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Publication numberUSRE26253 E
Publication typeGrant
Publication dateAug 15, 1967
Filing dateOct 24, 1961
Priority dateMay 17, 1963
Also published asUS3226436
Publication numberUS RE26253 E, US RE26253E, US-E-RE26253, USRE26253 E, USRE26253E
InventorsJournal American Chemical Society
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
And z-alkylamino-g-deoxytetracycline
US RE26253 E
Abstract  available in
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Description  (OCR text may contain errors)

United States Patent 7- AND Q-ALKYLAMINO-ti-DEOXYTETRACYCLINE Joseph Petisi, Suiiern, N.Y., and James Howard Boothe,

Montvale, N.J., assignors to American Cyanamid Company, Stamford, Conn., a corporation of Maine No Drawing. Original No. 3,226,436, dated Dec. 28, 1965,

Ser. No. 281,349, May 17, 1963, which is a continuation of Ser. No. 147,137, Oct. 24, 1961, and Ser. No. 161,412, Dec. 22, 1961, now Patent No. 3,148,212, dated Sept. 8, 1964. Application for reissue Dec. 20, 1966, Ser. No. 606,500

3 Claims. (Cl. 260-559) Matter enclosed in heavy brackets appears in the original patent but forms no part of this reissue specification; matter printed in italics indicates the additions made by reissue.

This application is a continuation of our copending applications Serial No. 147,137, filed October 24, 1961, now abandoned, and Serial No. 161,412 filed December 22, 1961, now US. Patent No. 3,148,212.

This invention relates to new compounds of the tetracycline family and, more particularly, is concerned with novel substituted 7-[and/ or 9-]amino tetracyclines which may be represented by the following general formula:

wherein R [is hydrogen or methyl and R and R are hydrogen, [mono(lower alkyUamino or] and R is di(lower alkyl)amino [with the proviso that R and R cannot both be hydrogen]. Typical compounds represented by the above general formula are, for example,

These new tetracycline derivatives may be prepared by a novel reductive alkylation process comprising interacting a compound of the following general formula:

n Nmrh):

on on" c ONH:

H H O OH O wherein R [is hydrogen or methyl] and Y [and Z] are hydrogen, and Z is amino, a substituent reducible to amino, mono(lower alkyl)amino or a substituent reducible to mono(lower alkyl)amino [with the proviso that Re. 26,253 Reissuecl Aug. 15, 1967 Y and Z cannot both be hydrogen], with [a carbonyl compound of the general formula:

Wherein R is hydrogen or lower alkyl and R is hydrogen or lower alkyL] formaldehyde 0racemldchyde, in the presence of a reducing agent.

It is to be understood that when the term lower alkyl" is used throughout this specification, it is meant to include [all lower alkyl groups having up to about 6 carbon atoms. Accordingly, aldehydes and ketones useful in carrying out this reductive alkylation include. for example, .formaldehyde, acetaldehyde, propionaldehyde, nbutyraldehyde, iso-butyraldehyde, acetone, methyl ethyl ketone, diethyl ketone, etc.] methyl and ethyl.

In the second general formula set forth above, the substituent[s] [Y and] Z [are] is defined as [hydrogen,] amino a substituent reducible to amino, mono (lower alkyl)amino or a substituent reducible to mono (lower alkyl)amino [with the proviso that Y and Z cannot both be hydrogen]. Suitable substituents reducible to amino may be, for example, nitro, nitroso, diazonium halide, beneneazo, substituted benezeneazo, etc. [Where] R [and/or R in the first general formula set forth above [are] being a disubstituted amino group[s] such products may be prepared in either of two ways. In the first situation, [Y and/or] Z may be amino or a substituent reducible to amino and reductive dialkylntion on an unsubstituted amino group occurs, whereby a disub stituted amino group is obtained. In the second situation, [Y and/0r] Z may be monoflower alkyl)amino or a substituent reducible to mono(lower alkyl)amino and reductive monoalkylation on a monoalkyl-substituted amino group occurs, whereby a disubstituted amino group is obtained. Suitable mono(lower alkyUamino groups [may be, for example,] are methylaminoL] and ethylamino[, n-propylamino, iso-propylamino, n butylamino, iso-butylamino, t-butylamino, etc]. Suitable substituents reducible to mono(lower alkyl)amino may be, for example, formylamino, acetylamino, N-(lower alkyl)hydroxylamino. and the like. Specific starting materials operable in this process include 7-nitro-6-deoxy-6-demethyltetracycline, 7-amino-6-deoxy-6-demethyltetracycline, [9-nitro-6-deoxy-6demethyltetracycline,] [9-amino6-deoxy-6-demethyltetracycline,] [7,9-dinitro-6-deoXy-6-demethyltetracyclineJ [7,9-diamino-6-deoxy-6-demethyltetracycline,] [7-nitro-6-deoxytetracycline,] [7-amino-6-deoxytetracycline,] [9-nitro-6-deoxytetracycline,] [9-amino-6-deoxytetracycline,] [7,9-diamino-6-deoxytetracycline,] [9 amino-7-nitro-6-deoxy-6-demethyltetracycline] [9-amino-7-nitro-6-deoxytetracycline,] 7-formylamino-6-deoxy-6-demethyltetracycline, [9-formylamino-6-deoxy-6 demethyltetracycline,] [7-acetylamino-6-deoxytetracycline.] [9-acetylamino-6-deoxytetracycline,] [7,9-diacetylamino-6-deoxytetracycline,] [7-nitro-9-acetylamino-6-deoxytetracycline] 6-deoxy-6-demethyltetracycline-7-diazonium chloride, [6-deoxy-6-de1nethyltetracycline-9-diazonium chloride,] [fi-deoxytetracycline-Q-diazonium chloride,] [9-nitro-S-hydroxy6-deoxytetracycline,] [9-amino-5-hydroxy-6-deoxytetracycline,]

and the like. The tetracycline starting materials for this process may be prepared by following the procedures set forth in Austrian Patent No. 212,308 to American Cyanamid Company, in the articles by Beereboom et al..

I.A.C.S. 82, 1003 (1960), and by Boothe ct al., J.A.C.S. 82, 1253 (1960), and in the copending application of Petisi and Boothe, Serial No. 65,584, filed October 28, 1960. The tetracycline starting materials may be employed either in the form of their free bases or in the form of their salts with various organic and inorganic acids depending upon whether solubility in polar or non-polar solvent systems is desired.

The reductive alkylation process may be accomplished by either chemical or catalytic reduction using procedures well-known to those in the art. Catalytic reduction, which is especially suited for the reductive alkylation of the tetracycline starting compounds set forth above, may be accomplished in a solvent for the tetracycline starting compound in the presence of [a carbonyl compound] formaldehyde r acetaldehyde and a metal catalyst and hydrogen gas at pressures from atmospheric to super-atmospheric. Ordinarily, the reductive alkylation is conveniently carried out at hydrogen pressures of from about one to about four atmospheres. Temperature does not appear to be critical in the catalytic hydrogenation. Temperatures of from 0 C. to 50 C., and usually room temperature, are preferred since they generally give best results. The metal catalyst may be of the base metal type, such as nickel or copper chromite, or it may be of the noble metal type, such as finely divided platinum, palladium or rhodium. The noble metal catalysts are advantageously employed on a carrier such as finely divided alumina, activated charcoal, diatomaceous earth, etc., in which form they are commonly available. The hydrogenation is carried out until the desired amount of hydrogen gas is absorbed at which point the hydrogenation is stopped. The solvents selected for the catalytic reduction should be reaction-inert, that is, they should not be capable of reacting with the starting materials, product, or hydrogen under the conditions of the reaction. A variety of solvents may be used for this purpose and minimum laboratory experimentation will permit the selection of a suitable solvent for any specific tetracycline starting compound. Generally, the catalytic reductive alkylation may be carried out in solvents such as water, lower alkanols, e.g. methanol, ethanol; lower alkoxy lower alkanols, e.g. Z-methoxyethanol, Zethoxyethanol; tetrahydrofuran, dioxane, dimethylformamide, etc.

A variety of chemical reducing agents may be used in the reductive alkylation process. These include reduction with active metals in mineral acids, e.g. zinc, tin, or iron in hydrochloric acid; reduction with metal couples such as the copper-zinc couple, the tin-mercury couple, aluminum amalgam, or magnesium amalgam; and reduction with formic acid. Of these, reduction with zinc and hydrochloric acid and reduction with formic acid are preferred. When aqueous systems are used in the aforementioned chemical reductive alkylations, it is at times desirable to utilized a water-miscible organic solvent, particularly when the tetracycline starting compound is of limited solubility in the reaction mixture. The watermiscible solvent does not alter the course of the reduction but merely provides for more efiicient reduction, e.g. a shorter reaction time by providing more intimate contact of the reagents. A large number of such solvents are available for this purpose and include, among others, dimethylformamide, dimethoxyethane, methanol, ethanol, dioxane, tetrahydrofuran, and the like.

The novel products of the present invention are obtained from the reductive alkylation reaction mixtures by standard procedures. For example, the products may be isolated from the catalytic hydrogenation reaction mixtures, after filtration of the catalyst, by precipitation with a solvent such as ether or hexane or by concentration, usually under reduced pressure, or by a combination of these. Work-up of the chemical reductive alkylation reaction mixtures to obtain the desired products may also be accomplished by known procedures such as precipitation, concentration, solvent extraction, or combinations of these procedures. After isolation, the products may 4 be purified by any of the generally known methods for purification of tetracycline compounds. These include recrystallization from various solvents and mixed solvent systems, chromatographic techniques, and counter current distribution, all of which are usually employed for this purpose.

The novel substituted 7-[and/ or 9-]amino tetracyclines of the present invention are biologically active and possess the broad-spectrum antibacterial activity of the previously know tetracyclines. In particular, the [7-methylamino] 7-dimethylamirto-6-deoxy6-demethyltetracycline possesses extraordinary activity both orally and parcnterally against Staphylococcus aureus, strain Smith, and Staphylococcus aureus, strain Rose, infections in mice.

Staphylococcus aureus, strain Smith, has been studied and described by J. M. Smith and R. J. Dubos in Journ. Expt. Med. 103, 87 (1956), at the Rockefeller Institute. Staphylococcus aureus, strain Smith, is coagulase positive, tcllurite negative and is sensitive to tetracycline, penicillin, streptomycin, erythromycin, carbomycin, neomycin, chloramphenicol and novobiocin in vitro. Attempts have been made for phage typing of this strain, but it has been determined that it is non-typable.

Staphylococcus aureus, strain Rose (ATCC No. 14,154) was isolated clinically from an abscess of a patient who did not respond to treatment with the tetracyclines. This organism has been found to be resistant to the clinically used tetracyclines in vitro and in vivo. Staphylococcus aureus, strain Rose, is coagulase and tellurite positive and is resistant to tetracycline, penicillin, streptomycin, and erythromycin. It is sensitive to carbomycin, neomycin, chloramphenicol and novobiocin in vitro. Staphylococcus aureus, strain Rose, has been phage-typed with the following results:

Staphylococcus aureus, strain RosePhage pattern 81.

It: has been determined that intravenously against Staphylococcus aureus, strain Smith, infections in mice, [7-methylamino]7 dimelhylamz'no 6 demethyl 6- deoxytetracycline is about 4 times as potent as tetracycline. When administered in a single oral tubing dose, against Staphylococcus aureus, strain Smith, infection, [7- methylamino]7 dimethyla'mino 6 demethyl 6 deoxytetracycline is 17 times more effective than tetracycline. Additionally, after single oral tubing doses in mice, plasma levels of [7-methylaminol7-dimethylamin0-6-demethyI-G-deoxytetracycline are about 5 times higher than those obtained with demethylchlortetracycline.

Of special interest is the fact that [7-methylamino]7- dimethylamino-6demethyl-6-deoxytetracycline is uniquely active among the tetracyclines in possessing unexpected high oral activity against the tetracycline-resistant strain Staphylococcus aureus, strain Rose. This is the only tetracycline so for known having oral activity against this tetracycline-resistant infection in mice.

Thus with oral doses as low as 16 mg./kg., 16 out of 20 mice infected with Staphylococcus aureus, strain Rose, and treated with [7-methylamino]7-dimethylamino-6-dernethyl-6-deoxytetracycline were alive 7 days after infection, whereas 19 out of 20 of the infected non-treated control mice died within 1 day. Under the same test conditions tetracycline is ineffective at the maximum tolerated dose of 2,048 mg./kg.

The new tetracyclines of this invention are amphoteric compounds and hence acid-addition salts, that is both monoand di-salts, may be readily prepared. The preferred acids are the non-toxic pharmaceutically acceptable acids, eg the mineral acids such as hydrochloric, sulfuric, and the like although organic acids such as trichloroacetic may also be used. The acid-addition salts may be prepared by treating the new tetracyclines with approximately two equivalents or more of the chosen acid in a suitable solvent.

The invention will be described in greater detail in conjunction with the following specific examples.

EXAMPLE 1 Reductive methylation of 7-amino-6-deoxy-6-demethyltetracycline to yield [7-methylamino]7-dimethylamina- 6-deoxy-fi-demethyltetracycline A solution of 792.9 mg. (1.5 millimoles) of 7-arnino- 6-deoxy-6-demethyltetracycline sulfate in 90 ml. of methyl Cellosolve, 1.5 ml. of 40% aqueous formaldehyde solu tion, and 300 mg. of palladium-on-carbon catalyst was hydrogenated at room temperature and atmospheric pressure. Uptake of between one and one and one-half equivalents of hydrogen was complete in one to two hours. The catalyst was filtered 01f and the orange solution poured into 1.5 liters of dry ether. The precipitate was filtered off, washed well with dry ether and dried, weight 391 mg. The turbidimetric assay was 852 grammas per milliliter. Eighty-three milligrams of the material was chromatographed on neutral diatomaceous earth using a partition system of heptane, ethyl acetate, methanol, water in the ratio 45:55:15z6. The compound was run as a free base, pH of sample was 5.0. The product was eluted in the second hold back volume and was mg. in weight.

The turbidimetric assay was 2190 gammas per milliliter. R; 0.65 (nitromethane:benzenezpyridinezpl-l 3,4, buffer- :10:323).

EXAMPLE 2 Reductive methylation of 7 amino-6-deoxy-6-demethyltetracycline to yield [7-methylamino]7-dimethylamino- 6-deoxy-6-demethyltetracycline A solution of 527 mg. of 7-amino-6-deoxy--demethyltetracycline sulfate, 0.25 ml. of 97% formic acid, and 0.2 ml. of 37% formaldehyde solution was heated to reflux for 2 hours. The cooled mixture was taken up in 100 ml. of water. Paper chromatography revealed the presence of [7 methylamino]7 dimethylamino-fi-deoxydemethyltetracycline and its 4-epimer.

EXAMPLE 3 Reductive methylation of 7 nitro-6-deoxy-6-demethyltetracycline to yield [7-methylamino]7-dimethylamino- 6-deoxy-6-demethyltetracycline A solution of 278.7 mg. of 7-nitro-6-deoxy-6-demethyltetracycline sulfate in 15 ml. of 93% methyl Cellosolve (7% water), 0.75 ml. of 40% aqueous formaldehyde solution and 50 mg. of 10% palladium-on-carbon catalyst was hydrogenated at room temperature and atmospheric pressure. Uptake was [complete four equivalents[)] in two hours. After removal of the catalyst by filtration, the solution was poured into 300 ml. of dry ether. The precipitate was collected by filtration, washed well with dry ether, and dried; weight, 200 mg.

EXAMPLE 4 [Reductive methylation of 9-amino-6-deoxy-6-demethyltetracycline to yield 9-methylamino-6-deoxy 6 demethyltetracycline] EXAMPLE 5 [Reductive methylation of 9-nitro-6-deoxy-6-demethyltetracycline to yield 9 methylamino-6-deoxy-6-demethyltetracycline] [A solution of 114.8 mg. of 9 nitro-6-deoxy-6-demethyltetracycline in 20 ml. of methanol containing 2.5 ml. of 0.1 N methanolic hydrochloric acid, 0.4 ml. of 40% aqueous formaldehyde solution, and 50 mg. of 10% palladium-on-carbon catalyst was hydrogenated at room temperature and atmospheric pressure. Uptake was complete of theory) in one hour. After filtration of the catalyst, the solution was evaporated to dryness; weight, mg]

EXAMPLE 6 Reductive ethylation of 7-amino-6-deoxy-fi-demethyltetracycline to yield [7-ethylamino]7-diezhylamino 6- deoxy-G-demethyltetracycline A solution of 396 mg. of 7-arnino-6-deoxy-6-demethyltetracycline sulfate in 50 ml. of methyl Cellosolve was hydrogenated at room temperature and atmospheric pressure using 2 m1. of acetaldehyde and mg. of 10% palladium-on-carbon. Uptake stopped after 3 hours and the catalyst was removed by filtration and the solution poured into 750 ml. of dry ether. The precipitate was filtered off, washed well with dry ether and dried; weight, 64 mg.

EXAMPLE 7 Reductive ethylation of 7-nitro-6-deoxy-6-demethyltetracycline to yield [7-ethylamino]7-diethylamino-deoxyfi-demethyltetracycline In 30 ml. of methyl Cellosolve was suspended 560 mg. of 7-nitro-6-deoxy-6-demethyltetracycline sulfate, 2.1 ml. of 1 N sulfuric acid, 1.0 ml. of acetaldehyde, and 100 mg. of 10% palladium-on-charcoal. The mixture was shaken with hydrogen for 1.5 hours and the catalyst was then removed by filtration. The filtrate was poured into about 400 ml. of ether which precipitated a light colored solid. The product after filtering and drying weighed 582 mg. and consisted mostly of [7-ethylamino]7-diethylamino- 6-deoxy-6-demetl1yltetracycline.

EXAMPLE 8 [Reductive iso-propylation of 7-nitro-6-deoxy-6-demethyltetracycline to yield 7 iso-propylamino-fi-deoxy-6-demethyltetracycline] [A solution of 200 mg. of 7-nitro-6-deoxy-6-demethyltetracycline sulfate and 0.15 ml. of acetone in a mixture of 5.5 ml. of water and 5.5 ml. of ethanol was reduced in a Paar shaker with hydrogen and platinum oxide as a catalyst. The system absorbed 42 ml. of hydrogen during a two hour period. The catalyst was filtered and the filtrate evaporated to dryness in vacuo. The residue was dissolved in 3 ml. of MeOH and diluted with 150 ml. of ether. The solid product that separated weighed mg] What is claimed is:

1. A compound of the group consisting of tetracyclines of the formula:

Rs CONH,

H H OH O H 0 wherein R [is selected from the group consisting of hydrogen and methyl, and R and R are each [selected from the group consisting of] hydrogen, and [mono (lower alkyl)amino] R is selected from the group consisting of dimethylamino and diethyl amino [with the proviso that R and R cannot both be hydrogen]; and the non-toxic acid-addition salts thereof.

2. [7 methylamino]7 dimethylamino-6-deoxy-6-demethyltetracycline.

8 [3. 9-methylamino-Qdeoxyb-demethyltctracycline.] UNITED STA S P T 4. [7-ethylamino]7 dz'cthylamin o 6 deoxy-6-de- 3148 212 9 9 4 Baothe at a]. 2 0 methyltetracycline.

[5. 7-isopropylamino 6 deoxy 6 demethylletra- OTHER REFERENCES Y -J 5 Boothe et al.: Journal American Chemical Society,

References Cited vol. 82, pages 1253-1255 (1960).

The following references, cited by the Examiner, are of record in the patented file of this patent or the original NICHOLAS Pnmary Examiner patent.

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US5248797 *Aug 13, 1992Sep 28, 1993American Cyanamid CompanyMethod for the production of 9-amino-6-demethyl-6-deoxytetracycline
US5281628 *Oct 4, 1991Jan 25, 1994American Cyanamid Company9-amino-7-(substituted)-6-demethyl-6-deoxytetracyclines
US5284963 *Aug 13, 1992Feb 8, 1994American Cyanamid CompanyMethod of producing 7-(substituted)-9-[(substituted glycyl)-amidol]-6-demethyl-6-deoxytetra-cyclines
US5328902 *Aug 13, 1992Jul 12, 1994American Cyanamid Co.7-(substituted)-9-[(substituted glycyl)amido]-6-demethyl-6-deoxytetracyclines
US5371076 *Apr 2, 1993Dec 6, 1994American Cyanamid Company9-[(substituted glycyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracyclines
US5380888 *Mar 2, 1994Jan 10, 1995American Cyanamid Company7-(substituted)-9-[(substituted glycyl)amido]-6-demethyl-6-deoxytetracyclines
US5386041 *Feb 8, 1994Jan 31, 1995American Cyanamid Company7-(substituted)-8-(substituted)-9-[(substituted glycyl) amido]-6-demethyl-6-deoxytetracyclines
US5401729 *Feb 24, 1994Mar 28, 1995American Cyanamid Company7-(substituted)-9-[(substituted glycyl)amido]-6-demethyl-6-deoxytetracyclines
US5401863 *Mar 29, 1994Mar 28, 1995American Cyanamid Company9-amino-7-(substituted)-6-demethyl-6-deoxytetracyclines
US5420272 *Aug 13, 1992May 30, 1995American Cyanamid Company7-(substituted)-8-(substituted)-9-](substituted glycyl)amido]-6-demethyl-6-deoxytetracyclines
US5430162 *Mar 21, 1994Jul 4, 1995American Cyanamid Company7-(substituted)-8-(substituted)-9-substituted amino)-6-demethyl-6-deoxytetracyclines
US5495030 *Sep 1, 1994Feb 27, 1996American Cyanamid Company9-[(substituted glycyl)amido)]-6-demethyl-6-deoxytetracyclines
US5529990 *May 31, 1995Jun 25, 1996American Cyanamid CompanyMethod for treating bacterial infection with novel 7-substituted-9-substituted amino 6-demethyl-6-deoxytetracyclines
US5530117 *May 31, 1995Jun 25, 1996American Cyanamid Company7-substituted-9-substituted amino-6-demethyl-6-deoxytetracyclines
US5567692 *May 18, 1995Oct 22, 1996American Cyanamid Company9-[(substituted glycyl) amido)]-6-demethyl-6-deoxytetracyclines
US5639742 *Aug 29, 1994Jun 17, 1997Lee; Ving Jick9-[(substituted glycyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracyclines
US5675030 *Nov 16, 1994Oct 7, 1997American Cyanamid CompanyMethod for selective extracting a 7-(hydrogen or substituted amino)-9- (substituted glycyl) amido!-6-demethyl-6-deoxytetracycline compound
US7001918Jun 1, 2004Feb 21, 2006Paratek Pharmaceuticals, Inc.7-pyrrolyl tetracycline compounds and methods of use thereof
US7094806Jun 10, 2004Aug 22, 2006Trustees Of Tufts College7, 8 and 9-substituted tetracycline compounds
US7176225Dec 8, 2004Feb 13, 2007WyethOxazole derivatives of tetracyclines
US7208482Aug 6, 2003Apr 24, 2007Paratek Pharmaceuticals, Inc.9-aminoacyl tetracycline compounds and methods of use thereof
US7323492Jan 5, 2004Jan 29, 2008Paratek Pharmaceuticals, Inc.7-pyrollyl 9-aminoacyl tetracycline compounds and methods of use thereof
US7326696Dec 15, 2003Feb 5, 2008Paratek Pharmaceuticals, Inc.Amino-methyl substituted tetracycline compounds
US7361674Jun 16, 2006Apr 22, 2008Trustees Of Tufts College7, 8 and 9-substituted tetracycline compounds
US7365087Dec 13, 2006Apr 29, 2008WyethOxazole derivatives of tetracyclines
US7521437Feb 13, 2007Apr 21, 2009Trustees Of Tufts College7-phenyl-substituted tetracycline compounds
US7553828Feb 24, 2004Jun 30, 2009Paratek Pharmaceuticals, Inc.9-aminomethyl substituted minocycline compounds
US7595309May 24, 2004Sep 29, 2009Trustees Of Tufts College7-substituted tetracycline compounds
US7652002Dec 20, 2006Jan 26, 2010Paratek Pharmaceuticals, Inc.9-aminoacyl tetracycline compounds and methods of use thereof
US7696186Dec 16, 2003Apr 13, 2010Paratek Pharmaceuticals, Inc.7,9-substituted tetracycline compounds
US7696187Mar 28, 2006Apr 13, 2010Trustees Of Tufts CollegeMethods of preparing substituted tetracyclines with transition metal-based chemistries
US7696188Mar 4, 2008Apr 13, 2010Trustees Of Tufts College7,8 and 9-substituted tetracycline compounds
US7696358Dec 2, 2005Apr 13, 2010Paratek Pharmaceuticals, Inc.Five-membered heterocyclyl tetracycline compounds and methods of use thereof
US7763735Oct 11, 2007Jul 27, 2010President And Fellows Of Harvard CollegeSynthesis of enone intermediate
US7807842May 20, 2005Oct 5, 2010President And Fellows Of Harvard CollegeSynthesis of tetracyclines and analogues thereof
US7812008Feb 14, 2006Oct 12, 2010Wyeth Llc9-substituted tetracyclines
US7820641Dec 18, 2003Oct 26, 2010Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
US7851460Apr 17, 2009Dec 14, 2010Trustees Of Tufts College7-phenyl-substituted tetracycline compounds
US7875649Mar 9, 2010Jan 25, 2011Trustees Of Tufts College7, 8 and 9-substituted tetracycline compounds
US7897784Nov 24, 2009Mar 1, 2011Paratek Pharmaceuticals, Inc.Process for preparing five-membered heterocyclyl tetracycline compounds and methods of use thereof
US7960559Jul 9, 2010Jun 14, 2011President And Fellows Of Harvard CollegeSynthesis of enone intermediate
US8048867May 4, 2004Nov 1, 2011Trustees Of Tufts College9-substituted minocycline compounds
US8088755Feb 6, 2006Jan 3, 2012Paratek Pharmaceuticals, Inc.11a, 12-derivatives of tetracycline compounds
US8101590Aug 31, 2006Jan 24, 2012Wyeth Llc9-aminocarbonylsubstituted derivatives of glycylcyclines
US8101591Nov 24, 2009Jan 24, 2012Paratek Pharmaceuticals, Inc.9-aminoacyl tetracycline compounds and methods of use thereof
US8106225Dec 3, 2004Jan 31, 2012Trustees Of Tufts CollegeMethods of preparing substituted tetracyclines with transition metal-based chemistries
US8119622Dec 10, 2009Feb 21, 2012Trustees Of Tufts College7-phenyl-substituted tetracycline compounds
US8168810Dec 14, 2010May 1, 2012Trustees Of Tufts College7-phenyl-substituted tetracycline compounds
US8211937Dec 3, 2007Jul 3, 2012Paratek Pharmaceuticals, Inc.7-pyrollyl 9-aminoacyl tetracycline compounds and methods of use thereof
US8252777Jan 24, 2011Aug 28, 2012Trustees Of Tufts College7, 8 and 9-substituted tetracycline compounds
US8258120Jan 9, 2009Sep 4, 2012Paratek Pharmaceuticals, Inc.9-substituted minocycline compounds
US8293920Mar 9, 2011Oct 23, 2012President And Fellows Of Harvard CollegeSynthesis of enone intermediate
US8304445Mar 1, 2011Nov 6, 2012Paratek Pharmaceuticals, Inc.7-pyrazolyl tetracycline compounds and methods of use thereof
US8466132Oct 25, 2005Jun 18, 2013Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
US8470804Dec 29, 2011Jun 25, 2013Paratek Pharmaceuticals, Inc.11a, 12-derivatives of tetracycline compounds
US8486921Apr 6, 2007Jul 16, 2013President And Fellows Of Harvard CollegeSynthesis of tetracyclines and analogues thereof
US8492365Jun 9, 2009Jul 23, 2013Trustees Of Tufts College7-substituted tetracycline compounds
US8518912Nov 28, 2008Aug 27, 2013Actelion Pharmaceuticals Ltd.Phosphonic acid derivates and their use as P2Y12 receptor antagonists
US8580969Sep 14, 2012Nov 12, 2013President And Fellows Of Harvard CollegeSynthesis of enone intermediate
US8598148May 12, 2010Dec 3, 2013President And Fellows Of Harvard CollegeSynthesis of tetracyclines and analogues thereof
US8907104Nov 11, 2013Dec 9, 2014President And Fellows Of Harvard CollegeSynthesis of enone intermediate
US9073829Apr 30, 2010Jul 7, 2015President And Fellows Of Harvard CollegeSynthesis of tetracyclines and intermediates thereto
US9090541Jul 12, 2012Jul 28, 2015Paratek Pharmaceuticals, Inc.9-substituted minocycline compounds
US9365493Oct 25, 2013Jun 14, 2016President And Fellows Of Harvard CollegeSynthesis of tetracyclines and analogues thereof
US9365500Jun 27, 2014Jun 14, 2016Paratek Pharmaceuticals, Inc.9-aminomethyl substituted minocycline compounds
US9533943May 19, 2014Jan 3, 2017Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
US9688644Jul 6, 2015Jun 27, 2017President And Fellows Of Harvard CollegeSynthesis of Tetracyclines and intermediates thereto
US20040192657 *Aug 6, 2003Sep 30, 2004Carmen Garcia-Luzon9-Aminoacyl tetracycline compounds and methods of use thereof
US20040224928 *May 24, 2004Nov 11, 2004Trustees Of Tufts College7-Substituted tetracycline compounds
US20040266740 *Jan 5, 2004Dec 30, 2004Sophie Huss7-pyrollyl 9-aminoacyl tetracycline compounds and methods of use thereof
US20050026875 *Dec 15, 2003Feb 3, 2005Paratek Pharmaceuticals, Inc.Amino-methyl substituted tetracycline compounds
US20050026876 *Feb 24, 2004Feb 3, 2005Nelson Mark L.9-aminomethyl substituted minocycline compounds
US20050143352 *Jun 25, 2004Jun 30, 2005Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
US20050187198 *Dec 3, 2004Aug 25, 2005Trustees Of Tufts CollegeMethods of preparing substituted tetracyclines with transition metal-based chemistries
US20050282787 *May 20, 2005Dec 22, 2005Myers Andrew GSynthesis of tetracyclines and analogues thereof
US20060084634 *Dec 2, 2005Apr 20, 2006Paratek Pharmaceuticals, Inc.7-Pyrollyl tetracycline compounds and methods of use thereof
US20060089336 *Nov 18, 2005Apr 27, 2006Paratek Pharmaceuticals, Inc.4-Dedimethylamino tetracycline compounds
US20060281717 *Feb 6, 2006Dec 14, 2006Joel Berniac11a, 12-derivatives of tetracycline compounds
US20060287283 *Jan 12, 2006Dec 21, 2006Paratek Pharmaceuticals, Inc.Prodrugs of 9-aminomethyl tetracycline compounds
US20070049560 *May 25, 2006Mar 1, 2007Lalitha KrishnanTigecycline and methods of preparing 9-nitrominocycline
US20070049561 *May 25, 2006Mar 1, 2007Lalitha KrishnanMethods of purifying tigecycline
US20070049562 *May 25, 2006Mar 1, 2007Lalitha KrishnanTigecycline and methods of preparation
US20070049563 *May 25, 2006Mar 1, 2007Lalitha KrishnanTigecycline and methods of preparing 9-aminominocycline
US20070049564 *Aug 31, 2006Mar 1, 2007Wyeth9-Aminocarbonylsubstituted derivatives of glycylcyclines
US20070155708 *Feb 13, 2007Jul 5, 2007Trustees Of Tufts College7-phenyl-substituted tetracycline compounds
US20070270389 *Dec 20, 2006Nov 22, 2007Paratek Pharmaceuticals, Inc.9-Aminoacyl tetracycline compounds and methods of use thereof
US20080167273 *Mar 4, 2008Jul 10, 2008Trustees Of Tufts College7,8 And 9-substituted tetracycline compounds
US20080177080 *Mar 24, 2008Jul 24, 2008WyethOxazole derivatives of tetracyclines
US20090093640 *Oct 11, 2007Apr 9, 2009Myers Andrew GSynthesis of enone intermediate
US20090306022 *Jun 9, 2009Dec 10, 2009Trustees Of Tufts College7-substituted tetracycline compounds
US20100075929 *Nov 24, 2009Mar 25, 2010Paratek Pharmaceuticals, Inc.9-aminoacyl tetracycline compounds and methods of use thereof
US20100081826 *Nov 24, 2009Apr 1, 2010Paratek Pharmaceuticals, Inc.7-pyrrolyl tetracycline compounds and methods of use thereof
US20100130451 *Apr 6, 2007May 27, 2010Presidents And Fellows Of Harvard CollegeSynthesis of tetracyclines and analogues thereof
US20100160656 *Dec 10, 2009Jun 24, 2010Nelson Mark L7-phenyl-substituted tetracycline compounds
US20100249076 *Jun 3, 2010Sep 30, 2010Paratek Pharmaceuticals, Inc.Prodrugs of 9-aminomethyl tetracycline compounds
US20110009371 *May 12, 2010Jan 13, 2011Myers Andrew GSynthesis of tetracyclines and analogues thereof
US20110009639 *Jul 9, 2010Jan 13, 2011Myers Andrew GSynthesis of enone intermediate
US20110118215 *Jan 24, 2011May 19, 2011Trustees Of Tufts College7,8 And 9-Substituted Tetracycline Compounds
US20110160165 *Mar 1, 2011Jun 30, 2011Paratek Pharmaceuticals, Inc.7-Pyrazolyl Tetracycline Compounds and Methods of Use Thereof
USRE40086Dec 23, 2005Feb 19, 2008Wyeth Holdings CorporationMethod for treating bacterial infection with novel 7-substituted-9-substituted amino 6-demethyl-6-deoxytetracyclines
USRE40183Jun 3, 2005Mar 25, 2008Wyeth Holdings Corporation7-Substituted-9-substituted amino-6-demethyl-6-deoxytetracyclines
EP0535346A1Aug 18, 1992Apr 7, 1993American Cyanamid Company9-amino-7-substituted-6-demethyl-6-deoxytetracyclines
EP2157085A1Dec 7, 2004Feb 24, 2010Wyeth a Corporation of the State of DelawareOxazole, derivatives of tetracyclines
Classifications
U.S. Classification552/205
International ClassificationC07C233/00
Cooperative ClassificationC07C233/00
European ClassificationC07C233/00