Pradimicin compounds

Details Pradimicin compounds Pradimicin compounds

1994-05-12

2001-08-28

Peselev, Elli (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S006400, C536S017900, C536S018100

Reexamination Certificate

active

06281342

ABSTRACT:

BACKGROUND OF THE INVENTION
Pradimicin antibiotics such as pradimicin A, pradimicin C, pradimicin FA-1, and pradimicin FA-2, as well as certain derivatives thereof, are known in the art (see, for example, U.S. Pat. Nos. 4,870,165; 4,973,673, and 5,053,395).
The pradimicin antibiotics known in the art possess good antifungal activity. It would be desirable to have antifungal pradimicin derivatives which still have good antifungal activity but also have other important characteristics such as improved water solubility.
SUMMARY OF THE INVENTION
The present invention is directed to a compound having the formula:
wherein R
1
is H, methyl, or hydroxymethyl, provided that when R
1
is methyl or hydroxymethyl, the resulting amino acid residue has the D configuration; R
2
is H or &bgr;-D-xylosyl; R
3
is H or alkyl; R
4
is —CN, —NO,
or a pharmaceutically acceptable salt thereof.
The present invention is also directed to a pharmaceutical composition comprising an antifungal effective amount of a compound of Formula I and a pharmaceutically acceptable carrier.
The present invention is further directed to a method for treating fungal infections in a mammalian host, preferably a human host, comprising administering to said host an antifungal effective dose of a compound of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “alkyl” includes both straight and branched alkyl chains of one to six carbon atoms; “pharmaceutically acceptable salt” includes acid addition salts formed with, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, tartaric acid, citric acid, methanesulfonic acid, succinic acid and the like; base salts with an alkali metal base such as sodium or potassium hydroxide, carbonate, and bicarbonate; and when possible internal salt (see, for example, “Pharmaceutical Salts”, J. Pharm. Sci. 66(1):1-10 (1977)). The pharmaceutically acceptable salts of the invention can be prepared by any of the standard methods disclosed in the literature, for example, acid addition salts can be prepared by reacting a suitable basic compound of the invention with an organic or inorganic acid, preferably by contact in solution. Generally, the counter-ion of the salts of the invention does not contribute significantly to toxicity or pharmacological activity. Preferred alkyl groups have 1 to 3 carbon atoms and the most preferred alkyl group is methyl.
Preferred compounds of the invention are wherein R
1
is methyl or hydroxymethyl. It is also preferred that R
2
is &bgr;-D-xylosyl. It is further preferred that R
3
is H or methyl.
A preferred compound of the invention has the formula:
wherein R
1
is as defined above and R
5
is NHCN, N(CH
3
)CN, N(CH
3
)NO, NHCNH
2
, NHC—NHNO or NHCH═NH, or a pharmaceutically acceptable salt thereof.
As used herein, the abbreviations “Me” shall mean methyl, “Et” shall mean ethyl, “Ac” shall mean acetyl, “Pd-C” shall mean palladium on carbon, “PBS” shall mean phosphate buffered saline.
Specific compounds of the invention referred to herein by the following alpha-numeric designations shall mean those compounds of Formula I having the following substitutions:
Compound
of the
Invention
R
1
R
2
R
3
R
4
KHM-1
methyl
&bgr;-D-xylosyl
methyl
—CN
KHM-2
methyl
&bgr;-D-xylosyl
H
—CN
KHM-3
hydroxy-
&bgr;-D-xylosyl
methyl
—CN
methyl
KHM-4
hydroxy-
&bgr;-D-xylosyl
H
—CN
methyl
KHM-5
hydroxy-
&bgr;-D-xylosyl
methyl
NO
methyl
KHM-6
methyl
&bgr;-D-xylosyl
methyl
NO
KHM-7
methyl
&bgr;-D-xylosyl
H
C(═NH)NHNO
2
KHM-8
methyl
&bgr;-D-xylosyl
H
C(═NH)NH
2
KHM-9
methyl
&bgr;-D-xylosyl
H
CH═NH
The starting material pradimicins A and C are produced by fermentation of
Actinomadura hibisca
strains P157-2 (ATCC 53557) and Q278-4 (ATCC 53646) as disclosed in U.S. Pat. No. 4,870,165 and the production of pradimicins FA-1 and FA-2 by mutant strains A2493 (ATCC 53815) and B0012 (ATCC 53816) capable of incorporating supplemented D-serine and derived from the parent strain P157-2 is disclosed in U.S. Pat. No. 4,973,673.
The 4′-cyanoamino and the 4′-guanidino derivatives of the invention can be synthesized from suitable pradimicin starting materials by treatment with a suitable silylation reagent such as N,O-bis(trimethylsilyl)acetamide (“BSA”), 1,1,1,3,3,3-hexanethyldisilazane, chlorotrimethylsilane/triethylamine, 1-(trimethylsilyl)imidazole, N-trimethylsilylacetamide, and the like followed by the substitution reactions. A preferred silylation reagent is BSA. The silylation reagent protects the hydroxyl groups and activates the 4′-amino group of pradimicins toward the substitution reactions at the same time. The treatment of the starting material with the silylation reagent can be carried out in an organic solvent such as dichloromethane, dichloroethane, tetrahydrofuran (“THF”) toluene, diglyme, dimethylformamide (“DMF”) or a mixture thereof for a time and temperature sufficient to activate the sugar amino group (4′-amino group). Typically, the activation reaction will be carried out between 5° C. and 50° C. for about 5 minutes to about 1 hour.
To prepare the 4′-cyanoamino derivatives, after activation the reaction mixture can be contacted with cyanogen bromide for a time and temperature sufficient to form the desired compound. Typically, a temperature of about room temperature to about 80° C. is employed, with room temperature being preferred, for about 2 to about 18 hours. After the silylated 4′-cyanoamino derivative is formed, the reaction mixture can be treated with a chloride reagent to remove the silyl moieties on the pradimicin molecules, such as hydrochloric acid in methanol. Fluoride reagents such as tetrabutylammonium fluoride and sodium fluoride can also be used for this purpose. The desired product can then be isolated from the reaction mixture by standard techniques known in the art such as column chromatography. For example, pradimicins A, C, FA-1, FA-2 (see U.S. Pat. Nos. 5,053,395, 4,870,165, 4,973,673, 4,992,425 and 4,960,755, all of which are incorporated herein by reference in their entirety) can be reacted with a silylation reagent in dichloromethane and then, the mixtures can be treated with cyanogen bromide at room temperature to afford, after treatment with hydrochloric acid in methanol and column chromatography, the 4′-cyanoamino derivatives of the invention (see Scheme 1).
To prepare the 4′-nitroguanidino derivatives more severe reaction conditions are required after activation. The silylation reagent-treated starting material is reacted with N-nitro-S-methylisothiourea for a time and temperature sufficient to form the desired products. Typically, a temperature of 50° C. to 100° C. is employed, with about 80° C. being preferred, for about 2 to about 18 hours. After the silylated 4′-nitroguanidine product is formed, the silyl moieties can be removed and the resulting desired product can be isolated in a similar manner as the 4′-cyanoamino derivatives. The solvent for the substitution reaction can be several organic solvents but is preferably the same as used in the activating reaction. If it is desired to prepare the 4′-guanidino derivative, the 4′-nitroguanidine compound can be deblocked by standard techniques to give the desired compound. A typical deblocking technique is to hydrogenate with gaseous hydrogen in the presence of a catalytic amount of a catalyst for a time and temperature sufficient to form the desired product. A temperature of about 10° C. to about room temperature can be employed, with room temperature being typical, for about 10 to about 20 hours. A typical catalyst is palladium on carbon (charcoal). The solvent for the deblocking procedure can be mixtures such as MeOH—HCl, EtOH—HCl, MeOH—AcOH, THF—AcOH (or HCl), dioxane-AcOH (or HCl), and the like. A preferred mixture is MeOH—HCl. To illustrate the reaction of silylation reagent-treated pradimicin C with N-nitro-S-methylisothiourea such reaction can be carried out in DMF at 80° C. for 2 hrs, after a work-up similar to the 4′-c

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