CN101357918A - Penem derivative containing isothioureido sulfhydryl pyrrolidine - Google Patents
Penem derivative containing isothioureido sulfhydryl pyrrolidine Download PDFInfo
- Publication number
- CN101357918A CN101357918A CN 200810128943 CN200810128943A CN101357918A CN 101357918 A CN101357918 A CN 101357918A CN 200810128943 CN200810128943 CN 200810128943 CN 200810128943 A CN200810128943 A CN 200810128943A CN 101357918 A CN101357918 A CN 101357918A
- Authority
- CN
- China
- Prior art keywords
- ester
- methyl
- hydrogen atom
- hydrate
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- OBFCYFLHWMACIL-UHFFFAOYSA-N N(C(S)=N)C1N(CCC1)S Chemical compound N(C(S)=N)C1N(CCC1)S OBFCYFLHWMACIL-UHFFFAOYSA-N 0.000 title description 5
- 150000002961 penems Chemical class 0.000 title 1
- -1 sulfhydryl pyrrolidine Chemical compound 0.000 claims abstract description 137
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- 150000002148 esters Chemical class 0.000 claims abstract description 34
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- 239000003814 drug Substances 0.000 claims abstract description 18
- 208000035473 Communicable disease Diseases 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 31
- 239000002585 base Substances 0.000 claims description 23
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- 230000007062 hydrolysis Effects 0.000 claims description 17
- 238000006460 hydrolysis reaction Methods 0.000 claims description 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 13
- 125000006239 protecting group Chemical group 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 12
- OTTZHAVKAVGASB-UHFFFAOYSA-N hept-2-ene Chemical compound CCCCC=CC OTTZHAVKAVGASB-UHFFFAOYSA-N 0.000 claims description 12
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 125000006502 nitrobenzyl group Chemical group 0.000 claims description 9
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 6
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical group O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 claims description 5
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 claims description 3
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- 239000011701 zinc Substances 0.000 claims description 3
- 229910052725 zinc Inorganic materials 0.000 claims description 3
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 150000001447 alkali salts Chemical class 0.000 claims description 2
- 125000004849 alkoxymethyl group Chemical group 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 2
- 229910052788 barium Inorganic materials 0.000 claims description 2
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 claims description 2
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 229960002442 glucosamine Drugs 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- 238000001727 in vivo Methods 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 229960003194 meglumine Drugs 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 150000001735 carboxylic acids Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 abstract description 3
- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical class O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)NC1=CC=CC(C(O)=O)=C1 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 abstract description 2
- 239000011149 active material Substances 0.000 abstract 1
- 239000000890 drug combination Substances 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 33
- 239000000243 solution Substances 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 238000002347 injection Methods 0.000 description 21
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
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- 241000894006 Bacteria Species 0.000 description 8
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- 239000002775 capsule Substances 0.000 description 8
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000000463 material Substances 0.000 description 8
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
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- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- 229930188189 sulfomycin Natural products 0.000 description 1
- 108010051634 sulfomycin Proteins 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- JLZWQNRGNMXIJY-UHFFFAOYSA-N triethylstannane Chemical compound CC[SnH](CC)CC JLZWQNRGNMXIJY-UHFFFAOYSA-N 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 235000020985 whole grains Nutrition 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an ertapenem derivative which contains heter-thioureido sulfhydryl pyrrolidine, the ester which is easy to be hydrolyzed, pharmaceutically acceptable salt, isomer thereof, hydrate thereof and hydrate of ester or salt thereof shown in the formula (I) and a preparing method of the compound shown in the formula (I). The compounds are used as active materials, especially used for preparing the medicine for treating or preventing infectious diseases and to be used as a drug combination containing the compound shown in the formula (I). In the formula (I), the definitions of R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, and n are described in the sepcification.
Description
1, technical field
The present invention relates to contain Pennem derivates, the ester of its facile hydrolysis, its pharmacy acceptable salt, its isomer, its hydrate of isothioureido sulfhydryl pyrrolidine, and the hydrate of ester or salt, the preparation method of these compounds, the pharmaceutical composition that contains these compounds, and these compounds are used to prepare the purposes of the medicine that treats and/or prevents infectious diseases, belong to medical technical field.
2, background technology
Carbapenems is the New-type wide-spectrum that grows up the seventies in 20th century, anti-enzyme, efficient β-Nei Xiananleikangshengsu.1976, find first carbapenem antibiotic---sulfomycin, but because poor chemical stability fails to be used for clinical.Afterwards sulfomycin is carried out the chemical structure transformation and produced a series of carbapenem antibiotics.This similar drug that has gone on the market at present has imipenum, panipenem, meropenem, S-4661, biapenem, ertapenem etc.
First listing be imipenum, have better antibacterial activity, stable to various β-Nei Xiananmeis, there is not cross resistance with other microbiotic, but easily by dehydropeptidase of kidney-I (DHP-I) degraded rapidly, must share with dehydropeptidase of kidney inhibitor cilastatin clinically in vivo.
Discover, introduce 1 Beta-methyl, can strengthen the stability of carbapenem compound DHP-I.1 Beta-methyl carbapenem of first listing is a meropenem, can use separately clinically, need not to share with the dehydropeptidase of kidney inhibitor.
Because antibiotic abuse causes the continuous increase of bacterial drug resistance and the limitation that digestive tube absorbs, the carbapenems of listing clinically can only be as the injection administration at present, clinical availability is not high, and to the anti-microbial activity of MRSA a little less than, can not meet clinical needs.
3, summary of the invention
The inventor is through a large amount of research and practice, a series of new carbapenem compounds have been synthesized, gram-positive and negative, aerobic and anerobe especially resistant organism had the strong antibiotic activity, chemical stability is good, β-Nei Xiananmei and DHP-I had satisfactory stability, and has long post antibiotic effect (PAE), for clinical application provides new variety.Compare with immediate prior art and to have novelty and superiority.
Technical scheme of the present invention is as follows:
The invention provides the hydrate of ester, its pharmacy acceptable salt, its isomer, its hydrate and the ester or the salt of compound, its facile hydrolysis shown in the general formula (I):
Wherein,
R
1Represent hydrogen atom or carboxyl-protecting group;
R
2Represent hydrogen atom or C
1-6Alkyl;
R
3Expression hydrogen atom or amino protecting group;
R
4Expression hydrogen atom or C
1-6Alkyl;
R
5The expression hydrogen atom, C
1-6Alkyl or C
1-6Alkoxyl group;
R
6, R
7Independently represent hydrogen atom, trifluoromethyl, C respectively
1-6Alkyl, hydroxyl C
1-6Alkyl, amino C
1-6Alkyl, carboxyl C
1-6Alkyl, C
1-6Alkyl sulphonyl, carbamyl or C
1-6Alkylcarbamoyl group;
N represents 1～5 integer.
Preferred compound is:
Wherein,
R
1Represent hydrogen atom or carboxyl-protecting group,
Described carboxyl-protecting group is selected from methyl, ethyl, the tertiary butyl, methoxymethyl, first thiomethyl, benzyloxymethyl, phenacyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl;
R
2Represent hydrogen atom or methyl;
R
3Expression hydrogen atom or amino protecting group,
Described amino protecting group is selected from methyl, ethyl, the tertiary butyl, benzyl, formyl radical, ethanoyl, allyloxy carbonyl, phenacyl, tert-butoxycarbonyl, to the nitro benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl, 3-acetoxyl group propyl group or diazo;
R
4Expression hydrogen atom or methyl;
R
5The expression hydrogen atom, methyl or methoxy;
R
6, R
7Independently represent hydrogen atom, trifluoromethyl, C respectively
1-4Alkyl or carbamyl;
N represents 1,2 or 3.
Further preferred compound is:
Wherein,
R
1Represent hydrogen atom or carboxyl-protecting group,
Described carboxyl-protecting group is selected from methyl, the tertiary butyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl;
R
2Represent hydrogen atom or methyl;
R
3Expression hydrogen atom or amino protecting group,
Described amino protecting group is selected from methyl, the tertiary butyl, formyl radical, allyloxy carbonyl, tert-butoxycarbonyl, to the nitro benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl or diazo;
R
4Expression hydrogen atom or methyl;
R
5The expression hydrogen atom, methyl or methoxy;
R
6, R
7Independently represent hydrogen atom or methyl respectively;
N represents 1,2 or 3.
Table 1 part of compounds of the present invention
| Numbering | R 1 | R 2 | R 3 | R 4 | R 5 | R 6 | R 7 | n |
| 1 | H | -CH 3 | H | H | H | H | H | 1 |
| 2 | H | -CH 3 | H | H | H | H | H | 2 |
| 3 | H | -CH 3 | H | H | H | H | H | 3 |
| 4 | H | -CH 3 | -CH 3 | H | H | H | H | 1 |
| 5 | H | -CH 3 | -CH 3 | H | H | H | H | 2 |
| 6 | H | -CH 3 | -CH 3 | H | H | H | H | 3 |
| 7 | H | -CH 3 | H | -CH 3 | H | H | H | 1 |
| 8 | H | -CH 3 | H | -CH 3 | H | H | H | 2 |
| 9 | H | -CH 3 | H | -CH 3 | H | H | H | 3 |
| 10 | H | -CH 3 | H | H | -OCH 3 | H | H | 1 |
| 11 | H | -CH 3 | H | H | -OCH 3 | H | H | 2 |
| 12 | H | -CH 3 | H | H | -OCH 3 | H | H | 3 |
Particularly preferred compound is:
(4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [(isothioureido-ethane-1-yl) amino]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid, hereinafter to be referred as compd A:
" C of the present invention
1-6Alkyl " be the alkyl that contains the straight or branched of 1-6 carbon atom, comprise methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, amyl group, hexyl etc.
" halogen atom " of the present invention comprises fluorine atom, chlorine atom, bromine atoms, iodine atom.
" C of the present invention
1-6Alkoxyl group " comprise methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, pentyloxy, hexyloxy etc.
" hydroxyl C of the present invention
1-6Alkyl " comprise hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyl sec.-propyl, hydroxybutyl, the hydroxyl tertiary butyl, hydroxyl amyl group, hydroxyl hexyl etc.
" amino C of the present invention
1-6Alkyl " comprise amino methyl, amino-ethyl, aminopropyl, amino sec.-propyl, amino butyl, the amino tertiary butyl, amino amyl group, amino hexyl etc.
" carboxyl C of the present invention
1-6Alkyl " comprise carboxyl methyl, carboxy ethyl, carboxyl propyl group, carboxyl sec.-propyl, carboxybutyl, the carboxyl tertiary butyl, carboxy pentyl, carboxyl hexyl etc.
" C of the present invention
1-6Alkyl sulphonyl " comprise methylsulfonyl, ethylsulfonyl, third alkylsulfonyl, different third alkylsulfonyl, fourth alkylsulfonyl, uncle's fourth alkylsulfonyl, penta alkylsulfonyl, own alkylsulfonyl etc.
" C of the present invention
1-6Alkylcarbamoyl group " comprise first carbamyl, second carbamyl, third carbamyl, different third carbamyl, fourth carbamyl, uncle's fourth carbamyl, penta carbamyl, own carbamyl etc.
" carboxyl-protecting group " of the present invention refers to that routine is used for the blocking group of substituted carboxylic acid acid proton.This examples of groups comprises: methoxymethyl, the first thiomethyl, THP trtrahydropyranyl, tetrahydrofuran base, the methoxyethyl methyl, benzyloxymethyl, phenacyl, allyl group, to bromobenzene formyl methyl, the Alpha-Methyl phenacyl, to the methoxybenzoyl methyl, the diacyl methyl, the N-phthalimidomethyl, methyl, ethyl, diphenyl methyl, 2,2,2-three chloroethyls, the 2-halogenated ethyl, ω-chloro alkyl, 2-(trimethyl silyl) ethyl, 2-methylmercaptoethyl, 2-(p-nitrophenyl sulfenyl) ethyl, 2-(to the toluene sulfenyl) ethyl, 1-methyl isophthalic acid-styroyl, the tertiary butyl, cyclopentyl, cyclohexyl, two (ortho-nitrophenyl base) methyl, 9-fluorenyl methyl, 2-(9, the 10-dioxo) fluorenyl methyl, 5-hexichol sulfenyl, benzyl, 2,4, the 6-trimethyl benzyl, to bromobenzyl, adjacent nitrobenzyl, to nitrobenzyl, to methoxy-benzyl, piperonyl, the 4-picolyl, trimethyl silyl, triethylsilyl, t-butyldimethylsilyl, the sec.-propyl dimetylsilyl, the phenyl dimetylsilyl, the S-tertiary butyl, the S-phenyl, the S-2-pyridyl, N-hydroxy piperidine base, N-hydroxyl succinimido, N-hydroxyl phthaloyl imino, N-hydroxybenzotriazole base, O-acyl group oxime, 2,4-dinitrobenzene sulfenyl, 2-alkyl-1, the 3-oxazoline, 4-alkyl-5-oxo-1, the 3-oxazolidine, 5-alkyl-4-oxo-1, the 3-diox, the triethyl stannane, tri-n-butyl stannane; N, N '-di-isopropyl hydrazides etc.
" amino protecting group " of the present invention refers to that routine is used for the blocking group of substituted-amino acid proton, this type of examples of groups comprises: methyl, ethyl, encircle third methyl, 1-methyl isophthalic acid-ring third methyl, the diisopropyl methyl, the 9-fluorene methyl, 9-(2-sulfo-) fluorene methyl, furfuryl, 2,2, the 2-trichloromethyl, the 2-halogenated methyl, 2-iodine ethyl, 2-trimethyl silyl ethyl, 2-methylmercaptoethyl, 2-methylsulfonyl ethyl, 2-(p-toluenesulfonyl) ethyl, 2-phosphorus base ethyl, 1,1-dimethyl-3-(N, N-dimethylformamide base) propyl group, 1,1-phenylbenzene-3-(N, the N-diethylin) propyl group, 1-methyl isophthalic acid-(adamantyl) ethyl, 1-methyl isophthalic acid-styroyl, 1-methyl isophthalic acid-(3, the 5-dimethoxy phenyl) ethyl, 1-methyl isophthalic acid-(4-xenyl) ethyl, 1-methyl isophthalic acid-(to the phenylazo-phenyl) ethyl, 1,1-dimethyl-2,2,2-three chloroethyls, 1,1-dimethyl-2-cyanoethyl, isobutyl-, the tertiary butyl, tert-pentyl, cyclobutyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl, the 1-methylcyclohexyl, the 1-adamantyl, isobornyl, vinyl, allyl group, cinnamyl, phenyl, 2,4,6-tri-tert phenyl, the m-nitro base, the S-phenyl, the 8-quinolyl, N '-hydroxy piperidine base, 4-(1,4-lupetidine base), 4,5-phenylbenzene-3-oxazoline-2-ketone, benzyl, 2,4, the 6-trimethyl benzyl, to methoxy-benzyl, to methoxyl group benzyloxy base carbonyl, 3, the 5-dimethoxy-benzyl, to oxy-benzyl in the last of the ten Heavenly stems, to nitrobenzyl, to the nitro benzyloxycarbonyl, adjacent nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, to bromobenzyl, the benzyl chloride base, 2, the 4-dichloro benzyl, to the cyano group benzyl, adjacent (N, N-dimethylformamide base) benzyl, between-chloro-is right-the acyloxy benzyl, to (dihydroxyl boryl) benzyl, to (phenylazo-) benzyl, to (to the anisole azo-group) benzyl, 5-benzoisoxazole ylmethyl, 9-anthryl methyl, diphenyl-methyl, phenyl (ortho-nitrophenyl base) methyl, two (2-pyridyl) methyl, 1-methyl isophthalic acid-(4-pyridyl) ethyl, the isonicotine base, the S-benzyl, the fixed basic carbonyl of N '-piperazine, the carbamate of N '-p-toluenesulfonyl aminocarboxyl and N '-phenylamino thiocarbonyl; Formyl radical, ethanoyl, ethanoyl-pyridine, (N '-the dithio benzyloxycarbonyl amino) ethanoyl, 3-phenyl propionyl, 3-(to hydroxyphenyl) propionyl, 3-(ortho-nitrophenyl base) propionyl, 2-methyl-2-(ortho-nitrophenyl oxygen base) propionyl, 2-methyl-2-(adjacent phenylazo-phenoxy group) propionyl, 4-chloro butyryl radicals, isobutyryl, adjacent nitro cinnamoyl, the pyridine formyl radical, N '-acetyl methionyl, N '-benzoyl-phenylalkyl, benzoyl, to the phenyl benzoyl, to anisoyl, o-nitrobenzoyl, the acid amides of adjacent (benzoyloxy methyl) benzoyl and right-P-benzoyl; Phthaloyl, 2, the inferior acid amides of the ring of 3-phenylbenzene maleoyl and dithio succinyl; Tert-butoxycarbonyl; allyl group; allyloxy carbonyl; phenacyl; 3-acetoxyl group propyl group; 4-nitro-1-cyclohexyl-2-oxo-3-tetramethyleneimine-3-base; quaternary ammonium salt; methoxymethyl; 2-chloroethoxy methyl; benzyloxymethyl; the valeryl methyl; [1-(alkoxycarbonyl amido)]-2; 2; 2; trifluoroethyl; [1-Trifluoromethyl-1-(to the chlorophenoxy methoxyl group) 2; 2; 2;-trifluoro] ethyl; the 2-THP trtrahydropyranyl; 2; the 4-dinitrophenyl; benzyl; 3; the 4-dimethoxy-benzyl; adjacent nitrobenzyl; two (p-methoxyphenyl) methyl; trityl; (p-methoxyphenyl) diphenyl methyl; phenylbenzene-4-pyridylmethyl; 2-picolyl-N '-oxide compound; 5-two phenylpropyl alcohol suberane bases; N '; N '-dimethylaminomethylene; N '-isopropylidene; benzylidene; to the methoxyl group benzylidene; to the nitro benzylidene; salicylidene; 5-chlorine salicylidene; diphenylmethylene; (5-chloro-2-hydroxyphenyl) phenylmethylene; (acyl group vinyl); 5; 6-dimethyl-3-oxo-1-cyclohexenyl; borine; [phenyl (pentacarbonyl chromium or tungsten)] carbonyl; copper or chelates of zinc; nitro; nitroso-group; oxide compound; diphenylphosphino; diformazan sulfenyl phosphinyl; hexichol sulfenyl phosphinyl; the diethyl phosphoryl; the dibenzyl phosphoryl; the diphenylphosphine acyl group; phosphoryl; trimethyl silyl; thiophenyl; the ortho-nitrophenyl sulfenyl; 2; 4-dinitrobenzene sulfenyl; 2-nitro-4-anisole sulfenyl; three benzylthios; benzenesulfonyl; to the anisole alkylsulfonyl; 2; 4,6-Three methyl Benzene alkylsulfonyl; methyl sulphonyl; the benzene methylsulfonyl; to the toluene methylsulfonyl; trifluoromethyl sulfonyl; the phenacyl alkylsulfonyl; diazo etc.
The present invention also provides the preparation method of compound shown in the preparation general formula (I), but is not limited only to following preparation method, also can make by other method:
Reaction equation:
Experimental procedure:
The preparation of step 1, intermediate 1
In the exsiccant reaction flask, add (2S, 4S)-4-acetylthio-2-carboxyl-1-tetramethyleneimine (being raw material 1), anhydrous tetrahydro furan.Under nitrogen protection, add 1 in room temperature, 1-carbonyl dimidazoles (CDI), reaction, the tetrahydrofuran solution adding raw material 2 below 0 ℃ continues reaction.Drip 1mol/L hydrochloric acid then, with ethyl acetate extraction, organic phase is water, saturated nacl aqueous solution washing successively, and concentrating under reduced pressure, solid get intermediate 1 with the ethanolic soln recrystallization.
The preparation of step 2, intermediate 3
Add the dichloromethane solution of intermediate 1 in reaction flask, ice bath is chilled under 5 ℃, adds triethylamine, stirs the back and drips (Boc)
2The dichloromethane solution of O stirs.Add entry under the frozen water cooling, divide water-yielding stratum, water layer is used dichloromethane extraction again, merges organic layer, anhydrous sodium sulfate drying, be concentrated into dried, resistates adds the hydrochloric acid of 3mol/L, stir, be adjusted to alkalescence, separate out solid with dilute alkaline soln, solid gets intermediate 3 with acetonitrile and acetone mixing solutions recrystallization.
The preparation of step 3, intermediate 4
In the dry reaction bottle, add the acetonitrile solution of raw material 3, be chilled to below-20 ℃, add the acetonitrile solution of diisopropylethylamine and intermediate 3,0 ℃ of stirring.After reaction finishes, add the ethyl acetate dilution, water, saturated salt washing successively, organic layer drying, concentrated gets intermediate 4.
The preparation of step 4, The compounds of this invention
Intermediate 4 is dissolved in the methylene dichloride, adds methyl-phenoxide and Nitromethane 99Min., in-50 ℃ of Nitromethane 99Min. solution that drip the 1mol/L aluminum chloride down,-30 ℃ of stirrings add entry, separate out solid, filter, filter cake is dissolved in the mixed solution of THF and water, adds 10% palladium-charcoal, stirring reaction under the room temperature 5MPa hydrogen pressure, filtering palladium charcoal, add THF in the filtrate, water layer is collected in layering.In THF, add 5% magnesium chloride brine again, leave standstill, divide water-yielding stratum, repetitive operation.Water merges, and 0 ℃ slowly splashes into methyl alcohol, and-10 ℃ of stirrings are filtered, and filter cake water-Virahol recrystallization gets The compounds of this invention.
Each substituting group in above reaction equation and the step and the implication of n are as mentioned before; carboxyl in the The compounds of this invention can be protected by carboxyl-protecting group, the nitrogen-atoms on the pyrrolidyl can be protected by amino protecting group, and described carboxyl-protecting group and amino protecting group are as mentioned before.If in intermediate 2 and the intermediate 3, the H on pyrrolidyl among the NH is replaced the protection by Boc, also has other similarly active NH or NH
2, then H on the NH or NH
2On H replaced protection, for example compd A corresponding intermediates by Boc simultaneously.
The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention is organic acid salt, inorganic acid salt, organic alkali salt or inorganic base salts, and wherein organic acid comprises acetate, trifluoroacetic acid, methylsulfonic acid, toluenesulphonic acids, toxilic acid, succsinic acid, tartrate, citric acid, fumaric acid; Mineral acid comprises hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid; Organic bases comprises meglumine, glucosamine; Mineral alkali comprises the basic cpd of sodium, potassium, barium, calcium, magnesium, zinc, lithium.
The ester that the claimed compound of the present invention is easy to hydrolysis is the compound that its carboxyl exists with the ester group form that is easy to hydrolysis.These esters can be conventional, lower alkane acyloxyalkyl group ester for example, acetoxyl methyl ester, pivalyl oxygen methyl ester, 1-acetoxyl ethyl ester, 1-pivalyl oxygen ethyl ester; Lower alkoxycarbonyl oxyalkyl ester, methoxycarbonyl oxygen methyl ester, 1-ethoxycarbonyl-oxygen ethyl ester, 1-sec.-propyl ketonic oxygen ethyl ester; The lactone group ester, cumarone ketone group ester, sulfo-benzo furanonyl ester; The lower alkoxy methyl ester, methoxymethyl ester; Lower alkane acyl amino methyl ester, the acetylamino methyl ester.The ester that also can use other is for example: benzyl ester and cyano methyl ester.Other examples of these esters are as follows: (2,2-dimethyl-1-oxygen propoxy-) methyl ester; (1RS)-1-acetoxyl group ethyl ester; 2-[(2-methyl propoxy-) carbonyl]-the pentenyl ester; The 1-[[(1-methyl ethoxy) carbonyl] oxygen] ethyl ester; 1-(acetoxyl) ethyl ester; (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl ester; The 1-[[(cyclohexyloxy) carbonyl] oxygen] ethyl ester; 3,3-dimethyl-2-oxo butyl ester.It is evident that for the professional of this area the ester that is easy to hydrolysis of The compounds of this invention can form at the free carboxy place of this compound.
Isomer of the present invention is meant its all differences to stereoisomerism, diastereo-isomerism and tautomeric form.When a key was represented with a wedge, this showed that this key will come out from paper on three-dimensional, and when a key was shade, this showed that this key will return in the paper on three-dimensional.Formula (I) compound has many three-dimensional centers, that is: on the 4-position, on the 5-position, the 6-position is first-class.
The ester of the compound shown in the general formula (1), its pharmacy acceptable salt, its facile hydrolysis, its isomer can be hydrate forms.Hydration can be finished in preparation process or can be utilized the water absorbability of original anhydrous product to carry out gradually.
The present invention includes the hydrate of ester, its isomer, its hydrate or its ester or the salt of arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis, with the pharmaceutical composition of other active pharmaceutical ingredients, as cilastatin and sodium salt thereof, Betamipron.
The present invention is the claimed hydrate that comprises ester, its isomer, its hydrate or its ester or the salt of arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis further; pharmaceutical composition with one or more pharmaceutical carriers and/or thinner; for clinically or pharmaceutically acceptable arbitrary formulation, be preferably oral preparations or injection.Wherein contain the compound 0.05g～5g shown in the general formula (1) of physiology significant quantity, can be 0.05g, 0.1g, 0.125g, 0.2g, 0.25g, 0.3g, 0.4g, 0.5g, 0.6g, 0.75g, 1g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 4g, 5g etc.
The ester of The compounds of this invention, its pharmacy acceptable salt, its facile hydrolysis, its isomer, its hydrate, with and the hydrate of ester or salt, can be oral or mode such as administered parenterally be applied to the patient who needs this treatment.
When being used for administered parenterally, can be made into injection.Injection means the intravital solution of confession injection, emulsion or the suspension that medicine is made and supplies to face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or strong solution that injection can be divided into injection liquid, injectable sterile powder and concentrated solution for injection.Injection liquid means that the confession that medicine is made is injected into sterile solution type injection liquid, emulsion-type injection liquid or the suspension type injection liquid of using in the body, can be used for intramuscularly, intravenous injection, intravenous drip etc.; Its specification has 1ml, 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml etc., and wherein large volume (generally the being not less than 100ml) injection liquid of using for intravenous drip also claims intravenous infusion.Injectable sterile powder means that confession that medicine is made is faced with the suitable sterile solution of preceding usefulness and is mixed with settled solution or the evenly sterilized powder or the aseptic block of suspension, available suitable solvent for injection preparation back injection, also available intravenous infusion preparation posterior vein instils; Sterilized powder makes with solvent crystallization, spray-drying process or freeze-drying etc.Concentrated solution for injection means that confession that medicine is made faces the aseptic strong solution of using for intravenous drip with preceding dilution.
When making injection, can adopt the ordinary method production in the existing pharmacy field, optional use solvent or non-aqueous solvent.The most frequently used aqueous solvent is a water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solution; Non-aqueous solvent commonly used is a vegetables oil, is mainly the injection soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, polyoxyethylene glycol etc.During the preparation injection, can not add additives, also can add suitable additives, as osmotic pressure regulator, pH value conditioning agent, solubilizing agent, weighting agent, oxidation inhibitor, fungistat, emulsifying agent, suspending agent etc. according to the character of medicine.Osmotic pressure regulator commonly used comprises sodium-chlor, glucose, Repone K, magnesium chloride, calcium chloride, sorbyl alcohol etc., preferred sodium-chlor or glucose; PH value conditioning agent commonly used comprises acetic acid-sodium-acetate, lactic acid, Citric Acid-Sodium Citrate, sodium bicarbonate-yellow soda ash etc.; Solubilizing agent commonly used comprises Polysorbate 80, propylene glycol, Yelkin TTS, polyoxyethylenated castor oil etc.; Weighting agent commonly used comprises lactose, N.F,USP MANNITOL, sorbyl alcohol, dextran etc.; Oxidation inhibitor commonly used has S-WAT, sodium bisulfite, Sodium Pyrosulfite etc.; Fungistat commonly used is phenol, cresols, trichloro-butyl alcohol etc.Injection container commonly used has glass ampoule, vial, plastic ampoule, Plastic Bottle etc.
Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule means medicine or is added with the auxiliary material filling in Capsules or be sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable auxiliary material uniform mixing, and the spherical or near-spherical solid preparation so that proper method is made comprises dripping pill, sugar-pill, piller etc.Granule means that medicine and suitable auxiliary material make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral clarified liq preparation in suitable solvent.Oral suspensions means the insoluble solid pharmaceutical, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspensoid or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Typical binders comprises Xylo-Mucine, PVP-K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dry starch, polyvinylpolypyrrolidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.
Usually, carbapenem compound is nontoxic to warm-blooded animal, and this general rule also is applicable to The compounds of this invention.With preferred compound of the present invention can prevent the needed excessive dosage of infectation of bacteria, not to be noted by caused tangible poisoning aura of The compounds of this invention or side effect to the mouse administration.
The present invention also provide The compounds of this invention preparation be used for the treatment of and/or the medicine of prophylaxis against infection diseases in purposes.Pennem derivates of the present invention all has better antibacterial activity to Gram-positive and negative bacterium, aerobic and anerobe, can be used for treating and/or preventing the various diseases that is caused by pathogenic micro-organism, as respiratory tract infection and urinary tract infection.
The Pennem derivates that contains isothioureido sulfhydryl pyrrolidine of the present invention is compared with immediate prior art, has the following advantages:
(1) The compounds of this invention has good anti-microbial activity and shows hypotoxicity, can by safety be used for the treatment of and/or to prevent various Mammalss (as mouse, rat, rabbit, dog, cat, ox, pig etc.) to comprise human by the caused various diseases of germ, as pulmonary infection and urinary tract infections etc.;
(2) The compounds of this invention has a broad antifungal spectrum all has better antibacterial activity to gram-positive and negative bacterium, aerobic and anerobe;
(3) The compounds of this invention has high stability to β-Nei Xiananmei and DHP-I, can be used for β-Nei Xiananmei and produces bacterium, and do not need to share with other medicines;
(4) long half time in the The compounds of this invention body can reduce administration number of times, improves patient's tolerance;
(5) The compounds of this invention preparation technology is simple, and medicine purity height, yield height, steady quality are easy to carry out large-scale commercial production.
Below further set forth the beneficial effect that contains the Pennem derivates of isothioureido sulfhydryl pyrrolidine of the present invention by in-vitro antibacterial experiment, but this should be interpreted as that the southern antibiotics of training of the present invention only has following beneficial effect.
The antibacterial activity in vitro of experimental example The compounds of this invention
For trying bacterial classification: following clinical isolates strain
Gram positive organism: MSSA (MSSA), methicillin-resistant staphylococcus aureus (MRSA), methicillin-sensitivity staphylococcus epidermidis (MSSE), methicillin-resistant staphylococcus epidermidis (MRSE), the responsive streptococcus pneumoniae (PSSP) of penicillin, penicillin resistance streptococcus pneumoniae (PRSP), streptococcus pyogenes, enterococcus faecalis;
Gram-negative bacteria: hemophilus influenzae, escherichia coli, klepsiella pneumoniae, Proteus mirabilis, citrobacter freundii, enterobacter cloacae, Pseudomonas aeruginosa.
Trial-product:
Preferred compound A of the present invention, self-control, its chemical name and structural formula are as mentioned before;
Imipenum, meropenem: commercial.
Experimental technique: agar dilution.
Experimental result and conclusion:
Following experimental result shows, The compounds of this invention all has potent anti-microbial effect to gram positive organism, negative bacterium and resistant organism thereof and anerobe, compares with immediate prior art, and anti-microbial activity quite or better, and has a broad antifungal spectrum has the good clinical application potential.
Table 2 The compounds of this invention is to the anti-microbial activity of clinical separation gram positive organism
By table 2 experimental result as seen, compare with meropenem with imipenum, The compounds of this invention A all has the excellent antibiotic activity to the clinical isolating examination gram positive organism that supplies.
Table 3 The compounds of this invention is to the anti-microbial activity of clinical separation gram-negative bacteria
By table 3 experimental result as seen, compare with meropenem with imipenum, The compounds of this invention A comprises that to clinical isolating for the examination gram-negative bacteria Grain-negative anerobe has the excellent antibiotic activity.
4, embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The auxiliary material of each formulation can be replaced with acceptable accessories in following examples, perhaps reduces, increases.
Embodiment 1 (2S, 4S)-preparation of 4-acetylthio-2-formyl [(S-2-isothioureido-ethane-1-yl) amino]-tetramethyleneimine
In the exsiccant reaction flask, add (2S, 4S)-4-acetylthio-2-carboxyl-1-tetramethyleneimine 5.7g (30mmol), anhydrous tetrahydro furan 100ml.Under nitrogen protection, add 1 in room temperature, 1-carbonyl dimidazoles 6.5g (40mmol), reaction 0.5h at the tetrahydrofuran solution 100ml that adds S-2-isothioureido-1-ethylamine 6.0g (50mmol) below 0 ℃, continues reaction 1h.Drip 1mol/L hydrochloric acid 40ml then, extract with ethyl acetate (50ml * 2), organic phase is water, saturated nacl aqueous solution washing successively, and concentrating under reduced pressure, solid get solid 6.2g, yield: 71.5% with the aqueous isopropanol recrystallization.
Embodiment 2 (2S, 4S)-4-sulfydryl-2-formyl [(S-2-(N, N '-tertbutyloxycarbonyl) isothioureido-ethane-1-yl) amino]-pyrroles
The preparation of alkane
In reaction flask, add (2S, 4S)-the dichloromethane solution 100ml of 4-acetylthio-2-formyl [(S-2-isothioureido-ethane-1-yl) amino]-tetramethyleneimine 8.7g (30mmol), ice bath is chilled under 5 ℃, adds triethylamine 12ml, drips 25g (Boc) behind the stirring 5min
2The dichloromethane solution 100ml of O stirs 1h.The frozen water cooling adds 100ml water down, divide water-yielding stratum, water layer is used the dichloromethane extraction of 50ml * 3 again, merges organic layer, anhydrous sodium sulfate drying, be concentrated into dried, resistates adds the hydrochloric acid 100ml of 3mol/L, stirs 2h, is adjusted to alkalescence with dilute alkaline soln, separate out solid, solid gets product 14.6g, yield: 88.9% with acetonitrile and acetone mixing solutions recrystallization.
Embodiment 3 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [(S-2-(N, N '-tertbutyloxycarbonyl) isothioureido-ethane-1-yl) ammonia
Base]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid is to nitro
The preparation of benzyl ester
In the dry reaction bottle, add (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] the acetonitrile solution 200ml of hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 18g (30mmol), be chilled to below-20 ℃, add diisopropylethylamine 8ml and (2S, 4S)-4-sulfydryl-2-formyl [(S-2-(N, N '-tertbutyloxycarbonyl) amino isothioureido-ethane-1-yl)]-the acetonitrile solution 200ml of tetramethyleneimine 17.6g (32mmol), 0 ℃ is stirred 24h.After reaction finishes, add ethyl acetate 600ml dilution, water, saturated salt washing successively, organic layer drying, concentrated gets solid 19.4g, yield: 72.5%.
Embodiment 4 (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [(isothioureido-ethane-1-yl) amino]-tetramethyleneimine-4-yl] sulfenyl
-6-[(1R)-the 1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid
With (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [(S-2-(N, N '-tertbutyloxycarbonyl) amino isothioureido-ethane-1-yl)]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 26.8g (30mmol) is dissolved in the 100ml methylene dichloride, adds methyl-phenoxide 25ml and Nitromethane 99Min. 40ml, in-50 ℃ of Nitromethane 99Min. solution 200ml that drip the 1mol/L aluminum chloride down,-30 ℃ are stirred 4h, add entry 300ml, separate out solid, filter, filter cake is dissolved in the mixed solution of THF 600ml and water 50ml, adds 10% palladium-charcoal 8g, stirring reaction 2h under the room temperature 5MPa hydrogen pressure, filtering palladium charcoal, add THF 150ml in the filtrate, water layer is collected in layering.In THF, add 10% magnesium chloride brine 30ml again, leave standstill, divide water-yielding stratum, repetitive operation 1 time.Water merges, and 0 ℃ slowly splashes into methyl alcohol 60ml, and-10 ℃ are stirred 1h, filters, and the filter cake recrystallization gets white crystal 6.0g, yield: 43.5%.
Molecular formula: C
18H
27N
5O
5S
2
Molecular weight: 457.57
Ultimate analysis: C, 47.02%; H, 6.16%; N, 15.13%; S, 13.81% (calculates: C, 47.25%; H, 5.95%; N, 15.31%; S, 14.02%)
The preparation of embodiment 5 The compounds of this invention aseptic powder injections
1, prescription:
Prescription 1:
Any one 250g (in compound) in the compd A or derivatives thereof
Prepare 1000 altogether
Prescription 2:
Any one 500g (in compound) in the compd A or derivatives thereof
Prepare 1000 altogether
Prescription 3:
Any one 1000g (in compound) in the compd A or derivatives thereof
Prepare 1000 altogether
Prescription 4:
Any one 2000g (in compound) in the compd A or derivatives thereof
Prepare 1000 altogether
2, preparation technology:
(1) will prepare used antibiotic glass bottle, plug etc. and carry out aseptically process;
(2) take by weighing raw material (feeding intake after the conversion) by prescription, sterilized powder is placed the portioning machine packing, detect loading amount at any time;
(3) jump a queue, gland, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 6 The compounds of this invention tablets
1, prescription:
Prescription 1:
Any one 250g (in compound) in the compd A or derivatives thereof
Pregelatinized Starch 50g
Low-substituted hydroxypropyl cellulose 40g
Microcrystalline Cellulose 40g
The 2%HPMC aqueous solution is an amount of
Micropowder silica gel 4.0g
Magnesium Stearate 4.0g
Carboxymethylstach sodium 2.0g
Prepare 1000 altogether
Prescription 2:
Any one 125g (in compound) in the compd A or derivatives thereof
Pregelatinized Starch 50g
Low-substituted hydroxypropyl cellulose 40g
Microcrystalline Cellulose 40g
The 2%HPMC aqueous solution is an amount of
Micropowder silica gel 4.0g
Magnesium Stearate 4.0g
Carboxymethylstach sodium 2.0g
Prepare 1000 altogether
2, preparation technology:
(1) raw material pulverizing is crossed 100 mesh sieves, all the other auxiliary materials are crossed 100 mesh sieves respectively, and are standby;
(2) take by weighing raw material and auxiliary material according to recipe quantity;
(3) hypromellose 2% the aqueous solution made soluble in water is standby;
(4) The compounds of this invention A or derivatives thereof, pregelatinized Starch, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose are mixed, the adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable softwood;
(5) cross 20 mesh sieve system particles;
(6) particle is dried under 60 ℃ condition;
(7) dry good particle adds Magnesium Stearate, micropowder silica gel and carboxymethylstach sodium, crosses the whole grain of 18 mesh sieves, mixes;
(8) sampling, the work in-process chemical examination;
(9) the sheet weight sheet of determining according to chemical examination;
(10) finished product is examined entirely, the packing warehouse-in.
Claims (10)
1, the hydrate of the ester of compound, its facile hydrolysis, its pharmacy acceptable salt, its isomer, its hydrate and ester or salt shown in the formula (I):
Wherein,
R
1Represent hydrogen atom or carboxyl-protecting group;
R
2Represent hydrogen atom or C
1-6Alkyl;
R
3Expression hydrogen atom or amino protecting group;
R
4Expression hydrogen atom or C
1-6Alkyl;
R
5The expression hydrogen atom, C
1-6Alkyl or C
1-6Alkoxyl group;
R
6, R
7Independently represent hydrogen atom, trifluoromethyl, C respectively
1-6Alkyl, hydroxyl C
1-6Alkyl, amino C
1-6Alkyl, carboxyl C
1-6Alkyl, C
1-6Alkyl sulphonyl, carbamyl or C
1-6Alkylcarbamoyl group;
N represents 1～5 integer.
2, the hydrate of the ester of compound as claimed in claim 1, its facile hydrolysis, its pharmacy acceptable salt, its isomer, its hydrate and ester or salt:
Wherein,
R
1Represent hydrogen atom or carboxyl-protecting group,
Described carboxyl-protecting group is selected from methyl, ethyl, the tertiary butyl, methoxymethyl, first thiomethyl, benzyloxymethyl, phenacyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl;
R
2Represent hydrogen atom or methyl;
R
3Expression hydrogen atom or amino protecting group,
Described amino protecting group is selected from methyl, ethyl, the tertiary butyl, benzyl, formyl radical, ethanoyl, allyloxy carbonyl, phenacyl, tert-butoxycarbonyl, to the nitro benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl, 3-acetoxyl group propyl group or diazo;
R
4Expression hydrogen atom or methyl;
R
5The expression hydrogen atom, methyl or methoxy;
R
6, R
7Independently represent hydrogen atom, trifluoromethyl, C respectively
1-4Alkyl or carbamyl;
N represents 1,2 or 3.
3, the hydrate of the ester of compound as claimed in claim 2, its facile hydrolysis, its pharmacy acceptable salt, its isomer, its hydrate and ester or salt:
Wherein,
R
1Represent hydrogen atom or carboxyl-protecting group,
Described carboxyl-protecting group is selected from methyl, the tertiary butyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl;
R
2Represent hydrogen atom or methyl;
R
3Expression hydrogen atom or amino protecting group,
Described amino protecting group is selected from methyl, the tertiary butyl, formyl radical, allyloxy carbonyl, tert-butoxycarbonyl, to the nitro benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl or diazo;
R
4Expression hydrogen atom or methyl;
R
5The expression hydrogen atom, methyl or methoxy;
R
6, R
7Independently represent hydrogen atom or methyl respectively;
N represents 1,2 or 3.
4, compound as claimed in claim 3, be (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [(isothioureido-ethane-1-yl) amino]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3, the hydrate of 2,0] hept-2-ene"-2-carboxylic acid, and the ester of facile hydrolysis, its pharmacy acceptable salt, its isomer, its hydrate or its ester or salt.
5, the described compound of each claim of claim 1～4, its pharmacy acceptable salt is organic acid salt, inorganic acid salt, organic alkali salt or inorganic base salts, and wherein organic acid comprises acetate, trifluoroacetic acid, methylsulfonic acid, toluenesulphonic acids, toxilic acid, succsinic acid, tartrate, citric acid, fumaric acid; Mineral acid comprises hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid; Organic bases comprises meglumine, glucosamine; Mineral alkali comprises the basic cpd of sodium, potassium, barium, calcium, magnesium, zinc, lithium.
6, the described compound of each claim of claim 1～4; the ester of its facile hydrolysis is for being hydrolyzed into the ester of corresponding carboxylic acid in vivo; comprise lower alkane acyloxyalkyl group ester; lower alkoxycarbonyl oxyalkyl ester; the lactone group ester, lower alkoxy methyl ester, lower alkane acyl amino methyl ester; benzyl ester, the cyano methyl ester.
7, comprise the described compound of each claim of claim 1～4, its pharmacy acceptable salt, the ester of its facile hydrolysis, its isomer, its hydrate, or the pharmaceutical composition of the hydrate of its ester or salt and one or more pharmaceutical carriers and/or thinner.
8, pharmaceutical composition as claimed in claim 7 is pharmaceutically acceptable arbitrary formulation.
9, pharmaceutical composition as claimed in claim 7 contains the described compound of each claim of claim 1～4, its pharmacy acceptable salt, the ester of its facile hydrolysis or its isomer, its hydrate, perhaps the hydrate 0.05g～5g of its ester or salt is as essential activeconstituents.
10, the described compound of each claim of claim 1～4, its pharmacy acceptable salt, the ester of its facile hydrolysis or its isomer, its hydrate, with and the hydrate of ester or salt in the application that is used for preparing the medicine that treats and/or prevents infectious diseases.
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| CN2008101289437A CN101357918B (en) | 2007-06-22 | 2008-06-20 | Penem derivative containing isothioureido sulfhydryl pyrrolidine |
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| CN2008101289437A CN101357918B (en) | 2007-06-22 | 2008-06-20 | Penem derivative containing isothioureido sulfhydryl pyrrolidine |
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| TWI663168B (en) * | 2015-03-12 | 2019-06-21 | 日商四國化成工業股份有限公司 | Mercaptoethylacetylene urea compound and application thereof |
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| HRP970281B1 (en) * | 1996-05-28 | 2002-04-30 | Merck & Co Inc | Carbapenem antibiotic, composition and method of preparation |
| PL366943A1 (en) * | 2001-05-21 | 2005-02-07 | Kyoto Pharmaceutical Industries, Ltd. | Carbapenem compound |
| BRPI0413842A (en) * | 2003-08-25 | 2006-10-24 | Sankyo Co | compound of 1-methyl carbapenem or a pharmacologically acceptable salt thereof, ethanolate and tetrahydrate of 1-methyl carbapenem compound, process for preparing the crystalline form, process for preparing an ethanolate trihydrate of compound 1-methyl carbapenem, 1-methyl carbapenem compound ethanolate trihydrate, pharmaceutical composition for preventing or treating bacterial infections, and use of the crystalline form |
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| TWI663168B (en) * | 2015-03-12 | 2019-06-21 | 日商四國化成工業股份有限公司 | Mercaptoethylacetylene urea compound and application thereof |
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Address after: 050000 Beijing Tianjin Hebei Collaborative Innovation Demonstration Park 203c507, 769 Taihang street, high tech Zone, Shijiazhuang City, Hebei Province Patentee after: Xuanzhu Biotechnology Co.,Ltd. Address before: 050000 Beijing Tianjin Hebei Collaborative Innovation Demonstration Park 203c507, 769 Taihang street, high tech Zone, Shijiazhuang City, Hebei Province Patentee before: Xuanzhu Biotechnology Co.,Ltd. |