TW295587B - - Google Patents

Description

895 & B7 A6 B6 V. Description of the invention (The treatment of skeletal system diseases has become increasingly important. For example: osteoporosis is a common skeletal disease. Many types of osteoporosis lose a lot of bone tissue, so they finally lose their bones The mechanism is stable. The rate of formation of osteoblasts and contact bone cells in healthy people can balance bone formation and bone resorption. The balance of osteoporosis is disturbed, so bone destruction occurs. Known guanidinyl-1,1-bisphosphonic acid derivatives are suitable for the prevention and / or treatment of osteoporosis (EP 0 546 548). In an effort to explore other treatment and prevention of osteoporosis, with active compounds with fewer side effects At this time, it has been found that the guanidinyl-1,1-bisphosphonic acid according to the present invention can reduce bone resorption. Therefore, the present invention relates to tautomeric compounds of formula I a, I b or I c

OR

NH IIC-N-C-N-CH II I I

/ CH \ .OR

OR (I. .............................................. ........................ Pretend ........................ ... order ........ line (please read the precautions on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs-3-This paper standard applies to China National Standard (CNS) A 4 Specifications (210X297mm) 5. Description of invention (

NH R—C-N-C-N-CH II IΟ Η on ρ ρ π ο / CH \ A6 B6 R R R R ο ο ο ο b (please read the precautions on the back before filling this page)

R NIH I cno H c test 2 NH 0 NI c RRRR oooo // \ / on pp M o / H \ / c \ and / or physiologically acceptable salts of compounds of formula I a, I b or I c; R As defined below, I) Free radicals of formula V

Printed by the Beigong Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, R11 or R12 is as defined below a) Rn-S (0) n or

This paper scale is applicable to the Chinese National Standard (CHS) A4 specification (210x297 mm). V. Description of the invention (A6 B6 R13 is 1 in the printed form of the Employees Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs) (CfC,)-alkyl, 2 ) (C5-C7) -Cycloalkyl, 3) Cyclopentylmethyl, 4) Cyclohexylmethyl, 5) Phenyl, 6) One to three times substituted phenyl with 6.1 fluorine atoms' 6.2 chlorine atoms , 6.3 methyl or 6.4 methoxy, where η is an integer 0, 1 or 2 'where R14 and R15 are the same or different, and are as defined below · · υ hydrogen atom, 2) (CrC,)-alkyl. , 3) Phenyl, 4) One or two times substituted phenyl by the following groups: 4.1 fluorine atom, .4.2 chlorine atom, 4.3 methyl or 4.4 methoxy, 5)-(CH2) m-phenyl, Where m is an integer from 1 to 4, or 6)-(CH2) m-phenyl, where m is an integer from 1 to 4, and phenyl is from -5 -... ..................................._ .................. .... installed ..................... ordered ........................... ...... Line {Please read the precautions on the back before filling out this page) This paper uses the Chinese National Standard (CNS) A4 specifications (210x297 Cli) A6 B6 Printed by the Employee Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy V. Invention description () Primary or secondary substitution by radicals as shown in 4.1 to 4.4, 7) R14 and R15 together form 4 to 7 carbon atoms Straight or branched chain, the following groups may be interspersed in the chain: 7.1 Ο, 7.2 S or 7.3 NR10 where R1 (> is 1) hydrogen atom or 2) methyl group, or 8) R14 and R15 and the attached Nitrogen atoms form together: 8.1 indoline, 8.2 tetrahydroquinoline, or 8.3 tetrahydroisoquinoline ring and other substituents R11 or R12 represent a) hydrogen atom, b) halogen atom, such as: fluorine, gas , Bromine or broken atom, c) (CrC4) -alkyl, d) alkoxy, e) phenoxy, f) phenoxy substituted one to three times with the following groups 1) fluorine or chlorine atom, 2) A Radical, or 3) methoxy, g) R13-S (0) n, where η is an integer η, 1 or 2, and R13 is as defined above 6 — .................. ». .........; ..............-......................... ............. installed ............-............ ordered .................. ........ Line (please read the precautions on the back before filling out this page) This paper scale is applicable to the Chinese National Standard (C NS) A 4 specifications (210X297 mm) 2 & S & S1 A6 B6 V. Description of invention (meaning, or

Where R14 and R15 are as defined above, or Π) formula VI radical R21

Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs a) hydrogen atoms, b) halogen atoms, such as fluorine, chlorine, bromine, or broken atoms, or c) (CrC12) -alkyl groups, where R21, R22 or R23 One substituent may also represent 1) n3 '2) CN, 3) OH, 4) (CrC1 ())-alkoxy, 5) R24-CnH2n-〇m-where m is the number 0 or 1, η is the number 0, 1, 2 or 3, R24 is a 7 — .........: '·: .............................. ............................. I ...................... ΤΤ ..................... I (Please read the precautions on the back before filling in this page. J This paper size applies to China National Standard (CNS) A4 specifications (210X297mm) A6 A6

Where P is the number 1, 2 or 3, but n must be the number 0 or 1, 2) (cVc12 cycloalkyl, 3) phenyl, 4) P ratio > 7 definitive, 5) cinnoline or 6) Isodocinolyl, in which the ring systems in free radicals 3) to 6) are unsubstituted or substituted with one of the following free radicals: 3.1 gas atom, 3.2 rat atom, 3_3 CF, j ~ 3_4 methyl, 3.5 methoxy or 3.6 NR25R26, where R25 and R26 are the same or different, and are as defined below: or :: V ..................... ............................... " ........... ........... pretend ............................................................ ....... line (please read the precautions on the back before filling in this page) 3.6.1 hydrogen atom or 3.6.2 (CrC4) -alkyl melon printed by Beigong Consumer Cooperative of Central Bureau of Standards of the Ministry of Economic Affairs Free radical

(VII) One 8 one paper scale is applicable to the national standard (CHS) A 4 specifications (210X297 mm) of country t. 5. Description of the invention (where r3, r32, r33 or r34 are as defined below. A) Hydrogen atom, I · (1) by atoms such as m or c) -CN, one, d) -N〇2, e) -N ,, f)-(CrC6)-burned group, straight chain or branch, Λ „35 _ 一 乂 g) R -CnIl2n-Z- where n is a number 〇 '1' 2, 3, 4, 5. or 6 '-CnH2n- is a straight chain or branch, and wherein one of the carbon 晼 base chain or nitrogen atom replacement,,, j gas breaking, sulfur R35 is 1) ammonia atom, 2) (C3-C6) -alkenyl, 3) (C5-C8) -cycloalkyl, 4) (q-C8) -cycloalkyl, through a Hydroxyl substitution, or one of the methylene groups is replaced by oxygen, sulfur or nitrogen atoms, or 5) phenyl group, unsubstituted or substituted by three or more free radicals selected from the following 丨 to 3 free radicals of the Ministry of Economic Affairs, Central Bureau of Standardization, Beigong Consumer Cooperative Print 5.1 halogen atoms such as fluorine, chlorine, bromine or broken atoms, 5.2 CF3, 5.3 CH "S (0) y, -9. The paper size is not in accordance with Chinese National Standard (CNS) A 4 specifications (210X297 mm)

-Please read the back of the first page:! I will pay attention to the matter before filling the nest page). Order A6 B6 Printed by the member of the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperation V. Invention description (8) where X is the number 0, 1 or 2 , 5.4 R36-Wy where R36 is a hydrogen atom, methyl or ethyl, W is an oxygen atom, NH or NCH3, and y is 0 or 1, 5-5 CmF2m + 1 > 5.6 p vs p definite, 5.7 octaline Group, or 5.8 isodocinol group, Z is 1) -C0- 2) -CH2- '3)-[CH (OH)] q_ where q is the number 1, 2 or 3, 4)-[C (CH3) (OH)] q-, where q is the number 1, 2 or 3, 5) -0- '6) -NH-, -N-, 7) I ch3 8) -S (0) x-, where X is 0, 1 or 2, 9) -S〇2-NH-, or — 10- .................................... ............... Bu ....................: Attack .................. ....... 、 町 ..................... line. (Please read the precautions on the back before filling this page. A paper standard applies to China National Standard (CNS) A 4 specifications (210X297 mm) 9 V. Description of the invention (iO) ^ S〇2 »jj-

I Bu burning group, X is defined as follows · a) N or b) C-R37,) -alkyl or Μ), group, wherein R37 is a hydrogen atom, (c Y is defined as follows: ‘‘

a) NH b) -N- (c) -c6) ~ alkyl, c) —N ~ (c2-c4) -alkenyl, or d) r35-ch2N-z-, 5 where r35, 11 and 2 are as Definition of item g), RR, R are the same as or in line with the ruler, five or eight s (4 a) hydrogen atoms, and as defined below b) (C〗 -C5) -alkyl, straight or branched, c) Phenyl if the substituents R11, R12, R 'r22, r23 25 Γ, r33, r3, r35 contain one or more asymmetric middle V, R: Ming Hanyu main S and compounds in R configuration. . Compounds Diastereomers, secretions or mixtures of them. The alkyl group as defined by h isomer may be linear or branched. Preferred compounds of formula I a, I b or IC, and / or formula J a, industrial & or J < physiologically tolerable salts of compounds are defined as R in the formula as follows: 'A6 B6 Employee of Central Bureau of Standards, Ministry of Economic Affairs Consumer Cooperation Du Printed V. Description of the invention () I) Formula V radicals, where R11 is defined as follows: a) Fluorine atom, b) Chlorine atom, R 丨 5, c), where R14 and R15 are as defined above, R1 'd) R13-S (0) n-, where η is the number 0, 1 or 2, or e) phenoxy, where R12 is as defined below: a) R13-S (0) n, where η is zero , 1 or 2, or R wb) where r14 and R] 5 are as defined above, or R15 Π) Formula VI radical, where R21, R22 or R23 are as defined below: a) hydrogen atom, b) halogen atom, such as ·· Fluorine, gas or bromine atom, or c) (CrCJ-alkyl, where one R21, R22 or R23 substituent can also represent 1) OH, 2) (qC,)-alkoxy. 24 3) R -CnH2n-〇m, where m is the number 0 or 1, η is the number 0, 1, 2 or 3, —12 — ..... '' i: .... ..................................................... ...................... order ............... line {please read the back first Please pay attention to this page and then fill out this page) This paper scale is applicable to the Chinese National Standard (CNS) A 4 specifications (210x 297 mm) V. Description of the invention (11

R24 represents υ CPp2p + 1 where P is the number 1 'the constant η is the number 〇 or], 2) (c5-c7) -cycloalkyl, 3) phenyl, 4) pyridyl, 5) octylinyl , 6) Isocinolinyl, in which radicals 3) to 6) are substituted from the following groups: ¥ is unsubstituted or 3 · 1 fluorine atom, 3-2 chlorine atom, and 3.3 CF3, 3 · 4 CH3, or 3 · 5 methoxy, or m) free radical of formula vii 'where a) an ammonia atom, b) a halogen atom, such as ·· fluorine, chlorine, bromine or iodine atom, or c) (C, -C6) -Emperor, straight chain or branch, or select r33 or R34 as follows: (Please read the precautions on the back before writing this page) -Binding. Thread 丨 丨 Ministry of Economic Affairs Central Standards Printed by Bureau M Industry and Consumer Corporation 35 d) R ^ ηΗ2η-Z- Let n be the number Ο '1 or 2, and the sub-dry bond -CnIi2n- is a straight bond or branch, and one of the carbon atoms can be oxygenated 'Sulfur or nitrogen atom replacement, R35 is 13 · This paper standard applies ⑽)> 4 specifications (2 songs 297 published) A6 B6 Printed by the employee consumer cooperative of the Central Bureau of Standards of the Ministry of Economy V. Description of invention (12) 1) Hydrogen atom, 2) (C5-C8) -cycloalkyl, 3) (C5-C8 ) -Cycloalkyl, substituted by a hydroxyl group, or one of the methylene groups is replaced by an oxygen, sulfur or nitrogen atom, or 4) Phenyl, unsubstituted. Or substituted by 1 to 3 groups selected from • I4.1 halogen atoms, such as: _, chlorine, bromine or discriminating atoms, 4.2 CF3, 4_3 CH3-S (0) x, where X is the number 〇, 1 or 2, 4_4 · R3, Wy. Where R36 is Hydrogen atom, methyl or ethyl, W is oxygen atom, NH or NCH3, and y is 0 or 1, 4-5 CmF2m + 1-where m is the number 1, 2 or 3, 4.6 p than the base, .4.7 σ quinolinyl, or 4.8 isocinolinyl, Z is 1) -C0-, 2) -CH2-, 3)-[CH (OH)] q-, where q is the number 1, 2 or 3, 4) -[C (CH3) (OH)] q-, where q is the number 1, 2 or 3; -14- Pack -..................... Order ; .................. line (please read the notes on the back before filling in this page) This paper size is applicable to the Chinese National Standard (CNS) A 4 specifications (210x297 C) A6 B6 5. Description of the invention (13) 5) ~ 〇 ~ or 6) -S (〇) ", where X is 〇, 1 or 2, X is defined as follows: a) Ν 'or., B) CH , Y is as defined below a) -N- (cvc6) -alkyl, b) ~ N ~ (C2-C4) -alkenyl, or c) R35CnH2n-Z—, where R'n and Z are as defined in item d), RR, R and r8 are the same or different, and are as defined below a) wind atom, b) (Ci ~ c5) -alkyl group, straight Chain or branch. Particularly preferred compounds of formula Ia, Ib or Ic are Ru in the formula as defined below: -......... ΤΓ .................. Line (Please read the precautions on the back before filling the nest page)

Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs where R14 and R15 are the same or different and represent the following: 1) Hydrogen atom or ^ 2) (CVC4) -alkyl, or R14 and R15 are formed together (C4-C7) -Alkyl chain or -15 — This paper scale is applicable to the national standard (CNS) A4 specification (210X297 mm) of A paper. A6 _______ Β6 14. V. Description of invention () Central Indian Bureau of Economics, Ministry of Economic Affairs, Shell Industry Consumer Cooperation Du Duin R13-s- wherein R13 is a) phenyl or b) phenyl substituted with chlorine at the para position, wherein R12 is as defined below: a) CH3-S〇2-, b) H2N-S〇2-, c) Phenoxy, or d) phenoxy substituted with chlorine at the para position, R5, R6 'R7 and R8 are the same or different, and are as defined below: a) hydrogen atom or' b) (C! -C4) ~ Burn-in groups, and physiologically tolerable salts of compounds of formula Ia, Ib or Ic. Particularly preferred is methyl p-docarbonyl)-(aminoiminomethyl) amino] ethane-1,1_bisphosphonic acid tetraethyl § Purpose, 2-[(1-methyl-2-p noise Carbonyl) _ (aminoiminomethyl) amino] ethane-U-bisphosphonic acid, 24 (3-methanesulfonyl M-hexahydropyridinebenzyl)-(aminoiminomethyl ) Amino] ethane-1,1 ~ bisphosphonic acid, 2-[(3-methoxypyridyl-4-4-hydrogen p ratio benzyl H aminoaminoiminomethyl) amino] ethyl amine -1,1-bisphosphonic acid tetraethyl ester, 2-[(3,5-dichlorobenzyl)-(aminoiminomethyl) amino] ethane-U-bisphosphonic acid tetraethyl ester 'And 2-[(3,5-difluorobenzyl)-(aminoiminomethyl) amino] ethane bisphosphonic acid. The compound according to the present invention can be prepared according to, for example, the following preparation method: The compound of formula IV—16 — ^ ................................. ................... line (please read the precautions on the back before writing this page) This standard is applicable to China National Standards (CNS) A4 specifications ( 21〇Χ297 公 f) 5. Description of the invention (15 A6 B6

Where R, R6 'R7 and R8 are as defined in formula I a, a) reacts with a compound of formula m in the presence of an inert solvent

Printed by the Beigong Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs to produce compounds of formula Ia, Ib or Ic, where R11 and R12 are as defined in formula Ia, Ib or Ic, and if appropriate, B) use formula The bisphosphonate of the compound I a, I b or I c is converted to the corresponding bisphosphonic acid, or the compound of formula IV, where R5, R6, R7 and R8 are as defined in formula I a, C) and the compound of formula Reaction in the presence of an inert solvent nh2 -N — C == Ν Η (VIII) Η -17-

The size of this paper is in accordance with Chinese National Standard (CNS) Grade 4 (210X297mm) ........................., yes ... ............... ^ (Please read the notes on the back before filling out this page)

V. Description of the invention (16 produces compounds of formula Ia, Ib or IC, where R21, ruler 22 and ruler 23 are as defined in formula Ia, Ib or Ic, and if appropriate, D) use formula Ia , The bisphosphonate of the compound of I b or I c is converted into the corresponding bisphosphonic acid, or the compound of formula IV, where R5, R6, / and (as defined in formula〗 & E) and the compound of formula IX in Anti-numb in the presence of inert solvents (please read the precautions on the back before filling the nest page)

V II ο νη2C = ΝΗ installed Η

(I order 33 and R34 as printed by the Beigong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs to produce compounds of formula la, lb or Ic, where r31, r32, r are defined in formula la 'I b or Ic, and if appropriate, The bisphosphonate of the compound of formula Ia, Ib or Ic is converted into the corresponding bisphosphonate. The optimal process of item A) is to make the compound of formula in equal to the molar amount or three times the excess, if Where appropriate, in an inert solvent such as: dimethylamine (dms〇), dimethylformamide (foot) 1 benzene '(M)-alkanol, tetrahydrofuran (THF), dioxan or diethyl ether, and The compound of formula Han reacts with the addition of a base such as: carbonate, carbonate, hydroxide, triethylamine, diethylamine, or without the addition of a base to produce compounds of formula I 3, I 6 or 丨 c. The reaction temperature is -18-

This paper scale is applicable to the Chinese National Standard (CNS) Grade A (210x297 g U :: ί) 5537 Α6 Β6 Printed by the Employee Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy V. Description of invention () Approximately 25 ° C to 100 ° C, and When a solvent is used, a temperature between about 25 ° C and the boiling point of the solvent is preferred, specifically 70 ° C. The reaction time is 6 to 48 hours, preferably 12 to 24 hours. Whether the reaction is completed is determined by, for example, thin layer chromatography. When isolating and purifying compounds of formula Ia, Ib or Ic, the reaction mixture can be purified on a silica gel column using, for example, a mixture of eluents of ethyl acetate and alcohol (volume ratio 6: 1). The resulting compound of formula Ia, Ib or Ic can be converted into the corresponding bisphosphonic acid by hydrolysis (item B), for example: refluxing in concentrated hydrochloric acid, or in an anhydrous solvent, with strong acid or trimethyl silicate After the alkyl halide treatment, hydrolysis is carried out. The acetic acid solution containing anhydrous hydrobromic acid can be used directly or after appropriate dilution, or a solution of trimethylsilyl iodide in a solvent such as tetrachloromethane, dimethylformamide: chloroform or toluene can be used. Hydrolysis can be carried out by cooling or heating. For example, S can be reacted with trimethyl pyrocalyl halide while being cooled at a temperature of -10 ° C or below to obtain a partial hydrolysate. The starting materials of the preparation method A), the compounds melon and IV can be prepared in a simple manner according to the preparation methods known in the literature (EP 0 298 553; EP 0 416 499). The best process of the method C) is to make the compound of formula vm with an equivalent molar amount or a three-fold excess, if appropriate in an inert solvent, such as: dimethyl sulfa (dmso), dimethylformamide (DMF) , Toluene, -alkanol, tetrahydrofuran (THF), dioxan or ether, with the compound of formula IV, in the addition of bases such as potassium carbonate, sodium carbonate, potassium hydroxide, triethylamine, diethylamine, or not Adding the assay reaction produces compounds of formula Ia, Ib or IC. The reaction temperature is about 25 ° C to 100 ° C, and when a solvent is used, the temperature is preferably about 25 ° C to the boiling point of the solvent, specifically 70 ° C. The reaction time is 6 to 48 hours, packed in 12-19 -................................................. ......... Line (please read the precautions on the back before filling in this page ~ This paper size is applicable to the Chinese National Standard (CNS) A4 specifications (210X297 mm) A6 B6 V. Invention description (iS) It is preferably up to 24 hours. For example, thin-layer chromatography determines whether the reaction is complete. When isolating and purifying the compounds of formula Ia, Ib, or Ic, the reaction mixture can be placed on a Glue column, using, for example, ethyl acetate It is purified with a dissolution mixture of alcohol (volume ratio 6: 1). The resulting compound of formula Ia, Ib or Ic can be converted into the corresponding bisphosphonic acid by hydrolysis (item D), for example: in concentrated hydrochloric acid Heated at medium reflux, or treated with strong acid or trimethylsilyl halide in an anhydrous solvent, and then hydrolyzed. The acetic acid solution containing anhydrous hydrobromic acid can be used directly or after appropriate dilution, or it can be dissolved using trimethylsilyl iodide Such as a solution in solvents such as tetrachloromethane, dimethylformamide, gasform, or toluene. Hydrolysis can be carried out by cooling or heating, for example: ester can be combined with trimethylsilyl Compound reaction, while cooling at a temperature below -10 ° C · ^, to obtain a partial hydrolysate. Preparation method C) The starting material, compound IV can be prepared in a simple manner according to the preparation method known in the literature (EP 0 298 553; EP 0 416 499). The compound of formula

0 Pack .................... Order ............... Thread (please first Read the notes on the back and fill in this page) Printed by the Peking Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs and prepared by reaction with guanidine, where R1 to R3 are as defined above, and L is a free radical for easy nucleophilic substitution. Activated acid derivative of formula Π, where L is alkoxy, methoxy, benzene-20- This paper scale is applicable to China National Standard (CNS) A 4 specifications (210x297 mm). Printed by the consumer cooperative A6 B6 V. Description of the invention (19) Oxycarabine 'Benshuyl' methylthio, 2K thio, nitrogen heterocycle, preferably based on the method known per se The basic carbonyl chloride (formula Π, L = C1) is prepared, and the latter is prepared from the basic carboxylic acid (formula Π, L = 〇H) in a manner known per se, for example, by reacting with sulfite gas. In addition to formula π complexyl chloride (α = α), other activated acid derivatives of formula Π can also be prepared, which are prepared directly from their basic benzoic acid derivatives (formula Π 'L = 0H) in a known way 'For example, when preparing methyl ester of formula Π, when L = 〇CH3, it is treated with methanol solution of HC1 gas, when preparing formula Π imidazolide (imidazolide)' is treated with carbonyl diimidazole (η-imidazolyl, history Tower (staab), Angew, Chem. Lnt. Ed Engl, 丨, Be-367 (1962)), in the preparation of mixed acid fiber Π 'in the presence of diethylamine. In an inert solvent, with C1-C〇 (X: 2H5 or toluenesulfonyl chloride treatment, and the activation of benzoic acid, with dicyclohexylcarbodiimide (DCC) or with 0 _ [(cyano (ethoxycarbonyl) methylene) amine] -U, 3,3-tetramethyl uraldehyde painted tetrafluoroborate (__τοτυ ") treatment (Weiss and Krommer, Chemiker Zeitung 98, 817 (1974)]. Many are suitable for the preparation of formula Π The method of activating carboxylic acid derivatives is described in J. March's 咼 级 organic chemistry, 3rd Edition (Qianweili Father and Son Press, 1985) (J. March, Advanced Organic Chemistry, T hird Edition (John Wiley & Sons, l985) page 35, which indicates the source of the document. The reaction of the formula II activated retinoic acid derivative with guanidine is in a protonic or aprotic polarity, but inert, in a manner known per se In organic solvents. At this point, it has been confirmed that methanol or THF is suitable for the reaction of methyl benzoate (Π, L = OMe) with guanidine at a temperature between 20 ° C and the boiling point of these solvents. Most Compound E and non-salt guanidine should be in aprotic inert solvents, such as: -21-............................. .................................................. ........ installed .............. tr .......................... line {please Please read the precautions on the back before filling in this page.) The paper size is suitable for China National Standard (CNS) Grade 4 (210x 297 Gongmeng) A6

Printing of THF by the Zhengong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, Dimethoxyethane: ^ Dioxo Luzhong. However, when the reaction of π is used, for example, as a solvent, for example, the integrated ant's tree fairy water 0. If L--C1, it is advisable to add an acid absorbent, for example, in the form of excess guanidine, combined with hydrogen acid. .. Some basic benzoic acid derivatives of formula II are known and described in the literature. Known compounds of formula Π can be prepared according to methods known in the literature. The traitor of formula Π or its vinegar (for example: .L = —〇H or —〇_ 曱 基), where R is halogen or R is schottky, is a versatile starting compound, other formula carboxylic acids can be used without synthesis Among them, the element in the R2 position is easily replaced by many kinds of nucleophilic reagents such as phenol, or the alcohol R4-CnH2n-OH or its metal-detecting salt in a manner known per se to form the corresponding benzoic acid derivatives. Nitro can also be reduced to the corresponding amino benzoic acid, through the Sandmeier or Ulmann reaction, to form the desired compound, in particular, the benzoic acid derivative substituted by . In many cases, Friedel-Crafts catalysts can also be used for direct functionalization in a manner known per se to introduce gas, gas, or water into specific benzoic acid. Method E) The best process is to make the compound of formula JX equal to a molar amount or a three-fold excess, if appropriate in an inert sword such as: dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), toluene, (CrC4) -alkanol, tetrahydrofuran (THF), dioxan or ether, and the compound of formula IV, with the addition of alkali such as: acid breaking but sodium carbonate, potassium hydroxide, triethylamine, diethylamine, or The reaction without addition of base produces compounds of formula Ia, Ib or IC. The reaction temperature is 22-This paper scale is applicable to the Chinese National Standard (CNS) A 4 specifications (210x297 degrees 7 (please read the precautions on the back and then fill out this page). 装 * ^ τ Fifth, invention description (fifth, invention Description (printed by the Beigong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs and when using a solvent, at a temperature between about 25 ° C and the boiling point of the solvent), preferably at a temperature of 7 {rc. The reaction time is 6 to 48 Hours, with 12 buttons :: time is better. (Iv) Determine whether the reaction is complete if the thin layer riding method can be used on the reaction mixture 1 and 2 columns when using compounds of formula 1 a, 16 or 1 ^, for example · Ethyl acetate and alcohol (volume ratio: 6 ·· 1) are purified by the separation of the compounds. The resulting formula is a,〗. The decomposition of the compound is converted into the corresponding bisphosphonic acid (preparation method), for example: Yu Con After heating, or after using strong acid or trimethylheteroyl in an anhydrous solvent, hydrolyze it. The acetic acid solution containing anhydrous hydrodesic acid can be used directly or after appropriate dilution, or it can be dissolved in trimethyl residues such as 4 Chloromethylformamide 1 imitation or toluene and other solvents ^ solution hydrolysis can be cold Or heating, for example: the ester can react with the trimethylsilyl compound, while hydrolysing the product at a temperature of _1glxt. The starting material is prepared by Qiao I cut, prepared, item E), the compound Bei Ke can be prepared according to known methods in the literature. It is prepared in a simple manner (ΕΡ 〇298 553; £ Ρ 0 416 499). The compound of formula K can be prepared in a known manner (DE 43 26 〇〇55). The present invention also relates to containing at least an effective amount of at least one formula ja, Worker b or I c compound and / or formula ja, j or b. Physiologically acceptable compounds and auxiliary substances and excipients, diluents and / or other that are physiologically acceptable and physiologically tolerable Active substances. The present invention also relates to the use of formula Ia, 113 or 1 (; compounds and / or their physiologically tolerable salts in the production of drugs for the prevention and treatment of degenerative diseases of the skeletal system. 23 (Please read the back Please note this page again. Binding. Binding-line. The paper size is suitable for the country's Η specifications m〇X297 male dragon) A6 B6 22 '5. Description of the invention (The present invention also relates to compounds of formula h, IbiUc and / Or its physiologically tolerable (salt can be used in production treatment and bone resorption The pathological determination of ^ metastatic bone cancer 'Bertrand's disease' hyper-emia or osteoporosis drug use. The drug according to the present invention can be percutaneously, transdermally, intranasally, intravenously 'intramuscularly 'Intraperitoneal' skin τ 'intra-arterial, peripheral arterial, intrarectal or oral administration. The production of the medicament according to the present invention for the prevention and treatment of osteoporosis consists of at least one compound of formula 1a, ΪΙϊ or Ic and / or It is a physiologically tolerant substance and, if appropriate, is converted into a suitable dosage form together with auxiliary substances and / or excipients. Auxiliary substances and excipients are derived from the group of carriers, preservatives, and other conventional auxiliary substances . The compounds of formula Ia, Ib or Ic can be used alone or in combination with medical auxiliary substances in this case, specifically in veterinary medicine and human medicine. The auxiliary substances suitable for the required pharmaceutical preparations are those of the relevant technical experts based on their professional knowledge. In addition to solvents, gel formers, suppository bases, 'bonding agent auxiliary substances, and other active substance carriers, for example, antioxidants' dispersants 'emulsifiers, antifoaming agents' fragrances, preservatives, dissolving agents or pigments can also be used . The form for oral administration is a mixture of active compounds and additives suitable for this purpose, such as excipients, stabilizers, or inert diluents, and converted into suitable dosage forms such as tablets, coated tablets, according to conventional methods Hard gelatin capsules, aqueous' alcoholic or oily solutions. An example of an inert carrier that can be used is gum arabic 24 --.......................................... ............................................. installation .. .................................................. line ... (please read the back page first Matters needing attention and refill this page) The standard of private paper printed by the Employee Consumer Cooperative of the Ministry of Economic Affairs of the Ministry of Economic Affairs is applicable to the home standard Bijia 4 specifications mQx297 ^^) A6 B6 Printed by the Beigong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy (1. Magnesium oxide, sulfonium carbonate, potassium phosphate, lactose, dextrose or dextrose, especially corn starch. The products of such preparation methods can be dry granules and wet granules. Examples of suitable oily excipients or solvents are vegetable oil or animal oil , Such as Mohua oil or cod liver oil. For subcutaneous or intravenous administration, if necessary, the substances used for this purpose such as: dissolving agents, emulsifiers or other auxiliary substances can be used to convert the active compound into a solution, suspension or emulsion Examples of suitable solvents are: water, physiological saline or alcohols, such as ethanol, propanol, glycerin, and sugar solutions, such as glucose or mannitol solutions, Mixtures of the above-mentioned solvents. Examples of pharmaceutical formulations suitable for administration in the form of aerosols or sprays are active substances of formula Ia, Ib or IC contained in a pharmaceutical acceptable solvent such as ethanol or water in specific terms, or Solutions, suspensions or emulsions in a mixture of these solvents. If necessary, the formulation may also contain other medical auxiliary substances such as surfactants, emulsifiers and stabilizers, and propellant gases. Active substances in such products The content concentration is usually 0.1 to 10, specifically 0.3 to 3% by weight. Agent gas. The content concentration of the active substance in such products is usually 0.1 to 10, specifically 0.3 to 3% by weight. Formula I a, I b or I c The dosage and frequency of administration of the active substance depends on the efficacy and duration of the compound used; it also depends on the nature and severity of the condition to be treated, and the sex, age and weight of the mammal or human being to be treated The dosage depends on many factors, such as the dosage form of the drug, the pathological condition of the patient, body weight and severity. However, about 5000 per day Gram. The dose of the drug according to the present invention should only be temporarily exceeded. -25- Pack ..................... Order ... ............. Line (please read the precautions on the back before filling the nest page) This paper size is applicable to China National Standard (CNS) A 4 specifications (210x297 mm)

Description of the invention (printed by the Beigong Consumer Cooperation Department of the China Bureau of Standards, Ministry of Economic Affairs. For humans weighing 70 kg, the daily dose is 10 to 25,000 mg. It is more consistent with the daily dose of the drug according to the present invention. The drug is administered twice or divided into small doses. It is better to administer 3 to 8 times a day. The following examples illustrate the present invention in more detail. Unless otherwise stated, the eight ratio data refers to the volume%., Is Example 1, 2-[(3- Preparation method of mesylate_4_hexahydropyridinebenzyl Haminoiminemethylamino] ethane-U-bisphosphonic acid tetraethyl ester 3.24 g (10 mmol) ( 3-Methanesulfonyl_4_hexahydropyridylbenzyl)-(aminoiminomethyl) amine and 3.0 g (1Q mmol) of tetraethylethenediphosphonate dissolved in 4 ML of anhydrous tetrahydrofuran. To this was added 0.5 g (3.6 mmol) of anhydrous potassium carbonate, and the mixture was heated to boiling hours under a protective gas. Subsequently, 0.33 g (2.4 mmol) of potassium carbonate was added, The mixture was heated to boiling for 2 hours. The reaction mixture continued to be stirred at room temperature for 6 hours. Filtration and removal of the solvent produced 4.5 g of crude material. . Analysis of the upper gel column using the eluent containing 10% of ethanol, acetic acid acetic cool ethanol Yield: 3.2 g (52% of theory Zhi) said

Melting point: 148 to 152 ° C 31P-NMR spectrum: (CDCl3) 5P = 21.77ppm Example 2 2-[(3-Methacryl-4-hexahydropyridine-benzylamide (aminoiminomethyl ) 26, ............................................... .................................................. ..........., 11 ............ ί 犄 first read the precautions on the back and then fill this page) i paper standard universal ta ϋ home standard $ ( cns 丨 A4 specifications (21Gx297 public love * " " ----------------- 一 — A6 B6 Central Standards Bureau of the Ministry of Economic Affairs®: Printed by Industrial and Consumer Cooperatives V. Inventions Explain the preparation method of (amino) ethane-1,1-bisphosphonic acid so that 1.5 g (2.4 mmol) of 2-[(3-methanesulfonyl-4-hexahydropyridinebenzylamide from Example 1) )-(Aminoiminomethyl) amino] ethane-1,1-bisphosphonic acid tetraethyl ester was dissolved in 60 ml of anhydrous dioxane at 60 ° C. The reaction mixture was then allowed to return to room temperature , 1.64 g (10.8 mmol) of bromotrimethylsilane was added. The mixture was stirred at room temperature for 16 hours and then heated at 60 ° C for 4 hours. The solvent and volatile substances were removed at 40 ° C / 0.1 ° C. Then add 15 ml of water to the residue, The mixture was stirred at room temperature for 4 hours. The resulting residue was filtered and washed several times with ethanol. The resulting residue was boiled in 20 ml of methanol and 10 ml of water. Yield: 460 g (38% of theory) * r, .

Melting point: 209 ° C 31P-NMR spectrum: (Na0D / D20) 19.13ppm Example 3 2-[(3,5-dichlorobenzyl)-(aminoiminomethyl) amino] ethane- U-bisphosphonic acid tetraethyl ester is prepared by making 650 mg (2.4 mmol) (3,5-dichlorobenzyl)-(aminoiminomethyl) amine and 730 mg (2.4 mmol) Tetraethyl vinyl bisphosphonate was dissolved in 30 ml of toluene and 6 ml of dimethylformamide (DMF). 0.17 g (2.4 mmol) of anhydrous potassium carbonate was added thereto, and the mixture was heated to slump for 21 hours. The reaction solution was then filtered and concentrated in a rotary evaporator. 1.8 g of crude product was obtained. The material was purified on tapping tube columns. Use propanol as the eluent. Yield: 450 mg (35% of theoretical value) -27- ..................-: ............... ............................................. installation .. ....... TΓ line (please read the precautions on the back before filling in this page) This paper uses the National Standard (CNS) A4 specifications (210X297 mm) of the paper 295587 A6 B6 Central Bureau of Standards, Ministry of Economic Affairs Printed by Beigong Consumer Cooperative V. Description of the invention (26) Melting point: 146 to 149 ° C 31P_NMR spectrum: (CDCl3) 21_73ppm Example 4, 2-[(3,5-dichlorobenzyl)-(amino sub Aminomethyl) amino] ethane-1,1-bisphosphonic acid is prepared so that 350 mg (0.62 millimoles) of 2-[(3,5-difluorobenzyl)-(aminoiminomethyl Group) amino] ethane-U-bisphosphonic acid tetraethyl ester dissolved in 20 ml of acetonitrile. Under argon, 0.3 g of sodium iodide and 0.41 ml (3.10 mmol) of bromodimethylsilane were added. The mixture was stirred at room temperature for 16 hours, and then stirred at 40 ° C for 1 hour. Subsequently, the sodium bromide formed was filtered, and the mother liquor was freed from solvents and volatile substances at 40 ° C / 0.1 ° C. Add 20 ml of dichloromethane to the residue and filter the solid formed by suction filtration again. Exclude dichloromethane at 40 ° C /0.1 ° C. Then 15 ml of water was added and the mixture was sandalwood mixed at room temperature for 15 minutes. Drain water at 60 ° C / 12 degrees. Add 10 ml of isopropanol to the resulting residue and add about 1 to 2 ml of water. The mixture was heated for 5 minutes. After cooling, the colorless crystals were filtered by suction and dried under 12 dolmens. Yield: 170 mg (60%) Melting point: 267 ° C 31P-NMR spectrum: (Na0D / D20) < 5 31P = 19.09ppm iH-NMR spectrum: 28-^ ... ................................................ (Please read the precautions on the back before filling in this page) The paper scale is in accordance with Chinese National Standard (CNS) A4 specifications (210x297 mm) A6

Printed by Beigong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of invention (27) (Na0D / D20) δ = 1.90 (tt, 2JPB-14 H2, A „6 Hz, 1H); 3.48 (td, 3jm» 14 HZ | 3Jm β 6 Hz, 2H); 7.45 (s, 1H); 7.54 (sf 2H). 31C-NMR spectrum: (Na0D / D20) δ = 43.8 (Cl); 44.1 (c-2); 129.9 (〇-3Ί; 133.0 (C-4); 136.7 (0-5 / C-5Ί; 142.0 (C-6); 162.5 (C-Gua); 174.9 (C = 〇). MS: m / e = 419 Example 5 methyl-2-indolecarbonyl) _ (amine, iminomethyl) amino] ethane_ 丨, bisphosphonate tetraethyl acetate> — make ι · 〇 g (3.9 mmol) _Methyl_2_indolecarbonylguanidine hydrochloride and 12 g (4 C mol) of ethyl triethylpyrrolidone; contained in 40 ml of tetrahydrofuran (thf) and 15 ml of dimethyl To formamide (DMF). To this was added 055 grams (4 millimoles) of anhydrous potassium carbonate, and the mixture was heated to boiling for hours. The reaction solution was then filtered and concentrated in a rotary hair dryer. 20 grams of crude product were obtained. The material was purified on a Zhenjiao column. Ethanol was used as the eluent. Yield 7 g (70% of theoretical value) 31p-NMR spectrum: (CDC13) 5 = 21.98ppm Example 6 2-[(1-methyl-2 _Hui Duo (Slow base)-(aminoiminomethyl) amino] ethane_u_ -29- --................................ .................................................. ............. installed ...................... ordered ............. ........ Line (please read the precautions on the back before writing this page) _The paper size is suitable for 4 China® home standard A4 specifications (210 > < 297 g *) A6 B6 Central Ministry of Economic Affairs Printed by the Bureau of Standards and Staff Consumer Cooperative V. Description of the invention (28) The preparation method of bisphosphonic acid is such that 1 gram ((1.8 millimoles) 2-[(1-methyl-2-indolecarbonyl)-( Aminoiminomethyl) amino] ethane-U-bisphosphonic acid tetraethyl ester was dissolved in 40 ml of acetonitrile. Under argon, add 0.6 g of mechanical fishing and 1.2 ml (90 mmol) Ear) Bromotrimethylsilane. After the mixture was stirred at room temperature for 16 hours, it was stirred at 40 ° C for 1 hour. The sodium bromide formed was filtered and the solvent was removed from the mother liquor at 40 ° C / 0.1 Duo. And volatile substances. Add 2◦mL of methane gas to the residue, and suck and filter the solid again. Remove methylene chloride at 40 ° C /0.1°. 15 ml of water was added, and the mixture was stirred at room temperature for 15 minutes. Drain water at 60 ° C / 12 degrees. Add 10 ml of isopropanol to the resulting residue and add about 1 to 2 ml of water. The mixture was heated for 5 minutes. After cooling, suction through the colorless crystals, and dried at 12 Duo. Yield: 300 mg (38%) 31P-NMR spectrum: (Na0D / D20) 5 31P = 18.07ppm iH-NMR spectrum: (Na0D / D20) δ > = 1.98 (tt, aJPH = 14 Hz, 3Jhh = 6 Hz, 1H); 3.65 (td, 3JPH »14 Hz, 3Jhh = 6 Hz, 2H); 7.08 to 8.56 (aromatic Er 5). 13c-nmr spectrum: (Na0D / D20) δ = 32.5 (Cl); 41.8 ( C-2); 41.9 (C-3); 103.2 (C-4); 105.2 (C-5); 120.2 (C-6); Ϊ22.0 (C-7); 124.1 (C-8); 126.2 (C-9); 137.8 (C-10); 139.2 (C-ll); 139.7 (C-12); 160.8 (C-Gua); 172.2 (C = 0). —30 — Pack ... ............ Order .................. 'line (please read the notes on the back before filling this page) Use the Chinese National Standard (CNS) A4 specifications (210X297 mm> V. Description of the invention (29) A6 B6 Printed MS by the employee consumer cooperative of the Central Bureau of Economic Affairs of the Ministry of Economic Affairs: m / e-419 Example 7 2- [ (3-Methanesulfonyl-4-phenoxyphenmethyl)-(aminoiminomethyl) amino] ethane-U-bisphosphonic acid tetraethyl ester is prepared as described in Example 1, using 1.8 G (4.86¾ mol) (3-methylbenzyl-4-phenoxybenzyl)-(aminoiminomethyl) amine and 1.46 g (4.86 mmol) of vinyl diphosphonic acid tetraethyl Backlash The substance was chromatographed on a crushed rubber column. Using ethyl acetate: acetone = 1: 1 as the eluent. Weight: 800 mg (26%) Melting point: 145 ° C 31P-NMR spectrum: (CDC13) δ 31P = 22.10ppm NMR spectrum: (CDC13) δ = 1.35 (t, 12H); 3.31 (s, 3H)? 4.0 (me, 2H); 4.20 (me, 9H); 6.88 (df 1H); 7.13 (me, 2H) ; 7.24 (me, 1H); 7.42 (me, 2H); 8.35 (d, 1H); 8.89 (s, 1H) ppm. 13C-NMR spectrum: -31 — Pack ......... -............... Order ..................... line (please read the precautions on the back before filling out this page) Applicable to China National Standard (CNS) A4 specifications (210X297 mm) A6 B6 Printed by the Beigong Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs V. Description of Invention (3Q) (CDCI3) δ = 16.43; 29.30; 37.89; 43.36; 53.87; 63.14; 117.25; 120.36; 125.33; 129.72; 130.25; 155.06; 157.82; 175.0 ppm. Example 8 2-[(3-methylsulfonyl-4-N, N-diethylaminobenzyl)-(amine Iminomethyl) amino] ethane-U-bisphosphonic acid tetraethyl ester is prepared as described in Example 1, so that 1.0 brother (2.9 millimoles) (3-methanesulfonyl-4-N, N -Diethylaminobenzyl)-(aminoimine Yl) amine and 0.9 g (2.9 mmol) of ethylene diphosphonic acid tetraethyl ester reaction. The material was chromatographed on a silica gel column. Use ethyl acetate: acetone = 1: 2 as the dissolution solution. -Yield: 1_2 g (66.6%) Melting point: 121 ° C 31P-NMR spectrum: (CDC13) (5 31P = 22.12ppm ^ -NMRT ^ tf · '(CDC13) δ = 1.07 (t, 6H); 1.35 ( t, 12H); 3.18 (q, 4H); 3.34 (s, 3H); 3.98 (me, 2H); 4.20 (me, 9H); 7.32 (d, 1H); 8.36 (d, 1H); 8.92 (s , 1H) ppm. 13C-NMR spectrum: (CDC13) δ = 12.09; 16.38; 38.20; 42.59; 48.37; 63.34; 124.46; 137.21; 136.99; 153.34; 175.64 ppm. —32 — Ling ... .............- ΤΓ .................. line (please read the precautions on the back before filling the nest page) this The paper scale uses the Chinese National Standard (CNS) A4 specification (210x297 mm). V. Description of the invention (31) A6 B6 Example 9 2-[(3-〒 縒 縒 基 -4-Phenoxybenzoyl) -(Aminoiminomethyl) amino] ethane-1,1-bisphosphonic acid_ As described in Example 2, 35 mg (0.55 millimoles) 2 _ [( 3-Methanesulfonyl-4-phenoxybenzyl)-(aminoiminomethyl) amino] ethane-U-bisphosphonic acid tetraethyl ester. After hydrolysis with 40 ml of water The product was filtered with suction and washed with 30 ml of acetone. Yield: 150 mg (52.4%) Melting point: 242 ° C 31p-nmr spectrum: (NaOD / D2〇) 5 31P = 17.65ppm iH-NMR spectrum: (Na0D / D20) δ = 2.04 (ttf IB); 3.50 (s, 1H); 3.65 (td, 2H); 7.06 ( d, 1H); 7.26 (d, 2H); 7.38 (me, 1H); 7.54 (me, 2H); 8.20 (me, 1H); 8.55 (m, 1H) ppm. Pack ... ..! Order: .................. Line {Please read the precautions on the back before filling in this page) Printed example of the employee consumer cooperative of the Central Bureau of Economic Affairs of the Ministry of Economic Affairs 10 2-[(3-Methanesulfonyl ~ 4-N, N-diethylaminobenzyl)-(aminoiminomethyl) amino] ethane-U-bisphosphonic acid by example 2 described, so that 600 mg (〇.92 millimoles) from Example 8 2-[(3- -33- This paper scale is applicable to China National Standards (CNS) A 4 specifications (210x297 mm) V. Description of the invention (32 A6 B6 Methanesulfonyl-4-N, N-diethylaminebenzyl)-(aminoiminomethyl) amino] ethane-U-bisphosphonic acid tetraethyl ester reaction. After hydrolysis with 30 ml, the product was filtered with suction and mixed with acetone. Yield: 483 mg (100%) Melting point: 181 ° C '31P-NMR spectrum: (Na0D / D20) δ31P = 17.70 ppm (2JPH «20.9 Hz; 3Jph = 14.2 Hz) ifi-NMR spectrum: (Na0D / D20) δ = 1.03 (t, 6H); 2.11 (tt, 1H); 3.12 (q, 4H); 3.53 (s, 3H) J 3.65 (td, 2H)? 7.58 (d, 1H); 8.26 (mcf 1H); 8.58 (m, 1H) ppm. Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. Example 11 The activity of the compound according to the present invention was demonstrated in vitro according to the following experiment. Analysis of the 45 Ca released from the skull of a 20-day-old embryonic rat Decide on bone resorption. Two days before the dissection of the embryo skull, 200 / Z Ci / Kg45CaCl2 $ was injected into the body of the pregnant mouse to mark the bone with 45 Ca. 1. Bone culture The embryo skull is cut in half, half of the skull is used as a control group, and the other half is cultured with the compound according to the present invention. Each half of the skull is cultured in sterile plastic plates. Medium (BGJb medium, Gibco) — 34 — Pack ............................................ ............. ^ (Please read the precautions on the back before filling in this page) This paper scale is applicable to China National Standard (CNS) A4 specifications (210x297mm) A6 B6 V. Invention Description (33) Contains 10% fetal bovine serum, penicillin / streptavidin (100,000 units / liter, Chibuco) and ascorbic acid (50 mg / liter). The halved skull was incubated at 37 ° C in a gas containing 5% 0 2 and 95% 0 2. After 48 hours, the cultured medium was replaced with fresh medium, the compound according to the present invention and parathyroid hormone (HΓ7Μ) were added, and the culture was continued for 48 hours. Parathyroid hormone (10_7 Μ, Sigma) was added to the control group. At the end of the experiment, the 45Ca in the culture medium and bones was measured. The results in Table 1 show the percentage of inhibition of 45 Ca release into the medium. The result is an average value of 3 to 5 experiments. Table 1: Concentration of products inhibiting the release of 45Ca. Product concentration 10 1io " 8m io_6m Example 4 7% 21% Example 6 22% 29% Example 9 22% 21% Not tested ... ............- ΤΓ .................. ^ (Please read the precautions on the back before filling this page) Economy Printed by the Employees ’Consumer Cooperative of the Central Standards Bureau of the Ministry of Foreign Affairs — 35- This paper scale is applicable to the Chinese National Standard (CNS) Grade 4 (210X297 mm)

Claims (1)

Application for Patent Scope Patent Application No. 83100925 ROC Patent Appln. No. 83100925 Amended Claims in Chinese Scope 1 Annex 1 Amended Claims in Chinese — Enc 1. I Ί: Shigu M 10 U Month 27 U reach the main J I- -('S ^ jinniLted on November., 1995) 丨 Xiu Τ'84Ιί 1. Anniversary B;; Supplement (1. Tautomeric compounds of formula la, lb, or Ic o: R o RH c 'INIH Η I ΝΠ c .NIHI cno p H c R p VR oao R o N 1 c Η o I R (lb) --------- ^ ------ 、 玎 ------ @ (Please read the precautions on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs RNIH-c Π o H c I 2 NH m NIC ο Π p H c Η o-36 — R o R o R o R o This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 11 12 A8 B8 C8 D8, the scope of patent application and / or its physiologically tolerable salt; where R has the following definitions: I) as the basic V of formula V) where R11 Table-S〇2- (Ci-C6 ) -Alkyl group, and R12 represents a phenoxy group, a hexahydrocracker group or N ((Gl_Ce) _hyunyl) 2 H) such as the group VI of formula VI I------ I · 1.1.1 — -I— i I--1 I 2 · Shi-In H (Please read the notes on the back before filling this page) * 1T (VI) where R21, R22 and R23 independently represent hydrogen or a functional element; melon) a group VI of formula νπ!) Where Y is N (Ci-C6) -alkyl; R5, R6, R7 and R8 is the same or different and is independently a hydrogen atom or (Cl-C4) -hyunyl. _ 37.- This paper scale is applicable to the Chinese National Standard (CNS) Α4 specification (210Χ297 mm) Printed by the Ministry of Economy Central Standards Bureau Employee Consumer Cooperative 298587 -------- Applicable patent scope ABCD 2. If applying for a patent The compound of item 1 in the scope is selected from any one of the following: 2-[(Bumethyl ~ 2-Indolecarbonyl)-(aminoiminomethyl) amino] ethane-U-bisphosphonic acid tetraethyl Ester '2-[(Bumethyl-2-indolylcarbonyl) — (aminoiminomethyl) amino] ethyl pit • -Ι, Ι-bis-teng acid, 2-[(3-methylglucoyl -4-hexahydrop is better than bitten benzyl)-. (Aminoiminomethyl) amino] acetone-1,1-bisphosphonic acid, 2-[(3-methanesulfonyl-hexahydro Pyridinebenzyl)-(aminoiminomethyl) amino] ethane-1,1-bisphosphonic acid tetraethyl ester, 2-[(3,5-dichlorobenzyl)-(amine Iminomethyl) amino] ethene-1, tetraethyl ethyl bisphosphonate, and Diqimeng methyl group)-(aminoimine methyl Γ) amino] ethane-1, bis bis Phosphine Aya. 3. A method for preparing a tautomeric compound of formula I a 'I b or I c according to item 1 or 2 of the scope of the patent application, which includes: using compound IV of the formula IV R7 〇- R IV C II C ^- -----II------.il (please read the precautions on the back before filling in this page) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs \ p ___ 〇— Rb 丨 丨 \ 〇— R6 0 R5, R6, R7 and R8 are as defined in item 1 of the patent application scope. A) Reaction with formula melon compounds in the presence of inert solvents 38.- This paper scale is applicable to China National Standard (CNS) A4 specifications (2 丨0X297mm) apply for patent siege C II 0 AS B8 C8 D8 nh2 N — C = NH produces compounds of formula Ia, Ib or Ic, where as defined in formula JJ.b or Ic, and if appropriate, B) makes formula Ia ' The bisphosphonate of I b or IC compound is converted to the corresponding bisphosphonate, or, the compound of formula IV, where FT5, R6, R7 and R8 are as defined in formula 3, C) and the compound of formula Xinjiang in an inert solvent React in the presence of 2 1 nh2N — C- N Η VIII The Ministry of Economic Affairs Central Standards Bureau employee consumer cooperative printed and produced the compound of formula I a, I b or IC, where r21, R22 & R23 are as defined in formula a, I b or I c, and if Where appropriate, D) convert the bisphosphonic acid of the compound of formula I a 'I b or I, c into the corresponding bisphosphonic acid, or the compound of formula IV, where R5, R6' R7 and R8 are as in formula I a Definition E) React with the compound of formula K in the presence of an inert solvent ------------ installed ------ order 丨 ----- line (please read the notes on the back first (Fill in this page again) 39.- This paper scale applies the Chinese National Standard (CNS) A4 specification (210X297 public daughter) 8 8 8 8 ABCD 295587 VI. Scope of patent application NH, IC = NH (IX) produces a compound of formula la, lb or lc, where γ has the definition as in formula 丨 a, 丨 dagger or 丨 c, and if appropriate, F) makes formula I a, I b or The bisphosphonate of the I Hb compound is converted to the corresponding bisphosphonate. 4. A pharmaceutical composition for the treatment and prevention of degenerative skeletal lesions, which contains an effective amount of at least one tautomeric compound of the formula 1, a, lb or lc, as claimed in item 1 of the patent application, and / or at least A physiologically tolerable salt of a tautomeric compound of formula 丨 a, lb or lc, and pharmaceutically acceptable and physiologically tolerable auxiliary substances, and / or excipients, diluents and / or other Active substance. ----------- installed ------ order nickel (please read the precautions on the back before filling this page) Printed by the Ministry of Economic Affairs Central Standard Falcon Bureau Employee Consumer Cooperative -40.- This paper The scale is applicable to China National Standard (CNS) A4 specification (210X297mm)