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CN1092779A - The compound that can be used as the bone target medicine that has estrin structure - Google Patents

The compound that can be used as the bone target medicine that has estrin structure Download PDF

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CN1092779A
CN1092779A CN 93110919 CN93110919A CN1092779A CN 1092779 A CN1092779 A CN 1092779A CN 93110919 CN93110919 CN 93110919 CN 93110919 A CN93110919 A CN 93110919A CN 1092779 A CN1092779 A CN 1092779A
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compound
general formula
grams
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bone
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郑虎
翁玲玲
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MEDICINE INST HUAXI MEDICAL UNIVERSAL
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MEDICINE INST HUAXI MEDICAL UNIVERSAL
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Priority to CN 93110919 priority Critical patent/CN1092779A/en
Priority to CN 94111687 priority patent/CN1034942C/en
Priority to US08/338,505 priority patent/US5760214A/en
Priority to DE69426684T priority patent/DE69426684T2/en
Priority to RU94046140A priority patent/RU2138507C1/en
Priority to PCT/JP1994/000489 priority patent/WO1994021667A1/en
Priority to JP07786494A priority patent/JP3377856B2/en
Priority to EP94910542A priority patent/EP0643071B1/en
Publication of CN1092779A publication Critical patent/CN1092779A/en
Priority to US08/888,108 priority patent/US6028207A/en
Pending legal-status Critical Current

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Abstract

The present invention is to provide a kind of compound with above-listed formula.With the tetracyclines structure as the bone carrier that becomes, the piperazine oxyethyl group, the monoethanolamine of replacement or the amino polyoxyethylene glycol of replacement that replace are chain bridge, connect with one or two oestrogenic hormon through cyclopentanoperhydro-phenanthrene 3-, 6-or 17-position, can become the compound of the bone target medicine that is used to study and/or treat osteoporosis.

Description

The compound that can be used as the bone target medicine that has estrin structure
What the present invention relates to is a kind of compound that contains estrin structure, and specifically being a kind ofly can become the compound that has estrin structure and have the medicine of bone target function.
Osteoporosis is a kind of common disease that jeopardizes the senior health and fitness, particularly the women after climacteric or climacteric because the sex hormone level of body changes, is involved the change of parathyroid hormone secretion, cause body in-seam Calcium Metabolism Regulation to be affected, bone calcium is lost and is increased.Bibliographical information is arranged, good effect can be arranged with the treatment of oestrogenic hormon substitute.Discover that except that the internal secretion and hormonal readiness of influence and adjusting body, it also might work in osseous tissue oestrogenic hormon in vivo, showing has the acceptor that can combine with oestrogenic hormon to exist in the osseous tissue.This has just proposed new problem for oestrogenic hormon to the research of osteoporosis therapy mechanism and the development of medicine.But simultaneously, people also worry life-time service oestrogenic hormon except that influencing organism endocrine, the possibility that mammary cancer, uterus carcinoma sickness rate are increased.Therefore, it is strong to seek directional property, and the medicine that animal economy is influenced little prevention and treatment osteoporosis is essential.
Tetracycline medication comprises the local difference on indivedual substituted radicals, having essentially identical skeleton structure as tsiklomitsin, terramycin, duomycin and other derivative, is class antibiotic medicine commonly used.After it entered in the body, the deposition in tissues such as bone, tooth was the generally acknowledged and common side effect of of this class medicine, especially children or child also was limited or banned use of.Research report is arranged, oral or injected tetracycline medication, just can arrive the newborn position of bone in the body after 48 hours, still can not excrete in more than 70 day.According to these characteristics on the tetracyclines receptors bind in this class medicine and the osseous tissue, have it is applied in the research work that is called the bone double label method in the histological chemistry.Find in the research of the therapeutic action after tsiklomitsin is entered bone that tetracycline medication can promote gelatine proteic synthetic and to the restraining effect of osteoclast.This shows that all the bone characteristic that becomes of tetracycline medication paid attention to by people and be used.Can utilize the becoming the bone characteristic of tetracycline medication and to design a kind of compound that is expected to become for the medicine of research osteoporosis treatment mechanism and/or treatment osteoporosis be that the present invention is desired solves.
The purpose of this invention is to provide a kind of compound that has estrin structure and have the bone target medicine of bone characteristic that can be used as, for the research and/or the use of development osteoporosis remedy thing of osteoporosis treatment mechanism.
Compound of the present invention can be divided into three parts on structure, connect with chemical bond therebetween: estrin structure, tetracyclines structure and the chain bridge construction that it is coupled to each other.Its structure is that 3-, 6-in the chain bridge construction of 2-position acid amides N through containing 5 atoms at least and forming and the oestrogenic hormon cyclopentanoperhydro-phenanthrene structure in the tetracyclines structure or at least one position in the 17-position connect with ehter bond.This structural general formula is
Figure 931109191_IMG7
X in the general formula can for
Figure 931109191_IMG8
R 1Can be H or OH, R 2Can be H or OH,
R 3Can be H or CH 3, R 4Can be H, Cl or N(CH 3) 2,
R 5Can be OH or ketone group R 6Can for H or-C ≡ CH,
R 7Can be H or OH, R 8Can be OH or unsubstituted group,
R 9Can be CH 3Or (CH 2CH 2O) n-, the n in the formula is 1～5.
In the structure of above-claimed cpd (I), what connect with chain bridge by N through acyl is the general formula of tetracycline medication commonly used, for example, and R=R in formula 4=H, R 2=OH, R 3=CH 3The time, be tsiklomitsin; R 1=R 2=OH, R 3=CH 3, R 4It during=H terramycin; R 1=H, R 2=OH, R 3=CH 3, R 4During-Cl duomycin; R 1=R 2=R 3=H, R 4=NC(CH 3) 2The time be that diformazan is by tsiklomitsin; R 1=OH, R 2=R 4=H, R 3=CH 3The time be doxycycline etc.The present invention does not also lie in the structure that changes these tetracycline medications, and bone is inclined to and effect but will utilize this class medicine to become strongly with the osseous tissue bonded.Therefore all kinds of tetracycline derivant structures shown in the general formula all can be used in The compounds of this invention, that is, utilize the chemically reactive of acid amides N atom in its structure to link through chain bridge and oestrogenic hormon.
The main body of the chain bridge in the compound (I) is to replace oxyethyl group, and the number that wherein is the oxyethyl group that chain links can not wait for 1～5.The oxyethyl group of different numbers has determined the different lengths of chain bridge.After entering in the body, can utilize methods such as mark tracking, the bonding state of compound (I) in osseous tissue of understanding different chain bridge length can study tetracyclines and estrogens distribution situation and/or its space length etc. in osseous tissue all are very important data for mechanism research and drug development.The chain bridge of different lengths can be obtained by different ethylene glycol or polyoxyethylene glycol and derivatives reaction thereof.From chemical terms, connect with acid amides N in the tetracyclines structure for making this chain bridge main body, by being necessity and feasible through the methyne connection that formaldehyde is become with acid amides N condensation directly or indirectly with the terminal N atom that connects of oxyethyl group.For this reason, link with the oxyethyl group terminal carbon of chain bridge main body and the N atom that carries out condensation reaction can be a directly or indirectly form such as amido, substituted amido or piperazinyl.
Three positions of 3-, 6-in oestrogenic hormon cyclopentanoperhydro-phenanthrene structure and 17-are to be easy to connect substituent chemical reactivity commonly used position, thereby equally also all are can be used in The compounds of this invention and the joining position of chain bridge.Though in estrin structure, estradiol (R can be arranged with substituent difference on 16-, the 17-position 5=R 8=OH, R 6=R 7=H) female alkynol (R 5=R 8=OH, R 6=-C ≡ CH, R 7=H), trihydroxy-oestrin (R 5=R 7=R 8=OH, R 6=H) and estrone (R 8=OH, R 5Be the 17-ketone group) difference, they not only may be used to compound of the present invention, and since 3-and the 17-position in its structure have-Sauerstoffatom of OH or ketone group, therefore can be more convenient on these two positions with the chain bridge oxyethyl group in end position Sauerstoffatom be condensed into ehter bond and connect, when connecting with ehter bond with the 6-position, the chemically modified step that then will be necessary cooperates just can be finished.With aforesaid same meaning, chain bridge connects with estrogenic different positions, can obtain the compound that space length and/or sterie configuration, conformation are not quite similar.On the other hand, when two free oxyethyl group Sauerstoffatom ends are arranged in the chain bridge, this chain bridge also may connect two oestrogenic hormon cyclopentanoperhydro-phenanthrenes simultaneously, and the space length of the compound of gained and configuration, conformation are different again, and this all is very useful for development optimal treatment medicine undoubtedly.
The compounds of this invention can adopt following synthetic route and method to obtain:
Used main raw material compound is
Figure 931109191_IMG9
Tetracycline compound (IV), Paraformaldehyde 96 (V).
Figure 931109191_IMG10
C. modify oestrogenic hormon 16-earlier, 17 groups connect the tetracyclines structure then:
Figure 931109191_IMG11
What below introduce is the specific examples of compound of the present invention, but the scope of theme of the present invention is not limited only to these examples.
Example 1:
1 °, the female phenolic ketone of 3-chloroethoxy (compound IX) synthetic:
Female phenolic ketone 27.1 grams, chloroethyl-right-tosylate 22.2 grams and a little triethyl aniline vitriol add NaOH solution in toluene solution, make pH about 10, react 4 hours, and steaming desolventizes, and the solid ethyl alcohol recrystallization must compound (IX, wherein R 7=H), yield 79%, mp86-88 ℃, ultimate analysis: C72.4OH7.43Cl10.71.
2 °, N-(17-oxygen-female steroid 1,3,5(10) triolefin-3-oxygen ethyl) piperazine (compound VI) synthetic:
Last step product (IX) 7.8 grams, 120 milliliters of Piperazine anhydrous 46.6 grams and dimethyl formamides (DMF), 80～100 ℃ of reactions 5 hours, steam and remove DMF, the gained solid gets compound (VI) white crystals, yield 85% with ethanol-acetone recrystallization, mp140-142 ℃, ultimate analysis: C75.10H9.20N7.40.
3 °, N-[4-(17-oxygen-female steroid 1,3,5(10) triolefin-3-oxygen ethyl)-1-piperazine methyne]-tsiklomitsin (chemical compounds I) synthetic:
Last step product (VI) 3.8 grams, trioxymethylene 0.03 gram, 15 milliliters of Virahols after 2 hours, add tsiklomitsin 3.5 grams, stirring reaction 5 hours 40 ℃ of reactions.Reaction is finished, and filters, and after Virahol and ether washing, obtains product (the I) (R wherein of yellow solid 1=R 4=H, R 2=OH, R 3=CH 3).Yield 95%, mp160 ℃ of (dec.) ultimate analysis: C67.21H7.12N6.67.
Example 2:
1 °, N-(17 beta-hydroxy-female steroid 1,3,5(10) triolefin-3-oxygen ethyl) piperazine (compound X) synthetic:
Compound in the last example (VI) 3.0 grams are dissolved in the methyl alcohol, under alkaline condition, add potassium boron hydrogen 0.5 gram, heating reflux reaction 3 hours.Reaction solution steams and removes methyl alcohol with acid neutralization, and the gained solid crude product obtains white crystals product (X, wherein R after with ethyl alcohol recrystallization 7=H).Yield 91%, mp141-142 ℃, ultimate analysis: C75.21H9.23N7.41.
2 °, N-[4-(17 beta-hydroxy-female steroid 1,3,5(10) triolefin-3-oxygen ethyl)-1-piperazine methyne]-tsiklomitsin (chemical compounds I) synthetic:
Last step product (X) 3.84 grams, trioxymethylene 0.03 gram, 20 milliliters of Virahols after 2 hours, add tsiklomitsin 3.5 grams, stirring reaction 5 hours 40 ℃ of reactions.Reaction is finished, filter, after Virahol and ether washing, faint yellow solid (I) (R wherein 1=R 4=H, R 2=OH, R 3=CH 3).Yield 95%, mp165 ℃ (dec.), ultimate analysis: C67.30H7.34N6.54.
Example 3:
N-[4-(17 beta-hydroxy-female steroid 1,3,5(10) triolefin-3-oxygen ethyl)-1-piperazine methyne]-terramycin (chemical compounds I) synthetic:
Compound in the example 2 (X) 3.8 gram, trioxymethylene 0.03 gram, 20 milliliters of Virahols after 2 hours, add terramycin 3.5 grams, stirring reaction 5 hours 40 ℃ of reactions.Post-reaction treatment is with 3 ° of example 1, faint yellow solid product (I) (R wherein 1=R 2=OH, R 3=CH 3, R 4=H).Yield 93%, ultimate analysis: C65.62H7.10N6.67.
Example 4:
1 °, two [N, N-(17-oxygen-female steroid 1,3,5(10) triolefin-3-oxygen ethyl] ammonia (compound VIII) synthetic:
Mustine hydrochlcride 3.6 grams, female phenolic ketone 12 grams, sulfuric acid triethyl aniline 4 grams, water, toluene under agitation adds NaOH solution.Finish and refluxed 5 hours.After steaming desolventizes, solid after with ethyl alcohol recrystallization product (VIII, wherein R 7=H).Yield 72%, ultimate analysis: C78.50H8.60N2.31.
2 °, two [N, N-(17-oxygen-female steroid 1,3,5(10) triolefin-3-oxygen ethyl] ammonia methyne tsiklomitsin (chemical compounds I) synthetic:
Last step product (VIII) 6.1 grams, trioxymethylene 0.03 gram, 20 milliliters of Virahols add tsiklomitsin 3.5 grams, stirring reaction 8 hours again 40 ℃ of reactions after 2 hours.The 3 ° steps of aftertreatment with example 1 are finished in reaction.Get faint yellow solid product (I) (R 1=R 4=H, R 2=OH, R 3=CH 3).Yield 68%, ultimate analysis: C71.10H7.21N3.89.Its structure is:
Figure 931109191_IMG12
Example 5:
1 °, two [N, N-(17 beta-hydroxy-female steroid 1,3,5(10) triolefin-3-oxygen ethyl] ammonia (compound XI) synthetic:
Go up routine compound (VIII) 6.1 grams and under methyl alcohol and alkaline condition, add potassium boron hydrogen 0.5 gram, after the back flow reaction 5 hours,, steam and remove methyl alcohol with the acid neutralization, solid is refining with acetone-ethanolic soln, gets female steroid in the compound (VIII)-17-ketone and is reduced to the white product of-17 beta-hydroxies.Yield 82%, ultimate analysis: C78.41H8.51N2.33.
2 °, two [N, N-(17 beta-hydroxy-female steroid 1,3,5(10) triolefin-3-oxygen ethyl] ammonia methyne tsiklomitsin (chemical compounds I) synthetic:
Last step compound (XI) 5.4 grams, trioxymethylene 0.03 gram, 20 milliliters of Virahols add tsiklomitsin 1.7 grams, stirring reaction 8 hours again 40 ℃ of reactions after 2 hours.The 3 ° steps of aftertreatment with example 1 are finished in reaction.Get faint yellow solid product (I) (R 1=R 4=H, R 2=OH, R 3=CH 3).Yield 94%, ultimate analysis: C71.02H7.02N3.98.Its structure is:
Figure 931109191_IMG13
Example 6:
1 °, two [17 beta-hydroxyl-17 alphas-acetylene-female steroid 1,3,5(10) triolefin-3-oxygen ethyl] ammonia (compound X III) synthetic:
Compound in the example 4 (VIII) 6.1 gram is dissolved in 100 milliliters of tetrahydrofuran (THF)s and potassium hydroxide fine powder 1.0 grams, feeds acetylene gas and make and react completely under violent stirring and 0 ℃ of condition.Be neutralized to pH4 with acid then, steaming desolventizes, and washes with water to neutrality, and drying with ethanol and chloroform recrystallization, gets white crystals product (X III), yield 78%, and ultimate analysis: C79.21H8.56N2.18, its structure is:
Figure 931109191_IMG14
2 °, above-mentioned product (X III) 6.6 grams, trioxymethylene 0.03 gram, 20 milliliters of Virahols after 2 hours, add tsiklomitsin 3.4 grams, stirring reaction 8 hours 60 ℃ of reactions again.The 3 ° steps of aftertreatment with example 1 are finished in reaction, get faint yellow solid product (I) (R 1=R 4=H, R 2=OH, R 3=CH 3).Yield 93%, ultimate analysis: C72.01H7.12N3.90.Its structure is:
Figure 931109191_IMG15
Example 7:
1 °, N[17-oxygen-female steroid 1,3,5(10) triolefin-3-oxygen ethyl]-N-first ammonia (compound VII) synthetic:
Female phenolic ketone 2.7 grams, chloroethyl methylamine 1 gram and a little triethyl aniline vitriol add sodium hydroxide solution in toluene solution, make pH about 10, reacts 4 hours, and steaming desolventizes, and the solid ethyl alcohol recrystallization must compound (VII, wherein R 7=H), yield 71%, ultimate analysis C75.24H9.41N4.28.Its structure is:
2 °, on go on foot compound (VII) 3.3 gram, trioxymethylene 0.03 gram, 20 milliliters of Virahols add tsiklomitsin 3.5 60 ℃ of reflux and restrain stirring reaction 8 hours after 4 hours.The 3 ° steps of aftertreatment with example 1 are finished in reaction, get faint yellow solid product (I) (R 1=R 4=H, R 2=OH, R 3=CH 3), yield 90%, ultimate analysis: C68.80H7.22N3.62.Its structure is:

Claims (9)

1, a kind of compound with estrin structure, it is characterized in that also having the tetracyclines structure in the molecule, and chain bridge construction and 3-, 6-at least one oestrogenic hormon cyclopentanoperhydro-phenanthrene structure or at least one position in the 17-position through being made up of 5 atoms at least of the 2-position acid amides N in this tetracyclines structure links with ehter bond, and its general structure is
Figure 931109191_IMG2
X in the formula is
Figure 931109191_IMG3
R1 is H or OH, and R2 is H or OH,
R3 is H or CH3, and R4 is H, Cl or N (CH3) 2,
R5 is OH or ketone group, R6 be H or-C ≡ CH,
R7 is H or OH, and R8 is OH or unsubstituted group,
R9 is CH3 or (CH2CH20) n-, the n=1 in the formula～5.
2, compound as claimed in claim 1 is characterized in that the R in the general formula 1=R 4=H, R 2=OH, R 3=CH 3
3, compound as claimed in claim 1 it is characterized in that n=1～2 in the general formula, and X is
Figure 931109191_IMG4
4, compound as claimed in claim 1 is characterized in that the n=1 in the general formula, X and R 9Integral body be
Figure 931109191_IMG5
Structure.
5, compound as claimed in claim 1 is characterized in that the n=1 in the general formula, X and R 9Integral body be
Figure 931109191_IMG6
6, compound as claimed in claim 1 is characterized in that the R in the general formula 5=OH, R 6=R 7=H.
7, compound as claimed in claim 1 is characterized in that the R in the general formula 5=OH, R 6For-C ≡ CH, R 7=H.
8, compound as claimed in claim 1 is characterized in that the R in the general formula 5Be ketone group, R 7=H.
9, compound as claimed in claim 5 is characterized in that two oxyethyl groups in the said chain bridge link with ehter bond and two oestrogenic hormon cyclopentanoperhydro-phenanthrenes respectively.
CN 93110919 1993-03-25 1993-03-25 The compound that can be used as the bone target medicine that has estrin structure Pending CN1092779A (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
CN 93110919 CN1092779A (en) 1993-03-25 1993-03-25 The compound that can be used as the bone target medicine that has estrin structure
CN 94111687 CN1034942C (en) 1993-03-25 1994-03-23 Compounds useful as bone-targeted drugs with an estrogenic structure
US08/338,505 US5760214A (en) 1993-03-25 1994-03-25 Bone resorption inhibition/osteogenesis promotion compound
DE69426684T DE69426684T2 (en) 1993-03-25 1994-03-25 CONNECTION TO INHIBIT BONE RESORPTION AND ACCELERATE BONE FORMATION
RU94046140A RU2138507C1 (en) 1993-03-25 1994-03-25 Tetracycline derivatives
PCT/JP1994/000489 WO1994021667A1 (en) 1993-03-25 1994-03-25 Compound for inhibiting bone resorption and accelerating osteogenesis
JP07786494A JP3377856B2 (en) 1993-03-25 1994-03-25 Bone resorption inhibitor / bone formation promoting compound
EP94910542A EP0643071B1 (en) 1993-03-25 1994-03-25 Compound for inhibiting bone resorption and accelerating osteogenesis
US08/888,108 US6028207A (en) 1993-03-25 1997-07-03 Bone resorption inhibition/osteogenesis promotion compound

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CN 93110919 CN1092779A (en) 1993-03-25 1993-03-25 The compound that can be used as the bone target medicine that has estrin structure

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CN 93110919 Pending CN1092779A (en) 1993-03-25 1993-03-25 The compound that can be used as the bone target medicine that has estrin structure
CN 94111687 Expired - Fee Related CN1034942C (en) 1993-03-25 1994-03-23 Compounds useful as bone-targeted drugs with an estrogenic structure

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CN 94111687 Expired - Fee Related CN1034942C (en) 1993-03-25 1994-03-23 Compounds useful as bone-targeted drugs with an estrogenic structure

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CN100368426C (en) * 2004-12-30 2008-02-13 中国人民武装警察部队医学院 Anthraquinone ramification of rhubarb, preparing method and combination of medication by using the ramification as active ingredient
CN111534488B (en) * 2020-04-03 2021-12-21 浙江大学 Chemically modified osteoclast, preparation method and application

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CN1105669A (en) 1995-07-26

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