Intermediates for the preparation of 3-demethoxyfortimicins

Disclosed herein are fortimicin derivatives represented by the formula: ##STR1## wherein R.sub.z is a monocyclicaryloxycarbonyl amine protecting group, or is loweralkyl, hydroxyloweralkyl, loweracyl, hydroxyloweracyl, or a monocyclicaryloxycarbonyl-protected aminoloweralkyl, diaminoloweralkyl, N-loweralkylaminoloweralkyl, N,N-diloweralkylaminoloweralkyl, aminohydroxyloweralkyl, N-loweralkylaminohydroxy-loweralkyl, N,N-diloweralkylaminohydroxyloweralkyl, aminoloweracyl, diaminoloweracyl, N-loweralkylaminoloweracyl, N,N-diloweralkylaminoloweracyl, or aminohydroxyloweracyl; R.sub.1 is hydroxy or loweracyloxy; R.sub.2 is hydrogen, hydroxy or --OR.sub.4, wherein R.sub.4 is tert-butyldimethylsilyl or thiocarbonylimidazoyl; or R.sub.1 and R.sub.2 can be taken together to form ##STR2## wherein R.sub.5 and R.sub.6 are loweralkyl; R.sub.3 is hydroxy or loweracyloxy; and z is a monocyclicaryloxycarbonyl amine protecting group. The compounds are useful as intermediates in the preparation of 3-demethoxyfortimicins.

BACKGROUND OF THE INVENTION 
The present invention relates to 3-demethoxyfortimicin A, 
3demethoxyfortimicin B, 4-N-substituted derivatives of 
3-demethoxyfortimicin B, and their pharmaceutically acceptable salts, to 
intermediates useful in the preparation of these compounds, and to 
compositions comprising these compounds and pharmaceutically acceptable 
carriers or diluents. 
The fortimicins are a relatively new class of aminoglycoside antibiotics 
which are useful in the treatment of susceptible bacterial infections. 
Fermentation produced fortimicins include fortimicin A, disclosed in U.S. 
Pat. No. 3,976,768; fortimicin B, disclosed in U.S. Pat. No. 3,931,400; 
and fortimicin C, disclosed in U.S. Pat. Nos. 4,048,015 and 4,097,428. 
Other fermentation fortimicin factors have also been isolated. 
Once an aminoglycoside antibiotic has been in clinical use for a period of 
time, resistant microorganisms may develop. In many cases, the resistance 
is R-factor mediated and is attributed to the ability of the bacteria to 
enzymatically modify the amino or hydroxyl groups of the aminoglycoside 
antibiotics and thereby reduce or eliminate their antibacterial 
properties. Thus, there is also a need for new entities which can be held 
in reserve to combat strains which have become resistant to treatment by 
the clinically used antibiotics. In the past, it has been found that the 
antibacterial and pharmacological properties of many naturally produced 
aminoglycoside antibiotics can be altered by structural modifications. As 
an example, certain chemical modifications in the gentamicin and kanamycin 
family of aminoglycoside antibiotics provide structures which are less 
toxic than the parent antibiotic. Further, in the same series, certain 
modifications alter the antibacterial spectrum advantageously either by 
increasing the intrinsic activity or increasing activity against resistant 
strains. 
It has been previously determined that certain chemical modification of the 
parent fortimicins can also result in derivative compounds which exhibit 
increased antibacterial activity with respect to particular 
microorganisms, reduced toxicity, or equivalent of reduced activity, but 
nevertheless are useful as reserve antibiotics in the event resistant 
strains develop after a period of clinical use of one or more of the 
fortimicins. For example, 4-N-acyl and -alkyl derivatives of fortimicin B 
and techniques for forming these compounds are disclosed in U.S. Pat. Nos. 
4,091,032; 4,155,902; 4,173,564; 4,174,312; 4,220,775 and 4,231,924; the 
disclosures of which are specifically incorporated herein by reference; 
and others. The fortimicin compounds have also been demethylated at the 
3-position to provide useful derivatives. For example, 
3-O-demethylfortimicins are disclosed in U.S. Pat. Nos. 4,124,756; 
4,187,297; 4,220,756; 4,230,848; 4,242,503; 4,251,516 and 4,293,689. 
While a number of fortimicin derivatives have been made to date, and 
valuable therapeutic agents have been identified, it is desirable to 
obtain new fortimicin antibiotics which exhibit a broader or different 
antibacterial spectrum, less toxicity, oral activity, or other desirable 
properties, or which can be held in reserve and used to treat infections 
caused by organisms which become resistant to other fortimicin therapy. 
The present invention relates to novel 3-demethoxyfortimicins which exhibit 
antibacterial activity. More specifically, the present invention relates 
to 3-demethoxyfortimicin A, 3-demethoxyfortimicin B, and 
4-N-substituted-3-demethoxyfortimicin B, to intermediates and processes 
useful in the production of these novel compounds, and to compositions 
comprising these compounds and a pharmaceutically acceptable carrier or 
diluent. 
DETAILED DESCRIPTION OF THE INVENTION 
The 3-demethoxyfortimicin compounds of the invention differ from fortimicin 
A, fortimicin B, and fortimicin B derivatives, in their absence of a 
methoxy group at the 3- position of the cyclitol ring of the 
aminoglycoside. These 3-demethoxyfortimicins can be represented by the 
following structural formula: 
##STR3## 
wherein R is hydrogen, loweralkyl, aminoloweralkyl, diaminoloweralkyl, 
N-loweralkylaminoloweralkyl, N,N-diloweralkylaminoloweralkyl, 
hydroxyloweralkyl, aminohydroxyloweralkyl, 
N-loweralkylaminohydroxyloweralkyl, 
N,N-diloweralkylaminohydroxyloweralkyl, loweracyl, aminoloweracyl, 
diaminoloweracyl, hydroxyloweralkyl, N-loweralkylaminoloweralkyl, 
N,N-diloweralkylaminoloweracyl, or aminohydroxyloweracyl, and the 
pharmaceutically acceptable salts thereof. 
Intermediates of the invention useful in preparing the 
3-demethoxyfortimicins of formula I can be represented by the structural 
formula: 
##STR4## 
wherein R.sub.z is R as defined in formula I or a 
monocyclicaryloxycarbonylamine protecting group, or when R is an amino 
containing group then R.sub.z is monocyclicaryloxycarbonyl-protected R; 
R.sub.1 is hydroxy or loweracyloxy; R.sub.2 is hydrogen, or --OR.sub.4, 
wherein R.sub.4 is tert-butyl- dimethylsilyl or thiocarbonylimidazoyl; or 
R.sub.1 and R.sub.2 can be taken together to form 
##STR5## 
wherein R.sub.5 and R.sub.6 are loweralkyl; R.sub.3 is hydroxy or 
loweracyloxy; and Z is a monocyclicaryloxycarbonyl amine protecting group. 
The term "loweralkyl," as used herein, refers to straight or branched chain 
alkyl radicals having from 1 to 7 carbon atoms, including, but not limited 
to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 
n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2,2-dimethylbutyl, 
1-methylpentyl, 2-methylpentyl, n-heptyl and the like. 
The term "loweracyl" as used herein refers to acyl groups represented by 
the formula 
##STR6## 
wherein R.sub.7 is loweralkyl, as defined above. Representative loweracyl 
groups useful in the invention include acetyl, propionyl, butyryl, valeryl 
and the like. 
The term "loweracyloxy" as used herein refers to acyloxy groups of the 
formula --O--R.sub.8, wherein R.sub.8 is loweracyl, as defined above. 
The terms "aminoloweracyl," "diaminoloweracyl," etc., include the naturally 
occurring aminoacids such as glycyl, valyl, alanyl, sarcosyl, leucyl, 
isoleucyl, prolyl, seryl, and the like as well as other amino-substituted 
lower acyl groups such as 2-hydroxy-4-aminobutyryl. The aminoacids residue 
included in the above terms can be in the L- or D- configurations or a 
mixture thereof, with the exception of glycyl. 
The term "monocyclicaryloxycarbonyl" as used herein refers to protecting 
groups such as benzyloxycarbonyl, paramethylbenzyloxycarbonyl, 
paramethoxybenzyloxycarbonyl or orthonitrobenzyloxycarbonyl which are 
commonly used as N-protecting groups in peptide synthesis and in other 
areas where N-protection is required. 
The term "pharmaceutically acceptable salts," as used herein, refers to the 
nontoxic acid addition salts of the compounds of this invention. These 
salts can be prepared in situ during the final isolation and purification 
or by separately reacting the free base with a suitable organic or 
inorganic acid. Representative salts include the hydrochloride, 
hydrobromide, sulfate, bisulfate, acetate, oxalate, valerate, oleate, 
palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, 
tosylate, citrate, maleate, fumarate, succinate, tartrate, napsylate and 
the like. It will be apparent to those skilled in the art that, depending 
upon the number of available amino groups for salt formation, the salts of 
this invention can be per-N-salts. 
The 3-demethoxyfortimicin compounds of the invention may be prepared from a 
per-N-protected fortimicin such as tetra-N-protection fortimicin A, 
according to the following reaction scheme: 
##STR7## 
In the foregoing reaction sequence, per-N-protected-3-O-demethylfortimicin 
(1), such as tetra-N-benzyloxycarbonyl-3-O-demethylfortimicin A (see, for 
example, U.S. Pat. No. 4,124,756), is converted to 
per-N-protected-3-O-demethylfortimicin-2,3-acetonide (2) by dissolving the 
starting material in an aldehyde or ketone such as acetone and treatment 
with ferric chloride in silica gel. The 2,3- acetonide is then acetylated 
at the 5- position to form 
tetra-N-protected-3-O-demethyl-5-O-acetylfortimicin-2,3-acetonide (3), 
such as by treatment with acetic anhydride and an organic base in a 
suitable solvent, and then treated with a mineral acid in methanol to form 
per-N-protected-3-O-demethyl-5-O-acetylfortimicin (4). Dissolution of (4) 
in dimethylformamide and treatment with tert-butyldimethylsilylchloride in 
the presence of a catalyst results in the formation of 
per-N-protected-3-O-demethyl-5-O-acetyl-fortimicin-3-O-tert-butyldimethyls 
ilylether (5) which is converted to the corresponding 2,5-bisacetyl 
intermediate (6) by treatment with acetic anhydride and an organic base in 
a suitable solvent. The silylether group is cleaved with 
tetrabutylammonium fluoride in the presence of acetic acid to form 
per-N-protected-3-O-demethyl-2,5-bis-fortimicin (7), which is reacted with 
N,N'-thiocarbo-nyldiimidazole in a suitable solvent to form 
per-N-protected-3-O-demethyl-2,5-bisacetylfortimicin-3-O-thiocarbonylimida 
zolide (8). The 3-O-thiocarbonyl-imidazolide (8) is refluxed with 
tri-N-butyltinhydride in a suitable solvent to form the N- and O-protected 
3-demethoxyfortimicin intermediate (9). The protected compound is then 
O-deprotected by treatment with sodium ethoxide and N-deprotected by 
hydrogenation, as is known in the art, to form the desired end product, 
3-demethoxyfortimicin (11). 
When R in the foregoing reaction sequence is hydrogen, the resulting 
1,2',6'-tri-N-protected 3-demethoxyfortimicin B (10) can be acylated with 
N-(N-benzyloxycarbonylglycyloxy) succinimide to give 
1,2',6'2"-tetra-N-protected-3-demethoxyfortimicin A (10). Catalytic 
hydrogenation of 1,2',6',2"-tetra-N-protected 3-demethoxyfortimicin A 
produces 3-demethoxyfortimicin A, which can be isolated as a 
pharmaceutically acceptable salt, as is known in the art. Alternatively, 
3-demethoxyfortimicin A can be produced directly from the foregoing 
reaction sequence by using tetra-N-protected-3-O-demethylfortimicin A as 
the starting material (1). The per-N-protected-fortimicin B intermediate 
can also be alkylated and acylated at the 4-N-position to produce 
4-N-alkyl or 4-N-acyl-substituted-3-demethoxyfortimicin B by 
4-N-alkylation and 4-N-acylation techniques well known in the fortimicin 
art, such as by techniques referred to in the issued patents cited supra. 
The foregoing reaction scheme may be better understood in connection with 
the following examples: