TW458963B - 2,3,5,6-tetrahydro-benz[e]azulen derivatives inhibiting the binding of vitronectin receptor Α v β3 or other integrins having vitronectin as ligand to their natural ligand, their preparation process and the pharmaceutical compositions - Google Patents

Abstract

The subject of the invention is the products of formula (I): in which R1, R2, R3, R4, R5 and G are as defined in the description, the dotted lines represent an optional second bond, as well as the addition salts with acids and bases and the esters, their preparation process and the intermediates of this process, their use as medicines and the pharmaceutical compositions containing them.

Description

458963 Λ7 B7 Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs Μ

• N- ~ G V. Description of the invention (I) The present invention relates to a novel tricyclic compound ', a method for producing the same, and an intermediate of the method, its use as a medicine, and a pharmaceutical composition containing the same. 'Prior Technical Information U.S. Patent No. 5,430,020 discloses a tricyclic benzodiazepine derivative that has an activity to inhibit fibrinogen binding to the G P I I b I I I a receptor. U.S. patent U S 5 6 0 2 1 7 3 discloses cyclohexyl-phenyl derivatives which can be used as inhibitors of phosphodiesterase IV. The compounds of the present invention are structurally and primarily biologically active (as vitronectin receptor antagonists in vitro) different from these prior art compounds. Detailed description of the present invention One of the objects of the present invention is the compound Ry (I) of the general formula (I) .: a [B] —C 〇R 6, CH di CH-[: A]-[B]-C 0 R 6, (CHj) ”— [a]-[B]-C〇R, — 0 — [A! B; l-C 0 R — CHC 0-[A] — (B) —This paper is applicable to Chinese countries Standard (CNS) A4 specifications (^ 7 x 7 mm) -4-

In —--- 111-* equipment ---- 11--order ---- II I-* 5 ^ (please read the precautions on the back before filling this page) 45 89 63 A7 ________ B7 five 、 Invention note €) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs C 0 R 1 — f VA] Show — —. — —: Price smoke-m chemical base m its derivative L white-saturated and unsaturated The branch structure contains 1 to 1 2 protons and 1 to 6 white oxygen, nitrogen or sulfur: a heteroatom f — or a divalent group, which is derived from white — saturated or unsaturated, Straight or branched non-MMH hydrocarbon generation 1 containing 1 to 1 2 carbon atoms CB: phenyl 1 C Η rz) group »or single bond j Z shows — hydrogen, atom ί one of the following groups; (D ) 0 6 NR a R b ϊ (D) 0 6 — Ν Η — S 〇2-'RC ϊ (D) 0 -6 — Ν Η-C 〇2 " 一 RC ΐ (D) 0 6 — Ν Η — c 0 — RC > (D) 0 —ei — I Η-s 0 丨 2 -N Η — RC, ( D) 0 e — Ν Η-c 〇 ·-Ν Η — RC > (D) 0 -6 — C 〇2--R 彳 Γ »(D) 0 —6 S 0 2 — RC t (D) 0 6 — C 0-R c or CD) C 1 6 —-RC where (D) 0-6 is a non-cyclic hydrocarbon containing 0 to 6 7 * Sm atoms derived from a white saturated or unsaturated straight or branched line R a > R b and R c represent — hydrogen atom 1 (C Η 2:) 〇 一 3 — A ι- 蕋 (—11: v-, middle A r shows — containing 6 to 1 Carbocyclic aryl group of 8 carbon atoms) 1 (Ο Η-) 0 —. (Η e 甚 even (Μ: Η 不 et al are differently saturated to unsaturated) · 7 or non-family /, I 7I 1 to 9 carbon atoms and 1 to 5 impurities The original paper size is applicable to China National Standard (CNS) A4 specifications (2) 0 * 297 mm) -5- I I--installation -------- order ---- --- I r line (Please read the precautions on the back before filling out this page) 4 5 8963 At noon (A): 86113S48 Chinese manual amendment page 円 Zhu Republic of China presented to the Intellectual Property Bureau of the Ministry of Economic Affairs in August 89 for consumption by employees Cooperation V. Description of the invention θ) f Λ r (selected from oxygen 'nitrogen or sulfur atom heterocycle), (ch2 A 1 K group (where A 1 k is not derived from a saturated or unsaturated, straight line , Branched or cyclic non-aromatic hydrocarbons containing 1 to 12 carbon atoms, η et, A! And A 1 k groups may be unsubstituted or substituted, or Ra and R b may be connected to them Nitrogen together shows a saturated or unsaturated, aromatic or non-aromatic helium heterocyclic ring 'which optionally contains one or more heteroatoms selected from oxygen, nitrogen or sulfur atoms' This group may be substituted or unsubstituted, —Re shows meridian, 0 — 厶 11 ^, 〇-octa 1 ′, 1 ″ 1112, 1 ^? 1-A 1 k 'N (A 1 k) 2 or the rest of L or D amino acid , A 丨 k and Ar are as previously defined and are arbitrarily removed or unsubstituted, -R2 and R3 are the same or different, showing a hydrogen atom, a radical, a 0-A1k group or 0- (CHs) 0- 3 — Ar group, A1 k and Ar as previously defined, or R2 and R3 — together form a ring of type 010 (CRdRe) η — 0 —, η represents an integer of 1 to 5, R d and Re are independent of each other A hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, or a phenyl group, —R4 represents a hydrogen atom Halogen atom, one of the following groups: hydroxyl, amine, nitro, cyano, CF3, fluorenyl or fluorenyl having 1 to 12 carbon atoms, alkyl, alkenyl, alkynyl, alkylthio, Alkoxy, alkylamino, dialkylamino, dialkylaminoalkyl, dialkylaminoalkoxy, wherein the alkyl group contains 1 to 6 carbon atoms, —R5 represents a hydrogen atom, a hydroxyl group, a halogen atom, 0 -A 1 k base or ◦ one (CHz). ― 3 — Ar-based, A 1 k and Ar are as defined above. — The basic paper size of G expression G 1 is applicable to the Chinese National Standard < CNS) A4 specification (210 χ 297 mm) nnn III n IIII n * — — — 1— ^ n * I u I n IE [r I (Please read the note i on the back before filling this page) 4 5 8 9 〇5 A7 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs B7 5. Invention Description $) —N — (Het1)

I

Rh wherein Rh is a hydrogen atom or an A 1 k group as previously defined and (Het <) is a heterocyclic ring of the following formula: -V > H > wherein (ii) and N = C-NH- units form a group containing 1 Rest of the mono- or bicyclic aromatic or non-aromatic heterocyclic ring to 9 carbon atoms and 2 to 5 heteroatoms selected from oxygen, nitrogen and sulfur atoms, this group may be substituted or unsubstituted, or NRaRb Group (G2 group), Ra and Rb are as defined above,-or (Het) group (G3 group) as defined above, or-NRh-C (= X)-NHRc group (G4 group), where X is sulfur or The oxygen atom or NH, Rh and Rc are as previously defined, or —NRh — S02Rc group (G5 group), in which the ruler and ^^ are as previously defined, the dashed line shows any second bond, and the Addition of salt and vinegar. One [A] One Show-a divalent group derived from a saturated or unsaturated, straight or branched acyclic hydrocarbon containing 1 to 12 carbon atoms and 1 to 6 selected from oxygen, nitrogen and sulfur Heteroatoms of atoms, in particular, mean derived from certain carbons by oxygen or sulfur atoms' or by the following groups: c = 〇 's ^' S〇2, NH, N (Aik), NH-CO , N (Alk) This paper size applies the national standard (CNS) A4 specification (210 x 297 public love)

------------ ^ · I ---- Order ------ — -line_ (Please read the note on the back before filling out this page) Staff Consumption of Intellectual Property Bureau, Ministry of Economic Affairs The paper size printed by the cooperative is applicable to China National Standard (CNS) A4 (210 x 297 mm) 458963

Sh S. 05 A7 ____________ B7_ V. Description of the invention < p) -CO > CO-NH c〇-N (A1 k), SO2-NH 'S〇2-N (Alk)', the group replaced, ( Alk) is as defined above. It can therefore be the following group: -CH2— CH2 — 0 -CH2-CH2-,-Ch2-CH2-N (CH3) -C Η a-C Η 2-'c Η 2-c Η 2-C (0 ) -CH2-CH2, CH2-C (〇) — c (Me) 2-CH2. When A shows a divalent group derived from a saturated or unsaturated, straight line or branched acyclic smoke containing 1 to 12 carbon atoms, it particularly means an alkylene of the formula-(CH2) η- Group, where 11 is an integer between 1 and 12, such as —CH2 — > --CH2CH2 — > — CH2CH2CH2 — or —CH2CH2CH2CH2- or alkenyl or alkenyl such as _CH = C Η — C Η 2 — Or —C ^ C — CH2 — a When these divalent groups are branched, they can be -CH (

C Η 3) — '-C (Me) 2 —, -CH2— C (Me) 2-, -CH (Et)-, -CH (C = CH) — or —c (C ξ CH) (Et) _ Group. When [B] TF-Ph-divalent group, COR6 may be in the ortho, meta or para position. It is preferably in alignment. When (D) Q-6 is a divalent group derived from a saturated or unsaturated, straight or branched acyclic hydrocarbon of 30 to 6 carbon atoms, (D) 16 is selected from the above [A] 値. (D). This means that this group does not exist-but again a single covalent bond. (D) is preferably a single bond or (CH2) η group, and η is an integer selected from 1, 2, or 3. When Ra, Rb and Rc show (CH2) 〇-3 — Ar, (0 " _____ ------- J Order -------- I (Please read the notes on the back before filling in this Page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs ^ 5 8 9 6 3 A7 B7 V. Description of the invention e) C Η 2) π-.1-H et '(CH2) 0—3-Alk base time, ( C))-γ is a single bond in the example of (CH 2) n, or -C Η 2-, — (CH-)) 2-or — (CH2) 3-. (AI ·) shows a carbocyclic aryl group containing 6 to 18 carbon atoms, meaning a group derived from an aromatic cyclic hydrocarbon such as phenyl, naphthyl 'phenanthryl or a fused benzene-containing group Cyclic bicyclic or tricyclic hydrocarbons, such as indanyl'indenyl, dihydronaphthyl, tetrahydronaphthyl or fluorenyl. The coupling takes place to the extent of a benzene ring. It is preferably a phenyl group. (Het) shows a group derived from a saturated or unsaturated, aromatic or non-aromatic heterocyclic ring containing 1 to 9 carbon atoms and 1 to 5 heteroatoms selected from oxygen, nitrogen and sulfur atoms, especially Means:-a monocyclic heterocyclic group, such as the following groups: thienyl, furyl, pyranyl, pyrrolyl, imidazolyl 1 pyrazolyl 1 pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl , Thiazolyl, oxazolyl, furaza, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, tetrazolyl,-fused heterocycles, such as benzofuranyl, Benzothienyl, benzimidazolyl, benzothiazolyl, naphtho [2,3-b] thienyl, thienanyl, isobenzofuranyl, chromenyl, glutenyl, phenoxathienyl ( phe η ο X athi η ny]), indolazinyl, isoindolyl, 3 Η —indolyl, indolyl, indazolyl, purinyl, quinazinyl, isolinolinyl, quinolinyl , Phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, sulfonyl, pteridinyl 'carbazolyl, monocarbinyl, acridine S, phenazinyl, phenothiazinyl, Phenomenal feeding, ind Porphyrinyl, isoindolyl, imidazopyridyl, imidazopyrimidine, or a fused polycyclic ring system consisting of a single heterocyclic radical defined by IΊ ', such as 炚 _ 炚 [2' 3-b: 1 Pyrrole or thieno [2,3-b This paper size applies to the SE § standard (〇 奶) VIII.1 specifications (2) 0 > ^ 97 mm) .Q. I · 装 ---- ί · Order --------- line (please read the precautions on the back before filling in this page> 45 89 6 3 A7 ____B7__ V. Description of the invention): Furan II South,-or saturated heterocyclic group • Groups such as pyrrolidine, piperidine 1 morpholine. (Please read the notes on the back before filling this page) (H et)-The word further includes (H et ') 値 as previously defined. (A 丨 k ) Shows a group derived from a saturated or unsaturated, linear, branched or cyclic non-aromatic hydrocarbon, meaning in the example of acyclic hydrocarbon, it is methyl, propyl, isopropyl, butyl , Isobutyl, tert-butyl, n-pentyl, n-hexyl, 2-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 2, 2-dimethyl Amyl, 3, 3-dimethylpentyl, 3-ethylpentyl, n-octyl, 2 2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl- 3-ethylpentyl, nonyl, 2,4-dimethylheptyl or n-decyl, alkenyl such as vinyl , Propenyl, isopropenyl, allyl, 2-methylallyl, butenyl or isobutenyl, or alkynyl, such as ethynyl, propynyl, propargyl, butynyl, or isobutynyl And in the example of a cyclic group, it is a cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl group. Consumer Cooperatives, Intellectual Property Bureau, Ministry of Economic Affairs When R b forms a nitrogen heterocyclic ring together with the nitrogen to which it is attached, they are especially the following saturated heterocyclics: morpholine, _D, _ azine, α-pyridine or unsaturated heterocyclic ring such as pyrimidine, pyridine or pyridine Azine. When R 2 > R 3 'R 4 and R 5 show a 0- [A 1 k) group containing 1 to 12 carbon atoms' which is preferably a methoxy, ethoxy, propoxy, isopropyl Oxy, butoxy, 燏 propoxy 蕋 or propargyloxy. When R2, R3, R and R π are not 0-(CH.-3 _ A r group, it should be benzene: ½ ethyl gas M: and benzene internal gas group. -10- This paper uses China National Standard (CNS) A4 specification (2) 0 × 297 mm) A7 4 5 89 6 3 --------- B7_ V. Description of the invention ㊁) When R 2 and R — form the same — 0 — (c R d R e) — ring of type 'and η is an integer up to π, which is especially one ο — C Η 2 _ ◦ —' 〇 ~ C (Me) 〇— 0, 〇— C (Ph2) — The 0 groups' ° R 2 and R a must each be in the ortho position. When Rfi shows an OA 1 k or 0-Ar group and A 1 k and Ar are substituted or unsubstituted, it is in particular one of the following groups: (C! -C 8) Hydroxy '(Ci- C ,.,) Aryl, (Ci-Ce) alkoxy, (C6-Ch) aryloxy, (C) -C8) alkylcarboxyoxy, (

Ci—C8) dialkylaminocarbonylmethoxy, (Cs—C ^) aryl, (C] —C〇dialkylaminocarbonylmethoxy ”When R6 $ NH—a 1 k, NH (a 1 k) 2 or NH — Ar group, it is especially one of the following groups: (c! _ C 8) alkylamino 'di- (Ci-Ce) alkylamino group, (C6_Ch) aryl group, ( C2-Ca) alkylamino group, (C6-Ch) arylamino group. When Rs shows amino acid residue, it can be L or D amino acid. -------- pack ---- -I--Order ---- I ---- line (please read the notes on the back before filling this page) The L or D amino acid printed by the Employee Cooperative of the Intellectual Property Bureau of the Ministry of Economy can be natural or non- Natural. They are preferably α-amino acids. For example, those in Houben-Weyl, Methoden der organischen Chemie, Volume XV / 1 and 2, Georg Thieme Verlag, Stuttgart, 1974: A ad, A b υ, rabu, A bz »2 A bz, CA ca A ch, A c P, A d P d, A hb _ 'A i, b β A ib A 1 a, β A 1 a 1 Δ A la 5 A] I gi A 1 1 'A in a • A mt, A pe, A pm' AP Λ r ii • A sn 'Asp, A su, A ze | A z -11-Paper: Degree Applicable to Chinese national standards (CNSM4 specification (2K) x 297 mm) 458963 A7 B7 V. Description of invention P) Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs Β ai! Β ρ h C a η τ c 1 t »cys» ( C ys) > C yta ί D aad D ab D add Ί D a Ρ ϊ D a P my D as UD je η > D Ρ a D t CF e 1 G 1 n 1 G 1 u > G 1 y , G u V 1 h A 1 a 1 h A rg 1 h C y S ϊ h G 1 η 1 h G 1 ur H ish 1 1 eh L e U 1 h L ys 7 h M et 1 h Ρ he 1 h P r 〇5 h Ser > h T h Γ ih T r P ih Τ yr > Η y 1 1 H y P t 3 Η y P 1 I 1 ej I se IV at Κ yn L ant > L cn JL eu > L sgj L ys »β L 7 s 1 Δ 1 ys M et Let M 1 n» M in > η A rgj N 1 ei NV a Ϊ 0 1 y »0 rn > Ρ an ί Ρ ec P en > ρ he P hg P ic > P r 0, Δ P r 〇P se? P yaj Ρ ryry P za) Q in »R 〇s > sar, secsem > Ser, T hi 1 β T h 1 T hr > T hy »Τ h X, T ia ♦ Τ 1 e 1 Τ 1 y 1 T r P j τ rta, 1 T y Γ, V a 1 tert-butyl glycine (butyl bg) neopentyl glycine (NP g) 1 cyclohexyl glycine (chg) cyclohexyl alanine (cha) 2 — Thienylalanine (T h 1 3) 2 ϊ 2 — diphenylaminoacetic acid 2 — (p-tolyl) 2 — anilinoacetic acid 1 2 — (p-chlorophenyl) amine or its pyrene acetate or 2-pyrrolidine acetic acid τ 1 y 2 f 3 4 — tetrahydroisoquinoline 3 — acetic acid T decahydroisoquinoline 3 octahydroisoindole 2 — acetic acid 1 decahydroII | morpholine 2 octahydroacetic acid |: f »q [b] Pyrrole 2 — m acid t 2 — azabicyclo I 2,2,2 丨 octane 3 —carboxylic acid, 2-azabicyclo [This paper size applies to China National Standard (CNS) A4 specifications (2) 0 «297 mm) -12- 1 ------ J -pack --------- order --------- line (please read the precautions on the back before filling this page) A7 458963 _B7_ V. Description of the invention 0〇) 2,2,1: 1 heptane-3-carboxylic acid, 2-azabicyclo [3,1,0] hexane-3-carboxylic acid, 2-azaspiro [4, 4 Nonane-3 —hydroxy acid, 2-azacyclo [4,5] decane_3-carboxylic acid, spiro [bicyclo '[2,2,1] heptane] -2,3-pyrrolidine-5 —Carboxylic acid, spiro [bicyclo [2,2,2] octane] -2,3-pyrrolidine-5-xiang acid, 2-azatricyclo [4,3,0, I6 · 9] decane_ 3-carboxylic acid, decahydrocycloheptane [b] pyrrole-2-carboxylic acid, decahydrocyclooctane [c] pyrrole-2-carboxylic acid, octahydrocyclopentane [c] pyrrole-2-carboxylic acid, Eight-gas oddity 丨 Noise_1—residual acid, 2, 3 '3a' 4 '6a_hexahydrocyclopentane [b] pyrrole-2-carboxylic acid, 2, 3, 3a, 4' 5 '7 a_ Hexahydroindole-2-carboxylic acid, tetrahydrothiazole_4-carboxylic acid, isoxazolidine-3-carboxylic acid, pyrazolidine-3-carboxylic acid, hydroxypyrrolidine_2_carboxylic acid, if appropriate Can be replaced (see the following formula): I—If ------------ I --------- (Please read the precautions on the back before filling this page) Ministry of Economy Wisdom The paper size printed by the employee's consumer cooperative of the Property Bureau applies the Chinese National Standard (CNS) A4 specification (2) ϋχ297 mm -13- 4 5 89 6 3 Α7 Β7 V. Description of the invention 0 co-:

co

co ·

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: < CVc〇 ·: u co ^. -: 9 > c〇.

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This paper is fully compliant with the Chinese National Standard (CNS) A4 specification (21ϋ X 297 mm) -14- A7 4 ^ 8 9 6 3 ___B7____ V. Description of the invention (2) Heterocyclic residues such as the above are from the following patents or Patent string filings are known: US-A-4,344 '949: US — A- 4 5 3 7 4 1 8 4 7 US — A — 4 3 5 0, 7 0 4: Ε Ρ — A — 2 9 4 8 8 EP — A--3 1, 7 4 1 »Ε Ρ — A — 4 6 9 5 3 EP-A--4 9 f 6 0 5 • Ε Ρ — A — 4 9 6 5 8 EP — A--5 0 »8 0 0» Ε Ρ — A — 5 1 0 2 0 EP — A--5 2 1 8 7 0 »Ε Ρ — A — 7 9 0 2 2; EP — A--8 4 1 1 6 4 > Ε Ρ — A — 8 9 6 3 7 EP — A--9 0, 3 4 1 t Ε Ρ — A — 9 0 3 6 2 »EP — A--1 0 5 1 0 2; Ε Ρ — A — 1 0 9 〇 2 0 EP -A-1 1 1 8 7 3 Ε Ρ — A — 2 7 1 1 8 6 5 and EP--A — 3 4 4 6 8 2 0 The base acid can be of the ester or amidine type such as methyl ester, ethyl ester, isopropyl ester, isobutyl ester, t-butyl ester > ester, acetamidine Card bar hydrazine or ω - amine group (c 2 - -C 8) Amides hospital. is \ After taking this, the official functional group of the ih amino acid can be protected. Suitable protective groups such as urethane protecting group, li-protecting group, carboxy protecting group or side chain protecting group are

Hubbuch, Kontakte (Merek) 1979, N c 3, p '14 -23 and described by Biilesbach, kontakte (Merdk) 1 980, N r 1, p 23-35. For example, the following may be mentioned: A 1 oc, P yoc, F moc, T cboc, Z, B ◦ c, D dz, B poc 'Λ doc' M sc · M oc · Z (N 0 ^), Z (This paper size applies to China National Standard (CNS) A4 specification (2) ϋ X 297 mm) 1 I --------- I! Packing --------- Order -------- -Line < please read the notes on the back of 1 * before filling out this page) 8-industry consumer cooperation du printed 15- and (H. et 458963-A7: .r,, Ά _Β7_ Description of the invention (13)

Ha 1 η)-B ob 2, I boc, Adpoc, Mb〇c 1 A cm 1 tertbutyl, Ob z 1 j Onb zi, Onib z 1, Bzl, Mob, Pic, Trt ° When G is a group of formula G 1 -N 一 (Hetr) i

When Rh is a heterocyclic ring of the formula —C (H). (H) and N = C- NH — the unit forms a hetero containing 1 to 9 carbon atoms and 2 to 5 selected from oxygen, nitrogen and sulfur atoms Atomic mono- or bicyclic aromatic or non-aromatic heterocyclic ring, this group may be substituted or unsubstituted, G 1 especially shows the following heterocyclic ring: ----------- --- Order ---------. (Please read the notes on the back before filling in this page)

-HN N, -HN. HN- Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs -HN- · ΗΝ · N ^ 〇]

• HN

-HN

This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) A7 A7

Five X) — NHRc group (group, description of the invention (4) where P represents an integer of 1 to 4. When G is an NR a R b group (called G 2), R a and R can be Argon atom, (C Η 2).-3-A r, (c H 〇

He t or (CHs) — — A 1 k group. And the A 1 k group may be substituted by a group defined below. G 2 may in particular be N Η 2, N Η — A 1 k such as NHM e, NHeT, N (Alk) 2 such as NMe2, NEt2, NMeEt, NH-(CH2) 〇- i-Ar such as NHPh 'NHCH2Ph or NHCH2He t Such as NHCH2-□ than slightly ~ 2-base. When Ra is a hydrogen atom or (A 1 k) and when Rb is (He t-), G] _ 値 is found. When R a and R b together with the nitrogen atom to which they are attached form an air-heterocyclic ring, especially the above heterocyclic groups, these may be substituted or unsubstituted-when G is a (He t) group (group G3), this group may be substituted or unsubstituted, which is in particular the heterocyclic ring listed above and in particular the heterocyclic ring of the general formula (He t ') as defined above. When this heterocyclic ring is attached to the extent of its nitrogen atom, G 2 値 is found, in which Ra and R b together with the nitrogen atom carrying them form a heterocyclic ring. —When G is —NRh — C (= \ MG 4), or NR h S 0 ″ R c group (group G 5), where X is a sulfur or gas atom or N Η, R h and R c are as before When it is defined, its special N Η Μ ------— 定 ------ ί · # f Please read 11 on the back of y Note *? 搴 Item and then #Writing this paper Standards applicable in China® National Standard ( CNS) A4 Regulations (2) ϋ 297 mm) -17- 39 6 3 at 1 B7 5. Invention Description) (Please read the notes on the back before filling this page) -NH-c (= 0)-NH: > or -NH-C (= S) -NH2, ~ nh- C (= NH) — NHCH2-Ar like -N Η-c (= NH) -NHCHePh < -NH-C (= NH) — NHCH2 -He t '-NH-C (= NH) -NHCH 2-H et ^, — NH-C (= NH)-NH -A 1 k such as -NH-C (= NH) — NHCH3' or —NH S 0 2 P h-Ar, Het, Het 'or Aik group is substituted or unsubstituted. The possible substituents of (Aik), (Ar) '(Het)' (Het ^) or NR a Rb forming a heterocyclic ring are preferably the following groups: halogen: fluorine, chlorine, bromine, iodine '— Alkyl 'alkenyl' alkynyl 'containing 1 to 12 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl'isobutyl' tert-butyl, vinyl or propadienyl; These groups are arbitrarily replaced by one or more halogen atoms, such as fluorine, such as methylfluoromethyl1. Employees ’cooperatives of the Intellectual Property Office of the Ministry of Economic Affairs, Consumer Aza-keto, cyano, nitro, formamyl, carboxyl And carboxyalkylcarboxamides containing 1 to 6 carbon atoms, an alkoxy group containing 1 to 12 carbon atoms, such as methoxy'ethoxy'propoxy'isolamyloxy, butoxy ' -Said thio group containing 1 to 12 carbon atoms, such as methylthio group, ethylthio group, propylthio group, P, jthio group, 1 thio group, amine group, and 1 to 12 carbon atom alkyl group Amine groups such as methylamino or ethylamino, 3: 2 to 2 4 carbon atoms _Γ :. Alkylamine, such as dimethylamine 菡 'diethylamine, -18- This paper has been used in accordance with Chinese national standards (CNS) AJ specifications (2〗 ϋ mm) A7 458963 _B7_____ Five Description of the Invention (6) Methylethylamino groups, each of these dialkylamino groups is oxidized arbitrarily 0 (please read the note on the back before filling this page)-containing 1 to 12 carbon atoms Amine alkyl, such as amine methyl or amine ethyl, -dialkylamine alkyl having 3 to 25 carbon atoms, such as dimethylamine methyl or ethyl, -dialkylamine alkoxy having 3 to 25 carbon atoms Radicals such as dimethylamine ethoxy,-any fluorenated hydroxyl group containing 1 to 12 carbon atoms, such as ethoxyl,-fluorenyl groups containing 1 to 12 carbon atoms, such as formamyl, ethyl Fluorenyl, propionyl, butylfluorenyl, isobutylfluorenyl, pentamyl, isopentamyl, succinyl, pentamyl, phenylfluorenyl, which are optionally substituted with, for example, chlorine, iodine or fluorine atoms: mention may be made Chloroethenyl, dichloroethenyl, trichloroethenyl, bromoethenyl or trifluoroethenyl. -Carbocyclic or heterocyclic aryl groups such as phenyl, furyl, thienyl, pyridyl or aralkyl groups such as benzyl, these groups themselves may optionally be halogen, alkyl, alkoxy, alkane as specified above Substituted by a thio group, an amine alkyl group, or a dialkylamino group. Of course, there may be one or more of the same or different substituents. In the example of (H e t), the substituents can be at the level of NH or carbon atoms. 0 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs These groups also explain the definition of R 4. It is understood that when Ri, R2, R3'R'i'R5'Re'Ra'Ri, ', contain alkyl, aryl or heterocyclic groups as defined above, they may be the same or different from each other independently. The invention naturally extends to salts of compounds of formula (I). For example, when compounds of formula (I) contain amine or guanidine functions, they are compatible with the following acids. ) A4 specification (210 X 297 male «) 458963 A7 V. Description of the invention (17) Salts formed: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, formic acid, propionic acid, Benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid, alkanesulfonic acids such as methyl- or ethanesulfonic acid, aromatic sulfonic acids such as benzene- or p- Toluenesulfonic acids and aromatic carboxylic acids' or salts of alkali or alkaline earth metals or any substituted ammonium salts when the compound of formula (I) contains an acid function. The invention also extends to esters of compounds of formula (I). In the first preferred group, the subject of the present invention is a compound of general formula (I) as defined previously, which is equivalent to the general formula (1 >): Η

(Please read the note on the back before filling out this page.) ------------ Order --------- line. The Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs printed R1, which shows the following groups One: —C two C-[A "-[B]-COR, 'CH- [A >]-[B" -COR ,,-(CH2) 2 b "-c〇r,' -ch2c〇- [A ^]-[b] _ COR,-[A >] _ shows a divalent alkylene, alkenyl or alkynyl group containing 1 to 6 carbon atoms, and [B ^] shows a CH (Z) group Or a single bond shows a hydrogen atom 'One of the following groups: -20-This paper size is applicable _ National Standard (CNS) A4 (210 x 297 public love) V. Description of the invention (18 C Η 2 C Η, 0 6 NR a R b Α7 Β7 > 0-6-I \ TH-S〇2 — Rc r CH2) 0 „6-nh-C〇2-Rc, cH2) 〇.6-NH-CO-Rc '^ H 2) ο-s -NH— S〇2 — NH- Rc, CH2) 〇-6-NH-CO-NH-Rc,

CHC H. CH 0-6 C 0 2 — R c S 〇2-R c C〇—R c or (CH2) Q-6 — rc 'Ra, Rb and Rc are as previously defined, R represents OH' amino 'Or an alkoxy group containing 1 to 8 carbon atoms, which is optionally substituted with-or more groups selected from the group consisting of hydroxyl, amine, phenylalkylamino or dialkylamino, R ^ 2 and R ~ 3 It shows a hydrogen atom or a methoxy group and G is as defined above. The dashed line shows an arbitrary second bond, and in the preferred group of addition salts and esters with acids and bases, the subject of the present invention is as previously defined. Zhitong ------------. Installed. ------- order! ------ Line · (Please read the note on the back before filling this page) The compound of formula (I) is printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, where Re shows ~ 〇CH3--CH2CH : 3--Ο- (C Η 2) 2-Ο Η -Ο — CH2-CH-CH2OH, 〇Η 〇 一 (CHs) 2 — NH ;: '— 〇_ (CHs) 2 — Ν — (CH〇) 2, _ΝΗ2 or -〇- (CH2) -phenyl, and the standard of Chinese paper (CNS) A4 (210 X 297 mm) with acid paper size A7 458963 ____B7___ 5. Description of the invention 9) Addition salts and esters with alkali. < Please read the notes on the back before filling this page) In the third preferred group, the subject of the present invention is a compound of general formula (I) as previously defined, wherein Ri represents 0—. (CH2) U — SCH (Z —) —C0〇H or mono (CH2) 〇-7-CH (Z ^) — C ◦ ◦ and addition salts and esters with acids and bases. In the fourth preferred group, the subject matter of the present invention is a compound of the general formula (1) as previously defined, wherein (Z >) is a hydrogen atom, and addition salts and esters with acids and bases. In a fifth preferred variant, the subject of the present invention is a compound of general formula (I) as previously defined, where (ζ /) is (CH2) Q-6-NH-C〇2-Rc or (CH2). -6-NHRb, Ra and R c are as previously defined 'and addition salts and esters with acids and bases. In a sixth preferred group, the subject of the present invention is a compound of general formula (I) as previously defined, in which Rb and Rc represent ((: 1 " 12). -3-A r, A r is as previously defined It can be substituted or non-substituted, as well as addition salts and esters with acids and bases. The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs is printed in the seventh preferred group. The object of the present invention is as previously defined. Compounds of general formula (I), where G is a G 4 group of the formula _NH— C (= NH) = N HR c 'R c is as previously defined, and addition salts and esters with acids and bases In the eighth preferred group 1 the subject of the present invention is a compound of general formula (I) as previously defined, wherein G is G 4 戦 of the formula N Η — c (= N Η) — N Η 2 and Additive salts and esters of acids and bases. In the ninth preferred group, the subject of the present invention is Tongtong, as previously defined. 22- This paper standard applies to China National Standard (CNS) A ·! Specifications (规格】 0 X 297 public address) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs ^ 5 89 6 3 A7 ------- B7___ '' ---- V. Description of the invention) Formula (I) 1 where G is as One of the previously defined ^ 疋 saddles N Η H e t /, Η. Especially Ο

P is an integer equal to 2, 3, or 4. This & heterocyclic ring can be substituted or unsubstituted, as well as addition salts and brews with acids and bases. In the tenth preferred group, the subject of the present invention is a compound of general formula (I) as previously defined, wherein G is the following group

P is an integer equal to 2, 3 or 4, and addition salts and esters with acids and hydrazones. In the tenth preferred group, the subject of the present invention is the compound of Formula II) as defined previously, each of which is as follows: n ^ I ϋ n I nnn I > H ϋ ϋ ϋ n —ί = flJ III * n ϋ III (please read the notes on the back before filling this page) This paper size is applicable to China Store Standard (CNS) A4 (2) 0 X 297 mm -23- A7 B7 458963 V. Description of the invention θ) _ 4-((4 mono ((aminoiminomethyl) iminomine) -9, 10-dimethoxy-1, 2, 3, 4, 5, 6-hexahydro-8 — (Please read the notes on the back before filling out this page) Benzo chamoyl) oxy) -butyric acid,. _ 5-((4-((aminoiminomethyl) imine)) -9, 1 0-dimethoxy-1, 2, 3, 4, 5, 6, 6-hexahydro-8- benzochamoyl) oxy) -valeric acid, -5-((4-((amine Iminomethyl) imidinyl) -8, 10-dimethoxy-1,2,3,4,5,6-hexahydro-9-benzochamoyl) oxy) -valeric acid, -6 — ((4-((aminoiminomethyl) imine) _9, 10 —dimethyl 1,2,3,4,5,6,6-hexahydro-8- benzochamoyl) oxy) hexanoic acid, 7- ((4-((aminoiminomethyl)) Amine) _9, 10-dimethoxy-1, 2, 3, 4 1 5, 6-hexahydro-8- benzochamoyl) oxy) -heptanoic acid, -5-((9, 10 — Dimethoxy-1,2,3,4,5,6-Hexahydro-4_ ((4,5_dihydro-1H-imidazol-2-yl) imino))-8-benzochamoyl) Oxy) valeric acid, printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs -5-((4 (((aminoiminomethyl) imino) imine) -1,9,10-dimethoxy-1 , 2,3,4,5,6-hexaargon-8-benzo chamomile ring) oxy) -valeric acid ethyl ester hydrochloride, 4- 4 ((4- 1 (aminoiminomethyl)) Hydrazine) -8,9-Dimethyl ketone-1,2,3,4,5,6-hexahydro-10-benzochamomile ring 坫) gas; ^-butyric acid 1 -24-this paper size applies Medium ® 0 standard (CNS) A4 specification (210 * 297 mm) A7 458963 _B7 V. Description of the invention) 5-((4 monoaminoimine (Methyl) imilidene) -8,9 -dimethoxy -1,2,3,4,5,6 -hexahydro-10 -benzochamoyl) oxy) valeric acid,. • a 5-((4-(((amino) carbonyl) iminylene))-9, 1 0 -dimethoxy-1, 2, 3, 4, 5, 6-hexahydro-8-benzochamocyclyl ) Oxy) -valeric acid, _ 5 _ ((4 _ (((amino) thiocarbonyl) imine)) 9, 10 -dimethoxy-1, 2 1 3, 4, 5, 6 —Hexakis benzochamoyl) oxy-valeric acid, —4 — ((4- (aminoiminomethyl) iminylene) -8, 10-dimethoxy-1, 2, 3 , 4,5,6-hexahydro-9-benzochamoyl) oxy) -butyric acid 1 -6-((4-((4,5-dihydro-1H-imidazol-2-yl) subunit Amine) -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benzocamocyclyl) oxy) monohexanoic acid, a 5-((4 a (( Aminoiminomethyl) imimine) -9, 10-dimethoxy-1, 2, 3, 4, 5, 6-hexahydro-8-benzo chamoyl) oxy)- 3,3-Dimethyl-4 4-keto Valeric acid, —5 — ((4 — ((4,5—monohydro-1H-imid_2_yl) imine))-9,1 ◦dimethoxy-1,2,3,4 , 5, 6_hexahydro-8-benzochamoyl) oxy) _ 3,3-dimethyl-4 monoketo_valeric acid, a 5 _ ((Amine S iminomethyl) S) imimine) —9, nil I I --- I ^----- Jf — order --- ------ line < please read the notes on the back before filling this page) The paper size printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs applies to the Chinese family standard (CNS) A4 specification (2) 0 X 297 mm. -25- A7 458963 _B7_ V. Description of the invention P) 10 —Dimethoxy 1 1,2,3,4,5,6,6-Hydrogen-8-benzochamoyl) oxy) -valerate, (Please read the precautions on the back before filling this page) 1-4— ( (4 — ((4,5 —dihydro 1H -imidazol-2-yl.) Imine)) 9,9-dimethoxy_1,2,3,4,5,6-hexahydro— 8-benzochamoyl) oxy) -butyric acid, 5-((8-((aminoiminomethyl) imine))-6, 7, 8, 9, 1 0,1 1-hexahydro-chamomile cyclo (5,6-d) -1,3-benzodioxo-4-yl) oxy) _valeric acid, _5_ ((8_ ((aminoiminomethyl Amidinyl) imino) _2,2-diphenyl-6,7,8,9,10,1 1-hexahydro-chamomile cyclo (4,5-e)-(1,3) _benzo Dioxomono-4-yl) oxy) valeric acid, ~ 4 ~ ((9! 10 ——methoxy_4_ ((1 '4' 5, 6 -tetrahydro-2 -pyrimidinyl) -diphenylene Amine) _1,2,3,4,5,6-Hexahydro_8_benzochamoyl) oxy) _ Butanoic acid, -2-((4 — (4,5 —dihydro-1H-imidazole) -2 -yl)-imimine) -9,1 0_dimethoxy-1,2,3,4,5,6-hexahydro-8-benzochamoyl) oxy) _acetic acid, Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs—3 — ((4 — (4,5 —dihydro-1H —imidazole — 2 —yl) —iminomine) — 9, 1 0 —dimethoxy — 1, 2, 3, 4, 5, 6-hexahydro-8-benzochamoyl) oxy) -propionic acid, -4-((4 — (4,5 -dihydro-1H -imidazole-2- Group) monoimino group) -1,2,3'4,5 '6-Hexahydro-8 9-benzochamomile ring oxy) monobutyric acid -26- This paper size applies to China National Standard (CNS) A4 (210x 297 public love) Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs Preparation 458 ^ 63 A7 _B7_ V. Description of the invention θ) — 4 — ((4 — (4,5 —digas — 1 Η —imidazole — 2 —yl) imimine) — ，, 2, 3, 4, 5, 6-hexahydro-8-benzochamoyl) oxy) monobutyric acid,--0-[4 [(4,5 -dihydro-1Η-imidazol-2-yl) -iminoimido]- 9, 10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benzochamoyl] -N _ [(phenylmethoxy) carbonyl] -DL-homoserine, -〇 一 [4 [(4,5-dihydro-1Η-imidazine-2-yl) -imino) -1,2,3,4,5,6_hexahydro-8-benzochamomile ring Group] -N — [(phenylmethoxy) carbonyl] —DL — homoserine, —0 — [4 [(1,2,3,4-tetrahydro-6 —pyrimidinyl) imidino] 9 , 1 ◦-dimethoxy-1,2,3'4,5,6 hexahydro-8-benzene And chamomile ring group) _N _ [(phenylmethoxy) carbonyl group] -DL-Chantamine'-0- (9,10-dimethoxyl1,2,3,4,5,6-hexahydro —4— [1,4,5,6_tetrahydro_2_pyrimidinyl] iminomine)]-8-benzochamoyl]] N — [(phenylmethoxy) carbonyl] —DL — (2,3-Hydroxypropyl) ester of homoserine, —0- [4- [4,5-dihydro-1H-imidazol-2-yl) -iminomine) _9, 1 0 —dimethyl Gaso_1, 2, 3, 4, 5, 6, 6-hexakis-8-benzochamomile ring fluorene] -N-[(8-αquinolinyl) sulfo: 1-DL-homoserine, -0 -L4!., 5 -dihydro-1Η-imidazole-2 -yl) -I --t -.—------ order, —-----! Line (please read the note on the back first) Please fill in this page again on this page) The national standard (CNS) A4 specification of this paper standard (22 适用 297mm) -27- A7 458963 _B7_ V. Description of the invention) Amine group) — 9, 10 — Dimethylamino group 1,2,3,4,5,6-Hexahydro-8-benzochamoyl group) -N — [[3 — [4 — (3-pyridyl) -1 1 Η_imidazole-1 Propoxy Carbonyl] _ — DL-homoseric acid monohydrochloride, —5-[4 — [(4,5 -dihydro-4-keto-1Η-imid-2-yl) — aziridine Group) _9,10_dimethoxy-1,2,3,4,5,6-hexahydro-8-benzochamoyl) oxy] valeric acid, -0 — [9,10 —dimethoxy Amidino-1,2,3,4,5,6-hexahydro-4 — [(4,5,6,7-tetrahydro-1,1-1,3,3-diazamin-2-yl) aziridine Group]-8-benzochamoyl group] -N-[(phenylmethoxy) carbonyl] _DL -homosenic acid * -◦- [9,10 -dimethoxy-1,2,3,4, 5,6 —hexahydro-4 — [(3a, 4,5,6,7,7a —hexaki —] _H -imidazol-2-yl) imidino] -8-benzochamoyl] -N — [(Phenylmethoxy) carbonyl] -DL _ homoserine. Moreover, one of the subject matter of the present invention is a method for preparing a compound of the general formula (I), which is characterized in that the compound of the formula (II) ----^ i ------ Ϊ-order -------- • 'Line (Please read the precautions on the back before filling out this page) Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperative

R5. This paper size applies to the Chinese National Standard (CNS) A4 (210x297 male f) -28- 458963 A7 B7 V. Description of the invention ㈡) where R :, R, R, and R 5 are as previously defined, but In addition to hydroxyamidine, 1 is affected by a compound of formula (F 1) in the presence of a base,

Hal-[A]-[B]-COR, (FI) or, in the presence of phosphine and diethyl azodicarboxylate, the compound of formula (F,

HO- [A]-[B] -c0R 6 (F1,) where Hal is a halogen atom, [A], [B] and Re as described previously, [B] can also represent a -CH- group, p It is an amine-functional protected NΗ group in order to obtain a compound of formula (ma): 〇IIRg _ -I ------! 11111 ^ ^ 1--IIII — I--I-- (please read the back first) (Please note this page before filling out this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

R A B

: 0 R5 * (Gonggong la) or a compound of formula (II) is subjected to the action of an activating group, and then to a compound of formula (F 2) in the presence of a catalyst: The dimensions of this paper apply to Chinese national standards (CNS> A4 specification (210x 297 mm) • 29- 4 5 8 ^ 6 'A7 B7 V. Description of the invention θ) 0 HCC- [A]-[B] -C-Rg (F2) In order to obtain the compound of formula (III b)

0II

R5-KB

A

： 0 R5 Effect of compound of formula (I I I a) or (I I lb) to compound of formula (F3):

Η 2 N — G (F 3) where G is defined previously to obtain compounds of formula (IV a) and (IV b), which are equivalent to certain compounds of formula (I): I--I ----- -II — I --I — ----. Ϊ I --- I I-- (Please read the notes on the back before filling in this page)

： N —G fv (IVa) This paper size is in accordance with Chinese National Standard (CNS) A4 (2) 0 X 297 mm. -30- 45 8963 A7 B7 Printed by the Consumers ’Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs Bang o HC 1 ¾

If appropriate, these two compounds are subjected to the following—or multiple reactions—in the proper order: the action of a base or acid 'is to cleave the ester and obtain the corresponding acid,-the action of a reducing agent suitable for reducing the unsaturation partially or fully, -The action of the hydrating agent of the triple bond '-the action of the dealkylating agent'-when [B] shows the CH-NHP group, the 'action of the N Η-P functional deprotecting agent at the CO-position'-from CORT ; NH-S〇2Rc, NH-COiiRc 'NHC 0 R c' NHSO2-NH-R c 'NH — C 0-NHR c. Zhuang's formation' at the 2/3 position to get the corresponding For the compound of formula (1.), the core is suitable for being subjected to the action of acid or base to get the right — If--1 IIIIII ^ --- III order i! — — — — * (Please read the precautions on the back before (Fill in this page) The size of this paper applies to Chinese Gardener's Standard (CNS) A4 (2) 0297 mm -31-A 5 8 9 6 3 A7 B7 V. Description of the invention p) Salts or esterifications Agent to get the corresponding esters. Formula H a 1-[A]-[B]-C 0 R 6 Compound (F 1) < Please read the precautions on the reverse side before filling out this page) The two should be an inorganic base such as potassium carbonate or carbonic acid It is carried out in the presence of sodium in the presence of a protic 'inert dipolar solvent such as dimethylformamide. H a 1 is preferably a chlorine or bromine atom.

Compounds of the formula HO — [A] — [B]-COR6 (F's role is in the presence of a phosphine, such as triphenylphosphine, and a reagent such as diethyl azodicarboxylate (DEAD) in a protonic solvent such as The effect of the formula H—CeC— [A]-[B] -CORe compound (F 2) in methylene chloride is to interact with an activating group in the presence of a base such as pyridine to form the related formula (CF3S〇2) 2 After trifluoromethanesulfonic anhydride, palladium derivatives (Pd °) such as Pd (PPh) 4 are implemented. NH2-G (F 3) is used in the absence of a solvent or in an alcoholic solvent such as ethanol or It is implemented in butanol. The synthetic fibers N Η 2-G are arbitrarily used in the form of a salt such as hydrogen chloride or hydrogen bromide. The saponification reaction of the ester-functional saponification reaction of the consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, such as the use of a basic alkali such as soda The effect of potassium or alkali is carried out in tetrahydrofuran or a lower alcohol such as methanol or ethanol. This ester can also be cleaved in an acid medium according to methods known to those skilled in the art. The reduction of unsaturation can be completely effected by the action of hydrogen Test on catalysts such as f G / carbon or rhodium catalysts such as W Π kins ο η 's Embodiment presence or partially (alkynyl becomes stretched alkenylene group) by poisoned catalyst such as pyridine or triethylamine in 耑 of palladium / barium sulfate as catalyst River implemented.

Make -CH :: CO — [Α] — 〔Β〕 — cORu Since a C 32 paper size, the Chinese National Standard (CNS) A4 specification (2) 0 * 297 g t) Consumer Cooperatives, Intellectual Property Bureau, Ministry of Economic Affairs Printing 4 5 89 6 3 a7 _____B7____ 5. Description of the invention (? 〇) The hydration reaction obtained by three C— [A] — [B] —CORfi should be performed by water in the presence of mercury sulfate. The product of formula I in which R 2, R 3, R! Or R 5 shows a hydroxyl group is obtained. The dealkylation reaction is carried out in the presence of aluminum chloride or boron tribromide. The functionalization of NH2 in the alpha position of CORs ([B] represents CH—NH2 or CH—NH2, HC i) is performed according to standard methods known in organic chemistry. The effect of forming NHS0 2 R c from the corresponding amine is preferably carried out in the presence of a base, such as triethylamine, by the effect of R c S0 2 Ha 1. The formation of NHC0 2 R c from the corresponding amine should preferably be performed by R c 0H according to the method described in J. Org. Chem., Red, 3929-3934, and reacted in the presence of sodium bicarbonate in advance. This is carried out after isocyanate is obtained in the middle of the gas. The salting reaction can be carried out under general conditions. For example, to saltize the terminal CO 2H of R i, this operation is performed in the presence of a sodium salt such as sodium carbonate or sodium bicarbonate. Similarly, the salinization of amines or aminoguanidines (shown by G) is carried out under normal conditions. This operation is carried out, for example, with hydrochloric acid, for example in an ether solution. Any esterification of the product is carried out under standard conditions known to those skilled in the art ^ + F. This operation is usually carried out by reacting an acid or functional derivative of formula (I) with a reagent capable of introducing an ester group. The non-exhaustive description of this reagent is given in the above R definition. China National Standard (CNS > A4 Specification (2) ϋ * 297 mm) -33- ---, ^ Order -------- line (please read the note f on the back before filling in this purchase) 4 5 8 9 6 3 A7 __B7 V. Description of the invention) The products of the general formula (F1) '(F, 1), (F2), (F3) are known or prepared according to methods known to those skilled in the art 》 ≪ Please read the notes on the back before filling this page) The grafting order of different reagents can also be reversed, that is, the compound of formula (II) is affected by the compound of formula F 3 to obtain formula (III) in the middle. c) the product:

R5 is subjected to the action of a compound of formula (F 1), (F v 1) or (F 2) to obtain the corresponding products of formula (I V a) and (I V b). In this example, it may be necessary to provide protection of the G group of the product of formula (III c), and then after introduction of (FI) 1 (Fei) * (F2), protect it by methods known to those skilled in the art (TW, GREENE Protective Groups in Organic Synthesis, John Wiley and Sons Inc. 1991). The deprotection reaction of the NH — P group ([B] shows CH -N Η P group) printed by the employee consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs is also based on this. The method known to the skilled person to implement it, especially when p shows a C 0: t B u group, is performed by a debasing reaction, for example, by the action of hydrochloric acid. The bone is constantly subjected to a dynamic process, which Including bone loss and bone formation. This process is performed by specialized cells. Bone formation is a mineral-based bone formation. -34-This paper size applies to Chinese national standards (CNSXA4 specifications (210 * 297)) 458963 Economy Printed by A7 B7, Shellfish Consumer Cooperative of the Ministry of Intellectual Property Bureau 5. Description of the Invention 芩) The result of cell-induced deposition and bone loss is the result of osteolysis caused by osteoclast. Activated mature osteoclasts adhere to bone by secretion of proteolytic enzymes • Consumption of bone and protons inside the adhesion zone cause decay or holes in the bone surface, which decay or holes are in osteoclasts It appears after detachment from the bone. (I) Compounds and their pharmaceutically acceptable addition salts have useful pharmacological properties. These compounds inhibit bone loss mediated by osteoclasts. The compounds of the present invention are therefore useful in the treatment of diseases caused by bone loss, especially bone Looseness, malignant hypercalcemia, lack of bone due to bone metastasis, periodontitis, hyperparathyroidism, erosion around joints in rheumatoid arthritis, Paget's disease, caused by Bone deficiency caused by immobilization. Corticosteroid treatment or lack of male or female hormones. They can also be used to treat inflammation, cancer, and recurrence of cardiovascular disease such as arteriosclerosis or stenosis. They can eventually be used as angiogenesis inhibitors Agent and its use for the treatment of cancer, diabetic retinopathy and nephropathy by its inhibition of neovascularization. Recent studies have shown that the fixation of osteoclasts to bone is mediated by the receptors integrins ° Integrins are a superfamily of receptors that mediate cell / cell and more specifically cell / matrix adhesion processes, In particular, it includes a 2 b yS 3 (fibrinogen) as a platelet receptor and in vitro connexin (— — — — — — — — — — — — ^ III — — — — ^ * I ---- 111 (Please read the notes on the back before filling in this page) This paper size is applicable to Chinese standards (CNSM4 specification (210x 297 mm) -35- 4 5 89 6 3 A7 B7 V. Description of invention ㈤) vitronectin) And sialoproteins such as bone sialoprotein and thrombosialin receptors av / 5 3. {Please read the notes on the back before filling this page) These receptors are composed of two subunits α and ./3 Protein heterodimers have divalent ions, such as Ca 2 ·. They have a fixed address and a confirmatory address for a ligand that is predefined by the quality of the subunit. The αV3 receptor is a transfer membrane glycoprotein, which is expressed in a variety of cells, including endothelial cells, smooth muscle cells, osteoclasts and cancer cells, thus giving the compound according to the present invention multiple effects. The α V / 5 3 receptor expressed on the osteoclast membrane is the basis of the adhesion / depletion process, promotes cytoskeletal tissue, and is related to osteoporosis (Ross et al., J. Bi〇1.Chem. , 1 987,262,7703) c The av-point 3 receptors expressed in aortic smooth muscle cells will stimulate their movement towards the neovascular intima, causing the formation of arteriosclerosis and the recurrence of stenosis after vascular angioplasty (Brown et al. Cardiovascular Res. (1994), 28, 1815). Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Endothelial cells secrete growth factor ’This growth factor is responsible for mitosis in the endothelium and contributes to the formation of new blood vessels (angiogenesis). Angiogenesis Stimulation causes new blood vessels to form. Antagonists of integrin a v / 3 3 can therefore cause cancerous tumors to decline due to the necrosis of angiogenic blood vessels (Brook et al. Cell (1 994) 7 9, 1 1 5 7). The natural ligands of integrin α γ / 3 3 all contain R G D units (

A r g-G 1 y-A s p). Peptides containing this RGD unit and anti-ovv / 3 3 antibodies are known for their ability to inhibit dentin loss' the ability to prevent adhesion of osteoclasts # mineralized on the callus (Horton et a). E -36- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (2) 0 X 297 male dragon> A7 458963 _B7____ 5. Description of the invention M) xp.Cell.Res' (] 99]), 19 5,368). (Please read the notes on the reverse side before filling out this page) The peptide echistatin isolated from snake venom also contains RGD unit, which is described as an inhibitor of osteoclast adhesion to bone ', And is therefore a potent inhibitor of bone loss in tissues cultured in vitro (Sato et al. J. Cel]. Bio]. U990), 1111, 1713) and in groups cultured in vivo in mice Potent inhibitor of bone loss (Fisch et al., Endocrino logy (1993), 132, 1441). Compounds of formula (I) and their pharmaceutically acceptable addition salts and their esters may in particular have an affinity for in vitro connexin receptor av point 3 or relative to other integrins with in vitro connexin as a ligand (avy51 ,, a2b / S3), which is caused by the inhibition of the binding of their natural ligands. This property therefore makes the compounds of the present invention useful in the prevention and treatment of diseases whose underlying pathology is caused by ligands or cells that interact with connexin receptors in vitro. These compounds also have activity relative to other integrins that interact with their ligands via the R G D tripeptide sequence, making them pharmacologically useful for treating conditions associated with these receptors. The consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs printed this relative integrin activity thus making the compounds of the present invention useful in the treatment of many diseases, as described above or as described in the review of Dermot Cox DN & P8 (4) May 1995 The author, its content is incorporated in this application. One subject of the present invention is therefore the compound of formula (I), and its pharmaceutically acceptable addition salts and its esters, as a medicament. Among the medicines of the present invention, the ones mentioned in the experimental part can be mentioned in particular -37- This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 4 5 8 9 b 3 pj ____ _B7__ 5. Compounds of the invention <? 5). Among these products, a more particular object of the present invention is the compound of formula (I) which is a forefront of the drug. · 'The dosage will vary depending on the disease to be treated and the route of administration: By oral administration, it can vary from 1 mg to 100 mg per day for adults. The invention extends to a pharmaceutical composition containing at least one drug as defined above as an active ingredient. The compounds of formula (I) are used by a digestive, parenteral or topical route ', for example by the epidermal route. They can be specified in the form of simple or sugar-coated tablets, capsules, granules, medicinal preparations, pessaries, injection preparations, ointments, emulsions, gels, microbeads, beads, plant preparations, and patch preparations prepared by the usual methods. The active ingredient can be different from the excipients commonly used in these pharmaceutical compositions, aqueous or non-aqueous carriers, animal or vegetable origin fatty substances, paraffin derivatives, glycols, different wetting, dispersing or emulsifying Agents, preservatives, and excipients such as talc, acacia, lactose, starch, magnesium stearate, and coconut fat. The product of formula (II), in which the hydroxyl group hydroxyl group is at position 10, only 2 at position 8 and R3 at position 9, showing 0— (A 1 k) or 0— (CH :) u — 3-Ar Group, ruler ^ and! ^ Is a hydrogen atom and is prepared according to the method described in the experimental part (Preparation 2) of European Patent Application 0 7 2 9 9 3 and below. The following structures can be used to prepare Xing structures in other positions: This paper size applies the Chinese National Standard (CNS) A4 Regulation (210 X U97 mm) -38- I— if--II ^ IIIIII ^. --- ---- II, 1 (Please read the precautions on the reverse side before filling out this page) 458963 A7 B7 V. Description of the invention P) Compound of formula (IIA)

: 0 (IIA) is subjected to a dealkylating agent to obtain a compound of formula (I I B)

0 (IIB) The compound of formula (IIB) is subjected to: the action of a diol-protecting agent in the presence of a basic medium to selectively obtain the product of formula (IIC) ------- Order -------- Line · (Please read the notes on the back before filling this page)

〇 Among them, P indicates that the basic paper size of the diol protective reagent is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (Industrial 1C) 458963 Α7 B7 V. Description of the invention ¢ 7) Formula (IIC) product sequence It is protected by a phenol protecting agent, a diol deprotecting agent, and a debasing agent, and then the deprotecting agent of phenol is used to obtain a compound of formula (IID), which is equivalent to the formula having Η in position 8 (II Tri-substituted products:

0 (IID) or a compound of formula (IIB) is subjected to: a phenol protecting agent, an alkylating agent, and then a deprotecting agent to obtain a compound of formula (II Ε), which is equivalent to formula (II) having 0 Η in position 9 ) Of the tri-substitution product: (Please read the notes on the back before filling out this page > Printed by the Employee Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

0 (ΙΙΕ) A dealkylating agent preferably means an agent such as boron tribromide or aluminum chloride. The diol-type protective reagent reacted on the product of the formula (IIB) may be a foot · boron derivative 'such as boric acid, an acid trialkyl ester, such as trimethyl borate or triethylene glycol, or facial sand. This paper size applies to China's Standard for Domestic Standards (CNS) A4 (210 * 297 public love) -40- Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs and printed by a consumer cooperative

45 89 6 3 A7 _ B7 V. Description of the invention (? 8) The protective agent of phenol especially means a halide, such as methanesulfonium- or tosylsulfonium chloride or -bromo, or a base derivative such as benzyltoluenesulfonate Ester or sulfamate mesylate 0 'Glycol deprotecting agent means especially a strong acid such as hydrochloric acid, sulfuric acid or p-toluenesulfonic acid or in the case of protection by a boron derivative, an oxidizing agent such as Hydrogen oxide. Alkylating agent means any standard agent for alkylating phenols known to those skilled in the art " Can be mentioned, for example, alkyl halides such as methyl or ethyl chloride, alkyl sulfates such as methyl sulfate Or ethyl or diazomethane. Deprotection agent means a base, such as soda, potassium base or sodium carbonate or potassium carbonate, a monosubstituted product of formula (II), wherein R2, R3, feet 4 and 115 represent hydrogen atoms, according to European Patent Application 1 ^ ° 0729933 is prepared in a similar manner to: (1) a compound of formula (a) human

(Alk) O where 〇— (A 1 k) is between or in the para position of the alkyl carboxylic acid group, and (A 1 k) is, as previously defined, subjected to the action of a halogenating agent to obtain a corresponding fluorenyl halide. For the standard, use China National Standard (CNS) A4 (210 x 297 mm) -41------— — — — — ^ lull — — ------- I Please fill in this page again for matters) 4 5 B c; c 3 A7 ------------ 5. Description of the invention) (ii) This fluorenyl halide is affected by the reagent of formula (b)

R (IR (II

R (and R) or Ti, i-based R-alkanes of the original carbon 6 to the next one contains the shown ’it is the same as 5 or I is the same as I R I and 1 is the first 6 nitrogen or from

物 合 合 原 原 杂} It C C ί Ν f Please read the notes on the back before filling in this page)

Hal can be used as the agent of halogenated halogen a Η, its original halogen is shown in formula C > Chemical V \ 1 / .1 0 / Γν formula Μϋ, which is used as an acid, is easy to pass to the target compound -42- This paper size applies to China National Standard (CNS) A4 (210 * 297 mm) Α7

_Β7 V. Description of the Invention (40) (Alk) O

(V) The compound of formula (e) is subjected to a dealkylating agent to give a product of formula (I IF), which corresponds to the expected monosubstituted product of formula (I I): H0- {0

(IIF) Bis substituted product of formula (I I), which shows ◦— (Aik) or 0— (CH2). -3-Ar, R3, Ri and Rs are hydrogen atoms and 0H and R2 is in the 8, 9 or 10 position, according to the method described above, from the compound of formula (a >): -! Order ---- I ---- line (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs

Where 0-(A 1 k) and R 2 are between or in the para position of the alkyl carboxylic acid group, and R ″ is 0 _ (A 1 k) or — (C Η ″) 〇 — — A r, formula (a The compounds were sequentially reacted by (1), (1i) '(ill)' (1v) and (v) and the product of formula (IIG) was obtained. This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -43-Printed by the Shellfish Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 45 89 6 3 Α7 Β7 V. Description of the invention (41) It is equivalent to the expected disubstituted product of formula (II)

Thiochlor, chloram or any other agent known to those skilled in the art for the preparation of an acid halide. The reagent of formula (b) is prepared from cyclopentanone and a secondary amine such as diethylamine, piperidine, piperazine or desmoline. This operation is carried out in the presence of a strong acid catalyst such as p-toluenesulfonic acid. The effect of the enamine of formula (b) on the acid halide is preferably carried out in the presence of a tertiary amine such as triethylamine or pyridine. The halogenating agent reacted on the compound of formula (c) or its two substituted equivalents of formula (c <) may be, for example, thionyl chloride, phosgene, phosphorous oxychloride or desirably chlorhexyl chloride. Cyclic compounds of formula (d) or disubstituted equivalents of formula (d >) The Lewis acid used is, for example, aluminum chloride, titanium tetrachloride, or suitably iron chloride or tin tetrachloride. This reaction is similar to the former, and can be carried out, for example, in a halogenated solvent such as dichloromethane, chloroform, and dichloroethane. In order to obtain the corresponding phenols, the dealkylating agent of the compound of formula (e) or the disubstituted equivalent of formula (e-) is preferably a product of aluminum chloride or boron tribromide (C I). R, different from hydrogen atom, depends on this paper size. Applicable to China's national standard (CNS) A4 specification < 210χ297 male ¾) -44---------- installation ----- -II order --------- line (please read the notes on the back before filling out this page) 458963 7 A7 ------- B7 V. Description of Invention (42) Method known to the artist The preparation of chaos is in particular according to the method described in the European patent application N ° 0 7 2 9 9 3 3, that is to say by halogenation followed by the action of water or a suitable alcohol. The product of formula (ί I), in which ruler 5 is a hydrogen atom and in which there is a double bond in positions 1-2, is prepared according to methods known to those skilled in the art and in particular according to European patent application N " The method described in 0 7 2 9 9 3 3, that is, by dehydration or dealkoxylation, is prepared in an anhydrous acidic medium. The product of formula (I I), in which the ring in position 5 and the ring in position 7 are saturated, are prepared according to standard hydrogenation methods corresponding to double bonds, especially in the presence of palladium / carbon. The introduction of R4 and Rs and the hydrogenation reaction are preferably carried out on a compound of formula (IIA), (IID), (IIE), (IIF) or (IIG). The product of formula (II), in which R 2 and R 3 are each in the ortho position, forming a ring of the form —0— (CRdRe) n —O as previously defined, also prepared according to methods known to those skilled in the art and in particular According to the experimental part below ------------- installation -------- order --------- line (please read the precautions on the back before Λ- (k page) The Ministry of Economic Affairs ’Intellectual Property Bureau's X Xia Fei Cooperative Co., Ltd.'s printed property room also works. The descriptions of the prepared formulas are as follows: including non-benzene ~ £ hydroxyl b

C 4 Cyclomethanine Hydrogen Η 合 4 in 4 1 化 I ί 6 and the solution of the product is solved According to the combination of the material and 8 I 氧 甲 甲 甲

And 'Ketone 8-1) M basic paper size is applicable to Chinese national standard (€ Yang) 8 4 specifications < 210 > * 297 public «) -45- A7 458963 __B7 ----__ V. Description of the invention)- -Benzochamomile ring 4 (1 Η)-_. The preparation of these two compounds appears in the experimental section below. The following examples illustrate the invention without limiting it. i Please read the precautions on the back before filling this page) Preparation of 1,2,3,5,6-tetrahydro-8,9,10-trihydroxy-benzo chamomile ring-4 (1Η)-crude stage A : 3 '4' 5_dimethoxy-phenylpropionic acid 6-8 grams of potassium carbonate was added to a solution of 2 1 · 44 grams of 3,4,5-trimethoxyphenylacrylic acid and 4 5 ml of water, and then This medium was hydrogenated at a pressure of 1200-1300 mbar for 1 hour in the presence of 1.8 g of activated carbon and 10% palladium, and in this way absorbed 2.1 liters of hydrogen. The reaction medium is filtered, washed with water and acidified with 50 ml of hydrochloric acid. After separation, the residue was washed with water and dried under reduced pressure at room temperature. In this way, 19.8 g of expected product was obtained. (M.P = 102- «· 1 0 3 ° C). 1 R spectrum (c HC, 3) carbonyl: max) Consumers of Intellectual Property Bureau of the Ministry of Economic Affairs M. Cooperative cooperation: ii Yinzhan {1 7 4 0 cm 1 (sh) Aromatic: 11592cm 1 {15 10cm 'NMR spectrum (CDC < )

2 · 6 9 t) 丨 cC-CHs-Cl-h-CO 2. 9 1 t) j -46- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) Intellectual Property Bureau, Ministry of Economic Affairs Printed by the employee consumer cooperative 458963 A7 ___B7__ 5. Description of the invention (44) 3.83 (s)} 3H; 3CO-C- 3-85 (s)} 6.43 (s) Aromatic 2H < s • 10.50 (out) move 1 Stage B: 6 g of 3,4,5-trimethoxy-phenylpropanyl chloride. The solution of the product obtained in stage A in 21 ml of dichloromethane was dried over 1.5 g of magnesium sulfate and filtered. After that, the reaction medium was cooled to 5 ° C and 2.2 ml of thionyl chloride was added, and the solution was stirred at room temperature for 20 hours. By entrainment with cyclohexane, it was evaporated to dryness under reduced pressure and collected in this manner] 6.46 g of the product sought. (M.P. 60t). Stage C: 2- [3-(3,4,5-trimethoxyphenyl) -1-ketopropyl] -cyclopentanone 4.27 g of a solution of the product obtained in stage B in dichloromethane Within 1 hour and 30 minutes, add at + 5 ° C to 2.4 ml of 1- (N-morpholinyl) cyclopentene, cooled to 5 ° C, 2 · 3 A solution of 1 ml of triethylamine and 15 ml of dichloromethane. The reaction medium is stirred at + 5 ° C for 1 hour, and then while increasing the temperature, 10 ml of 2 N hydrochloric acid is added, followed by stirring at room temperature for 1 hour, decanted, washed with water, and then saturated sodium bicarbonate The solution was washed, dried, filtered and evaporated to dryness under reduced pressure. 5 ^: expected product was obtained. The prepared product was dissolved in 10 volumes of ethyl acetate and extracted with 1 N soda solution. 'Alkaline This paper is applicable to the size of the national standard (CNS) A4 regulations (210 X 297 public «) -47-I- --- I--I ^ in--II ^ * — — — — — 1 I — ^ < Please read the notes on the back of the page before filling in the poor page) Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs Consumer Cooperatives 4 5 8 9 6 3 A7 _B7_ V. Description of the invention (45) The phase was washed with ethyl acetate, acidified with concentrated hydrochloric acid to P 氯, then extracted with dichloromethane, dried and evaporated to dryness under reduced pressure for purification. . Collected 2,75 grams of purified product. IR spectrum (CHC < 3) carbonyl: {1 7 4 1 cm 1 {1 7 0 9 cm-1 aromatic: {1592cm — 1 {1 5 0 9 cm-1 carbonyl: {1658cm — 1 ten C = C {-lGlOcm — 1 while OH is chelated NMR spectrum (CDCi3) 6. 41 (s) aromatic. 2H (integrated base) 3.81 (s) 3.82 (s)} 9H all 3.83 (s) 3.85 (s)} Type 4 C Η 3 0-C =

I

1.86 (m) CH2-CH2-CH2 to 1. 5H 1.95 to 2.95 (m) to 7.5H All of several types = C-C Η 2 3.26 (t) ~ 0.4Θ CO-CH — CH2

I

CO 1 1 · 2 (width m) mobile 尺度 This paper size applies to China National Standard (CNS) A4 (210 * 297 mm) -48-I f I--IIII ------ ^ * I- ---- I. (Please read the notes on the back before filling the page) 4 5 89 b A7 _____B7___ V. Description of the invention (46) 1-(N-morpholinyl) -cyclopentyl used in stage C so far Preparation of olefin 100 ml of cyclohexane, 20 ml of cyclopentanone, 50 ml of sodium chloride and 100 mg of p-toluenesulfonic acid solution were stirred under reflux for 4 hours and 3 minutes, and the formed water was removed. . After the solvent was evaporated under reduced pressure, distillation was carried out under a pressure of 1 2 to 13 mbar and 2 7 · 44 g of the desired product was collected. (B. P. = 83 ° C). Stage D: 1— (2-chloro-1—cyclopentyl-1-yl) —3— (3,4,5-trimethoxyphenyl) propan-1-one 1 ml of chloramphenicol at room temperature Add to a solution of 23 g of the product obtained in stage C and 230 ml of chloroform. The reaction medium is stirred at room temperature for 3 hours, and concentrated under reduced pressure by performing a mist of cyclohexane. 28 g of crude product were obtained which, after partial concentration, were recrystallized from a mixture of 50 ml of cyclohexane and 50 ml of diisopropyl ether. The crystals were separated, washed with diisopropyl ether and dried under pressure. This gave 1 624 g of the expected product. (M.P. = 93 ° C). < Please read the notes on the back before filling in this page > IR Spectrum Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs 1 Cost-saving method (CHC ί 3): 1 6 5 9 C τη _ 1: Carbonyl 1 5 9 9 C m 1 1 5 8 6 C m 1: c = c + aromatic 1 5 0 8 C m 1 N MR spectrum c DC, 3 1 9 3 (m): center CH j 2.69 (m)-2-8 1 (η): Cyclopropene-49- This paper size is applicable to National Standards (CNS) A4 (210 X 297 public love) ___ ^ 87____ ___ ^ 87____ Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 458963 A7 5 Explanation of the invention (47) C — C Η 2-C = 2.85 (t, j = 7.5)-3.08 (t, j-7.5): Others = C — CH:-C's 2.44: CH: 3 — C = 3'68-3.81: OCH, rs 6. 59 — 6. 68 (d 'j 22: 2): In-coupling aromatic C Η = ^ s 7-31-7-80 (d'j = 8): Fang Family. Stage E: 2,3,5,6-tetrahydro-8,9,10-trimethoxy-benzo chamomile ring 4 (1H) -one 900 mg of the product obtained in stage D '9 ml 1 , 2-dichloroethane and 0.9 ml of tin chloride were stirred at room temperature for 20 hours. Then 9 ml of water and ice were added and the mixture was decanted, washed with water and subjected to re-extraction once with dichloromethane, then dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure to give 1 g of the expected (crude) The product was purified by chromatography on silica using cyclohexane with 10% ethyl acetate and then with 25% acetic acid. After concentration, 700 mg of product was collected, which was crystallized from 5 ml of n-hexane, then cooled to 0 ° C, separated, washed with a small amount of n-hexane, and dried under reduced pressure at room temperature to obtain 630 mg of the expected product. (M · P. 2 10 t) a NMR spectrum (CDC, 3) 1. 8 6 (m) center CH 2 This paper size is applicable to the national standard of Chinese painting (CNS > A4 specification (210 ^ 297 male 3)) -50- ------- I ---- 11 ------ — * 53 ^ (Please read the unintentional items on the back before filling in this page) Λ5 89 6 3 A7 ______B7__ V. Description of the invention (48) 2. 6 5 (dd) 2 Η} 2 7 2 (t) 2}} Other c Η ”one s (Please read the precautions on the back before filling this page) 2. 8 4 (dd) 2 Η} 3.0 6 2 Η} 3.84} 3. 8 6} Ο M e ^ s 3.90} 6 · 5 9 (s) aromatic Η order _j by F: 2 '3,5' 6 -tetrahydro-8 '9, 1 The 0-trihydroxy-benzo chamomile ring 4_ (1H) -one was obtained by the operation of stage B of 1a to obtain the expected demethylation product. Preparation of 1g: 2'3'5, 6-tetrahydro-8 , 9,10—Trihydroxy-benzo chamomile ring 4 (1H) —Ketone Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs, printing stage A: 2, 3 '5' 6—tetrahydro-8, 9, 10— Trimethoxy-benzo chamomile ring 4 (1H) -one 6 g of the product obtained in Preparation 2, 600 ml of 1,2-dichloroethane, 3 4 2 ml of 2 N soda, 1.2 g of tetrabutylammonium bromide and 33 ml of dimethyl sulfate were allowed to stand for 2 hours and 30 minutes at 20 ° C. Then 39 ml of triethylamine was introduced to destroy excessive Dimethyl sulfate a is stirred for 1 hour at 20 ° C ± 2 t. Add 3 4 2 ml of Delu-51-This paper is in accordance with China National Standard (CNS) A4 (210x297 mm) 45 B9b3 A7 B7 Member of the Intellectual Property Bureau of the Ministry of Economic Affairs X. Consumption Co., Ltd. V. Invention description (49) Materialized water, then stirred at 20 " C ΐ 2 t for 20 minutes, and decanted, the water phase Extract twice with 120 ml of 1,2-dichloroethane (each time). The 1 '2-dichloroethane phase is combined and washed with 4 x 2 40 ml demineralized water and then with 1 x 300 ml N hydrochloric acid, followed by 3 X 240 ml demineralized water (until neutral). The combined organic phases are dried over sodium sulfate, filtered and at 8 3 ° C, ordinary Concentrate to a residual volume of 480 ml under pressure. Stage B: 2, 3, 5, 5, 6-tetrahydro-8, 9, 10-trihydroxy-benzo chamomile ring 4 (1H)-ketone 480 ml (A) Medium The obtained solution was heated and 102 1 hour 2.3 g of anhydrous aluminum chloride together under reflux. The medium is cooled to 0 ° C ± 2 ° C, and then a mixture of 600 ml of demineralized water and 192 ml of pure sulfuric acid (concentrated) is pre-cooled to about 0 ° C and added within 2 hours, while Keep the temperature of the reaction medium below 20 ° C. 300 ml of demineralized water was introduced within 5 minutes at 20 ° C ± 2 ° C and stirred at 20 ° C ± 2 ° C for 16 hours, and then separated into 60 ml 1 , 2-dichloroethane (each time) was washed twice, and then washed with demineralized water, dried under reduced pressure and 52.2 g of the desired mash was obtained. Preparation 2: 8,9-dimethoxy-10-hydroxy-2,3'5,6-tetrahydrobenzo chamomile ring 4-(1 Η)-ketone stage A: 3,4-dimethoxy 5 — 〔〔(4 π bundle stupid) I — · Nong -------- Order --------- line (please read the first one on the back; I will fill in the poor pages before the matter ) This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) -52-458963 8a s. Os a7 B7 V. Description of the invention roxy potassium sulfonyl] oxy] -phenylpropionic acid As in stage A of Preparation 1, 29.6 g of 3,4_dimethyl-5 _ [[[(4-methylphenyl) amoyl] oxy] benzyl

U to mimi N group _] 1, 6 Lycra 8 ° C) v M = axnfnfaxnfnf MR. 4 cinnamic acid (the preparation is given below), 43.5 g of carbonic acid, 0 ml of methanol and 1.48 g of 10% palladium Do this with activated carbon. In this way, the form of colorless crystals is obtained

The product sought by G. (M. P spectrum (E t 〇 Η) 3 8 9.4 2 2 6 nm ε 1 2 6 3 nm ε 1 2 6 9 η m ε 2 7 4 η m ε 1 2 7 9 η m ε 1 3 0 7 η m ε spectrum (CDC 3) 2 2 10 0 2 0 0 2 4 0 0 2 8 0 2 5 0 0 4 5 0 14 8-14 (Please read the precautions on the back before filling this page) Clothing · —------ Order -------— 1 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

5 (s) C Η a -2. 6 1 (m) 2 C-CH2— CH .8 6 (m) • 6 .8

8 '(s) 2 C Η 3 Ο-C d d

2) H .1 H This paper size is applicable _ National Standard (CNS) A4 size (210x297 mm)

C 4 5 89 6 3 A7 ------- B7_____ V. Description of the furnace 1) 7 3 2 (wd) Η 3 Η 5 ^ · 8 0 (wd) Η 2 Η s (Please read the praise on the back first Note for refilling this page) 'Ji Ji: 3, 4-dimethoxy-5-[[(4-methylphenyl) -sulfofluorenyl] oxy] -phenylpropanyl chloride as in Preparation 1 In stage B, this operation was carried out using 1.9 g of the product obtained in stage A, 9.5 ml of dichloromethane and 0.7 ml of thionyl chloride. There was obtained 2.24 g of the sought product, which was used in its present form in the following stages. Stage C: 2-[3-[3,4-dimethoxy-5 — [[(4-methylphenyl) sulfonyl] oxy] -phenyl] ketopropyl] cyclopentanone such as Stage C of Preparation 1, starting with 2.24 grams of the acid chloride obtained in Stage B and using 770 mg of 1- (N-morpholinyl) -cyclopentene (prepared in Stage C of Preparation 1 ), 6 ml of dichloromethane and 0.77 ml of triethylamine. After recrystallization from diisopropyl ether, 1.27 g of the desired product were obtained (M.P. = 84 ° C). Member of the Economic and Intellectual Property Bureau, M Consumer Cooperative printed 1 R spectrum (CHC < 3) carbonyl group: il742cmlp-S〇2il374cm 1 {1 7 0 9 cm 1 1178cm 1 1 6 5 8 cm 1 (: = 〇 + aromatic 11608 <: 1 1 5 9 9 cm 1 1 5 8 6 cm 1 1 5 0 8 cm 1 -54- This paper size applies to Chinese National Standards < CNS) A4 size (210 X 297 mm) 458963 A7 _B7_ V. Description of the invention 2) NMR spectrum (CDCi.!) (Please read the notes on the back before filling this page) 2-44 (s) CH3-0 3. 6 7 (s)} 2 〇C Η 3 3.79 ( s) 3-81 (s)} 6. 59 to 6.65 (m) Aromatic 2 is in the ortho position to s. 7 · 3 2 (w d) Η 3 Η 5 7. 89 (wd) H2 Η 6

13.58 (wide m) enol type OH 1.8 to 3.4 (m) 10 to 11H Other proton UV spectra 1 — EtOH (+ dioxane) vs. M = 446. 52 max225nm ε 2 3 0 0 0 max282nm ε 7 9 0 0 infi 270, 277, 290, 300, 3 1 3 π m 2-E t Ο Η (〇. 1 N Ν a Ο Η) max3 1〇nm ε = 2 1 6 0 0 infl268'272'276nm Ministry of Economic Affairs Intellectual property bureau employee consumer cooperative printing stage D · _ 1— (2-chloro-1 1-cyclopentanyl) — 3-[3, 4-dimethoxy-5-[[(4-methylbenzene ) Sulfonium berry] oxy] -phenyl] propane-1 _one as in stage 1 of Preparation 1 | using 8.7 g of the product obtained in stage C, 70 ml of chloroform and 3.5 ml of chloracetin Do this. -55- This paper size is suitable for China S Standard Standard (CNS) A4 specification (210x 297 cm) A7 __B7 V. Invention Description Furnace) Consumption cooperation with employees of the Jiji Village Intellectual Property Bureau. After recrystallization? 7.7 • 5 g of the desired product (M-P • — r-Ύ 3 V) is obtained a. This product is used in its current form in the following stage Q by 2 5 volumes of dichloromethane And recrystallized from 5 volumes of diisopropyl ether »then concentrated to 3 volumes-separation • L diisopropyl was washed and dried at room temperature to reduce the turbidity to obtain an analytical sample (M.P. = 7 7 7 8 ° c) α IR spectrum (C Η C t 3,) ¥ Shanm radical {1 6 5 9 C m-] L aromatic C — C; {1 5 9 9 C m -1 L — 15 8 6 cm '1 — 1 5 0 8 C m-] l UV spectrum (E t 〇Η) ma X 2 2 7 η m £ = 2 6 1 0 0 i η f 1 2 4 8 η m £ = 1 2 8 0 0 i η f 1 2 7 2 η m £ = 5 3 0 0 i η f 1 2 8 0 η m £ = 3 2 0 0 η f 1 3 2 0 η m NR spectrum (CDC e 3) 1 • 9 3 (m) center — c — C Η 2 -c-} 2 • 6 9 (m) C — c Η 2 _ —1 C: = s} 2 • 8 1 (m)}} 2 8 5 (tj 7 5) ί Other = c-c Η 5-C > s3.08 (tj = 7.5) l- ----------- Installation --- I I --- Order i! T ---- line < Please read Note i on the back before filling this page) This paper is applicable a Standard for Standards for Households (CNS) A4 (210 X 297 mm), 56- A7 B7 ------ 5. Description of the invention <? 4) 2-4 4 C Η: 1-C 3 6 8} 0 C Η 5 3.81} 6 · 5 9 (d-j = 6. 6 8 (d, j = 7. 3 1 (d, j = 7.8 0 (d * j di 2) aromatic CH 2) Coupling 8)} 8)}

Stage E 8 —dimethoxy-1 0 —) sulfofluorenyl] oxy] -4 (1-) -one 2 5, 6 [(4-methylphenyltetra # —benzo chamomile ring < Read the notes on the back and fill in this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 16 6 The solution obtained in stage C is extracted with ice and mixed with alkane, dried and chromatographed. The crystals were obtained to obtain 75 g of 98% ferric chloride in 50 ml of the obtained product. The mixture was stirred at room temperature. 1 The mixture was stirred vigorously. 1 The liquid was washed with water, and then evaporated to dryness under reduced pressure to obtain 2 cyclohexane and 50% acetic acid. The sought product was added at room temperature, 2-dichloroethane was added for 48 hours 1 and then poured into water for 5 minutes, and then washed with dichloromethane and an aqueous sodium chloride solution.

.15 g of crude product, ethyl acetate was eluted, collected in 1.8 diisopropyl ether mixture and re-cooked (M. P. = 1 38 ° CIR spectrum (CHC < 3) carbonyl group: 11 6 5 0 cm 11 5 9 9 cm 1 to 2. 3 2 grams -57- This paper size is applicable to China National Standard (CNS) A4 size mo X 297 male «) Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs for consumer cooperation 4 5 8b A7 _B7_ V. Inventive furnace) C = C + (1 5 5 6 C m 1 Aromatic (15 12cm 1-1 4 9 8 cm 1 UV spectrum (E t Ο Η) max 2 3 0 η m ε ^ 2 5 3 0 0 ι η f 1 2 5 4 η m ε = 9 4 0 0 max323nm £ = 1 0 3 0 0 Ν Ε Spectrum (CDCi3) ~ 1.61 (m) (2H) Center CH2 ~ 2. 41 P h-C Η 3 to 2.50 to 2.80 C Η 2-C = ι 3 · 8 8 (s)} 0 CH 3 ^ s 3 · 9 0 (s)} 6-74 H 4 7.21 (d)} C- P h-S 0 2 7.64 (d)} Stage F: 8, 9-dimethoxy-10-hydroxy-2, 3, 5, 6-tetrahydro-benzo chamomile ring 4 (1H) -one 3 5 A mixture of 0 g of the product obtained in the above stage F, 175 ml of methanol, 350 ml of demineralized water and 350 ml of pure caustic soda water (concentrated) is returned in the Heating for 2 hours. The reaction medium was cooled to about 20 ° C ± 2t and 4 67 ml of concentrated hydrochloric acid was introduced in a 15 minute anchor while maintaining the temperature at 2 C ± 2 t; " 1 6 4 5 Milli III I--II------- I ^-------- (Please read the notes on the back before filling this page) This paper size applies to China National Standard Sheep (CNS) A4 Specifications (210 X 297 Gong) -58-Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 458963 A7 ___B7_____ V. Description of the invention) The mineralized water is removed and added within 10 minutes while maintaining the temperature at 2 soil Then, the reaction medium was still stirred for 30 minutes at 2 ° C ± 2 t. The formed crystals were separated, and each time it was absorbed by 700 ml of demineralized water at 20 t, it was cleared. Rinse and then dry at 40 ° C under reduced pressure to give 9.9 g of the desired product. Preparation of 3,4-dimethoxy 5 -— [[(4-methyl-benzene] -sulfonyl] -gas]] _ cinnamic acid, this compound is used in the beginning of preparation 2 stage A: 3,4- Dimethoxy-5 ~ [[(4-methylphenyl) -sulfofluorenyl] oxy] benzoic acid methyl ester 3 0 3 ml triethylamine was added to 20 0 in 10 minutes at room temperature To a stirred mixture of methyl peperate and 2 liters of dichloromethane. After dissolution, the reaction medium is cooled to 0-5 ° C, and then 130 ml of dichlorodimethylsilane are added within 1 hour at this temperature. Stir at this temperature for another 30 minutes. While the temperature was maintained at 0-5 t, 33.2 ml of triethylamine was added in 25 minutes, and 227.6 g of tosylsulfonium chloride was added in 15 minutes. Stir continuously at 0-5 ° C for 1 hour, and add 200 ml of acetic acid with stirring within 10 minutes, then 500 ml of demineralized water and at the same time raise the temperature to 20-2 2aC, and Stir at 20 ° C for 15 minutes. Dichloromethane was distilled off at a constant volume (3.3 liters) under reduced pressure, and replaced with demineralized water, and washed with demineralized water to obtain 5 2 3 g (wet redisperse) 3 -4 -Dihydroxy-5-[[(4-methylacrylphenyl) -sulfomethyl] oxy] benzoic acid methyl ester (3-tosylsulfonate methyl ester) "The obtained wet product III ----- ---- Order J ------- (Jing first read the precautions on the back and then fill in this page) This paper size applies + National National Standard (CNS) A4 specification (210 * 297 public «) -59- 45 8963 Consumption cooperation with employees of the Intellectual Property Bureau of the Ministry of Economic Affairs, printed A7 B7 V. Description of invention π) Absorbed into 2.1 liters of de soda (2 N) and 2.1 liters of dichloromethane. Stirring was performed at 20 ° C until dissolution was achieved, then 18 g of tetrabutylammonium bromide was added at 20 t, and then 237 ml of dimethyl sulfate was added at 15 ° C for 15 minutes. The reaction medium is stirred at 20-22 ° C for 1.5 hours. At 20-22 t; add 78 ml of triethylamine and stir overnight at 20-2 2 t, then decante and wash with 400 ml of demineralized water, add 20 ml of pure acetic acid to the organic phase Then, it was stirred for 15 minutes, and 400 ml of demineralized water was added, followed by decantation. The combined organic phases are concentrated to dryness, which is carried out first at atmospheric pressure and then at a reduced pressure of 4 mmHg and an external temperature of 60 ° C. Use 400 ml of methanol to perform the misting, and then the obtained three dry extracts are absorbed into 600 ml of methanol, heated under reflux until the product has completely dissolved, and then cooled to 0-5 t at this temperature. Stir for 1 hour. After separation, it was washed twice with 200 ml of methanol at -10 ° C and dried under reduced pressure at 40 ° C, so 330.4 g of 3,4-dimethoxy-5 — [[ (4-methylphenyl) monosulfonyl] oxy] -methyl benzoate. The crude product was purified by recrystallization from 330 ml of toluene. After stirring for 2 hours at -10 ° C, separation was performed, followed by washing twice with 8 2 ml of toluene, cooling to -15 and at 4.0. Drying under reduced pressure to obtain 2,303 grams of the desired product. Stage B: 3,4-dimethoxy — [[(4 ~ methylphenyl) sulfonyl] oxy]- Cinnamic acid a) 600 ml of toluene cooled to 70% of EL 202¾ liters — — — — — — — — — I nf I ^ .1 ϋ I nn ^ aJI I n III ί I {Guess to read Note 4Ϋ on the back before reading Fill in this page) This paper size is in accordance with Chinese National Standards < CNS) A4 specifications (210 X 297 male; -60-d5 89 〇 Economic, Smart, and Time Production Bureau Employees' Cooperatives printed A7 B7 V. Inventory Ping)

The toluene solution of Vitride® was added at 0 " C and 6-7 ml of morpholine was added within 1 hour at 0-2 " C and the temperature was raised to 18 'ca. The solution thus obtained was immediately used In the following stages. • b) 200 grams of 3 ′ 4-dimethoxy-5 5-[[(4-methylphenyl) monosulfonyl] oxy] benzoate and 140 ml obtained in stage A The toluene was stirred at 20-22 ° C until all dissolved. Add the reagent solution obtained above at 10 ° C over 1 hour and continue mixing for 1 hour, while increasing the temperature to 18 ° C. A solution of 200 ml of concentrated sulfuric acid and 100 ml of demineralized water cooled to 10 ° C was introduced within 1 hour at 10 t. Stirring was carried out at 20 ° C for 16 hours, then the organic phase was decanted, washed with 5 X 2000 ml of demineralized water, dried, filtered and washed with 3 X 100 ml of dichloromethane. The intermediate aldehyde solution thus obtained is used in its existing form in the following stages. c) The intermediate aldehyde solution obtained above, 200 ml of 2-picoline '120 g of malonic acid and 20 ml of piperidine were heated at 70 ° C ± 2 ° C for 16 hours (at the same time at normal pressure Remove methylene chloride). The reaction medium is cooled to 20-22 ° C, and while maintaining this temperature, 200 ml of concentrated hydrochloric acid and 400 ml of demineralized water are added within 15 minutes. Stir at 2-2 2 ° C for 2 hours, and then cool down to 0 ° C. The crystals formed are separated, washed with demineralized water, and dried under reduced pressure of 40 t to obtain 1 7 1 7 grams of expected 3,4-dimethylamino-5 — [[(4-methylphenyl) —sulfofluorenyl] oxan] phenylhydrazine] —cinnamic acid This paper applies Chinese national standards < CNS) A4 specifications (210 X 297 public love) -61-4 ^ 4 ------ 11 ^, --------- line (please read the precautions on the back of the page before filling the poor page) Economy Printed by the Consumer Cooperatives of the Ministry of Intellectual Property Bureau W963 A7 _____B7_______ V. Description of the invention) Preparation 3: 9, 10-dimethoxy-8-hydroxy-2, 3, 5, 6, 6-tetrahydro-benzo chamomile ring 1 4 (1H) -one stage A: 9, 10-dihydroxy-8-[[(4-methylphenyl) sulfonyl] oxy] -2,3,5,6-tetrahydro-benzo chamomile ring one 4 (1 Η) -one

30 g of 2,3,5,6-tetrahydro-8,9,10-trihydroxy-benzo-chamomile ring 4 (1H) -pyrene '300 ml tetrahydrofuran, 60 ml triethylamine according to preparation 1 or 1 a And 12.9 ml of trimethyl borate were stirred at 20 ° C ± 2 ° C for 1 hour and 30 minutes. Add 30 grams of tosylsulfonium chloride and stir at 20 ° C ± 2 ° C for 16 hours, then at 20 ° C ± 2 ° C for 10 minutes, and pour 900 ml of demineralized reaction medium To the stirred mixture of water and 150 ml of concentrated hydrochloric acid, 90 ml of tetrahydrofuran and 60 ml of dichloromethane were added. The resulting solution was stirred at 20 ° C for 1 hour, and then 150 mL of dichloromethane was introduced, and stirring was continued for 15 minutes, followed by decantation and re-extraction with 2 X 7 5 mL of dichloromethane. The combined organic phases were washed with 4 X 150 ml of demineralized water and re-extracted with 75 ml of dichloromethane, and concentrated under reduced pressure of 20 mbar until distillation had stopped at 50 t. In order to obtain 47.6 g of the sought-after product. Stage B: 9, 10-dimethoxy-8 — [[((4-methylphenyl) catSI group] oxy]-2 '3' 5 '6-tetrakis-benzo chamomile ring-4 (1 ))-Ketone paper size applies to 10 national standards < CNS) A4 size (210 X 297 mm) -62- --------------- Order --------- -(Qi first read the notes on the back and then fill in this page) 45 89 63 A7 B7 V. Description of the invention 怦) 4 7.6 g or more of the tritium obtained, 300 ml of digas methane, 300 ml Soda (2 N) '0.6 g of tetrabutylammonium bromide and ((read the unintentional matter on the back before filling this page) 30 ml of dimethyl sulfate was stirred at 20 t for 16 hours . Then introduce 30 ml of triethylamine to destroy the excess of dimethyl sulfate, the reaction medium is at 20 t ± 2. (: Stir for another 1 hour, and then add 150 ml of demineralized water, keep stirring 15 minutes, followed by decantation. The aqueous phase was re-extracted with 2 X 7 5 ml of dichloromethane, and the combined organic phases were washed with 3 X 120 ml of demineralized water, and then 120 ml of N-hydrochloride Wash with acid and 3 X 120 ml demineralized water, organic phase was Combine and dry on sodium sulfate, then add 120 grams of de silicone (60 mesh) at 20 ° C ± 2 ° C with stirring and stir at 20 ° C for another 1 hour, then Filtered, washed with dichloromethane and concentrated to dryness under reduced pressure at 50 ° C to give 47.4 g of the desired product. This crude product was purified by recrystallization from 390 ml ethanol, After distillation in 90 ml of ethanol, stirring was performed at 0 ° C ± 2 t for 3 hours. The residue was separated, washed with 30 ml of ethanol at Ot, and then dried under reduced pressure at 40 ° C to obtain 41. 1 gram of required product. (MP = 129 ° C). Printing stage of consumer cooperatives of employees of the Intellectual Property Bureau of the Ministry of Economic Affairs C: 9, 10-dimethoxy-8-hydroxyl-2, 3, 5, 6 —Tetrahydrobenzo chamomile — 4 (1H) —one 4.5 g of potassium base, and then 10 ml of triethylamine was added to the suspension, the latter containing 10 g of 9 obtained in stage B, 10 — Dimethoxy-8 — (((4-methylphenyl) sulfonyl) sulfonyl) —2,3,5'6-tetrafluorenylbenzo chamomile ring ~ 4 (1 Η) — ffi and 1 〇〇 MI-63- This paper is in standard size Gardeners Standard (CNS) A4 size (210x297 Kimiyoshi >? 458963 Ministry of Economic Affairs Intellectual Property Office HIGHLAND consumer cooperatives and India burn A7 B7 V. description of the invention (1) liter of methanol. The reaction medium is heated under reflux for 1 hour 1 and acidified by adding 20 ml of ethanol, and then 20 ml of water are added. The extraction was carried out with dichloromethane, the extract was washed with water, the solvent was distilled off under reduced pressure at 40 ° C and '5.7 g of the expected product was collected. Preparation 4: 2 1 3, 5,6 -tetrahydro-8-meryl-a-methoxy-benzo chamomile ring-4 (1H) -fluorene and 2,3,5,6-tetrahydro-9 ~ Radical 8-methoxy-benzo chamomile ring 4 (1H) -fluorene is equivalent to the preparation of 2 stages B, C, D, E and F, but using 3- (3,4-dimethoxy Phenyl) propionic acid started to perform this operation and gave 1.08 g of a crude product containing a mixture of monohydroxylated products (8—〇ί · ί / 9_〇Me and 9—〇H / 8_〇Me), which Chromatography was performed on silica using cyclohexane / ethyl acetate 丨 Kun # @ (7/3) as the eluent. In this way, the following 2 @g gioisomers (regioisomers) were obtained: 8 — OH / 9 — M e 0. 4 9 4 g Rf (cyclohexane / ethyl acetate 6/4) == 〇. 428 -〇Me / 9-〇H 0 · 0 4 1 g R f (cyclohexane / ethyl acetate 6/4) = 0.33 Preparation 5 · '2, 3' 5 '6: tetrahydro — 8 — 10-methoxy-benzo chamomile ring-4 (1H) -one and 2,3'5,6_tetrahydro-1 10-hydroxy-8-methoxy-benzo chamomile ring 4 (; 1 H) -m is equivalent to the preparation of 2 stages β 1 C 'D, E, and F, but this paper size applies the national standard (CNS) A4 specification < 210 X 297 cm) -64-— — — — — -III--II · I ί --- II (Please read the precautions on the back before filling out this page) 45 S963 A7 _________B7 V. Description of the Emperor 2) (谙 Please read the respected matters on the back before filling in this Page) Starting with 3- (3,5-dimethoxyphenyl) propanoic acid, this operation was carried out and 1.4 2 8 g of the monohydroxyl-containing product (8-0H / 1 0-〇Me and 1 O-OH / 8 — 〇Me) and a dihydroxylated product (8 — OH / 10 — OH), Analysis of surgery, on silica, using cyclohexane / ethyl acetate mixture (7/3) are separated. Preparation of 6: 2,3,5,6-tetrahydro-9-hydroxy-benzochamomile ring-4 (1 fluorene) -one in a manner equivalent to the preparation of 2 stages B, C, D, E and F, but with 3 -(4-Methoxy-phenyl) propionic acid was started to carry out this operation and 0.448 g of expected product was obtained. Dimethylation was performed using boron tribromide. (Rf = 0.15 cyclohexane / ethyl acetate 7/3). Preparation 7: 2, 3, 5, 6 —tetrahydro-8-hydroxy-benzo chamomile ring 4 (1 Η) — Ketone of Intellectual Property Bureau of the Ministry of Economic Affairs, printed by the consumer co-operative so as to be equivalent to preparation stage 2 B, C, D , E and F, but starting with 10-0 grams of 3- (3-methoxyphenyl) propanoic acid to perform this operation and get 2.9 grams of the expected product. Dimethylation was performed using boron tribromide. (Rf = 0 15 methylene chloride / ethyl acetate 9 5/5). Preparation 8: (DL) _4 —Bromo-2-(phenylmethoxycarbonylamino-65-) This paper size is applicable to China National Standard (CNS) A4 (210 x 297 public love) A5 8963 A7 B7 Ministry of Economy Wisdom Printed by the Shellfish Consumer Cooperative of the Property Bureau V. Description of the invention ㈣)) Methyl butyrate 25 g 2-amino 4-butyrolactone hydrobromide in 200 ml contains 24% gaseous hydrobromic acid The resultant in acetic acid was stirred in a sealed chamber at 12 0 3 C for 18 hours. The reaction medium was cooled to room temperature, returned to atmospheric pressure, concentrated under reduced pressure, and the residue was absorbed into 200 ml of methanol, and then the hydrochloric acid flow was bubbled for 2 hours while maintaining the temperature below 3 5 ° C under. The solvent was distilled off under reduced pressure and methyl 2-amino-4-bromomonobutyrate was obtained, which was absorbed into 250 ml of acetone and 100 ml of water. The solution was neutralized with 2 N soda ', and then Slowly add 3 5 ml of phenyl chloroformate. Stirring was performed for 4 8 hours, followed by filtration, extraction with ethyl acetate, the solvent was distilled off, the residue was chromatographed on silica (eluent: cyclohexane-ethyl acetate 7-3) and 27.9 g of the expected product was recovered. . M.P. = 90 t. Preparation 9: 4 Monobromo-2- (t-butoxycarbonylamino) butyric acid methyl ester 5.7 g of the 2-amino 4-bromobutyric acid methyl ester prepared in Preparation 8 at room temperature at 1 20 ml of methanol, 24 ml of triethylamine and 9 g of di-tert-butyl carbonate were stirred for 48 hours. The solvent was distilled off and the residue was absorbed into water and dichloromethane, and the solvent was distilled off. The residue was chromatographed on silica (eluent: cyclohexane-Ας〇Ε t — TEA7 — 3 — 0.5) And 1.575 g of the expected product was obtained, Rf di 0.52 ** Preparation 1 0: 4-(3-pyrimidinyl) 1 H-Mi 11 sitting 1-Propanol The paper size applies Chinese National Standard (CNS) A4 specifications mo X 297 male «) -66-I— J 11111 11! Round 11 ---- IJ i I (Please read the notes on the back before filling in this page) Member of the Intellectual Property Bureau of the Ministry of Economic Affairs 1-Printed by Consumer Cooperative 458963 A7 ___________ V. Description of the invention ㈣) 5 0 5 mg of sodium ethyl acetate is mixed with 12.5 ml of dimethylformamide, 1 g of 3- (1H-imidazol-4-yl) pyridine, and then 0.6 4 ml is added. Chloropropanol and stirring was performed at 55 ° C for 16 hours. The solvent was distilled off under reduced pressure, and the residue was chromatographed (eluent: C Η 2 C < 2 = -Me〇H98-2) and 1.015 g of the expected product was recovered = IR spectrum (CHC < " ) OH 3626cm_1 + combined heterocyclic 1601, 1578, 1551, 1499 cm'1 Preparation 1 1: Hexahydro-2H— 1,3_diazapyrene-2-ketofluorene—containing 3.3 g of nitroguanidine, 7 ml A suspension of water, 3.47 g of potassium base and 5 g of dihydrochlorinated diamine was heated at 65 °-70 ° C for 1 hour; 10.5 g of zinc was added, and stirring was performed at room temperature for 30 minutes, and then added 2 ml of acetic acid were all heated at 40 ° C for 1 hour, then filtered and 3 g of ammonium chloride were added, followed by 4 g of sodium bicarbonate. Extraction with dichloromethane was performed and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica (eluent: CHsC / a-MeOH-NHiOH-S — d-2) and 1.650 g of the expected product was recovered. Preparation 12: 33,4,5,6'7,73-Hexahydro 2- (propylthio) 1 hydrazone-benzimidazole monohydrobromide 1 g octahydro 2 hydrazone —benzimidazole 2- 2-thione And 1.3 ml of bromopropane were heated in 20 ml of ethanol under reflux until completely dissolved. Solvents This paper is sized for China National Standard (CNS) A4 (210 * 297 mm) -67- Packing -------- Order · -------- Thread Please fill in this page again) A7 5 8963 ___B7_____ V. Inventive furnace) Evaporate under reduced pressure, absorb the residue into a small amount of dichloromethane, add isopropyl ether > solvent evaporate under reduced pressure, the residue Recrystallization from isopropyl ether, the expected product was isolated and dried in a yield of 9 5% a • M. P. = 13 6 ° C. Example 1: 7-((4-(((Amino) iminomethyl) imine))-9,10-dimethoxy-1,2,3,4,5,6-hexahydrobenzene And chamomile ring-8-yl) oxy) -heptanoic acid stage A: 7- (4-monoketo) -9,10-dimethoxy-1, 2, 3, 4, 5, 6-hexahydrobenzo Camomile ring—8-yl) oxy) methyl ester of heptanoic acid—contains 684 g of 2,3,5,6-tetrahydro-8-hydroxy-9,10-dimethoxy-benzochamomile ring-4 ( 1H); ketone ----- ··· .L · _ (Preparation 3), 12 ml of dimethylformamide (DMF), 12 ml of tetrahydrofuran (THF), 0.7 g of potassium carbonate and 0. A suspension of 835 g of methyl 7-bromoheptanoate was heated at 40 ° C for 4 hours. After evaporation under reduced pressure, the crude product was chromatographed on silica using dichloromethane (C Η 2 C < 2) / Acetone mixture (9 5/5) to elute. In this way, Q 0 g of purified product was obtained as a yellow oil.

Rf CH.2C <2 / Acetone 95/5: 0.5 IR (CHC 《3) C 201 7 3 2 cm 1 〇 M e 1 4 3 8 cm 1 This paper size applies to China National Standard (CNS) A4 specifications ( 210 X 297 mm) I ------ · I--IIII ----- I 11 ^. {Please read the precautions on the back before filling this page. Consumption Hewang printed -68- A7 45 89 6 _B7_ V. Description of the invention) Conjugated ketone 1 6 4 1 C m 1 C = C 1 5 9 2 cm 1 '1 5 5 7 cm' 1 -1 4 9 2 cm &quot; 1 + Aromatic stage B: 7 a 4,5,6 hexahydro-benzo chamomile ring 8-yl) oxy) heptanoic acid 0.5 g of the product of the previous stage A, 5 ml of ethanol and 0.33 g of aminoguanidine hydrochloride The suspension was stirred at room temperature for 4 8 hours. The solvent was distilled off under reduced pressure and the crude product was chromatographed on silica using CH 2 C &lt; 2 / methanol (Me OH) / ammonium hydroxide mixture (8 ◦ / 2 0/4). In this manner, 0.466 g of purified product was obtained in the form of a white foam.

Rf CH2C &lt; 2 / Methanol (Me〇H) / Ammonium hydroxide 80/2 0/4: 0.8 1 R (Nuiol) Ν Η / Ν Η 2 3495cm-1, 3155cm 1 + Joint C = 0 1731cm. L_ C = N 1 6 7 4 cm 1 C = C 1 6 2 5 cm1 --------- Line (Please read the notes on the back before filling in this page) Printed by the Intellectual Property Bureau Staff Consumer Cooperatives of the Ministry of Economic Affairs The paper size is applicable to the National Garden Standard (CNS) A4 specification (210 X 297 Male S) -69-Printed by I-Consumer Cooperative of Intellectual Property of the Ministry of Economic Affairs 45 8963 A7 ---__ B7 V. Invention Description @ 7) E-E_C_: 7 ~ ((4 _ (((Amine group) Iminomethyl)) imino))-9,10-dimethoxy-1'2'3,4,5,6-'hexahydrobenzochamoyl-8-yl) oxy) heptanoic acid contains 0.44 g of the product obtained in the previous stage 'a solution of 5 ml of ethanol and 2 ml of 1 N soda was stirred at room temperature for 3 hours' and then neutralized with 2 ml of 1 N hydrochloric acid. After evaporation under reduced pressure, the crude product was purified by chromatography on silica using CH2C &lt; 2 / methanol (Me OH) / ammonium hydroxide mixture (80/20/4). In this way, 0.192 g of purified product was obtained, which was recrystallized from methanol. R f CH2C &lt; 2 / methanol (MeOH) / ammonium hydroxide 80/2 2 0/4: 0.17 NMR (D20 + 1 drop of 1N soda) 3. 9 2 w t 2 H C H a-〇

2-1 7 t 2 Η CiLa-COOH 1.34m 4 Η 1.55m 2 中心 Center CH.2's + CHj-c = 1.70m 4 Η _ 2. 50 to 2. 90m 8 Η 6.62 s 1 Η Aromatic Η 7 3.64 s 3 Η OC 1L. '

3.73 s 3 Η 0 C H_: J This paper size is applicable to China National Standard (CNS) A4 specifications &lt; 210 «297mm S) -70- Packing -------- Order -------- -Line &lt; Please read the notes on the back before filling this page &gt; A7 ___B7____ V. Description of the invention f8) Micro-analysis Ν 1 2. 2 1% Found C 6 2.9 Η 7. 5 Ν 1 2. 1 Example 2: 4-((4- (((amino) iminomethyl) imine))-9,10 -Dimethoxy_1,2'3'4,5,6—hexahydrobenzo chamomile-8-yl) oxy) butanoic acid Example 3: 5-((4-(((amino) imine) (Methyl) aziridinyl) -9,10-dimethoxy-1,2,3'4'5,6-hexahydrobenzochamoyl-8-yl) oxy) valeric acid Example 4: 5- ((4-(((Amino) carbonyl) imine))-9 '10-dimethoxy-1,2,3,4,5'6-hexahydro-8-benzochamoyl) oxy 5) Printing example of employee co-operatives of the Intellectual Property Bureau of the Ministry of Economics of Valeric Acid 5: 6 (((((amino) iminomethyl) imine) 9,10-dimethoxy-1,2,3'4'5'6-hexahydro-8-benzochamoyl) oxy) hexanoic acid Example 6: 5-(9,10-dimethoxy —1 '2,3' 4 '5,6 —hexahydro-4_ (4,5 —dihydro-1Η —imidolin — 2 —yl) imidino) — 8 —benzochamoyl) oxy ) Valeric acid ----- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm). Member of the Economic and Intellectual Property Bureau 1. Printed by the Consumer Association. M 89 6 3 A7 __________B7 5. Invention Explaining birch) Examples (.5 — ((4 (((amino) thiofluorenyl) iminylene))-9,10 -dimethoxy-1, 2 '3, 4, 5, 6 — Hexa + a-8 ~ benzochamoyl) oxy) valeric acid Example 8: 6- (4 ((4,5-dihydro-1Η-imidazoline- 2 -yl) imidino) -9,10 -Dimethoxy_1'2,3,4,5,6, hexahexahydro-8-benzochamoyl) oxy) hexanoic acid Example 9: 5-((4-(((amino) Aminomethyl) imimine) _9,10-dimethoxy-1,2,3,4,5'6 —hexahydro-8 — Benzochamoyl) oxy)-3,3- —methyl-4-keto-valeric acid Example 10: 5- (4 — ((4,5-dihydro-1H-imidazolin-2-yl) Imimine) _9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benzochamoyl) oxy) -3,3-dimethyl-1 4 a Examples of ketomonovaleric acid 1 1: 4-(4 (((4,5 -dihydro-1 fluorene-imidazolin-2 -yl) imidino) -9,10 -dimethoxy) -1, 2, 3, 4, 5, 6, 6-Hydroxy-8-Benzochamoyl) oxy) monobutyric acid The paper size is applicable to the national standard (CNS) A4 specification (210x 297 mm) -72- II — — — — — — — — -------- ^ — — — — — — — I— (Please read the notes on the back before filling out this page) 45 896 3 A7 _B7_ V. Description of the invention "0" Example 12: 4- ((9,10-dimethoxy-4-[(1, 4, 5, 6-tetrahydro-2-pyrimidinyl) imidino) -1,2,3,4, 5,6_hexahydro-8-benzochamoyl) oxy) -butanoic acid Example 13: 2-(4 ((4,5-dihydro-1H-imidazoline- 2-yl) aziridinyl) -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benzochamoyl) oxy) -acetic acid Example 14: 3 -(4 ((4,5 -dihydro-1H-imidazoline-2-yl) imine))-9,10-dimethoxy-1,2,3 &gt; 4,5,6-hexa Hydrogen_8_benzochamoyl) oxy) -propionic acid &quot; ---- 1ΙΪ! Order --------- line (please read the precautions on the back before filling, this page} Ministry of Economy Printed by Clear Hui Property Bureau employee consumer cooperatives -73- This paper size applies to Chinese National Standard (CNS) A4 (210 x 297 mm) 458963 A7 B7 V. Description of Invention π) Printed by Employee Consumer Cooperatives of Intellectual Property Bureau of Ministry of Economic Affairs Example starting product fluorinated product.g-nh2 Rf'⑴ 2 P3 Br * (CH ^) 2'C〇2 ^ C H2N-NH-C (= NH) -NH2 'HC1 0-rl2 3 P3 Br- (CH2) 4-C〇2Et h2n-nh-c (= NH) -nh2 .HC1 0,12 4 P3 Br- (CHn) ^ -C02Et H2N-NH-C (= 0) -nh2.hci 0,13 \ 5 P3 Br · (CH2) sC〇2Et H2N-NH-C (= NH) -nh2.hci 0,17 6 P3 Br- (CH2) 4-C〇2Et h2n-nh- ff KM .HBr 0,27 7 P3 BrMCH2) 4-C〇2Et H2N-NH-C (= S) -nh2.hci 0,2S 8 P3 Br- (C H2) 5-C〇2Et H2N-NH- ^ J.HBr HH 0,6 9 P3 BrCH2C (0) C (Me) 2-CH2C〇2Et H2N-NH-C (= NH) -nh2.HC1 0,3 10 P3 BrCH2C (0) CtMe) 2- CH2C〇2Et H2N-NH '/' .HBr 〇, s 11 P3 (CH ^) 3 &quot; h2n-nh- .HBr 0,3 12 P3 Br- (CH2) 3- C〇2EC H2N-NH- e // — \ .HBr • · '0,63 13 P3 ～ Br- (CH2) -C〇2Et H2N-NH- ^ | .HBr 0,3 14 P3 Br- (CH2) 2-C〇2Et HN-NH- 1 .HBr *, J HH 0,22 (1) Diazomethane / methanol / ammonium hydroxide 8 0/2 0/4 This paper size is applicable to China National Standard (CNS) A4 (210 ^ 297 Gong) -74-. I t ----- install -------- order if ------ line (please read the precautions on the back before filling in this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5 8 9 6 3 A7 __B7_ V. Description of the Invention β) Example 15: 5 — ((4 _ (((amino) iminomethyl) imine) —9,10 —dimethoxy-1,2,3,4,5,6 hexahydrobenzo chamomile ring — 8-yl) oxy) -valeric acid hydrochloride 86 6 mg of the product of Example 3 was mixed With 2 ml of water and 4 liters of 0.1 N hydrochloric acid, after a few minutes, the medium was spray-dried. This gave 91 mg of the expected product. Example 1 6: 4-((4-(((Amine) imine) methyl) imine) -8,9-dimethoxy-1,2,3,4,5,6 Hexahydro-1 0-benzochamoyl) oxymonobutyric acid Example 1 7: 5— ((4-(((amino) iminomethyl) iminoimino) -1,9-dimethyl Oxy-1,2,3,4,5,6—Hexahydro-1 0_benzochamoyl) oxymonopentanoic acid is used in the same manner as in Example 1 stage A | B and C, but using 2, 3, This operation was carried out starting from 5,6_tetrahydro-1,10-hydroxy_8,9-dimethoxy-benzo chamomile ring-4 (1 fluorene) -one (Preparation 2). Example Starting Product Alkylation Product G ^ Ν Η 2 Rf. 16 (ΙΙ) λ Br- (CH small-C ⑴Et H> N-NH-C (= NH) ^ NH2.HCI 0.07 17 (ιι) λ Br- (CH small-CChEt H: N -NH-C (= NH) -NH2.HCI 0.07 Example 1 8: 4 One ((4-(((Amino) iminoformamidine)) Asia Union This paper size applies Chinese National Standard (CNS) A4 specifications ( 210 X 297 mm) -75- ------------- install ---- a __ order --------- line (please read the precautions on the back first) Fill in this page) A7 458963 B7 Employee Consumption Printed by Sakusha 5. Description of the invention (Γ3) Amine group) 8,10—dimethoxy—1,2,3,4,5,6—hexahydro-9-benzochamoyl) oxy) — Example of butyric acid 19: 5 _ ¢ (4 — (((Amino) Sinylene) Methylene) Amine) -8,1 ◦ -Dimethoxy-1,2,3,4'5 ' 6_Hexamin-9-benzochamoyl) oxy) pentanoic acid is used in the same manner as in Example 1, stages A, B and C, but using 2,3,5,6_tetrahydro_9_hydroxy_8 This operation was carried out starting with 10-dimethoxymonobenzo chamomile ring 4 (1 fluorene) -one. Example Starting product Alkylation product G-NH2 Rf. 18 (II) e) Br- (CH〇3 -C〇2Et H] N-NH-C (= NH) -NHi.HCl 0.10 19 (π) E 丨 Br- (CH2) 4-C〇2Et H2N-NH-C (= NH) -NHz.HCl 0.07 Implementation 2 0: 4- ((4 ((4,5-dihydro-1—-imidazol-2-yl) imidino)) 1,2,3,4,5,6-hexahydro-9-benzene And chamomile) oxy) monobutyric acid stage A: 4 mono (4-monoketo) .- 1,2'3,4,5,6-hexahydrobenzo chamomile-9-yl) oxy) butanoic acid The ethyl ester contains 0.6 g of 2,3,5 '6-tetrahydro-9-hydroxyl-benzene And chamomile ring-4 (1H) -one (preparation 6), 12 ml of dimethylformamide (DMF), 12 ml of tetrahydrofuran (THF) 'Packing --- If order ------- --Line (please read the precautions on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) -76-4 5 8 9 6 ° a7 _____B7_____ 5. Description of the invention f4) (Please read the notes on the back before filling in this page) 〇 .7 g of potassium carbonate and ο, 7 ml of ethyl bromobutyrate suspension at room temperature overnight = after evaporation under reduced pressure, the crude product Chromatograph on silica and elute with a dichloromethane mixture (dichloromethane / acetone 9 5/5). • In this way, 0.68 mg of purified product was obtained as a yellow oil, 0IR (CHC ^ 3) C = 0 1728cm-1 conjugated ketone 1641cm'1 aromatic C two C one s 1610cm-1590cm — 1, 1569cm- ^ 1499cm_1 Phase B: 4 — ((4 — ((4,5 —dihydro-1H-imidazoline-2 —yl) imino)) — 1, 2, 3, 4, 5, 6-hexahydrobenzo chamomile ring 9-yl) oxy) -butyric acid ethyl ester 608 mg of the product of the previous stage A '10 ml of butanol and 600 mg of the following cyclic amine guanidine hydrobromide: (4 , 5 -dihydro_ 1 Η —imidazoline — 2 —yl) — hydrazine was stirred under reflux for 24 hours, dissolved in the incineration agent of the consumer cooperative of the employees of the Intellectual Property Bureau of the Ministry of Economic Affairs under reduced pressure, and the crude product was removed by Chromatography on silica was purified by eluting with CHC methanol (MeOH) / ammonium hydroxide mixture (80/20/4). In this way, 0.64 g of the expected product was obtained. IR (CHC ^ 3) = C-Ν Η-3 4 5 1 cm 1 C = 〇 1 7 2 8 c ra ι (ester) -77- This paper size is applicable to China Standard for Household Standards (CNS) A4 (210 * 297 male «) A7 458963 ___B7_____________ 5. Description of the invention P) C = N + C = C + Aromatic: 1627cm '(F) ^ 1 5 6 8 cm 1-1 5 4 8 cm 1' 1 4 9 7 cm! ' 1 4 8 8 cm1 Stage C: 7- ((4,5-dihydro-1H-imidazolin- 2-yl) imino) -1, 2, 3, 4, 5 1 6-hexahydrobenzo A solution of chamomile-9-yl) oxy) monobutyric acid containing 0 6 0 4 g of the product obtained in the previous stage '8 ml of ethanol, 5 ml of tetrahydrofuran and 2 ml of 2 N soda was stirred at room temperature for 4 hours, then Neutralize with 2 ml of hydrochloric acid. After evaporation under reduced pressure, the crude product was eluted by chromatography on silica with 'dichloromethane 0 (CH2CH2) / methanol (Me 0H) / ammonium hydroxide mixture (80/20/4) purification. In this way, 0.298 g of purified product was obtained, which was recrystallized from methanol.

Rf (dichloromethane / methanol / ammonium hydroxide 80/20/4): 0.2 NMR (D2〇) +1 1N soda) 1.71 (w) 2 H 0-CJL2-CH2-C0 1.96 ( m) 2 HC Η 2 in 2 position (cyclopentene) 2 · 3 0 (t) 2 H CHj — C〇 2.50 to 2. 75 8 H Cl2-C = 3 · 45 (ws) 4H C H_2 — N =

3. 8 9 (wt) 2 H Ph-O-CH.-C 6-7 0 (m) 2 Η H tn III H 8 The paper size is common to 47 national standards (CNS) A4 specifications (210 X 297 mm) ) --------------. IIIIIII ^ I --- III (Please read the precautions on the back before filling out this page) Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs Consumer Cooperatives -78- Economy Printed by the Consumer Cooperative of the Intellectual Property Bureau of the People's Republic of China 4 5 8 9 6 d A7 _ — B7 V. Description of Invention π) 7. 0 0 (d-J = 8) Η τ Example 2 1: 4-(4 ((4, 5-dihydro-1, hydrazone-imidazoline- 2-yl) imimine) ~ 1,2,3,4,5,6-hexahydro-8-benzochamoyl) oxy) -butyl The acid was carried out in the same manner as in Example 20, but with 0856 g of 2,3,5,6-tetrahydro-8-icyl-benzochamomile ring-4 (1H) -one (Preparation 7) and the operation was obtained. 2.9 g of expected product.

Rf (dichloromethane / methanol / ammonium hydroxide 80/20/4) 0.27 mm 2 2 5 _ ((8 — (((amino) iminomethyl) imine))-6 '7, 8 '9, 10, 1 1 Hexahydro-chamomile cyclo (5,6 — d) — 1' 3 —benzodioxanoxo-4-yl) oxy) -valeric acid stage A: 5_ ((( 4-keto) -9 1 10-dienyl, 2,3,4,5,6-hexahydro-benzo chamomile_9-yl) oxy) valeric acid 1) protection in an inert atmosphere, 4 4 2 ml of trimethoxyacetate and 2 ◦. 4 ml of triethylamine were added to 10 g of 2,3,5,6-tetrahydro-8,9,10 0-trihydroxy-benzo! Inch daisy ring one 4 (1 Η)-------------- install! I! — Order --------., Line (please read the notes on the back before filling this page) This paper size applies to China National Standard (CNS) A4 (210 * 297 mm) -79- Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 4 5 8 9 π A7 __B7 V. Description of the invention Γ) Ketone (preparation 1) in a solution of 1000 ml of tetrahydrofuran, while the temperature is maintained at 3 7 and 3 9 r The reaction medium is then stirred at room temperature for 3 hours. 2) Alkylation and deprotection

Next, 9.7 ml of ethyl bromo-5-pentanoate, 100 ml of dimethylformamide and 8.4 g of potassium carbonate were added and stirring was performed at 60 ° C for 2 days. The reaction mixture was then treated with 120 ml of water and 50 ml of 36N concentrated hydrochloric acid, and the mixture was stirred for 1 hour. Ethyl acetate was added to separate the organic phase and the aqueous phase. The organic phase was then decanted, dried and evaporated under reduced pressure. The crude product was obtained and purified by chromatography on silica, eluting with a cyclohexane / ethyl acetate mixture (70/30). 5.2 g of expected pure product were obtained.

Rf (dichloromethane / methanol 95/5) = 0.82 Rf (cyclohexane / ethyl acetate 70/30) = 0. 23 Stage B: 5— (((8-keto) -6, 7'8, 9,10,11 Hexahydro-chamomile cyclo (5 '6_d) — 1' 3-benzodioxo-4-yl) oxy) -valeric acid 2.5 g product obtained in the previous stage ' 17 ml of dimethylformamide, 3.6 g of CSF and 1.4 ml of dibromomethane were mixed at 60 ° C for 1 hour under an inert atmosphere. After filtration and washing with indanol, 'evaporation was performed under reduced pressure T, and the crude product was purified by chromatography on silica', eluting with a cyclohexane / ethyl acetate mixture (8 5/5) ... The paper size is applicable to the national standard (CNS) A4 specification (210x297); 80 -80- — — — — ——— IIII * ---- I order-I —- ----- (please first Read the notes on the back and fill out this page) A7 458963 B7_ V. Description of the invention) 1. 7g of expected pure product. (M. P. = 1 1 8 r). Rf (cyclohexane / ethyl acetate 80/20) = 0.25 (Please read the notes on the back before filling out this page> Stage C: 5-((8-(((amino) imine) imine Amidinyl) imino) -6,7'8,9,10,1 1-hexahydro-chamomile (5,6-d) _1,3-benzodioxo-4-yl) oxy) 5 51 mg of valeric acid and 4 67 mg of amine guanidine hydrochloride were mixed at 120 ° t overnight, and then chromatographed with dichloromethane / methanol / ammonium hydroxide The mixture (80/20/4) was eluted and purified to give 174 mg of the expected product.

Rf (dichloromethane / methanol / ammonium hydroxide 80/20/4) 0.98 ° stage D: 5 — ((8-(((amino) iminomethyl) imine))-6,7, 8,9,1 0,1 1-Hexahydro-chamomile cyclic (5,6 — d) — 1,3 —benzodipuro-4 —yl) oxy) — Consumption by employees of the Intellectual Property Bureau, Ministry of Economic Affairs The cooperative printed 274 mg of the product obtained in the previous stage and 1.86 ml of 1 N soda were mixed at room temperature for 1 hour and 30 minutes, and then the mixture was neutralized with a 1 N hydrochloric acid solution and evaporated under reduced pressure. " The crude product was purified by chromatography I eluting with a dichloromethane / methanol / ammonium hydroxide mixture (80/20/4). 141 mg of the expected product was obtained. R f (dichloromethane / methanol / hydroxide series 8 0/2 0/4) -81-This paper size is suitable for CNS A4 specification (210 X 297 mm) d 5 8 9 6 3 A7 _____-___ B7_____ V. Description of the invention f9) 0.23 NMR (D Μ S Ο) (Please read the notes on the back before filling in the reference page) 1- 55 to 1.9 (111) 41 ~ [

O-CHz-Cl · ^,-CH_2-cH2-CO

1-55 to 1 9 (m) 2H CH2 is in the second position (cyclopentanamine) 2. 2 6 (t) 2 H c Η_2 -c〇2- 65 to 3.00 (m) 8H C [2-C = 4-07 (t) 2H 0-c fi_2 -CH2- 5 · 9 5 (s) 2 H-0-c ϋ_2-0 6. 6 1 (m) 1 Η H 8 Move H 's (width 111) NH -C (= NH)-NH2 Example 2 3: 5 — ((8 — (((amino) iminomethyl) imine))-2,2-diphenyl-6,7 &gt; 8 , 9,10,1 1 Hexahydro-Chamomile Cyclo (4,5 — e) — 1, 3 —Benzodioxo-4 —yl) oxy) _Printed by the Employees ’Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs The procedure was performed in the same manner as in the previous example, starting with 374 mg of the product obtained in stage A of the previous example and 0.19 ml of diphenyldichloromethane. This gave 1 g of 8 mg of the expected product.

Rf (dichloromethane / methanol / ammonium hydroxide 80/20/4) = 0.17 Example 2 4: 0-[4 — [[4,5 —dihydro-1 1 Η —Mitte —quotation — -82- The standard is applicable to the national standard (CNS) A4 specification (2 Ιχχ297 mm) 45 89 6 3 A7 B7 V. Description of the invention ㈤) 2 -yl] imilidene]-9 '1 〇-dimethylamino group _ 1 '2' 3, 4, 5, Θ hexahydro-8-benzochamoyl]] N — [(benzylmethoxy) carbonyl] — DL-homoserine phase 4: ◦-[(4 — Keto) -9,10-methoxy_1,2,3,4,5,6-hexahydro-8-benzochamoyl] -N _ [(phenylmethoxy) carbonyl] _DL- Homoseric acid 0.6 g 2,3,5,6 -tetrahydro-8-transyl-9,10-dimethoxy-benzo chamomile ring 4 (1H) -one (Preparation 3), 10 ml Dimethylformamide (DMF), 10 ml of tetrahydrofuran, 1 g of potassium carbonate and 0,867 g (DL) of 4-bromo- 2-(phenylmethoxycarbonylamino) butanoic acid (as in the preparation (Prepared as indicated in 8) perturbed at room temperature overnight ° Evaporated under reduced pressure 'crude product in sand Chromatography on the stone was eluted with dichloromethane (CHsC ί 2) / propanium mixture [9 5/5]. In this way, 1.16 g of purified product was obtained as a yellow oil. IR (CHC ^ 3) C = Ο 1 7 4 0 C m 1 (sh.)-17 2 1 cm 1 conjugated ketone 1 6 4 2 cm1 aromatic C = s 1593cm1- 1559cm1 '1508cm1- 1 49 3 cm1 stage B: ◦ a [. 4-[(4,5-dihydro-1H-imidazole-2 — 坫) lS hydrazine] -9, 10 —dimethylamino-1, 2, 3, Xia- ---— I order --------- line &lt; Please read the notes on the back before filling in this page) This paper is also applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ) -83-A7 4 5 89 ____B7_____ V. Inventive furnace) 4,5 1 6 -Hexahydro-8 -benzo chamomile ring] -N [[benzene_methoxy) carbonyl] -DL-homoserine 5 39 mg of the product from the previous stage A, 15 ml of butanol and 600 mg of the following cyclic aminoguanidine hydrobromide: (4,5-dihydro-1H-imidazol-2-yl) -hydrazine at 120 It was stirred for 24 hours at ° C, the solvent was distilled off under reduced pressure, and the crude product was chromatographed on silica with CH2C methanol (MeOH) / dihydrogen hydroxide mixture (80 in this way, 0.6 4 1 g cm-1 + joint

s h.) 1 1 7 2 0 c m ^ 1 I Amine I I: 1 6 6 7 c m — ((F), cm'lj 1490 cm 1. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs / 2 0/4) Elution and purification 0 Expected product □ IR (C Η C t 3) Two C one N Η one 3 4 5 1 C = 〇1 7 4 0 C m ^] 1 (ma X) C = N + C = C + Aromatic + 醯 1 6 0 6 C m 1 5 0 8 Stage C: 〇— C 4 ((4-based) imimine) — 9 &gt; 1 0 1 5) 6 — -1 ^ hydrogen — 8 — benzooxy) m-based] — DL — Kose contains 0 6 g neutralized with 2 ml of hydrochloric acid and 2 ml of 2 N soda solution 〇 Chromatography on pressure stone with C Η 2 (〇 丨 ί 〇 / This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) (Jing first read the precautions on the back before filling in this page) —Dihydro—1 hydrazone —Mitriol 2 — —Dimethoxy-1,2,3,4 Camomile ring] -N-[(Phenylmethanine product obtained in the segment, 10 ml of ethyl in the chamber Stir for 2 hours at room temperature and then evaporate under use. The crude product was vaporized by ammonium-84 in silanol (Me OH) / M. A7 B7___ JL printed by the property co-operative consumer cooperative, and description of invention 2) The mixture (8 0/2 0/4) was eluted and purified. In this way, 0.3 4 g of purified product was obtained, which was obtained from methanol. R f CH2C &lt; 2/2 / methanol (MeOH) / ammonium hydroxide 80 / '20 / 4 = 0.37 Example 2 5: 0 — [4 — [(4,5 —dihydro-1H-imidazole-1 2-yl) fluorenylamino] -1,2,3,4,5,6-hexahydro-8-benzochamoyl] -N-[(phenylmethoxy) carbonyl] -DL-homoselide The acid was carried out in a manner equivalent to Example 24, but with 0.428 g of 2,3,5,6-tetrahydro-9-hydroxy-benzochamomile ring 4 (1H) -one (Preparation 7). This gave 2 4 5 mg of the expected product.

Rf CH £ C methanol (MeOH) / ammonium hydroxide 80/2 0/4: 0.5. Example 2 6: 0 — [4 — [(1,2,3,4_tetrahydro-6—pyrimidinyl) imidino] 9,10—dimethoxy—1,2,3,4,5, 6-hexahydro-8-benzochamoyl] N-[(phenylmethoxy) ring] DL_serosenic acid stage A: 0-[9, 10-dimethoxy-1, 2, 3,4,5,6-hexachloro-4-4 [[(1'4,5,6-tetraki-2-didrimidinyl) imidino] 8-benzochamoyl] N-[(phenyl Metal gas I I ----- I ϊ I ---- ^ ------ f I (Please read the note f on the back before filling in this page) This paper size applies to Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) -85- 4 5 89 A7 B7 V. Description of the invention Group) Carbonyl group] DL—mono-bromo compound of ψ ester of homoseric acid 200 mg of product in 2 ml of ethanol obtained in Example 24, stage A and 74.5 'mg of tetrahydro-2 (1 Η) _pyrimidinone 腙 monohydrobromide were started and heated under reflux 16 hours to implement this operation. The reaction medium is returned to room temperature 'and extraction is carried out with dichloromethane, the extract is dried, the solvent is distilled off under reduced pressure and 15 2 mg of the expected product are obtained. Stage B: 0_ [4 _ [(1'2,3,4-tetrahydro-6-pyridinyl) imidino] 9,10-dimethoxyl1,2,3,4,5,6 — Hexahydro-8-benzochamoyl group] N — [(phenylmethoxy) carbonyl] DL_homosenic acid In the manner of Example 24, stage C, 1 3.1 mg of the product obtained in the above stage A was used. (It is in the form of a solution in 1.3 ml of ethanol) and 0.43 ml of N soda to perform this operation. The reaction medium is neutralized by adding N hydrochloric acid, the solvent is distilled off and after filtering and drying, 78 mg of expected product was obtained. M.P. = 172 ° C. ------------- Installation .----- Order --------- Line {Please read the precautions on the back of the card before filling out this page &gt; Intellectual Property of the Ministry of Economic Affairs Bureau staff consumer cooperative printed spectrum c light o R 9 M '· Nl ™ 12 3 o 6 3 2 mmmc D c Η H 2

Upper position 9th in 2 Η C Η c in heart 0 8 7 6 4 7 2 3 3 to / [\ / 'H) (8 H 8 (4 7 o (0) 3 .m) 3 ws Η c I c H c) IHN 9 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -86-Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 4 5 89 b V. Description of Invention § 4) 4. Ο 1 (m) (1 Η) 4 4. 6 7 (p) '5. 14 (ws) 6.13 (d) 6.49 (ws) ~ 7.36 (m) (5 H) A7 B7

= C — OMe 's 7 Φ-0-C H j = C- CH-N-C COO-CH2 — (D = C-NH-CH H., Φ — C

7: 0 — (9,10 -dimethoxy4 5, 6 -hexahydro 4- [(1,4,5,6-tetrahydro 2 -pyrimidinyl) imino]] 8-benzo Camomile) -N-[(phenylmethoxy) curtain] DL-(2,3_ tris-propyl) ester of homoserine A: 0-[9,1 0,6-hexakis 4- 〔(1 4 &lt; Please read the notes on the back before filling in this page) 4 A tetrahydro_ 2 _ pyrimidinyl group] 8-benzo chamomile ring group] N — [(phenylmethoxy ) Carbonyl] DL-homosenic acid [(dioxolane-4-yl) methyl] ester 2-methyl 3-.3 g of the product prepared in Example 26 in 1 ml of methylformamide and 1 ml G of dichloromethane

Aminopropyl) 3-ethylcarbodiimide hydroxenide and 68 mg of 1-hydroxybenzotriazole hydrate were cooled to 0 ° C. The mixture was stirred for 30 minutes at the slaughter temperature, and 0.06 ml of solketal was introduced. R This paper size applies the national standard (CNS) A4 (210 X 297 mm) -87- A7 B7_ 5 、 Invention note 垆) (Please read the precautions on the back before filling in this page) Continue stirring for 3 hours and 30 minutes. The reaction medium was diluted with water, extracted with dichloromethane and 0.6 g of crude product was recovered, which was chromatographed on silica (eluent: C Η 2 C &lt; 2 — M e 〇 Η 9 0 — 1 0) and purification. 0.352 g of the expected product was obtained. IR spectrum (C. HC ί 3) NH 3400cm- 1 C 20 1745 (sh), 1719cm-1 C = N 'C = C} aromatic, amine I 1} 1672 (F), 1645' 159 7, 1565 (f) -1507 * 1492cm1 Stage B: 〇- (9,10_dimethoxy1,2,3,4,5,6-hexahydro-4- [(1,4,5,6-tetrahydro Hydrogen-2-pyrimidinyl) imilidene] -8-benzochamoyl) -N-[(phenylmethoxy) carbonyl] DL- (serine) (2,3-dihydroxypropyl) ester of homoserine 0.32 g of the product obtained in the Phase A of the Intellectual Property Bureau employee consumer cooperative printed in 3 ml of ethanol and 1 ml of 2 N hydrochloric acid, and stirred at room temperature for 6 hours. After evaporation of the solvent and chromatography on silica (eluent: C C 2 C &lt; 2-Me e Η Η -ΝΗ, ΟΗ-80-20-4), 0.112 g of the expected product was obtained. NMR spectrum (CDC &lt; 3) 1. 8 8 (m) (2 Η)} 1.98 丨 Center C Η ″ 's and C 上 2 at the 9th place 丨 2 -88- This paper size applies to Chinese national standards (CNS) A4 specification (210 * 297 mm) 4 5 8c A7 _B7_ V. Description of the invention 2-36} 2 · 60 to 3.10C8H)-C-C Η 2 (Please read the notes on the back before filling (This page) 3. 4 3 (m) (4 Η) = Ν-Ν-C Η 2 3-7 9 (s)} 3.81} Φ-Ο Μ e 3,6 ◦ to 3. 90 Ο — CH2-CH -〇

~ 4 00 to 4.30} C〇〇 一 CH2 — CH} 0-0-CH2-CH2 4.64 (m) (1 H) = C — CH — N— C =

5. 1 3 (s) COO-CHi-O 6 · 3 5 (s) H 4 7.20 to 7.38 Φ-C ^ s Example 2 8: 0- [4 — [(4,5-dihydro1H-imidazole— 2-yl) aziridinyl] 9,1 ◦-dimethoxy1,2,3,4,5,6-hexahydro-8-phenylchamoyl ring] N-[(8-quinolinyl) Sulfonyl] DL-DL-homoserine acid, Intellectual Property Bureau, Ministry of Economic Affairs, Employee Consumption Cooperative, Printing Phase A: 0— (9,10 —dimethoxy1,2,3,4,5 • 6-hexahydro_4_ Keto 87 benzochamoyl) ((1, 1-dimethylethoxy) carbonyl) DL-homoserine methyl ester 4.1 g of the product prepared in Preparation 3 and 5 g in Preparation 9 The prepared esters are stirred at room temperature in 50 ml of dimethylformamide and 50 ml of tetrahydrofuran in the presence of 5 g of potassium carbonate and dimethylamine pyridine -89- National Standard (CNS) A4 蚬 (210 X 297 mm) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 458963 A7 __B7___ 5. Description of the invention θ) Mix for 6 5 hours. The solvent was distilled off under reduced pressure and the residue was purified by chromatography on silica (eluent: CC2C &lt; a -acetone 9 5-5) and 7.3 g of the expected product was recovered. IR spectrum (CHC &lt; 3) = C-NH 3 4 3 0 cm'1 C = 〇1744cm-1 (methyl vinegar) 17 10cm &quot; 1 (NH-B 0 C) 1 648 cm_1 (conjugated ketone) aromatic + Pyramine II 1593, 1559, 1493cm — 1st stage B: 〇1 (9, 10 — —methoxyl 1, 2, 3, 4 * 5 '6 — hexahydro 4 — keto 8-benzochamoyl) DL 10 ml of monohydrochloride of methyl ester of homoserine, hydrochloric acid in ethyl acetate was added three times to 6 g of the product prepared in stage A (which was added to 10 ml of ethyl acetate) Middle), and then stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure and 0.656 g of the expected product was obtained, which was used in this existing form in the following stages. Stage C: 〇- (9,10-dimethoxy1,2,3 ', 4,5,6-hexahydro 4-keto 8-benzo chamomile ring) N-[(8-napholinyl) sulfonate Fluorenyl] DL — homoserine 0.6 6 6 g of the product obtained above is absorbed into 5 € liters — — — — — — — — — I * I! I — II Order-1111 — 1 -(Please read the precautions on the back before filling in this page> This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) -90- 4 5 8 9 6 ^ Α7 Β7 Ministry of Economy Smart Finances Printed by the Bureau ’s Consumer Cooperatives 5. Description of the invention 柙) To methyl chloride, add 1 ml of triethylamine and 0.638 g of 8-chloropyridylquineline and stir at room temperature for 2 hours. After evaporating the solvent under reduced pressure and performing chromatography on silica (eluent: CH2C &lt; -MeOH 95 ~ 5), 0.956 g of the expected product was recovered. Stage D: 0 — [4 ~ [(4,5 —dihydro-1H —mimid —2 —yl) imine]] 9,10 -dimethoxyl 1, 2, 3, 4, 5 1 6 —Hexahydro 8 —benzochamocyclyl] N — [(8—Darklinyl) sulfofluorenyl] DL-homosenic acid methyl ester 0.9 g of the product from the previous stage A, 5 ml of butanol and 0 6 G of the following cyclic amine guanidine hydrobromide: (4,5-dihydro1H-imidazol-2-yl) hydrazine was stirred at 1 2 01 for 16 hours, the solvent was distilled off under reduced pressure and 0. 7 8 was obtained 6 grams of the expected product, which is used in this existing form in the following stages. Stage E: 0-[4 _ [(4,5-dihydro1Η-imidazol-2-yl) imidino] -9,10-dimethoxyl 1,2,3,4,5,6-6 Oxy 8-benzochamoyl group] N-[(8-fluorenyl) sulfofluorenyl] DL-wenserine contains 0.78 6 g of the product obtained in the previous stage, 5 ml of methanol and 2 ml of 2 The solution of Ν soda was stirred at room temperature for 2 hours, then neutralized with 2 ml of 2 NH hydrochloric acid and kept stirring for 10 minutes. After evaporation under reduced pressure, the crude product was purified by chromatography on silica, eluting with CΗ2C &lt; j -methanol-ammonium hydroxide mixture (80-20-4). — 翁 — II—, --- ----- ^ 'I ---- ml ^ f Please read the notes on the back before filling in this page) This paper size is applicable to National Standards (CNS) A4 specifications ( 210 X 297 mm) -91-458963 A7 Β7 (Please read the unintentional matter on the back before filling out this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Invention Note

• After recrystallization from methanol, R f = 0 4 0 (C H C 8 0-2 0-4) is obtained.

.NMR — spectrum (DMSO 1. 8 1 (ws) 2. 4 0 to 3 2 0 3 · 3 5 (w) 3 · 5 5 (ws) 6 · 6 3 (ws) 7 · 5 8 (dd) 7 . 6 7 (t) 8.19 (d), 8 · 2 8.45 (d) 8.90 (d) 7.31 (ws) 7.97 10.40 (f) 12.62 Example 2 9: 0-[4-[—Amino) iminomine] 9,1,5,6-hexahydro 8-benzoglycine 3-pyridyl) 1 hydrazone-imidazole-homoserine monohydrochloride to 3.8 g of the expected product. t ι — M s 〇 Η Ν Η I 〇 Η) C Η2 = C -C C 2 's = N-C Η 2 ^ s = C Ο θ s H 4 H, H '6 9 (d) H, and H, H 4 H 2}} mobile H &gt; s (4,5-dihydro 1 H-imidazole-2 0-dimethoxy 1, 2, 3, 4, chrysanthemum Cyclic group] N-[[3- —4- (1- 1-yl) propoxy] carbonyl] DL 〇-92-This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 4 4 5 8 0 A7 _B7_ V. Description of the invention 卯) (Please read the notes on the back before filling this page) Stage A: 4 — 〔[9,1 ◦-Dimethoxyl1,2,3,4,5, 6-hexahydro 4-keto 8-benzochamoyl] oxy] 2-iso-isocyanate methyl ester 450 mg of the amine obtained in stage B of Example 2 at 0 ° C at 10.2 10 ml of saturated sodium bicarbonate aqueous solution and 10.2 ml of dichloromethane were stirred for 10 minutes. 204 mg of triphosgene was added to the organic phase of the reaction medium in 2 ml of dichloromethane solution, stirred for 10 minutes, then Extracted with dichloromethane, the extract was dried, and the solvent was evaporated under reduced pressure And 430 mg of the expected product was obtained, which was used in this existing form in the following stages: Stage B: 〇- [9,10-dimethoxy1,2,3,4,5,6-hexahydro 4_ Keto 8-benzochamoyl group] N — [[3- — 4- (3-pyridyl) 1H —imidazol-1-yl] propoxy] carbonyl] DL — Consumption by employees of the Intellectual Property Office of the Ministry of Economic Affairs Cooperative printed 4.30 mg of the product obtained in stage A was cooled to 0 ° C in 20 ml of dichloromethane and 4 14 mg of the alcohol prepared in Preparation 10 (in 10 ml of dichloromethane) was added. Methane). The reaction medium was returned to room temperature and kept under stirring for 4 8 hours | the f agent was distilled off under reduced pressure, and the residue was chromatographed on alumina (eluent: CH2C &lt; 2-MeOH) And 298 mg of the expected product was recovered. Phase C: 〇 一 [4- [(4,5-dihydro-1H-imidazole-2-93- This paper standard applies to the ten national standards (CNS) A4 specifications &lt; 210 «297 mm) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 45896ο Α7 __Β7 ____ V. Description of the invention θ) — Group) Amine group] 9, 1 0 — Dimethoxy 1 , 2, 3, 4, 5, 6-hexahydro-8-benzochamoyl ring N — [[3- [4- (3-pyridyl) 1 fluorene-imidazole-1yl] propoxy] carbonyl] DL -'Homoserine monohydrobromide. The procedure was carried out as in Example 2 in the manner of stage 4 ', starting with 277 mg of the product obtained in stage B above and 164 mg of cyclic aminoguanidine hydrobromide in 13 ml of butanol. Chromatography on alumina (eluent: CH2C "2-Me0H95-5), 298 mg of the expected product" IR spectrum (CHC, 3) C-0 1746 (sh) 1723 (max) cm-1 Conjugation system} + Aromatic} 1668, 1625 (F) &gt; 1 5 9 9 (sh) 1 1551 * 1509 1 1489cm 1 + pinamine II} 〇H 3 6 18cm-1 Stage D: 〇 一 〔4 — [(4,5-dihydro-1H-imidazol-2-yl) imidino] 9,10-dimethoxy1,2,3,4,5,6-hexahydro8-benzochamomile ] N — [[3_ [4- (3-pyridyl) 1H-imidazol-1-yl] propoxy] carbonyl] DL-monoseric acid monohydrochloride. 0 _ 3 ml Ν soda is added to 2 7 7 mg of the product obtained in stage 丨: Phase C (which is in 10 ml of ethyl alcohol), and mixed with 3 0 This paper size applies Chinese national standards (CNS &gt; A4 size (210 X 297 meals) -94- --------- I --- install --------- order ------- line (please read the note on the back first) Please fill in this page again) 45 89 6 A7 B7 V. Description of the invention p) Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs and added 10 ml of water) Anti-Jris medium using N hydrochloric acid P Η 2 &lt; 5 The solvent was distilled off the residue under reduced pressure on silica. Eluent: C 剂 2 C tt 5 —— -M [e C 丨 Η Ι \ Γ Η ι 〇 〇 4 4 0 2) j The filtrate was under reduced pressure. Evaporation 1 Residue absorbed into iso-y Precipitate is filtered off 1 Dried and collected 1 2 6 mg of expected product N MR spectrum (D Μ S 0) 1 • 7 8 (m) (2 Η)} 1 • 9 0 to 2 ♦ 3 0 (m) (5 Η)} 3 One C Η 2 1 • 6 0 to 2 9 0 (m) (8 Η) C Η 2-One S 3 * 5 3 (ws) ( 4 Η) Ν — C Η 2 C Η; 3 * 6 9 (s) t 3-7 1 (S) C Η 3 0 -C: 3. 9 0 to 4 2 0 (m) (7 to 8 Η) C Η 2 C Η 6 • 7 3 (s) Η 4 7. 2 0 (d 1 wide) C 0 — Ν Η — C Η 7 • 3 5 (dd) Η-5 8 • 0 4 (d) Η 1 1 8 • 3 7 (wd) Η-e 8 9 4 (ws) Η-2 7 2 (s) t 7 8 0 (S) C Η imidazole S and examples 3 0: 5 — [〔4 — [( 4,5 -dihydro-4 monoketo 1 H -imidazol-2-yl) imine group] 9, 10 -dimethoxyl 1, This paper is in accordance with China National Standard (CNS) A4 (210 x 297 mm) -95-(Please read the notes on the back before filling out this page) ο · :: Λ5 ^ Α7 Β7 Printed by the Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the Invention ㈤ 2, 3, 4, Acid The product was in 6 ml_ of ethyl acetate at room temperature. Solvent C Η 2 C — m-ethyl. 1 NMR spectrum of the expected product in milligrams of the expected product after being mixed with the reaction medium ~ 1. 7 3 (C Η 2 2-3 0 (t 2. 3 0 to 3 3. 7 3 (s 3. 8 3 ( w 4 0 2 (t 6 · 7 6 (s 7. 2 0 (w 8 · 2 8 (w 12-04 (5, 6-hexahydro 8-benzochamoyl) oxy) 3 0 in pentanol 0 mg was prepared in Example 3, stage A, and mixed with 61 mg of sodium bicarbonate and 0.7 ml of ethyl bromide. The residue was chromatographed on a stone (eluent: MeOH95-5) and 1 39 mg of Ten milligrams of this ester was 0.5 ml of 2 N threo 1 ml of ethanol at room temperature for 2 hours. In 2 N hydrochloric acid, the formed precipitate was filtered off, dried and recovered 4 4 (DMS. ) M) (6 Η)) (2 Η) .20) &gt; 3.75 Center C Η C-C Η s and the 9th position C — Ν — c. Η Φ — Ο — C Η!.! S) ( 1 Η)} s) (1 Η) 丨 Move Η 1 Η)} ---------- I-- · I ------- ^ in ------- (Please first (Read the note on the back and fill in this page)

C Window example 3: 〇 — [0 — 4 This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -96- 4 5 8 9 6 3 A7 ____B7___ V. Description of the invention β), 5, 6 —hexagas 4_ [(4 '5' 6 '7 —tetrahydro-1H — 1, 3 -diazacap — 2 —ylidenimine] 8 -benzo chamomile ring] N-[(benzene Methoxy) carbonyl) DL — homoserine • 1 g of the compound prepared in Example 2 Stage 4 A in 5 ml of ethanol and 0.9 g of the cyclic aminoguanidine prepared in Preparation 11 Mix for 16 hours at 130 ° C. The solvent was distilled off under reduced pressure, and the residue was chromatographed on silica (eluent: CH2C &lt; 2-MeOH90_10) and 0.8 g of the intermediate ester was obtained in 3 ml of methanol and 2 ml of 2 N soda in a chamber. Stir at temperature for 1 hour and 30 minutes. After neutralizing the reaction medium with 2 N hydrochloric acid and evaporating the solvent under reduced pressure, the residue was chromatographed on silica (eluent: C Η 2 C &lt; 2 — M e 〇 Η — NH .i Ο Η 90 — 15 — 2) and 22 g of expected product were recovered. Example 3 2: 〇_ [9,10-dimethoxy1,2,3,4,5,6-hexaaza 4_ [(3a'4'5,6,7,7a -hexahydro 1 Η-benzene Benzimidazol-2-yl) imidino] 8-benzochamoyl] N _ [(phenylmethoxy) carbonyl] DL_homosenic acid In the manner of Example 2 4 stages B and C, 2 0 0 Millions of the compounds prepared in Example A, Phase 4 and 176 mg of the cyclic aminoguanidines prepared in Preparation 1 2 were started to perform this operation. An intermediate ester of 102 mg was recovered, and 100 mg of this ester was used in the saponification reaction. Get 5 9 mg expected.

R f = 0.24 (CH2C ^ -MeOH-NH., OH 85-15-3). This paper size applies to Chinese national standard (CNS &gt; A4 size (210x297mm &gt; -------------------- I order --------- II (Please Read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs-97- 4 5 AW 'A7 B7 V. Description of the invention) Pharmaceutical composition (Please read the notes on the back before filling in this (Page) Preparation of tablets equivalent to the following: One product of Example 1 50 mg of an excipient (talc, starch, magnesium stearate) sufficient to make one tablet of 120 mg of the pharmacological study of the product of the present invention 11-Investigation of the substitution of the products of the present invention for binding: in vitro connexin (vitronectin) / in vitro connexin receptor (αΊ 3) Report: 100 / i &lt; human in vitro connexin (comparison) at 4 ° C rat 〇hg 〇 et. Diluent) to coat. MaxiSorp 96-well dish overnight. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. The holes were cleared. The ligand (connexin in vitro) is then fixed at room temperature under gentle stirring (see Fixing Buffer) for 1 hour. The wells are washed 6 times (see Washing Buffer), and the following are used as Sequentially add to each well:-40 g Μ dwell buffer_ 1 0 // &lt; dilution of the product to be tested ) —5 0 y &lt; Human α ... Ling :! Receptor (Comparison of Pytela et al. -98-) This paper is applicable _ National Standard (CNS) A4 (210 X 297 male; Ϊ) A7 458963 B7 V. Description of Invention ㈣)

Methods Enzymol (L 9 8 7) 144: 4 7 5) (diluent in holding buffer, depending on acceptor batch and ligand). Ligands, human av / 3 3 receptors and products to be studied at room temperature, • Incubate for 3 hours under gentle stirring. The wells were washed again 6 times, and then incubated at room temperature under mild stirring for 2 hours in the presence of 100 &lt; antireceptor. 4B 1 2 -HRP antibody was coupled to peroxidase (4 Β 1 2 -HRP antibody is diluted in incubation buffer. This dilution is used according to the recipient batch). Before the ligand-receptor binding was measured by a peroxidase display group (TMB Microwell Peroxidase Substrate System Kirkegaard: Ref.cat. 50-76-00), the wells were then washed 6 times. This group contains bottle A and bottle B (0.02% H2O2 in citrate / citrate buffer) containing a matrix (3'3-, 5,5 tetramethylbenzidine, 0.4g / &lt;). . The volume of 'A is temporarily mixed with the volume of B, and the reaction mixture is then distributed at a ratio of 1000 A pores. The in vitro connexin / av / 33 enzyme reaction developed for 12 hours, and then its development was stopped by adding 100 V &lt; 1M phosphoric acid. The optical density is measured at 450 nm. Buffering agent:-buffering agent for coating · carbonate 0. 05M, Na 0 Η Ρ Η 9.6-anchoring buffer: P β S (P 0 7) containing 0.5% β s Α 4) This paper size is applicable to the National Garden Standard (CNS) A4 (210 X 297 mm) -------- I I ---------- —Order ------ --- (Please read the precautions on the back before filling out this page) Printed by the Consumers ’Cooperative Act of the Economic Village Intellectual Property Bureau -99- Printed by the Economic Village Intellectual Property Bureau's Consumer Cooperative V. Description of the invention π)-Buffer for washing: PBS containing 0.05% Tween 20 (p Η 7 · 4)-Incubation buffer: 50 m TRIS pH7.4

• 0.5% B S A • 0 · 0 5% Tween 20 • 1 m M MnC "2 • 50 0 ^ M C a C ^ 2 • 50 0 ^ Μ M g C ^ 2 • 100 m M NaC". p-fruit expression: Find the following curve: as a function of the logarithm of the concentration of each product tested ′ Percent human connexin binding. For each product, IC50 I C50 — (B0 + Bmi η) / 2 B 0 = maximum binding in the absence of any product B m i η = minimum binding in the presence of the highest concentration of product.

2-Test on top of mouse head 1J Inject C a (C ac (2) in very few doses into pregnant female rats to measure the release from the cranial bone of newborn rats by measuring 1 ° C a. Bone loss. Molecular determination of bone loss activity, in vitro study; „— I— II —I— 'In--II t * Ϊ I — I --- (Please read the precautions on the back before filling out this (Page) This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) -100- Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 45896- A7 _____B7___ 5. Inventive Species) Product 1) The product to be tested contains Agent: DMSO, H20 / BSA (0, 1%) Dosage: Variable (10 μM in sieve analysis) 2) Reference product

Echistatin (refer to Η-9 0 1 0-BACHEM) Vehicle: Η 2 0 / BSA Dosage: 1 〇 # Μ 3) Radioactive tracer: C a C &lt; 2 in aqueous solution 4 5 C a —Reference c ES 3 AMERSHAM or NEZ-013 NEON. Vehicle: Physiological blood cymbal dose: 25 // Ci / mouse / 0.4 ml of culture medium with phenol red (refer to 04 1-0 1 53 5M / GI BCO) with 0.1% BSA and penicillin / streptomyces Streptomycin CMRL1066 ° Method 1) Inject 15 C a into pregnant rats (◦ f 1, strain = Switzerland) a) Preparation of labeling solution: 190 0 y &lt; 2 mci / d concentration &lt; Calcium mother solution was added to 6 ml of physiological blood pupa. b) Injection: This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 male; ¥) -101-------------- i I — II f order. --I I --- (Please read the precautions on the back before filling this page) 45 89 6 3 A7 __B7___ V. Description of invention) On the 17th day of pregnancy, rats received this solution by intravenous route. That is 2 5 μ C i / mouse. (Please read the precautions on the back before filling this page) 2) Removal of tissue (cranium above the head)) '6 days after birth, the newborn rat was decapitated 1 and then recovered the head and the skin was cut from the back of the neck to the neck front. The cranium was removed by cutting with scissors, and two punches (one on the left and one on the right) were cut from the top of the skull using a punch. One serves as a control 'and the other is used to test the product being investigated. 3) In the process of “淸 wash #”, each half of the head is placed in a well of a 24-well dish containing 1 ml of culture medium and 100 μm polyethylene and a nylex carrier to avoid all contact with the bottom of the well Λ 2 4 For one hour, the overhead polyethylene carrier was transferred to a new 24-well dish containing 1 ml of fresh medium and the product to be tested or its solvent. 200 culture medium from the first dish was removed from each dish and a first count of radioactivity (A 値) was performed. This modification of the medium allows the mechanical strain associated with removal to be eliminated. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 4)% Consumption Process After 48 hours of contacting the organization with the product under investigation, the medium of 0 0 # &lt; is removed from each well and counted (B 値) In order to determine the "5 Ca" released from the culture medium during the so-called depletion process, the head was completely demineralized in 1 ml of 5% trichloroacetic acid. After digestion, 2 0 0 v &lt; was also removed and Count to determine the -102- which is still contained in the bone. This paper size applies to the National Standard (CNS) A4 specification (210 X 297 mm) f5 8963 A7 ___B7 V. Description of the invention (00) Calcium content (c 値). The expression A% of bone loss is calculated for each half of the head (per well) as follows:

% Bone loss = dpmB / dpm (A + B + C) × 100 The sum of dpm A + B + C represents the amount of 4 5 C a combined in each bone part on the day of removal. To measure the effect of the product * the ratio of the percentage of bone loss in the treated wells and corresponding control wells was calculated for each point. The 値 that is found to be called the attrition index includes between 0 and 1, if the product inhibits bone loss and is greater than 1, and if the product increases bone loss. The average of 6 indices (as there are 6 points / group) for each product is then calculated to give an index / product. If this index is deducted by 1 値, the inhibitory power of the product is obtained, which can be expressed as a percentage. Furthermore, a statistical test is performed by comparing the points / points of the respective wear indices. — — — — — — — — — — — — — — — — — — II ^ ίιιιιιί {Please read the precautions on the back before filling out this page) Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives This paper is applicable National Standard (CNS) A4 specifications (210 X 297 mm) -103-3 6 9 8 5 4 A7B7 V. Invention description 0〇) Results Examples Competition test Vn / VR (((2 v accounts) combined with IC 5 〇en β Μ rat% inhibition rate at L 0 β M Example 2 0,45 19 Example 3 2,1-Example 6 0, IL 7,5 Example 8 2,79-Example 1 0 0, 8 8 Example 1 1 0,05 7 Example 2 2 2,36-Example 1 2 0,35 12 Example 1 4 0,75 14 Example 2 4 0,03 18 Example 2 0 0,079 1 1 Implementation Example 2 1 0,037-Example 2 5 0,013 26 Example 2 6 0,006 30 Example 2 7 0,170 39 Example 2 8 0,015 27 Example 2 9 0,028 18 Example 3 1 0,055 20 Example 3 2 0,035-^ I- -------------- (Please read the notes on the back before filling out this page). Home Standard (CNS) A4 size (210x297 mm) -104--

Claims (1)

4 5 89 6 3 Annex III (A): Chinese Supplementary Document No. 8011 ^ 48 Patent Application i Submitted in August of the Republic of China 458963 Physical data of the starting material (chemical compound). Ketone F = 155 ° C IR (CHC13) -OH 3540 cm'1 1641 cm'1 -c = c 1612 cm * 1 + aromatic 1568 and 1501 cmNMR (CDCla) 300MHz, H2 1.88 (m) OH 5.52 ( s) H7 6.58 (s) OMe 3.78 (s)-3.93 (s) 4 5 8 9 6 ::: / 1 * ten years I I i Supplement I VI. Patent Application Scope Annex A: Chinese Patent Application No. 861 13848 Amendment of the Chinese Patent Amendment R, July 1990, R, a compound of the type (I): 、 4 R. N — G (I) (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, π _ c :, where Ri is 101 [A]-[B]-CORs Among them, R6 represents a hydroxyl group, 〇1 ~ (: 6 alkoxy group or 〇-CH2-CH〇H-CH2〇H, [A] shows that it can be optionally substituted by a oxy group &lt;: 1-(: 6 Alkylene, [B] represents a CH [Z] group or a single bond, [Z] represents a NH ~ S〇2- Rc or a NH-C〇2- Rc, and R c represents a phenyl- (C i-c 4) alkyl, quinolyl or pyridinyl-imidazolyl (Ci-C4), R2 and R3 are the same or different, showing a hydrogen atom, a hydroxyl group, Ci-Ce alkoxy, or R2 and R3-the same Form —0— (Cl—C3alkylene) -10-yl or 0-C (phenyl 2) -0-yl, R 4 represents a hydrogen atom, R 5 represents a hydrogen atom, and order --- ---- The size of the paper is applicable to China National Standard (CNS) A4 (210 X 297 mm) 4 5 89 〇 A8 B8 C8 D8 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. NH — C (= X)-NH2 or a base of the formula Η π c i where X is not a sulfur or oxygen atom or NH, η represents 2 1 3, or 4 1 the dashed line shows an arbitrary second bond, and addition salts with acids and bases. 2 · As for the compound in the scope of application for item 1, wherein R6 is not one of the following groups: _〇Η 1 — 0CH.3, —OCH2CH3, — 0-CH2 — CH-CH2OH 'I OH, and. And and Addition salts of acids and bases. 3. The compound according to item 1 or 2 of the scope of patent application, wherein R 1 represents 0-(C Η 2) [-6-CH (Z)-COOH, and addition salts with acids and bases. 4. The compound as claimed in item 1 or 2 of the scope of patent application, where [Z] is -NH-C02-Rc group, RC is as defined in item 1 of the scope of patent application, and addition salts with acids and bases. 5. The compound according to item 1 or 2 of the scope of patent application, wherein G is a general formula -NH-C (= NH)-NHs group, and addition salts with acid and test. ----------- 'J Outfit -------- Order --------- Yin' &gt; (Please read the notes on the back before filling this page) This Paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 male dragon) -2- Α8 BS C3 D8 4 5 89 6 3 6. Application for patent scope 6. If you apply for the compound of item 1 or 2 of benefit scope, Wherein G represents the following heterocycle: class. IT n is equal to '(CH2) n N H — (CHZ) nH is an integer of 3 or 4, and an addition salt with an acid and a base 7. If the compound in the scope of patent application No. 6 'where G is the following (please read the precautions on the back before filling this page) Group η is an integer equal to 2 '3 or 4' and an addition salt with an acid and a base 8. As for the compounds in the scope of the patent application No. 1, each of them is: 4-((4-(Caminoiminemethyl) (Amino) imilide)-9 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1 0 -dimethoxy-1'2'3 benzochamoyl) oxy) -butyric acid 4,5,6-6 Gas 8 8 5 — ((4 — ((aminoiminomethyl) imine) —9, 10 —methoxy — 1 '2' 3 '4, 5 * 6 —hexamine — 8 —benzochamoyl) oxy) valeric acid * -5-((4-((aminoiminomethyl) iminylene))-8, 10-dimethoxy-1, 2 3,4,5,6-6-Hydrogen-9 A paper size is applicable to the National Standard for Difficulties (CNS) A4 (210 * 297 gong) -3- bj S3 AS BS C8 D8 t, Scope of patent application Chamomile) oxy) -valeric acid, -6-([4 monoaminoiminomethyl) imino) -9,1 0 -dimethoxy, 2,3,4,5,6 —Hexahydro-8—benzochamoyl) oxy) -hexanoic acid '—7— ((4-amine Iminofluorenyl) aziridinyl) -9,1 ◦ -monomethoxy-1,2 1 3,4,5,6 -hexahydro-8 -benzo chamoyl) oxy) heptyl Acid, '—5— ((9,10 —dimethoxy-1,2,3,4,5,6-hexahydro-4—1 ((4,5—dihydro-1H—imidazol-2-yl) ) Imimine)-8-benzochamoyl) oxy) -valeric acid, 5-(¢ 4-((aminoiminomethyl) imine))-9, 10-dimethyl Oxy-1,2,3,4,5,6-hexaargon-8-benzo chamoyl) oxy) -valeric acid ethyl ester hydrochloride, 4-((4-mono (aminoimino) (Methyl) imimine) -8,9 -dimethoxy -1,2,3,4,5,6-hexahydro-10-benzochamoyl) oxy)-butanoic acid, -5 -((4-monoaminoiminomethyl) iminomine) -8,9-dimethoxy_1, 2, 3, 4, 5, 6, 6-hexahydro-1 0-benzochamoyl ) Oxy) -valeric acid, 5-((4-(((amino) carbonyl) iminylene) -9, 10-dimethoxy-1,2,3,4,5,6_ six Hydrogen-8-benzochamoyl) oxy) ~ valeric acid, 5-((4-(((amino) thiocarbonyl) imidino))-9, 10-dimethoxy-1, 2 '3,4,5,6 -Hexahydro-8—C Please read the notes on the back before filling this page) Order --------- 嫜 v Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -4-Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy 58963 Jaw C3 DS, Scope of Patent Application Benzo camoyl) oxy Acid, 4-((4-((aminoiminomethyl) imine) -8, 10-dimethoxy-1,2,3,4,5,6-hexahydro- 9-benzochamoyl) oxy) monobutyric acid | 6-((4- ((4,5-dihydro-1H-imidazol-2-yl) imidino)) 9, 10-di Methoxy-1,2,3,4,5,6,6-hexahydro-8-benzochamoyl) oxy) -hexanoic acid, _5- ((4-[(aminoiminomethyl)) Hydrazine) -9, 10-dimethoxy-1, 2, 3 , 4,5,6 —Hexahydro_8 —benzochamoyl) oxy) -3,3-dimethyl-4 monoketo-valeric acid, —5-((4— ((4,5 — Dihydro-1H-imidazol-2-yl) iminylene) -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benzochamoyl) oxy )-3,3-dimethyl-4-keto-valeric acid, 5- (4-((aminoiminomethyl) iminylene) -9, 10-dimethoxy-1 , 2,3,4,5,6-Hexahydro-8-benzochamoyl) oxy) valerate, —4 — ((4 — ((4,5—dihydro-1H—imidazole) —2 -yl) imino))-9,10-dimethoxy-1,2,3,4,5,6_hexahydro-8-benzochamoyl) oxy) monobutyric acid, _5 -((8-((aminoiminomethyl) iminomine) -6, 7, 8, 9, 10, 1 1 hexahydro-chamomile cyclo (5,6-d) -1,3 _Benzodioxo-4-yl) oxy) ~ valeric acid, • ----------- * ------ f Order · ------- IV (Please first (Read the notes on the back and fill out this page) Standards are applicable to China National Standard (CNS) A4 specifications (210 X 297 public love.) -5- AS BS C3 D8 VI. Application for patent scope -5-((8-((aminoiminomethyl)) hydrazine Phenyl) -2,2--2-phenyl-6,7,8,9,]. 0,1 1-hexahydro-chamomile cyclo [4,5-e)-(1,3) -benzodioxo —4 monoyl) oxy) valeric acid 1-4 — ((9,10 —dimethoxy-1 —4 — ((1′4,5′6 —tetrahydro-2 —pyrimidinyl) —diamine Radical) —1,2,3,4,5,6—hexahydro-8—benzochamoyl / oxy) —butanoic acid, —2— ((4 — (4,5 —dihydro-1H —imidazole) -2 -yl) -iminolidene) -9,10 -dimethoxy-1,2,3,4,5,6-hexahydro-8-benzochamoyl) oxy) -acetic acid,- 3-((4- (4,5 -dihydro-1H-imidazol-2-yl) -iminolidene) -9 τ 1 0 -dimethoxy-1,2,3,4,5,6 -Hexahydro-8-benzochamoyl) oxy) -propionic acid 1-4- ((4- [4,5-dihydro-1H-imidazol-2-yl) -iminomine) -1, 2, 3 4,5,6-Hexahydro-8-benzochamoyl) oxy) -butanoic acid-4-((4-(4,5-dihydro-1H-imidazol-2-yl) -monoimido) ) —1,2,3,4,5,6—Hexahydro-8—benzochamoyl) oxy) -butanoic acid, —0-[4 [4,5—dihydro-1H—imidazole-2— Group) -iminomine group) -9,1 0 -dimethoxy-1,2,3,4,5,6 -hexahydro-8-benzochamoyl]] N _ [(phenylmethoxy ) Carbonyl] -DL —homosenic acid, —〇— [4 [(4 '5 — —Ga_1H — Taste_2 —Base) _ This paper size applies to China National Standard (CNS) A4 specification mo X 297 (.) (Please read the notes on the back before filling out this page) -------- Order ------------ ^. The Intellectual Property Bureau of the Ministry of Economic Affairs's Consumer Cooperatives printed the intellectual property of the Ministry of Economic Affairs Printed by the Consumer Cooperative of the Bureau, CS D8t, patented amine group) —i, 2, 3, 4, 5, 6, 6-hexahydro-8-benzochamoyl] _ N-[(phenylmethyl (Oxy) carbonyl] -DL —homoserine '-0 — [4 [(1,2,3,4-tetrahydro-6-pyrimidinyl) -iminomine) -9,10-dimethoxy-1,1,2,3,4,5,6-hexahydro-8 -Benzochamoyl] -N-[(phenylmethoxy) carbonyl] -DL-homosenic acid, -◦- (9,10-dimethoxy-1,2,3,4,5,6 —Hexaki—4_ [1,4,5,6—tetrahydro-2—dark dio]] imino)] _ 8_benzochamoyl]] N-[(phenylmethoxy) carbonyl]- DL — (2,3-hydroxypropyl) ester of homoserine, —〇- [4 [(4,5-dihydro-1H-imidazol-2-yl) -iminylene) -9, 1 0 —Dimethoxy—1,2,3,4,5 1 6—hexaamino-8—benzochamoyl) —N — [(8-quinolinyl) stilbenzyl] —DL-serine, 010- [4 [(4,5-dihydro-1H-imidazol-2-yl) -iminylene) -9,10-dimethoxy-1,2,3,4,5,6_ Hexakis-8-benzochamoyl) -N-[[[3- [4-((3-pyridyl) _1H-imidazol-1-yl] propoxy] carbonyl]] DL-homoseramine Monohydrochloride, a 5- [4- — [(4,5-dihydro-4-keto-1H —imidazol-2-yl) —iminolidene) — 9, 10 —dimethoxy— 1,2,3,4,5,6 —Hexahydro_8_benzochamoyl] oxy] pentanoic acid, this paper size applies to China National Standard (CNS) A4 (210 X 297 mm) --- ------- ---- 1 · * 1 ------ ^ ---------- Prostitute V r- (Please read the notes on the back before filling in this page) 458963 A8 B8 C8 D8 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs * 1 clothing Hal- [A]-[B] -C0Rs or the role of phosphine and azo) compounds, H0- [A]-[B] -C0R6 Sixth, the scope of the application for a patent a ◦ a [9, 1 ◦ a dimethoxy- 丄 '2'3,4,5,6 -hexahydro-4-[(4,5,6,7 -tetrahydro-1H — 1, 3 -diazepine cover 2 -yl) imimine]-8-benzo chamomile ring]-N-[(phenylmethoxy) carbonyl] _D: L-homoserine, -0 — [9,10-Dimethoxy__ 丄 '2'3,4,5,6 Hexagas — 4 — 丨: (33'4, 5, 6, 7, 73-hexahydro — 1 H -Imidazol-2-yl) subunit Yl] -8__ a benzo azulenyl] N - [(phenylmethoxy) carbonyl] _DIj a high serine. 9. A method for preparing a compound as described in item 1 of the patent application, characterized by a compound of formula (I I); Among them, R 2 'R 3, R 4 and R 5 are as defined in item 1 of the scope of patent application but are not hydroxyl groups, and are subjected to the action of a compound of formula (F) in the presence of a base, and (F1) is subjected to the formula of diethyl carboxylic acid in the presence of a base. (F — 1 (FO. ^ 1 ft I------ 1 ^ 1 τί. I--. Ϋ νΛ ^ «κ nn 11 n 1 I-eJ1 arc-I nn II— f— _ (please Read the notes on the reverse side and fill in this page) This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -8- 458963 Λ8 R8 CS 08 The scope of patent application where H a I is a halogen atom, [ A], [B] and R s are as defined in item 1 of the scope of patent application, [B] may also represent a C Η-group, P is an amine-functional protecting group |! Ν Η — ρ to obtain the formula (II 1 a ) Compound. 0 II Rg ——C- 巳 R : 〇R5 (I 工 工 a) (Please read the notes on the back before filling out this page)% Compound of formula (III a) is affected by compound of formula (F 3) HzN-G (F3) where G is as in the scope of patent application Definition of item 1 to obtain compounds of formula V a), which are equivalent to some compounds of formula (I):} ^ 衣 · ------- ^ 定 '-------- &quot; Ministry of Economic Affairs Printed by the Intellectual Property Bureau's Consumer Cooperatives 011% a c, B -N G (IVa) Applicable to this paper standard + national standard (CNS) A4 size mo X 297 public 芨 &gt; -9- 4 ^ 4 ^ Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs. FAJJc). 〇H A8 B8 C3 D8 6. If the scope of patent application is appropriate 'These two compounds are subjected to one or more of the following reactions in a suitable order:' Base or acid action, in order to cleave the ester and get the corresponding acid,-suitable for partial or The role of the reducing agent for reducing all unsaturation, the role of the hydrating agent of the triple bond, the role of the dealkylating agent, and the position of CO'-R6 when [B] shows a CH-NHP group The function of the N 剂 -P functional deprotecting agent, —from CORs; NH of the corresponding amine at the 3-position — s0 £ Rc, the formation of NH_CO2Rc group, in order to obtain the corresponding compound of formula (I) If appropriate, it is subjected to an acid or base to give the corresponding salt. 1 0 · A method for preparing a product of formula (I Ϊ) as defined in item 9 of the scope of the patent application 'where R2' R3, R4 and Rs are hydrogen atoms and 0Η is at the 8, 9 or 10 position, which It is characterized by (i) a compound of formula (a): (a) QU where 0— (A 1 k) is between or in the para position of the alkyl carboxyl group, (A 1 k) is as defined in the first scope of the patent application Under the action of halogenating agent to get the corresponding hafnium halide, ----------- D Pack -------- Order --------- Eat (Please read first Please fill in this page on the legal matters on the reverse side) ^ The paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -1〇- 468963 * · Six, the scope of patent application (1 丨) is subject to the formula R 0 v 8888 \} / ABCD b R (H) (b) where R (I) and R (II) are the same or different, showing alkyl groups containing 1 to 6 carbon atoms, or R ( &quot; and R &quot; &quot; together with the ^ atom it represents show a 5-6 membered saturated or unsaturated heterocyclic ring containing any other heteroatom selected from oxygen and nitrogen to obtain a compound of formula (c): ( Alk) 〇 0 i i ί) which is subjected to the action of a halogenating agent to obtain the formula (d This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling out this page} Λ} Install ---- Order 丨 ---- ^ ν -11- 45 896 3 A8 B8 C8 D8 〇 The scope of the patent application is subject to the application of a dealkylating agent to obtain a compound of formula (IIF), which is equivalent to the expected mono 'substituted product of formula (II): (IIF) Method of the compound of formula (II) as defined in range item 9 'wherein R2 is 0A 1 k group or 0- (C Η 2) 0-3 —A r group and R3' R4 and Rs ammonia atom, 0H And R2 is at the position of 8, 9 or 10, which is characterized by the compound of formula (a &gt;): ----- Ill --- / -------- subscription ------- -&quot; Smelling V (please read the note on the back 4 to fill out this page) fAJJc printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy) OH This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) (af) -12- 458963 AS B8 CS D8 t, among which the scope of patent application is, where R 2 and 0-A 1 k are located in alkyl carboxyl Between the acid groups or at the para position, they are sequentially reacted [1], (11), (ill), (1v), and (v) to obtain the product of formula (ί IG), which is equivalent to formula (II) The expected disubstituted product: 1 2. A method for preparing a compound of the general formula (II) as defined in item 9 of the scope of the patent application, wherein RdnRs represents 0— (A 1 k) or 0— (CH2) 0—a— (Ar) groups , R4 and R5 are hydrogen atoms, and OH is at the 9th position, which is characterized by the compound of formula (IIA): printed by M? Ο (HA) is subjected to the action of a dealkylating agent to obtain a compound of the formula [IIB]: This paper size applies the Chinese National Standard (CNS) A4 specification (210 * 297 mm) -13-1 ------- ----------- Order · -------, ^) &lt; Please read the notes on the back first. ^ Fill this page) 458963 ABCD VI. Patent Application Scope 0 (XIB) d The compound of the formula (I I B) is subjected to the action of a diol-type protective agent in an alkaline medium to selectively obtain the compound of the formula (I I c): 0 (IIC) Ύ ° The consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs prints the residues of the protective reagents in which ρ is a diol. 'And the role of the alkylating agent' and then the role of the deprotecting agent to obtain a compound of formula (I D), which is equivalent to the tri-substituted product of formula (II) having 0Ο at position 8: ----------------- Order ---------- ^ v (Please read the notes on the back before filling this page) This paper size is applicable to China Standard (CNS) A4 (210 X 297 mm &gt; -14-4 5 8 9 6 3 Α8 Β8 C8 D8 0 The scope of patent application (IID) or the compound of formula (IIB) is sequentially subjected to the protective agent of 1 to the phenol, and then the deprotecting agent to obtain the compound of formula (1 1 E), which is equivalent to Tri-substituted product of formula (II) with 0Η at position 9: -------- II ^^ ·!! (Please read the precautions on the back before filling this page) 0 (ΙχΞ) Order --------- ^ -Y Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 1 3. For example, the compound in the scope of patent application No. 1 and its pharmaceutically acceptable addition salt Class, which is used as a drug that inhibits binding (ie, antagonism) to connexin receptors in vitro. 14. The compound according to item 1 of the scope of patent application, and its pharmaceutically acceptable addition salts are used as medicines for inhibiting bone resorption. 15. The compound according to item 1 of the scope of patent application, and its pharmaceutically acceptable addition salts, which are used as medicines for bone loss diseases. The size of this paper is generally in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) -15- 4 5 89 6 A8 B8 C8 D8 6. Application for patent scope 16. For example, the compound in the first scope of patent application, and its A pharmaceutically acceptable addition salt, which is used as a medicine for preventing or treating osteoporosis. 17. A pharmaceutical composition for inhibiting binding to a connexin receptor in vitro, which contains at least one compound as the active ingredient in item 1 of the scope of patent application. 18 For the pharmaceutical composition of item 17 in the scope of patent application, f is used to inhibit bone resorption. 19. The pharmaceutical composition according to item 17 in the scope of patent application | It (is used for the disease caused by bone loss. 20. The pharmaceutical composition according to item 17 in the scope of patent application is used for treatment Or prevent osteoporosis. 21. — a compound of general formula (II), (II) printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 0 wherein R 2, R 3, R 4 and R 5 are as defined in item 9 of the scope of patent application, but these compounds do not include compounds of formula (IIC) and compounds, 3, 5, 6-tetrahydro-9, 1 0- Dimethoxy-8 8-hydroxy-benzo chamomile ring — 4 — (1H) — ketone and 16 (Please read the note on the back before filling out this page} This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm ·) 458963 A8 B8 C8 D8, patent application range-2,3,5,6 -tetrahydro -8,9 hydroxy -benzo chamomile ring _4_ (1H) _ ketomethoxy_ 1 (IIC) where p is as defined in item 12 of the patent application scope. 22. A compound of general formula (I I la), which is an intermediate product obtained by the method as claimed in item 9 of the patent scope, 0 Π -C B : 〇 R (Ilia) (Please read the notes on the back to complete this page) Among them, R2, R3, R4, and R apply for the 9th definition of patent scope. A Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs -17-This paper size applies to the Chinese National Standard (CNS) A4 (210 X 297 mm) V .. "| ί: Chinese specification of Patent Application No. 86113m (including Scope of patent application) Amendment of the application date of October of this year in the Republic of China ~ '_-- ·: Case number of September 23, 86 -------- Category 〇〇ic Ψ! 7〇σ 1Α / η Announcement This ^^ 8963 II patent says. The name of the invention, the novel name, the creator of the invention, Chinese and English, the in vitro 迚 knot egg Ι′ϋ (wifoncclin) receptor d V / 5 3 or other integrins with an amine exonectin as a ligand (丨 nlegrins) 2,1,5,6 · tetrakis-benzo <1> which binds to its natural ligands and has an inhibitory effect: 丨 · ju m derivative, its preparation method and its pharmaceutical composition_ ^ 2, 3,5,6-Tctrnhydrp-bci) z [c} azulcn derivatives inhibiting llie binding of vitroiieclin rccqjlor a olhci1 inlcgrins having vitronectin as ligand lo their natural ligand, their preparation pmccs.s pliarmncculical compositions containing (hem S0S residence v03 aiu) or the Séju * Bernard, Serge Dennis Carniato, Denis Gourvest, Jean-Francois (1) France (2) France 11) Pirehebe, France 20 Levi Saint-Lisse (3 France 20, route de Senlis, F 60330, Le Plessis Belleville, France 10, Avenue de l'Etang Neuf, F, Marcusses, France 91460, Marcoussis, Franc 12, 12, 1 rue de la Biberonne, F 77410, Claye-Soui1ly, Frani il) Roussel-Uclaf (2 Genentech il ! France 0 United States W France Romanville * Noz Road 102] 〇2, Route de Noisy, 93230 Rlomainvi 1] e, France! 2 South San Francisco, California, Poine, San Bruno 460 ⑴ Point 460 Bruno, South San Francisco, CA 94080-491) 0, USA Abandoned Claude, Vieillefosse, Jean-Claude 0 逹 瑞 · 温 恃 Winter, Daryl B. This paper is suitable for Sichuan, 丨., Valve Country 榡 挲 ί t, NS) Eight 4 Grid (2i () x 297 Public 漦) Binding. 41 4 5 8963 At noon (A): 86113S48 Chinese manual amendment page 円 Zhu Mingguo, August 89, printed by the Intellectual Property Bureau Employees Consumer Cooperatives of the Ministry of Economic Affairs 5. Description of invention θ) f Λ r (selected from oxygen 'nitrogen or sulfur (Atom) heterocycle), (ch2 A 1 K group (where A 1 k is not. A non-aromatic hydrocarbon containing 1 to 12 carbon atoms derived from saturated or unsaturated, straight, branched or cyclic, η et, A! · and A 1 k groups may be unsubstituted or substituted, or Ra and R b together with the nitrogen to which they are attached may represent a saturated or unsaturated, aromatic or non-aromatic helium heterocyclic ring. Arbitrarily contains one or more heteroatoms selected from oxygen, nitrogen or sulfur atoms. 'This group may be substituted or unsubstituted, —Re represents a radical, 0 — 厶 11 ^, 0-eight 1', 1 '' 1112, 1 ^? 1-A 1 k 'N (A 1 k) 2 or the remainder of the L or D amino acid, A, k and A r as previously defined and arbitrarily harvested or unsubstituted, —R2 and R3 are the same or different, showing a hydrogen atom, via a radical, 〇- A 1 k radical or 〇 (CHs) 〇 3 —Ar radical, A1 k and Ar are as previously defined, or R2 and R3 are formed together 〇 一 （CRdRe) η 〇-type ring, η is an integer of 1 to 5, R d and Re are each independently a hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, or a phenyl group, -R 4 represents a hydrogen atom, a halogen atom, and the following groups One group: hydroxyl, amine, nitro, cyano, CF3, fluorenyl or fluorenyl having 1 to 12 carbon atoms, alkyl, alkenyl, alkynyl, alkylthio, alkoxy, alkylamine Group, a dialkylamino group, a dialkylamino alkyl group, a dialkylamino alkoxy group, wherein the alkyl group contains 1 to 6 carbon atoms, —R5 represents a hydrogen atom, a hydroxyl group, a halogen atom, a 0-A 1 k group or ◦ One (CHz). ― 3 — Ar-based, A 1 k and Ar are as defined above. — The basic paper size of G expression G 1 applies Chinese National Standard &lt; CNS) A4 specification (210 χ 297 mm) nnn III n IIII n * — — — 1— ^ n * I u I n IE [r I (Please read the note i on the back before filling this page) 4 5 89 6 3 Annex III (A): Chinese Supplementary Document No. 8011 ^ 48 Patent Application i Submitted in August of the Republic of China 4 5 8 9 6 ::: / 1 * ten years I I i Supplement I VI. Patent Application Scope Annex A: Chinese Patent Application No. 861 13848 Amendment of the Chinese Patent Amendment R, July 1990, R, a compound of the type (I): 、 4 R. N — G (I) (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, π _ c :, where Ri is 101 (A)-[B]-CORs, Among them, R6 represents a hydroxyl group, 〇1 ~ (: 6 alkoxy group or 〇-CH2-CH〇H-CH2〇H, [A] shows that it can be optionally substituted by a oxy group &lt;: 1-(: 6 Alkylene, [B] represents a CH [Z] group or a single bond, [Z] represents a NH ~ S〇2- Rc or a NH-C〇2- Rc, and R c represents a phenyl- (C i-c 4) alkyl, quinolyl or pyridinyl-imidazolyl (Ci-C4), R2 and R3 are the same or different, showing a hydrogen atom, a hydroxyl group, Ci-Ce alkoxy, or R2 and R3-the same Forms —0— (Cl—C3alkylene) -10-yl or 0-C (phenyl 2) -0-yl, R 4 represents a hydrogen atom, R 5 represents a hydrogen atom, and order ----- ---- The paper size of the paper is applicable to China National Standard (CNS) A4 (210 X 297 mm)