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Publication numberUS3579579 A
Publication typeGrant
Publication dateMay 18, 1971
Filing dateApr 18, 1968
Priority dateApr 18, 1968
Publication numberUS 3579579 A, US 3579579A, US-A-3579579, US3579579 A, US3579579A
InventorsJoseph J Hlavka, Michael Joseph Martell, Adma Schneller Ross
Original AssigneeAmerican Cyanamid Co
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Substituted 7- and/or 9-amino-6-demethyl-6-deoxytetracyclines
US 3579579 A
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Description  (OCR text may contain errors)

United States Patent ABSTRACT OF THE DISCLOSURE This disclosure describes compounds of the class of 7- or 9-di(lower alkyl)amino-6-demethyl-6 deoxytetracycylines and 7-monoa1kylamino 6 demethyl-6-deoxytetracyclines useful as antibacterial agents.

BRIEF SUMMARY OF THE INVENTION This invention relates to new organic compounds and, more particularly, is concerned with novel 7- or 9-di (lower alkyl)amino-6-demethyl-6-deoxytetracyclines and 7-monoalkyl amino-6 demethyl-6 deoxytetracyclines which may be represented by the following general formulae:

TU sh II OH 0 wherein R is ethyl or isopropyl and R is cyclohexyl, 1,3- dimethylbutyl or lauryl.

DETAILED DESCRIPTION OF THE INVENTION The novel compounds of the present invention are typical tetracyclines, being yellow crystalline materials having characteristic melting points and absorption spectra. The free bases are appreciably soluble in many organic solvents such as lower alkanols, ethyl acetate, and the like, but are relatively insoluble in water.

The novel compounds of the present invention are amphoteric compounds and hence form both anionic and cationic salts with a variety of organic and inorganic saltforming reagents. Thus, acid-addition salts, formed by admixture of the organic free base with a non-toxic pharmaceutically acceptable acid, suitably in a neutral solvent, are formed with such acids as sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, citric, lactic, malic, succinic, tartaric, acetic, benzoic, gluconic, ascorbic, and the like. Base-derived salts, formed by admixture of the organic free base with base, suitably in a neutral solvent, are formed with such bases as sodium hydroxide, calcium hydroxide, magnesium hydroxide, tet- 3,579,579 Patented May 18, 1971 raethylammonium hydroxide, etc. For purposes of this invention, the organic free bases are equivalent to their anionic and cationic salts. These new compounds of the present invention also form typical Mannich derivatives with organic aldehydic compounds and nitrogen bases.

The novel compounds of the present invention are biologically active and have been found to possess antibacterial activity. The antibacterial spectrum of the compounds of this invention, representing the amount required to inhibit the growth of various typical bacteria, was determined by the agar dilution streak technique using a special nutrient agar at pH 6.0 (Difco No. 634) supplemented with 0.5% of neopeptone. The initial so lution of each compound was made in 0.1 N hydrochloric acid. Serial two-fold dilutions were then made using distilled water and one milliliter portions of the initial soluton and each dilution was mixed with measured volumes of warm fluid nutrient agar. After the agar had hardened overnight, broth cultures of the various test organisms were applied to the surface and the plates were incubated. End-points of activity were read after 24 hours. In a representative operation, and merely by way of illustration, the minimal inhibitory concentrations, expressed in micrograms per milliliter, of 7-methylethylamino-6-demethyl-6-deoxytetracycline 1) and 7-methylisopropylamino 6 demethyl 6 deoxytetracycline (2) against various test organisms are set forth in Table I below as compared with tetracycline hydrochloride (3) and 7-dimethylamino-6-demethyl-6-deoxytetracycline hydrochloride (4) as reference standards.

TABLE I Minimal inhibitory cone. (meg/ml.)

Organism (1) (2) (3) (4) Staphylococcus aureus, 4050Bl22-3 3. l 1. 6 100 1. 6 Staphylococcus aureus, 4050B1229 3. l 1. 6 100 3. 1 Staphylococcus aureus, 4050B122-11 3. 1 1. 6 100 3. 1 Staphylococcus aureus, 4050Bl22-l4 3. l 1.6 50 3. 1 Staphylococcus aureus, 4050B l2220 3. 1 1. 6 50 1. 6 Staphylococcus aurcus, Rose ATCC 14154 3. 1 1. 6 50 1. 6 Staphylococcus aureus, Smit ATCC 13709. 0. 8 0.8 0.8 0.4 Staphylococcus aurcus, Smith (T C-R) 0. 8 0.8 100 0.8 Staphylococcus aurcus, Smith (M-R) 6. 2 6. 2 26 6. 2 Streptococcus pyogertes, C203 0. 4 0. 2 0. 4 0.2 Entereococcus aerogc-nes, 75 12.6 12.5 6. 2 6. 2 Escherichia coli, 311 6. 2 6. 2 3. 1 3. 1 Escherichia coli, 311 (TC-R) 12. 6 6. 2 25 6. 2 Escherichia coli, 311 (RB) 25 12. 5 100 25 Escherichia 0012, 311 (DA) 25 12.5 100 25 Escherichia coli, 311 (DY) 25 12.5 100 25 Klebsiella pneumoniae, AD. 3. 1 3.1 1. 6 0. 8 Proteus morganii, ATCC 8019 12.5 50 1. 6 3. 1 Proteus vulgaris, ATCC 6380 12. 5 12.5 6. 3 3. 1 Proteus oulgaris, ATCC 9484 3. 1 6. 2 3. 1 0. 8 Pseudomouas aerugiuosa, ATCC 10145. 25 12.5 25 6. 2 Salmonella cholerasuis, ATCC 10708 6. 2 6. 2 3. 1 6. 2 Salmonella typhosa, ATCC 6539 6. 2 6. 2 1. 6 6. 2 Shigella flezueri, I 3. 1 3. 1 1. 6 1. 6

The high in vitro antibacterial activity of the novel compounds of the present invention makes them useful as additives to materials which are subject to microbial deterioration such as cutting oils and fuel oils. They are also useful in soaps, shampoos, and topical compositions for the treatment of wounds and burns.

The novel compounds of the present invention have also been found to be highly active in vivo against Stapylococcus aureus, strain Smith, ATCC 13709.

Staphylococcus aureus, strain Smith, ATCC 13709 has been studied at the Rockefeller Institute and has been described by J. M. Smith and R. I. Dubos in the Journal of Experimental Medicine 108, 87 (1956). This organism is coagulase positive, tellurite 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 nontypable.

Staphylococcus aurcus, strain Rose, ATCC 14154 was isolated clinically from an abscess of a patient who did not respond to treatment with the tetracyclines and has been described in G. S. Redin and M. E. McCoy in Antibiotics Annual 1959-1960, pp. 213-219. This organism has been found to be resistant to the clinically used tetracyclines in vitro and in vivo. Staphylococcus aureus, strain, Rose ATCC 14154 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, ATCC 14154 has been phagetyped with the following results: Phage pattern 80/81.

The in vivo activity was demonstrated by experiments carried out as follows:

Unit test groups consist of or Carworth Farms CFl female mice approximately 6 weeks old and averaging 18 to 21 grams of body Weight per mouse. Infections are produced by intraperitoneal injections of 0.5 milliliter volumes of a 10* trypticase soy broth (TSP) dilution of a 5 hour blood broth culture of Staphylococcus aureus, strain Smith, ATCC 13709 or Staphylococcus aureus, strain Rose, AT CC 14154, containing TAB LE II Staphylococcus aureus, strain Smith ATCC 13709 infections in mice Mice alive/mice tested 5 days after infection 1 Dose, mgjkg. of body weight l167/170 untreated infected control mice died within one day.

TAB LE III Staphylococcus aureus, strain Rose, AITC 14154 infections in mice Mice alive/mice tested 5 days after infection 1 Dose, mgJlrg. of body weight (1) (2) 203/210 untreated infected control mice died within one day.

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

EXAMPLE 1 Preparation of 7-monomethylamino-6-demethy1-6- deoxytetracycline The 7-amino-G-demethyl-6-deoxytetracycline free base (400 mg; 0.93 mole; previously chromatographed) Was dissolved in ethylene glycol monomethyl ether (28 ml.) containing 2 N sulfuric acid (2 m1.) and 37% formaldehyde solution (1.5 ml.). The palladium-on-carbon (10%) catalyst (100 mg.) was added and the mixture was reduced for about minutes until 26 ml. of hydrogen was taken up (1 equiv. +36 ml. for the catalyst). The cat- 4 alyst was then filtered, the filtrate poured into 600 ml. of anhydrous diethyl ether and the precipitate isolated by filtration. The crude product was purified by partition column chromatography after it was neutralized in methanol to pH 6.0 with the basic resin Amberlite IR-45 The R value in a methyl ethyl ketone-water system (pH 7.7) Was 0.65 (strong blue fluorescence after developing the dried sheet by dipping it in an acidic methanolic solution of magnesium acetate).

EXAMPLE 2 Preparation of 9-monomethylamino-6-demethyl-6- deoxytetracycline To a solution of 1.28 g. (2.7 mmoles) 9-amino-6-demethyl-6-deoxytetracycline hydrochloride in ml. of methyl Cellosolve plus 3.0 ml. of 4 N sulfuric acid was added 0.21 ml. (2.7 mmoles) 37% formaldehyde and 300 mg. 10% palladium-on-carbon. The solution was hydrogenated at room temperature and atmospheric pressure; uptake was 73 ml. in 40 minutes. The catalyst was filtered off through a Celite pad and the filtrate was poured slowly into 750 ml. diethyl ether. The yellow precipitate was filtered 01f, washed with diethyl ether, dried under vacuum, and dissolved in 500 ml. methanol. Methanol washed Amberlite IR-45 was added to pH 6.3, the resin 'Was filtered off, and the filtrate was evaporated to dryness, yield 0.9 g. Six hundred milligrams of this crude material was purified by partition column chromatography on neutral (acid Washed) Celite using a solvent system heptane ethyl acetate: methyl Cellosolve:water 9-monomethylamino-6-demethyl-6-deoxytetracycline was obtained in hold back volumes 3.0-4.0, 180 mg.

EXAMPLE 3 Preparation of 7-monoisopropylamino-6-demethyl-6- deoxytetracycline The 7-nitro-6-demethyl-6-deoxytetracycline sulfate salt (400 mg.) was dissolved in a mixture of ethanol 17 ml.) and water (16 ml.) containing 2 N H (0.72 ml.) acetone (0.5 ml.). The catalyst PtO (50 mg.) was added and the mixture was reduced under atmospheric pressure and room temperature for 1 hour and 45 minutes. Hydrogen taken up79 ml. (theory: 0.72 4 24=69 ml.+5 ml. for catalyst=74 ml.). The catalyst was filtered through a Celite precoated funnel under nitrogen and filtrate evaporated to dryness. It was purified by partition chromatography after neutralized (pH 6.3) in methanol with Amberlite IR45.

EXAMPLE 4 Preparation of 9-monoisopropylamino-6-demethyl-6- deoxytetracycline A mixture of 400 mg. of 9-amino-6-demethyl-6-deoxytetracycline hydrochloride, 0.5 ml. of acetone, and 0.43 ml. of 2 N sulfuric acid in 36 ml. of a 50% ethanol-water mixture was reduced at S.T.P. with 75 mg. of Pt0 and 35 ml. of hydrogen for 1 /2 hours. The mixture was filtered and the filtrate evaporated to dryness, yield 280 mg. R =0.9.

EXAMPLE 5 Preparation of 7-methylethylamino-6-demethyl-6- deoxytetracycline The chromatographed 7-monomethylamino-6-demethyl- 6-deoxytetracycline free base mg.) was dissolved in ethylene glycol monomethyl ether (6.3 ml.) containing 2 N H 50 (0.48 ml.) and acetaldehyde (0.225 ml.). The palladiumoncarbon (10%) catalyst (22.5 mg.) was added and the mixture reduced under atmospheric pressure and room temperature for two hours. Catalyst was then filtered, filtrate poured into 100 ml. of diethyl ether and precipitated solid filtered and dried. Yield-124 mg.

This material was neutralized in methanol with Amberlite IR45 (to pH 6.1) and chromatographed. The R; value in the methyl ethyl ketone-water pH 7.7 system was 0.87 while starting material has an R 0.65 in the same system.

EXAMPLE 6 Preparation of 9-methylethylamino-6-demethyl-6- deoxytetracycline To a solution of 111 mg. (0.25 mmole) 9-monomethylamino-6-demethyl-6-deoxytetracycline in 7 ml. of methyl Cellosolve plus 0.26 of 4 N sulfuric acid was added 0.25 ml. of acetaldehyde and 25 mg. of palladiumon-carbon. The solution was hydrogenated at room temperature and atmospheric pressure. The uptake (5.3 ml.) ceased after 30 minutes, but the hydrogenation was con tinued for and additional 90 minutes. The catalyst was filtered through a Celite pad and the filtrate was poured slowly into 200 ml. of rapidly stirred diethyl ether. The precipitate was filtered off, washed with diethyl ether, dried under vacuum, and dissolved in 60 ml. methanol. Amberlite liR-45 was added and the solution was stirred until the pH was 6.3. The resin was filtered off and the filtrate was evaporated to dryness. Yield 72 mg. The above crude material (55 mg.) was purified by partition column chromatography on neutral (acid washed) Celite using a solvent system heptane:ethylzacetatezmethyl Cellosolve water (55:45: :4). The product was eluted in hold back volumes 1.92.3, 23 mg.

EXAMPLE 7 Preparation of 7-methylisopropylamino-6-demethyl-6- deoxytetracycline The purified 7-monoisopropylamino-6-demethyl-6-deoxytetracycline free base (100 mg.) was dissolved in ethylene glycol monomethyl ether (7 ml.) containing 2 N H 50 (0.5 ml.) and 37% solution of formaldehyde (0.75 ml.). The palladium-on-carbon (10%) catalyst (25 mg.) was added and the mixture reduced under atmospheric pressure and room temperature for one hour. Catalyst was then filtered, filtrate poured into diethyl ether and precipitated solid was isolated by filtration. It was neutralized (pH 6.4) in methanol with Amberlite IR-45 and chromatographed.

EXAMPLE 8 Preparation of 9-methylisopropylamino-6-demethyl-6- deoxytetracycline By replacing the 7-monoisopropylamino-6-demethyl-6- deoxytetracycline employed in Example 7 with a like amount of 9-monoisopropylamino-6-demethyl 6 deoxytetracycline and following substantially the same procedure described in Example 7, there is obtained the 9-methylisopropylamino-6-demethyl-6-deoxytetracycline.

EXAMPLE 9 Preparation of 7-cyclohexylamino6-demethyl-6- deoxytetracycline A mixture of 200 mg. of 7-nitro-6-demethyl-6-deoxytetracycline sulfate, 0.36 ml. of 2 N sulfuric acid, 0.3 ml. of cyclohexanone and 60 mg. of PtO in 7 ml. of ethanol and 4 ml. of water was reduced at S.T.P. until the sys tern absorbed 45 ml. of hydrogen. The catalyst was filtered and the filtrate was evaporated to dryness, yield 225 mg. R in methyl ether ketone system buffered at 7.7=0.97.

6 EXAMPLE 10 Preparation of 7-(1,3-dimethylbutyl)amino-6-demethyl-6- deoxytetracycline Five hundred milligrams (0.9 mmole) of 7-nitro-6- demethyl-6-deoxytetracyline sulfate was dissolved in 21 ml. ethanol and 20 ml. water, and 450 ml. of 4 N sulfuric acid, 1.125 ml. of methyl isobutyl ketone, and mg. of platinum oxide were added. The solution was hydrogenated at room temperature and atmospheric pressure for 2 /2 hours, uptake 84 ml. The catalyst was filtered olf through a Celite pad and the filtrate evaporated to dryness. The product obtained from two such reactions was dissolved in 700 ml. methanol. Amberlite IR45 was added with stirring until the pH was 6.3. The resin was filtered off and the filtrate was evaporated to dryness, yield 700 mg. The above crude material was purified by partition column chromatography on neutral (acid washed) Celite using a solvent system heptanezethyl acetatezmethyl Cellosolve:water (70:30: 15 :4). The product was eluted in hold back volumes 1.9-2.4, yield 52 mg.

EXAMPLE 1 1 Preparation of 7-laurylamino-6-demethyl-6- deoxytetracycline A suspension of 500 mg. of 7-nitro-6-demethyl-6-deoxytetracycline sulfate in 30 ml. of methyl Cellosolve with 2 ml. lauraldehyde, 450 ml. of 4 N sulfuric acid, and 70 mg. of platinum oxide was hydrogenated on a Parr shaker for 2 /2 hours. The initial pressure was 29 pounds and dropped to 18 pounds. The catalyst was filtered off and the filtrate was poured into 1200 ml. of diethyl ether. Since the precipitate was too fine to be filtered off with a medium porosity funnel, the precipitate was allowed to settle and almost all the ether was removed with a filter stick. The remaining slurry was evaporated to an oil which was dissolved in 600 ml. of methanol. The solution was adjusted to pH 6.3 with triethylamine and then evaporated to an oil. The oil was triturated with ethyl acetate and the ethyl acetate was evaporated to an oil. The above crude material was purified by partition column chromatography on neutral (acid Washed) Celite using a solvent system heptanezethyl acetate:methyl Cellosolve: water (85 :15 :15 :4). The product, an orange solid, was obtained in hold back volumes 1.1-1.7, yield 64 mg.

We claim:

1. A compound selected from the group consisting of 7-cyclohexyla1nino-6-deoxy 6 demethyltetracycline and the acid-addition, alkali metal and alkaline earth metal salts thereof.

2. A compound selected from the group consisting of 7-laurylamino-6-deoxy 6 demethyltetracycline and the acid-addition, alkali metal and alkaline earth metal salts thereof.

References Cited UNITED STATES PATENTS 3,148,212 9/1964 Boothe et al. 260-559 3,226,436 12/ 1965 Petisi et a1. 260559 3,483,251 12/1969 Zambrano et al 260559 ALEX MAZEL, Primary Examiner A. M. T. TIGHE, Assistant Examiner U.S. Cl. X.R.

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Classifications
U.S. Classification552/205, 510/382, 510/119, 510/126, 510/386
International ClassificationC07C233/00
Cooperative ClassificationC07C233/00
European ClassificationC07C233/00