇4η9 (D14)

In this example, OH uses the general method disclosed by F. Texer-Boullet and A · Fou caud [Synthesis, 1982, 916]. First, the mixture of phosphite (7.73 ml, Ό.035 mole) and valeraldehyde (ιι · 51 ml, b.105 ml) was stirred at room temperature, and para-alumina (35 g) was added at once In it. Then, it was allowed to stand at room temperature overnight, and chloroform was added thereto, and then alumina was collected and washed with chloroform. Next, the obtained filtrate was evaporated to dryness, and the resulting oily product was chromatographed on a silica gel column (gradient elution, 50% pentane / ethyl acetate-ethyl acetate) to obtain a colorless oil The title compound (9.17 g, 76%). δ (CDCI3) 0.86 (3H, t), 1.20-1.80 (6H, m), 2.60 (lH, brs), 3.87 (1H, 2 overlapping triplets), 5.06 (4H, m), 7.34 (10H, S). Narrative Example 15 51 .................................................................................... ....... # (Please read the notes on the back before writing this page) Printed by the Central Bureau of Standards of the Ministry of Economic Affairs

15 o (ester phospate diphosphonyl pentyl oxygen fermentation sulfane methane trifluoride-X A 4 (210X 297 common eaves) 44 ~ 203008 A6 B6 V. Description of the invention (42) (PhCH2〇

II

(D15) The title compound was prepared from (1-hydroxypentyl) phosphonic acid dimethyl ester (DW) by the method described in Descriptive Example 9. δ (CDCI3) 〇.88 (3H, t) / 1.18-2.00 (6H, m), 5.03 (5H, m), 7.32 (10H, m). Descriptive example 16 3 one [N _ [N _ (1 — Phosphorous sulfhydryl)-(S) -leukoamino]]-(one) -aminoaminotricyclotridecane-2-ketodiphenylmethyl ester (D 16) (PhCH Ο) P2ιι 0

(D16) First, diethyl 1-tris (trifluoromethanesulfonyloxy) pentylphosphonate (D15) (0.96 g) and (S) — white amine-3_ (—) monoamine nitrogen Heterocyclic tridecane-2-one (DIO) (0.65g) was dissolved in methanol (2.5 ml). Then, 1,8-bis (dimethylamino) naphthalene (0.426 g) was added thereto, and the reaction mixture was stirred at room temperature in a dark state for 10 days. Next, the solvent in it was distilled away, and the resulting residue was dissolved in chloroform (50 ml), washed with water and dilute citric acid aqueous solution, and then dried with anhydrous sodium sulfate . Following the first 4 (210X297 public) 45 (please read the notes on the back before filling in this hundred) 203008 A6 B6 V. Description of the invention (43), remove the solvent in it, get the orange oily product, use silica gel column Chromatographically separated (eluent: ethyl acetate) to obtain the title compound (D 16) (6.4 g, 30%) presented as a mixture of two diastereomers. Observed FAB (M + H) + 656. ¢ 37 ^ 58 ^ 3 ^ 515 requires Μ 655.

Example 1 Ν— [Ν— [Ν— (1-phosphonocarboxyethyl) -leukominyl]] (S) —tryptophanyl] -1- (S) —methyl alanine (El) CBU

HO 0 P

Η (El) (Please read the notes on the back before filling out this page) Printed by the Central Bureau of Standards of the Ministry of Economy First, dissolve diethyl _ (D3) (0.2 g) in dichloromethane (10 ml), and Treat it with bromotrimethylsilane (b.5 ml). Then, the resulting solution was stirred at room temperature for 4 days, and then methanol (20 ml) was added thereto, and the solvent therein was evaporated to obtain a crude product. Then, chromatography was performed on a reverse phase silica column (eluent: 5% ~ 30% methanol gradient solution in water) to obtain the title compound (0.1 g of a mixture of diastereomers) ). Observed FAB (M + H) + 511 · 〇23Η35Ν4 ° 7ρ requires Μ 510. A 4 (210X 297 public) 46 2〇3〇〇8 A6 B6 V. Description of the invention (44) Example 2 N_ [N_ [Ν_ (1—Phosphorous carboxyethyl) -leukoamine] -10—methyl_ (S) —tyramine] _ (S) -methyl alanine (Ε 2) (please read the notes on the back first Please fill in this page again.) • Installed · Printed by the Central Bureau of Standards of the Ministry of Economic Affairs in this example, the title compound (ϋ. 1 g was prepared from D4 (Qin. 25 g) by the method described in Example 1 ). δ (CD3〇D): 0.83 (6H, m), 1.05-1.60 (9H, m), 2.38-3.30 (4H, m), 3.65-3.78 (6H, m), 4.40 (lH, m), 4.60 ( lH, m), 6.83 (2H, m), 7.18 (2H, m). Observed FAB (M + H) + 502. C22H36N3〇8P requires M 501. Example 3 3 — [N — [N— ((S ) — 1—Phosphoramidocarboxypropyl) — (E) —White Amino Acetyl]] one (one) one amino one nitrogen heterocyclic tridecane-2-one and 3_ [N — [N— ((S ) — 1—Meng Dian continued base internal group) one (S) a white amine amide]] one (one) _ amine group-aza heterocyclic thirteen burned one-ketone (E 3) • line ·

~ 47 ~ A 4 (210X 297 public) Α6 Β6 2〇3〇 ^ 8 V. Description of the invention (45)

CH

(Please read the precautions on the back before filling this page) (E3) j

Method A First, dissolve diethyl ester (D7 A) (0.78 g) in dichloromethane (30 ml) and treat it with bromotrimethylsilane (; 2.04 1111). Then, the solution was stirred at room temperature for 72 hours, and then methanol (20 ml) and water (-10 ml) were added thereto, and the resulting solution was evaporated by evaporation to obtain a white solid (E 3 A).

Observed FAB (M + H) + 448. C21H42N3O5P requires Μ 447. Similarly, using diethyl ester (D 7 C) (; 0.23 g), the title compound presented as a single diastereomer (E 3 C). [a] D20 = -58.75 ° (c = l% in methanol). mp 180-183 ° C. δ (CD3OD): 0.97 (6K, dd), 1.12 (3H, t), 1.25-1.93 (23H, m ), 2.79 (lH, m), 2.97 (lH, m), 3.66 (lH, m), 4.22 (lH, m), 4.40 (lH, dd).

Observed FAB (M + H) + 448. C21H42N3O5P requires M 447. Printed by the Central Bureau of Standards of the Ministry of Economics β First, diphenylmethyl ester (D 11) (4.19 g) was dissolved in ethanol (Gamma 4 (210X297) ) A6 B6 ^ q3〇〇 ° Fifth, the description of the invention (46) (please read the precautions on the back before filling in this page) ml), and at atmospheric pressure, using 10% palladium attached to charcoal as a catalyst for hydrogenation 24 hours. Then, the resulting solution was filtered, and the solution was distilled away to obtain a mixture consisting of two diastereomers, followed by hplc [Hamilton PEP-1 column (300 X 7 coffee); Mobile phase, 2 · nitrile / water (17.5 / 8.25) + 0.1% TFA; flow rate, 6 ml / min] Separate it and obtain a single diastereomer (E 3 C), from the above two preparation methods A and β, it seems that the isomer E3 C is 3- [Ν— [N — ((S) —1-Carbonylene) propyl)-(S) -leukoamine [Acyl]] one (one) monoamino azetyl tridecane-2-one. Therefore, the isomer Ε3 Α must be 3-[N- [N- ((S)-1-phosphorous carboxypropyl)-(E)-leukoamino]] (a) monoamine aza Cyclotridecane-2-one. The process of coupling (D 丨 2 Β) with (一) -3-aminoazacyclotridecane-2-one and then hydrogenating 10% palladium on charcoal at atmospheric pressure as a catalyst can Provide another article to obtain 3 — [Ν — [N— ((S) — 1 -disc carboxypropyl)-(S) —leucine_yl]] one (one) -amino aza heterocyclic thirteen-burning one 2-The route of ketone (Ε3 C). Example 4 The Central Bureau of Standards of the Ministry of Economic Affairs 3— [Ν— [N — (—— Phosphoramidocarboxypropyl (s) -leukoamine]] One (one) -amino-azatridecane One 2-ketone (E 4) A 4 (210X297 public) ~ 49 2〇3〇08 A6 B6

(E4) First, disodium methyl ester (D 11) (〇.19 g) was dissolved in ethanol (JOO ml) and hydrogenated at atmospheric pressure with 10% palladium on charcoal as a catalyst. Then, the resulting solution was filtered, and the solvent in the filtrate was distilled off to obtain a mixture consisting of two diastereomers E 3 C and E 4 C; afterwards, a bp lc [Hamilton PRP-1 column (300 X 7®j); mobile phase, acetonitrile / water (17.5 / 8.25) + 0.1% TFA; flow rate, 6rol / min], at a holding time of 37 minutes, a single diastereomer was obtained. δ (CD3〇D): 1.00 (6H, t) / lH (3H, t) / 1.24-2.13 (23H, m), 2.74 (2H, m), 3.64 (lH, m), 4.32 (lH, m ), 4.53 (lH, t)

Observed FAB (M + H) + 448. C21H42N3O5P requires M 447. Printed by the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling in the hundred). The difference between the isomer E4 and the isomer E3 C is: The asymmetric center adjacent to phosphorus has the opposite configuration. Therefore, it appears that the isomer E 4 is a 3-CN— [N— ((R) — 1-phosphoramidoxypropyl)-(S) -leukoamine]]-(一) -aminoamino heterocyclic ring Thirteen burn one 2.-Ketone. Example 5 N-[N-(i-(R)-phosphoramidocarboxypropyl)-(S)-white amino acetyl]-0-methyl one (S)-tyrosine mono N-(2- Hydroxyethyl) amide (E 5) A 4 (210X297 public splash) 50 Α6 Β6 2〇3〇〇8 V. Description of the invention (48) (HO), Ρ ΊΙ 0

{Please read the precautions on the back before filling out this page) First, dissolve Ν — [Ν — (R) —phosphoramidoxypropyl) _ (S) _leucine amide] —〇 一 methyl one (S) —Tyrosine mono-N— (2-hydroxyethyl) amide diphenylmethyl ester (〇13) (206 rag, 0.00032 mole) in methanol solution, attached to charcoal (50 mg) at atmospheric pressure In the above, 10% palladium is used as a catalyst for hydrogenation. Then, the catalyst therein was filtered off and washed with methanol, and then the resulting filtrate was evaporated to dryness. Next, the residue was dissolved in water, and filtered and freeze-dried to obtain a white solid (120 mg).

Observed dynamic FAB (M + H) + 474. C21H36N3O7P requires M 473. On HPLC, with a holding time of 18.57 minutes, it has a single peak [RP Select β, 125 Χ4_, 394 R. With mobile phase, 5 : 95 acetonitrile: 0.05 M phosphate ester aqueous solution (ρ Η 2.5), flow rate 2 ml Printed by the Central Bureau of Economic Affairs of the Ministry of Economic Affairs / min] 〇Example 6 3 — [Ν — [Ν-((S)-phosphoramidite Group) One (S) -leukoamine]] One (one) monoamino-azacyclotridecane-2 2-one ketone ethyl ethyl ester (E 6) A 4 (210X 297 public) 51 2 〇3〇〇8 A6 B6 V. Description of the invention (49) CH.C2H5〇χ Na—O / "丨 Ο

First, diethyl ester (D7 C) (015 g) was dissolved in methanol (3 ml) and treated with excess sodium hydroxide dissolved in water at room temperature for 5 days. Then, the solvent therein was distilled off to obtain a white solid product. Next, the product was purified by chromatography on a reverse phase silica column (eluent: 5% to 10% methanol gradient in water) to obtain the title compound (0.01 g).

Observed FAB (M + H) + 476, (M + Na +) 498. C23H46N3O5P requires M 475. δ (CD3OD) 0.88 (6H, t), 0.96 (3H, t), 1.20-1.90 (28H, m) 2.52 ( ΙΗ, ΓΠ), 2.98 (lH, m), 3.43 (2H, m), 3.90 (2H, m), 4.22 Example 7 3-[N.-[N-(1-from the base carboxypropyl)- (S) —leucine acid group]] ~~ (1) Monoamine gas heterocyclic dodecane-1 2-one ketone disodium salt (E 7) CH, (please read the precautions on the back before filling this page ) Printed by the Central Bureau of Standards of the Ministry of Economic Affairs

Na 0

Na + ~ 0 II 0

(E7) A4 (210X297 Gongmei) 52 ~ ^ 〇3〇 ^ 8 A6 ____B6___ V. Description of the invention (50) In this example, it is the two diastereomers prepared in Example 4 Mixture (before HPLC separation) 'to prepare the title compound. First, the isomer mixture (709 mg '0.0 016 mole) in water (I50 ml) was cooled on an ice bath. While cooling, it was stirred with sodium hydroxide solution (10%' 1.2 6 ml, 2 is called 11〗 vs) to deal with it. Then, the resulting solution was filtered and freeze-dried to obtain the title compound (746 mg, 96%) as a white solid.

First, dipicolinate (D 16) (0.4) was dissolved in ethanol (gamma ml) and hydrogenated at atmospheric pressure using 0% palladium attached to charcoal as a catalyst for 24 hours. Then, the resulting solution was filtered and the resulting solution was evaporated to obtain the title compound (b. 2 8 g) in the form of a mixture of two diastereomers. Printed by the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page)

Observed FAB (M + H) + 476. C23H46N3O5P requires M 475. Collagenase inhibitor analysis This test was mainly published by Anaw. Aaw 4 (210X297 public) according to Cawston and Barrett et al. ~ 33 ~ 〇q3〇〇8 as Z .___ B6 V. Description of the invention (51)

Biochem. 99, 340 — 345 (1979). The compound to be tested is dissolved in methanol + and is added to the purified rabbit collagenase, or to human collagen prepared from the purification of the tissue liquid obtained from the human lung connective tissue cell line WI-38 Enzyme. After pre-incubating at 37¾ for 5 minutes, the analytical test tube was cooled to 4 ° C, and 14 C-acetylated rat skin type I collagen was added thereto. Next, the assay tube was incubated overnight at 37 * c. Among them, 14 C-collagen forms insoluble microfibers, which are enzymes of enzymes. After that, to stop the analysis, the analysis test tube was rotated at 12000 rpm for 25 minutes. Uncut w C-collagen is still insoluble microfibrous and granulated, and the principle of cut 14 C-gel is still soluble in the liquid. Take a liquid sample for liquid scintillation counting. The activity of collagenase inhibitors (IC50: 50% inhibitory concentration) is defined as a compound concentration that can inhibit 50% of the enzyme concentration (standard), or at a certain concentration of the compound, due to the compound (standard )% Inhibition of collagen deterioration caused by enzyme concentration. The activity of representative compounds of the present invention during the test is shown in the table below. Inhibition of rabbit collagenase Examples Isomer IC50 ()

El Mixture of diastereoisomers 2.4 Printed by the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before writing this page) E 2 " 3.1 Human lung connective tissue cell collagenase inhibition example isomers ICg〇 () A4 (210X 297 public) ~ ^ 〇3〇〇β A6 B6 V. Description of the invention (52) Ε 3 CS, S, (1) 0.04 5 Ε 4 R > S? (-) 0.166 Ε 8 E, S, (one) and S, S, (one) 丨 9. 4 9 (please read the precautions on the back before filling the nest page). Install · Order · Line · Central Bureau of Standards of the Ministry of Economic Affairs Printed armor 4 (210X 297 male)

Claims (1)

Public A7 B7 C7 D7 VI. Scope of patent application A compound with the following general formula (I), or its subordinates, Employee Consumer Cooperative Printed by the Central Bureau of Standards of the Ministry of Economic Affairs® ----------------- 1 ------ installed ------ order ------ 『(please read the notes on the back before writing This page) This paper scale is applicable to the Zhongyuan ajia standard (CNS) A 4 now branded (210 X 297 mm) 2030 ° 8 A7 B7 C7 D7 VI. Scope of patent application Pseudo η 4 is m in the R-shaped 6 or C of the hydroxy group, or the base of the hydroxy group, the number of ι'ίιΑπ 6 of the base-R ,, s 6 or c® or chloro-Λ) ^ R Z 3 tH R Or c and; (The base can be combined as a counterfeit R. Among them. Γ1, the item of its sulfidation combination 1st Fan Fanli C Specialist 0 Keshen B or Yiji. A2. The hydrogen pseudo-R is among the others . Ding Xiangzheng of the merger of the group is the first or the first group of C Fan Fan benefits, please apply for Ji Shen Yi Yi,. Base 3 A 'hydrogen 4 Ke Ding Zheng 5 1 of the 1st base Ding Wai Fan Fan Fan Li The first advantage or special request base. Please apply for Ding Shen Yi Yi Yi Pseudo 2 R The item of the compound of the R R The item of the compound of the pseudo Η 4 CRI, or the base 3 A Η 基 C 晬 ο ind 2-) 3 2 or Η-based C-toluene I group-gas Η meth ー AZ 4 > or 2, Η-based C-toluene benzene-Η c Η c 2 ο c is a forming joint & 4 Ra 3 R (please read the precautions on the back before writing this page)-Pack. Order. The Η C person-£ 6 base 4 B pseudo or 3 base butyl diethylbenzene 1 or-the third base 3 Enclosing B or Fan, Glycylmethyltoluene, If, Pseudomethylshen, 1, Chloro, R, Methyl, Hydrogen, R, H, Pseudo; c, R, R, P, D, P, D, Pseudo 4, Pseudo 4 »ζ ΏΡ 物 R, Η c Η c I or κ ο Η Ｃ Ｍ ZO is printed by the Central Standards Bureau of the Ministry of Economics and Industry and Consumer Cooperatives 2 Its Η »C object (combined with the item i—t-I rH-the mth circle is Fan Chengli-shaped special cooperation If the final application can be followed. 4 7 R and the others are not: 3 Garden R is collected in it, and the package number that is not included in the center of the physical center is self-recorded. The 0-shaped ones are pseudo-stars, and the structure is recorded as I. The standard S has a comprehensive system. In combination, when it is 8} The hydrogen paper size is applicable to the national standard (CNS) A 4 specifications (210 X 297 male) B7 C7 D7 ^ 0¾0 ° 8 VI. Scope of patent application (please read the precautions on the back before filling in this page) N — [N — CN-(1 a sulfonated ethyl carboxyl group)-white amine group J ~ (S)-tryptophanyl group] one (S ) —Alanine A § Purpose; lN — l N-a sub-dish chrysoethyl) a white amine IS group] — 0 — methyl one (S) — tyramine prosthetic group] one (S) — Methyl urethane; 3 — [Ν-[Ν-((S)-1 焵 瞵 carboxypropyl)-(R) -leucine acid group]] one (one) _ amino aza heterocyclic compound 1 2 —_; 3-C Ν-L Ν-((S) — 1 phosphinyl carboxypropyl)-i equipment · (S) —white amine sulfonyl group]} one (one) —amino amine heterocycle Thirteen House One 2 —M; 3 — [Ν-〔Ν — ((R) — 1-瞵 羵 carboxypropyl)-(S) a white amine licking group]: one (one) monoamino nitrogen heterocycle Tridecane-2 —Occupation, N — 〔N — 〔1-(R) -Phosphonocarboxypropyl)-(S) -leukoamine)〕 0 — Methyl- (S) —Cool S Acid-N — (2 -hydroxyethyl) ammonium amine; 3-: N-CN-i S) -phosphoranylidene propylidene)-(S) Mono-amine printed by R Industry and Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs Acetyl]]-(―)-aminoaminotricyclotridecane-2--diethyl monoethylesterate; 3 -— [Ν-[Ν-1 -phosphonocarboxypropyl)-(S) -leucine韹 基]] — (1) Monoamine azacyclotridecane-2-copper two-pile; and the standard of this paper is applicable to the national standard (CN S) A4 is now branded (210 X 297 mm)% 〇3〇〇B A7 B7 C7 D7 Six, apply for a patent Fan Garden 3 NN pentyl carboxym sub S group 0 according to the white 9 formula-meaning 2 The three items of the 10th ring in the embankment are «Vanilamide Special -if > Shen-such as prepared-I rJ species inert% (under R, cracking, opening and closing) in I store 丨 type fb The following halogens are composed of water or a combination of silicon oxychloride or pseudo-alkaline acid acid, and dissolve I. According to R, it is appropriate. Ϋ: those who decompose fi in the step of water, or hydrogen, or Σ, turn R20 crack R The situation will happen now, and it is worth R or it (please read the notes on the back before writing this page) NE R II »Z group R The R generation of A and benzene 1, which is selected from the group consisting of methylbenzene or Z00 R or the alkyl group is selected from the group consisting of alkyl, {hydrogen RR if necessary + In R and please apply for the time when the Fan Li specializes in the treasury department t 楊 棂 准 居 员 消 # Cooperative printing ο The Chinese chemical compound item changes to 1 1 Turn around C 1 Fan is UJ Lee 1 R Special 2 lilfR Shangshen In the formula of 0, the righteousness is determined, the base m is defined as m, and the compounded chemical compounds are included in the list. The selected papers are included in the sys. The paper size is applicable to the country ’s national standard (CNS) f 4 cash (210 X 297 public goods) A7 B7 C7 D7, the scope of patent application N-LN-N-(1-diethoxyphosphoryl ethyl)-a white amine 11 group]-(S) •-tryptamine certificate group j-( S) —Alanine methyl ester; N — LN — 〔N — (1 —diethoxy-dissiphylethyl) -white amine benzyl] ◦-methyl- (S) —tyramine ethyl] (S) — Propylamine methyl ester; 3 — [N — (R) _ white amine diethyl ester; 3 — CN-[N — ((S)-1-phosphorous carboxypropyl) _ group]] One (one) amine m heterocyclic tridecane-1 2_ (please read the precautions on the back before filling in this page) S) CN — ((S) one 1 one sub-disc chrysylpropyl group — (white amine cardinal ]] One (_)-amino azetyl tridecane-2-diethyl diethyl; 3 N • loaded. White ammonium [N-(1-phosphorous carboxypropyl) one (S)-( A) Monoamino nitrogen heterocyclic thirteen embankment 2-Yan 1 dibenzoyl ; N ： N ί 1 — (R) Phosphorous acid carboxypropyl (S) Negative work of the Central Standards Bureau of the Ministry of Economic Affairs # Cooperative printing-white amine amine] a 0-methyl one (S)-tyrosine -N-(2-hydroxyethyl) S-amine diphenylmethyl ester; and 3--; Ν-: Ν-(1-sulfonium carboxypentyl)-(S)-white amine yl]] _ (-) Aminoazacyclotridecane-2-tuned benzylidene methyl ester. 1 2. A pharmaceutical group of crops used to treat diseases caused by the degradation of connective tissues and other protein alcohols in the human body. The compound and the pharmaceutically acceptable carrier of item 1 of the patent scope. This paper scale is applicable to the Chinese National Standard (CNS) A4 specifications (210 X 297 public goods). Six, the patent application scope is A7 B7 C7 D7 for use. The disease, the combination of the physical and chemical transformation of the chemical retreat, 1 prime, fermentation, white Fan egg, altruism, special request and Shen Zhiyi M. Association 3 knot 1 body therapy -------------- ---------- installed ------ ordered (please read the notes on the back before writing this page) Central Bureau of Standards of the Ministry of Economic Affairs w industrial and consumer cooperatives printed this paper standard China National Standard (CNS) Grade A 4 (210 X 297 mm)