WO2000043399A1 - 3,6-disubstituted penam sulfone derivatives as antibacterials - Google Patents
3,6-disubstituted penam sulfone derivatives as antibacterials Download PDFInfo
- Publication number
- WO2000043399A1 WO2000043399A1 PCT/US2000/001630 US0001630W WO0043399A1 WO 2000043399 A1 WO2000043399 A1 WO 2000043399A1 US 0001630 W US0001630 W US 0001630W WO 0043399 A1 WO0043399 A1 WO 0043399A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- hydrogen
- methyl
- pharmaceutically acceptable
- carbamoyl
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the present invention is directed to ⁇ -lactamase inhibitors useful in combination with ⁇ -lactam antibiotics. More specifically, the present invention is directed to novel 3,6-disubstituted penam sulfone derivatives which demonstrate potent ⁇ -lactamase inhibitory activity.
- Penicillins and cephalosporins are the most frequently and widely used ⁇ -lactam antibiotics. However, the development of bacterial resistance to these antibiotics has had a damaging effect on maintaining the effective treatment of bacterial infections.
- U.S. Patent No. 4,234,579 discloses penicillanic acid 1,1 -dioxide (i.e., Sulbactam) useful for enhancing the activity of a number of ⁇ -lactam antibiotics.
- U.S. Patent No. 4,562,073 discloses a penicillin derivative (Tazobactam) useful as a ⁇ -lactamase inhibitor.
- U.S. Patent Nos. 4,287,181 and 5,637,579 disclose penicillanic acid derivatives useful in enhancing the effectiveness of ⁇ -lactam antibiotics.
- the present invention provides compounds having ⁇ -lactamase inhibitory activity against both Class A and Class C serine ⁇ -lactamases, which compounds have the formula (A):
- X is CH or NH;
- R j is cyano, methoxy or acetamido;
- R j is hydrogen, alkyl, a negative charge, a cation selected from the group consisting of sodium, potassium and tetraalkylammonium and acyloxyalkyl, or alkoxycarbonyloxyalkyl;
- R. is hydrogen, acyl, trisubstituted silyl, carbamoyl, di-(C M alkyl)aminocarbonyl or an amino acid residue; or pharmaceutically acceptable salts thereof.
- Heterocyclic rings for R can be aromatic or non-aromatic and have one to three heteroatoms, the same or different, selected from oxygen, nitrogen and sulfur. Examples include 1,2,3-triazole, isoxazole, imidazole or yridine.
- R when disubstituted amino are di-(C ⁇ - 4 alkyl)amino where the alkyl groups are the same or different.
- R when an ester are alkyl esters where the alkyl group has 1 to 4 carbon atoms.
- R 2 when trisubstituted silyl are tri-(C ⁇ - 4 alkyl)silyl where the alkyl groups are the same or different.
- R 2 when acyl are (C ⁇ . 4 alkyl)carbonyl.
- amino acid residues for R 2 are glycyl, alanyl, leucyl, isoleucyl and valyl.
- the compounds of the present invention are those of the formula set forth above where n is 1 and R is 1,2,3-triazole, isoxazole, imidazole or pyridine; R : is sodium; and R j is hydrogen; or pharmaceutically acceptable salts thereof.
- the asymmetric centres have the 2S, 3S, 5R, 6R configuration.
- the compounds of the present invention are: (2S, 3S, 5R, 6R)-6-Hydroxymethyl-3-methyl-4,4,7-trioxo-3-[l,2,3]triazol-l-ylmethyl- 4-lambda(6)-thia-l-aza-bicyclo[3.2.0)]heptane-2-carboxylic acid; (2S, 3R, 5R, 6R)-6-Hydroxymethyl-3-(methoxyimino-methyl)-3-methyl-4,4,7-trioxo- 4-lambda(6)-thia-l-aza-bicyclo[3.2.0]heptane-2-carboxylic acid; (Z)-(2S, 3S, 5R, 6R)-6-Hydroxymethyl-3-methyl-3-(3-nitrilo-propenyl)-4,4,7-trioxo- 4-lambda(6)-thia-l-azabicyclo[3.2.0]heptane
- alkyl and “alkoxy” are used to represent straight or branched carbon chains of 1-6 atoms.
- halogen is used to represent chlorine, bromine, fluorine and iodine.
- the compounds of this invention contain asymmetric carbon atoms and thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry, the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. It is recognized that one optical isomer, including diastereomer and enantiomer, or stereoisomer may have favorable properties over the other. Thus when disclosing and claiming the invention, when one racemic mixture is disclosed, it is clearly contemplated that both optical isomers, including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well.
- the compounds of the present invention may also be used in the form of a pharmaceutically acceptable acid addition salt having the utility of the free base.
- Such salts prepared by methods well known in the art, may be formed with both inorganic or organic acids, e.g., fumaric, benzoic, maleic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanolsulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, annamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene- sulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric, and nitric acids.
- inorganic or organic acids e.g., fuma
- This invention also provides a process for preparing compounds of formula A which comprise one of the following: a) deprotecting a compound of formula III:
- Removal of protecting groups, as illustrated by process a) can be carried out by processes known in the art to provide the compound of formula A.
- a racemic mixture may be converted to a mixture of optically active diastereoisomers by reaction with a single enantiomer of a 'resolving agent' (for example by diastereomeric salt formation or formation of a covalent bond).
- the resulting mixture of optically active diastereoisomers may be separated by standard techniques (e.g crystallisation or chromatography) and individual optically active diastereoisomers then treated to remove the 'resolving agent' thereby releasing the single enantiomer of the compound of the invention.
- Chiral chromatography using a chiral support, eluent or ion pairing agent
- the compounds of formula A may be isolated in the form of a salt of a pharmaceutically acceptable acid, e.g. an organic or inorganic acid by treatment with an acid such as described above.”
- the compounds of the present invention may be prepared by any suitable method which will be recognized by those skilled in the art. However, the present compounds may be advantageously prepared according to the Schemes set forth below.
- the monomeric formaldehyde/THF solution was prepared as follows: Paraformaldehyde (30 g. 1.0 mol) and ⁇ -toluenesulfonic anhydride (4.9 g, 15 mmol) were placed in a three-necked flask, and tetrahydrofuran (1.0 L) was added thereto. The mixture was heated and a slow distillation of the solvent was maintained.
- Representative compounds according to the present invention were tested in a microbiological assay in combination with the penicillin antibiotic piperacillin.
- the enhanced combined synergestic antibacterial activity is representative of the ⁇ - lactamase inhibitory properties of the compounds of the present invention.
- minimum inhibitory properties MIC's are determined in broth using several two-fold dilutions with a 1:1 ratio of piperacillin to inhibitor (N. A. Kuck, N. V. Jacobus, P. J. Peterson, W. J. Weiss, and R. T. Testa, Antibiotic Agents and Chemotherapy. 33:1964-1969 (1989)). The results are set forth in Table 1.
- Representative compounds of the present invention were also tested against a comercally available inhibitor, tazobactam, to determine inhibition of the AmpC and
- TEM-1 ⁇ -lactamase enzymes IC 50 values were determined spectrophotometrically using a 10 minute preincubation of enzyme with inhibitor at 25°C before addition of nitrocefin as a substrate. The results are also set forth in Table 1.
- the present compounds When the present compounds are employed for the above utility, they may be combined with one or more pharmaceutically acceptable carriers, e.g., solvents, dilutents, etc., and may be administered parentally in the form of sterile injectable solutions or suspensions containing from about 0.05% to about 5% suspending agent in an isotonic medium.
- Such pharmaceutical preparations may contain from about 0.05% to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and about 60% by weight.
- the effective dosage of active ingredient employed may vary depending upon the particular compound used, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 2 to 100 mg/kg of animal body weight, preferably given in divided doses two to four times a day. In general, the total daily dose is from about 100 mg to about 750 mg, preferably from about 100 to about 500 kg. Dosage forms suitable for internal use include from about 100 to 750 mg of active compound in intimate admixture with a liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the therapeutic situation.
- Liquid carriers include sterile water, polyethylene glycols, non-ionic-surfactants and edible oils such as corn, peanut, and sesame oils as appropriate.
- Adjuvants normally employed in the preparation of pharmaceutical preparations may be used, such as vitamin E, ascorbic acid, BHT and BHA.
- the present compounds may be administered parentally or intraperitoneally.
- Solutions or suspension of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
- Dispersions can be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
- the pharmaceutical forms suitable for injection use include sterile aqueous solutions and sterile powders for the preparation of sterile injectable solutions or dispensors. In all cases, the forms must be sterile and must be fluid so that easy syringability exists. It must be stable under conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms.
- the carrier may be a solvent or dispension medium containing, e.g., water, ethanol, apolyl (e.g., glyceol, propylene glycol and liquid polyethylene glycol) and vegetable oils.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Cephalosporin Compounds (AREA)
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EA200100813A EA200100813A1 (ru) | 1999-01-26 | 2000-01-26 | 3,6-дизамещенные производные пенамсульфона в качестве бактерицидных веществ |
PL00349874A PL349874A1 (en) | 1999-01-26 | 2000-01-26 | 3,6-disubstituted penam sulfone derivatives as antibacterials |
KR1020017009276A KR20010101649A (ko) | 1999-01-26 | 2000-01-26 | 항균제로서 3,6-이치환된 페남 술폰 유도체 |
JP2000594815A JP2002535335A (ja) | 1999-01-26 | 2000-01-26 | 抗菌剤としての3,6−二置換ペナムスルホン誘導体 |
AU26246/00A AU2624600A (en) | 1999-01-26 | 2000-01-26 | 3,6-disubstituted penam sulfone derivatives as antibacterials |
SK1014-2001A SK10142001A3 (sk) | 1999-01-26 | 2000-01-26 | 3,6-Disubstituované penamsulfónové deriváty ako antimikrobiálne prípravky |
BR0007729-1A BR0007729A (pt) | 1999-01-26 | 2000-01-26 | Composto, composição farmacêutica, e, métodos decontrole de infecções bacterianas em umhospedeiro em necessidade de tal terapia, e depreparo de um composto |
EP00904498A EP1144418A1 (en) | 1999-01-26 | 2000-01-26 | 3,6-disubstituted penam sulfone derivatives as antibacterials |
CA002355738A CA2355738A1 (en) | 1999-01-26 | 2000-01-26 | 3,6-disubstituted penam sulfone derivatives as antibacterials |
IL14411600A IL144116A0 (en) | 1999-01-26 | 2000-01-26 | 3,6-disubstituted penam sulfone derivatives as antibacterials |
NO20013640A NO20013640D0 (no) | 1999-01-26 | 2001-07-24 | 3,6-disubstituerte penamsufon-derivater som antibakterielle midler |
BG105737A BG105737A (en) | 1999-01-26 | 2001-07-26 | 3,6-disubstituted penam sulfon derivatives as antibacterials |
HK02100179.1A HK1038747A1 (zh) | 1999-01-26 | 2002-01-10 | 3,6-雙取代的penam(譯名不詳)碸衍生物作為抗菌物 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US23772699A | 1999-01-26 | 1999-01-26 | |
US09/237,726 | 1999-01-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000043399A1 true WO2000043399A1 (en) | 2000-07-27 |
Family
ID=22894903
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/001630 WO2000043399A1 (en) | 1999-01-26 | 2000-01-26 | 3,6-disubstituted penam sulfone derivatives as antibacterials |
Country Status (20)
Country | Link |
---|---|
EP (1) | EP1144418A1 (zh) |
JP (1) | JP2002535335A (zh) |
KR (1) | KR20010101649A (zh) |
CN (1) | CN1188417C (zh) |
AU (1) | AU2624600A (zh) |
BG (1) | BG105737A (zh) |
BR (1) | BR0007729A (zh) |
CA (1) | CA2355738A1 (zh) |
CZ (1) | CZ20012691A3 (zh) |
EA (1) | EA200100813A1 (zh) |
HK (1) | HK1038747A1 (zh) |
HU (1) | HUP0200013A3 (zh) |
ID (1) | ID29400A (zh) |
IL (1) | IL144116A0 (zh) |
NO (1) | NO20013640D0 (zh) |
PL (1) | PL349874A1 (zh) |
SK (1) | SK10142001A3 (zh) |
TR (1) | TR200102133T2 (zh) |
WO (1) | WO2000043399A1 (zh) |
ZA (1) | ZA200104323B (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20110125651A (ko) * | 2009-03-10 | 2011-11-21 | 레르 리키드 쏘시에떼 아노님 뿌르 레드 에렉스뿔라따시옹 데 프로세데 조르즈 클로드 | 저 유전상수 실릴화를 위한 시클릭 아미노 화합물 |
CN109422765B (zh) * | 2017-09-05 | 2020-08-28 | 香港理工大学深圳研究院 | C类β-内酰胺酶抑制剂及其制备方法和应用 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0041047A2 (de) * | 1980-05-22 | 1981-12-02 | Ciba-Geigy Ag | Dioxidverbindungen, Verfahren zu ihrer Herstellung und ihre Verwendung |
EP0083977A1 (en) * | 1982-01-11 | 1983-07-20 | Pfizer Inc. | 6-Alpha-hydroxymethylpenicillanic acid sulfone as a beta-lactamase inhibitor |
US4503040A (en) * | 1984-02-27 | 1985-03-05 | Pfizer Inc. | 6-(Aminoacyloxymethyl)penicillanic acid 1,1-dioxides as beta-lactamase inhibitors |
US4562073A (en) * | 1982-12-24 | 1985-12-31 | Taiho Pharmaceutical Company Limited | Penicillin derivatives |
US4591459A (en) * | 1984-12-03 | 1986-05-27 | Pfizer Inc. | Intermediates for 6-(aminoacyloxymethyl) penicillanic acid 1,1-dioxides |
US5637579A (en) * | 1993-08-24 | 1997-06-10 | Hoffmann-La Roche Inc. | Penam derivatives |
-
2000
- 2000-01-26 JP JP2000594815A patent/JP2002535335A/ja active Pending
- 2000-01-26 HU HU0200013A patent/HUP0200013A3/hu unknown
- 2000-01-26 SK SK1014-2001A patent/SK10142001A3/sk unknown
- 2000-01-26 CZ CZ20012691A patent/CZ20012691A3/cs unknown
- 2000-01-26 BR BR0007729-1A patent/BR0007729A/pt not_active IP Right Cessation
- 2000-01-26 EP EP00904498A patent/EP1144418A1/en not_active Withdrawn
- 2000-01-26 CA CA002355738A patent/CA2355738A1/en not_active Abandoned
- 2000-01-26 CN CNB008030766A patent/CN1188417C/zh not_active Expired - Fee Related
- 2000-01-26 ID IDW00200101522A patent/ID29400A/id unknown
- 2000-01-26 WO PCT/US2000/001630 patent/WO2000043399A1/en not_active Application Discontinuation
- 2000-01-26 KR KR1020017009276A patent/KR20010101649A/ko not_active Application Discontinuation
- 2000-01-26 TR TR2001/02133T patent/TR200102133T2/xx unknown
- 2000-01-26 EA EA200100813A patent/EA200100813A1/ru unknown
- 2000-01-26 AU AU26246/00A patent/AU2624600A/en not_active Abandoned
- 2000-01-26 IL IL14411600A patent/IL144116A0/xx unknown
- 2000-01-26 PL PL00349874A patent/PL349874A1/xx not_active Application Discontinuation
-
2001
- 2001-05-25 ZA ZA200104323A patent/ZA200104323B/en unknown
- 2001-07-24 NO NO20013640A patent/NO20013640D0/no not_active Application Discontinuation
- 2001-07-26 BG BG105737A patent/BG105737A/xx unknown
-
2002
- 2002-01-10 HK HK02100179.1A patent/HK1038747A1/zh unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0041047A2 (de) * | 1980-05-22 | 1981-12-02 | Ciba-Geigy Ag | Dioxidverbindungen, Verfahren zu ihrer Herstellung und ihre Verwendung |
EP0083977A1 (en) * | 1982-01-11 | 1983-07-20 | Pfizer Inc. | 6-Alpha-hydroxymethylpenicillanic acid sulfone as a beta-lactamase inhibitor |
US4562073A (en) * | 1982-12-24 | 1985-12-31 | Taiho Pharmaceutical Company Limited | Penicillin derivatives |
US4503040A (en) * | 1984-02-27 | 1985-03-05 | Pfizer Inc. | 6-(Aminoacyloxymethyl)penicillanic acid 1,1-dioxides as beta-lactamase inhibitors |
US4591459A (en) * | 1984-12-03 | 1986-05-27 | Pfizer Inc. | Intermediates for 6-(aminoacyloxymethyl) penicillanic acid 1,1-dioxides |
US5637579A (en) * | 1993-08-24 | 1997-06-10 | Hoffmann-La Roche Inc. | Penam derivatives |
Non-Patent Citations (1)
Title |
---|
P. BITHA ET AL.: "6-(1-Hydroxyalkyl)penam sulfone derivatives as inhibitors of class A and class C beta-lactamases II", BIOORG. MED. CHEM. LETT., vol. 9, no. 7, 1999, pages 997 - 1002, XP004162572 * |
Also Published As
Publication number | Publication date |
---|---|
IL144116A0 (en) | 2002-05-23 |
HUP0200013A2 (hu) | 2002-05-29 |
HK1038747A1 (zh) | 2002-03-28 |
NO20013640L (no) | 2001-07-24 |
CA2355738A1 (en) | 2000-07-27 |
CN1337965A (zh) | 2002-02-27 |
ZA200104323B (en) | 2002-08-26 |
SK10142001A3 (sk) | 2002-07-02 |
PL349874A1 (en) | 2002-09-23 |
BR0007729A (pt) | 2001-10-30 |
AU2624600A (en) | 2000-08-07 |
BG105737A (en) | 2002-05-31 |
HUP0200013A3 (en) | 2002-10-28 |
KR20010101649A (ko) | 2001-11-14 |
CN1188417C (zh) | 2005-02-09 |
ID29400A (id) | 2001-08-30 |
EP1144418A1 (en) | 2001-10-17 |
TR200102133T2 (tr) | 2001-12-21 |
EA200100813A1 (ru) | 2003-02-27 |
CZ20012691A3 (cs) | 2002-06-12 |
JP2002535335A (ja) | 2002-10-22 |
NO20013640D0 (no) | 2001-07-24 |
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