Cyclohexapeptidyl amine compounds

Details Cyclohexapeptidyl amine compounds Cyclohexapeptidyl amine compounds

1993-04-30

2001-07-31

Wessendorf, T. D. (Department: 1627)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S009100, C514S002600, C530S317000

Reexamination Certificate

active

06268338

ABSTRACT:

The present invention is directed to certain cyclohexapeptidyl amine compounds and to a process for their preparation.
The cyclohexapeptidyl amine compounds of the present invention, Compound X (SEQ ID NOS 1-7, 29) have one amine group directly on the ring and the second amine group as a substituent on the ether group, and may be represented by the formula
or its acid addition salt.
In the foregoing and succeeding formulas,
R
1
is H or OH;
R
2
is H or OH;
R
3
is QC
n
H
2n
NR
V
R
VI
, QC
n
H
2n
NR
V
R
VI
R
VII+
Y
−
, or Q(CH
2
)
1-3
CR
VIII
R
IX
NHR
X
R
4
is H or OH;
R
5
is H, OH or CH
3
;
R
6
is H or CH
3
;
R
I
is
wherein
R
a
is C
1
-C
10
alkyl; or
(CH
2
)
q
NR
b
R
c
wherein R
b
and R
c
are independently H, C
1
-C
10
alkyl or R
b
and R
c
taken together are
wherein
R
d
is C
1
-C
16
alkyl, phenyl or benzyl
R
II
is H, C
1
-C
4
alkyl or benzyl,
R
III
is H, C
1
-C
4
alkyl or benzyl
R
IV
is R
II
and R
III
taken together as —(CH
2
)
4
— or —(CH
2
)
5
—
R
V
is H, C
1
-C
4
alkyl or benzyl
R
VI
is H, C
1
-C
4
alkyl or benzyl or R
V
and R
VI
together is —(CH
2
)
4
— or —(CH
2
)
5
—
R
VII
is H or C
1
-C
4
alkyl
R
VIll
is H, (CH
2
)
m
H, (CH
2
)
m
OH, (CH
2
)
m
NH
2
or COX wherein X is NH
2
, OH or O(CH
2
)
m
H
R
IX
is H, (CH
2
)
m
H, or together with R
VIII
is ═O (carbonyl);
R
X
is H (except when R
VIII
and R
IX
are H), C(═NH)NH
2
, C(═NH)CH
2
)
0-3
H, CO(CH
2
)
0-3
H, CO(CH
2
)
m
NH
2
, (CH
2
)
2-4
OH or (CH
2
)
2-4
NH
2
.
Q is O or S;
Y is an anion of a pharmaceutically acceptable salt
each m is independently an integer from 1 to 3, inclusive, and
n is an integer from 2 to 4, inclusive;
p is an integer from 1 to 2, inclusive and
q is an integer from 2 to 4, inclusive.
Hereinafter, when the expression “amine compound” or “Compound X” is employed, it is intended to embrace the amine of formula (X), its acid addition salt or salts. It is to be noted that in Compound X, R
3
may be either an amino alkyl ether or a quaternary ammonium alkyl ether. Thus, the amine compound may be an uncharged compound having two amino groups or it may be a mono ammonium compound. When the “amine compound” is an amine, as above defined (Compound X) and R
3
is QC
n
H
2n
NR
V
R
VI
or Q(CH
2
)
1-3
CR
VIII
R
IX
NHR
X
, the ultimate compound is uncharged and may be referred to generically as Compound X-a. Compound X-a (Seq. ID No. 1-7, 29) may be represented by the following formula:
When in the “amine compound” R
3
is QC
n
H
2n
NR
V
R
VI
R
VII+
Y
−
, the charged portion of the molecule will reside in the amino ether portion and the compound may be referred to as Compound X-b (Seq. ID No. 1-7, 29). Compound X-b may be represented by the following formula:
Where the expression “alkyl”, “alkenyl” or “alkoxy” is employed, it is intended to include branched as well as straight chain radicals. It is also intended to include an alkyl chain having a cycloalkyl substituent.
Where the expression “ether” is employed, it is intended to include thioethers as will be evident from the context.
Pharmaceutically acceptable salts suitable as acid addition salts as well as salts providing the anion of the quaternary salt are those from acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, maleic, citric, acetic, tartaric, succinic, oxalic, malic, glutamic and the like, and include other acids related to the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977).
Representative nuclei for Compound X and the sequence IDs for these compounds may be seen in the following table. Since the peptide nuclei would be the same irrespective of substituents R
I
, R
II
, R
III
, or R
IV
and since the sequence identification number is assigned for the nuclear variations, the amines and ammonium salts have the same sequence ID's. Also, since the nucleus amino acid would be the same irrespective of the particular amino alkyl ether, i.e., irrespective of R
V
, R
VI
or R
VII
, R
3
is considered to be the same for purposes of sequence identification and is not on the table. Further, since the amino acid is not varied irrespective of the change in the lipophilic side chain, separate sequence numbers are not assigned merely on the basis of a different side chain. “Lipophilic side chain” as herein employed refers to R
I
.
AMINE
COMPOUND
NUCLEI
R
1
R
2
R
4
R
5
R
6
SEQ. ID
X-1
OH
OH
OH
H
CH
3
1
X-2
OH
OH
OH
CH
3
CH
3
2
X-3
H
OH
OH
CH
3
H
3
X-4
OH
H
OH
CH
3
CH
3
4
X-5
H
H
H
CH
3
CH
3
5
X-6
OH
OH
OH
OH
CH
3
6
X-7
H
OH
OH
H
H
7
X-8
H
OH
OH
H
CH
3
29 
When the compounds are free amines, they are soluble in lower alcohols and polar aprotic solvents such as dimethylformamide (DMF) and pyridine. They are insoluble in solvents such as ether and acetonitrile. When the compounds are quaternary ammonium salts or protonated amines, they are soluble in water and polar solvents.
The compounds of the present invention are useful as an antibiotic, especially as an antifungal agent or as an antiprotozoal agent. As antifungal agents they are useful for the control of both filamentous fungi and yeasts. They are especially adaptable to be employed for the treatment of mycotic infections in mammals, especially those caused by Candida species such as
C. albicans, C. tropicalis
and
C. pseudotropicalis
, and Aspergillus species such as
A. fumigatus, A. flavus
and
A. niger
. They are also useful for the treatment and/or prevention of
Pneumocystis carinii
pneumonia to which immune compromised patients are especially susceptible as hereinafter described.
The previously noted solubility properties are advantageous for utilization in therapeutic applications, especially in injectible compositions.
The compounds of the present invention may be obtained from derivatives of natural products through a sequence of reactions seen in the accompanying flow diagram.
The starting material represented by formula (E), which is generally a side chain derivative of a natural product and which may be obtained as hereinafter described, is first subjected to dehydration (Step A) to produce a nitrile of formula (F) which is then reduced (Step B) to an amine G (R
II
, R
III
are H). which if a substituted amine is desired, may be alkylated by reductive alkylation with an appropriate aldehyde and a reducing agent such as sodium cyanoborohydride to obtain Compound G (R
II
and R
III
are alkyl or benzyl).
When Compound G has a nuclear configuration which is different from that obtained from a natural product, it may be obtained by reduction of an OH.
Compound G is representative novel compound which is claimed in concurrently filed copending application in the name of James M. Balkovec, Milton L. Hammond and Robert A. Zambias Ser. No. 07/058,657.
Compound G may be converted to the aminoalkyl ether by adding 1 to 10 equivalents of strong organic or mineral acid such as camphorsulfonic acid or hydrochloric acid to a solution of cyclohexapeptidyl propanolamine (Compound G) and 20 to 200 equivalents of the appropriate amino alcohol or aminothiol in the form of an acid addition salt, such as the hydrochloride or hydrobromide, in an appropriate solvent such as dimethyl sulfoxide (DMSO) or dimethylformamide (DMF) and the mixture stirred at room temperature for one to seven days. The reaction is monitored by HPLC and when determined to be complete, the reaction mixture is diluted with 5 to 50 volumes of water and the entire mixture applied to reverse phase chromatography column. “LICHROPREP” C-18 (E. Merck) column is representative of an appropriate column. The column is then eluted with a weakly eluting solvent such as 5 percent acetonitrile in water (containing 0.1 percent trifluoroacetic acid (TFA) or acetic acid) to remove excess amino-alcohol or aminothiol, then with a stronger eluting solvent such as 10 to 50 percent acetonitrile to elute the product. Fractions containing the desired amine compound may be combined and concentrated to isolate the acid addition salt, Compound X-a, according to Step D.
Compound G may be converted to Compound X-b in a similar m

Affiliated with

Also associated with

Rating

Cyclohexapeptidyl amine compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Cyclohexapeptidyl amine compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Cyclohexapeptidyl amine compounds will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2440999