Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
2002-04-03
2004-02-10
Kifle, Bruck (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
active
06689881
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel method for the preparation of chiral [1,4]diazepino[6,7,1-
hi
]-indol-4-ones of use in the preparation of medicaments which make possible the treatment of ailments involving therapy by an inhibitor of phosphodiesterases 4 (PDE4). These medicaments are of use in particular as antiinflammatories, antiallergics, bronchodilators or antiasthmatics.
The international patent application published under No. WO 98/49169, the contents of which are incorporated in the present application by reference, discloses diazepino-indolones, which are compounds active as inhibitors of PDE4 enzymes, of formula
in which:
A is hydrogen, lower alkyl, lower alkoxy, nitro or amino;
B is hydrogen or optionally functionalized lower alkyl;
X
1
and X
2
, which are alike or different, can be hydrogen, halogen, lower alkyl, lower alkoxy or alternatively —CH
2
OH or —CO
2
H, which are optionally substituted;
Z is CH, then Z
1
and Z
2
are both CH or N; or Z is N, then Z
1
and Z
2
are CH.
In this Application WO 98/49169, the preferred diazepino-indolones of formula (I) are those in which the 3 carbon of the [1,4]diazepino[6,7,1-
hi
]indol-4-one nucleus has the S configuration.
These compounds were obtained in Patent Application WO 98/49169 as racemic compounds and could only be separated by chiral phase chromatography or else by the formation of salts with an enantiomerically pure amine. The synthetic process disclosed in Patent Application WO 98/49169 can exhibit disadvantages, including, on occasions, low yields and the need for a resolution stage.
SUMMARY OF THE INVENTION
In point of fact, an improved process has now been found for the preparation of these same products directly in the form of pure enantiomers, which process is efficient and economic and forms the subject-matter of the present invention. Consequently, the present process avoids the disadvantages of the known processes and it can be adapted to a larger scale.
The invention relates to an improved process for the preparation of chiral substituted [1,4]diazepino[6,7,1-
hi
]indol-4-ones of formula (I)
in which, in particular:
A is hydrogen, lower alkyl, lower alkoxy, nitro or amino;
B is hydrogen or lower alkyl;
Z is CH, then Z
1
and Z
2
are together CH or N; or Z is N, then Z
1
and Z
2
are CH;
X
1
and X
2
, which are alike or different, can be hydrogen, halogen, lower alkyl, lower alkoxy or alternatively —CH
2
OH or —CO
2
H, which are optionally substituted.
DETAILED DESCRIPTION OF THE INVENTION
The invention is targeted at a process for the preparation of the enantiomers of the diazepino-indolones (I) of formula
in which:
A is hydrogen, lower alkyl, hydroxyl, lower alkoxy, nitro, cyano or NR
1
R
2
; R
1
and R
2
are independently hydrogen or lower alkyl or form, together with the nitrogen atom to which they are bonded, a ring having 4 or 5 carbon atoms;
B is hydrogen or lower alkyl;
Z is CH, then Z
1
and Z
2
are together CH or N; or Z is N, then Z
1
and Z
2
are CH;
X
1
and X
2
are independently hydrogen, C
1
-C
4
alkyl, —(CH
2
)
j
—OR
3
, halogen, cyano, —O—(C
1
-C
6
alkyl), —C(═O)R
4
, —C(═O)OR
5
, —C(═O)NR
6
R
7
, or
R
3
, R
4
and R
5
are independently hydrogen, C
1
-C
6
alkyl, benzyl, phenethyl or —Q
1
—Q
2
;
R
6
is hydrogen or C
1
-C
4
alkyl;
R
7
is hydrogen, C
1
-C
4
alkyl, —CHR
A
—C(═O)OM
2
or —Q
3
—Q
4
;
R
8
is hydrogen, C
1
-C
4
alkyl or —Q
5
—Q
6
;
R
A
is a natural &agr;-amino acid residue, the carbon atom to which it bonded being able to have either the S configuration or the R configuration;
Q
1
is —(CH
2
)
k
—(CHOH)
m
—(CH
2
)
p
—;
Q
2
is hydroxyl, —O—(C
1
-C
6
alkyl), —OC(═O)—(C
1
-C
6
alkyl) or 4-morpholinyl;
Q
3
and Q
5
are independently a bond, —CH
2
—, —(CH
2
)
2
— or —(CH
2
)
3
—;
Q
4
is —NM
3
M
4
or 4-morpholinyl;
Q
6
is —M
5
or —OM
6
;
M
1
, M
2
, M
3
, M
4
, M
5
and M
6
are independently hydrogen or C
1
-C
4
alkyl;
j is 1, 2 or 3; k is 1, 2 or 3;
m is 0, 1, 2, 3 or 4; p is 0, 1, 2 or 3, with the proviso that, if m>0, then p>0;
their isomers, their racemic forms, as well as their salts, solvates, esters, amides and prodrugs which are pharmaceutically acceptable.
In what precedes and in what follows:
the term “halogen” is understood to mean fluorine, chlorine, bromine or iodine;
the term “lower alkyl” or “C
1
-C
4
alkyl” is understood to mean a linear or branched radical comprising from 1 to 4 carbon atoms or alternatively the cyclopropylmethyl radical;
the term “lower alkoxy” is understood to mean a radical of formula —O-Alk, where Alk is lower alkyl;
the term “C
1
-C
6
alkyl” is understood to mean a linear or branched radical comprising from 1 to 6 carbon atoms or alternatively the cyclopropylmethyl radical.
The process of the present invention makes it possible to obtain the chiral [1,4]diazepino[6,7,1-
hi
]indol-4-ones (I) directly, in the form of pure enantiomers, from optically active 3-aminobenzodiazepines (II) in a stage represented in Scheme 1,
where A, Z, Z
1
, Z
2
, B, X
1
and X
2
have the meanings defined above for (I);
R is a lower alkyl radical, preferably the methyl radical.
During this reaction, an intermediate (II) is cyclized, preferably at normal temperature or below 0° C., in the presence of a Lewis acid, such as scandium trifluoromethanesulphonate, to give the product (I).
The intermediate (II) is dissolved in a solvent and a catalytic amount of Lewis acid, preferably scandium trifluoromethanesulphonate, is added at normal temperature. The product (I) is obtained, the optical purity of which is confirmed by analytical HPLC.
More generally, the Lewis acids of use in the process of the present invention are described in particular in the following publications: i)
Advanced Organic Chemistry
, Third Edition, by Jerry March (John Wiley & Sons, New York, 1985); ii) “Friedel-Crafts Reactions”, Olah, G. and Meidar, D.;
Kirk
-
Othmer Encyclopedia of Chemical Technology
, Third Edition, 11, 269-300 (John Wiley & Sons, New York, 1978), iii) “Quantitative Aspects of Lewis Acidity”, Satchell, D. P. N. and Satchell, R. S.;
Quarterly Reviews
(The Chemical Society, London), 1971, 25: 171-199, iv) “Lanthanide triflates as unique Lewis acids”, Xie, W., Jin, Y. and Wang, P. G.;
CHEMTECH
, 1999, 29, 23-29, and v) Marshman, R. W., “Rare earth triflates in organic synthesis”,
Aldrichimica Acta
, 1995, 28, 77-84.
Strong Lewis acids (such as aluminium chloride, ferric chloride and equivalents) do not seem, in the present invention, as effective catalysts as weak Lewis acids.
Examples of Lewis acids of use in the present invention are compounds or complexes of formula:
[LX
x
Y
y
]
having a vacant orbital,
where L is a metal, boron, silicon or antimony,
X and Y are neutral or anionic, nonmetallic ligands, atoms or radicals,
x and y are each zero or an integer.
Typical values of L comprise boron, aluminium, silicon, scandium, titanium, gallium, indium, yttrium, zirconium, silver, tin, antimony, lanthanum and lanthanides, mercury, thallium, manganese, iron, cobalt, nickel, copper, zinc, calcium and magnesium or another transition metal. Preferred values of L comprise boron, silicon, aluminium, scandium, lanthanides, titanium, gallium, silver, tin, iron, zinc and magnesium.
Typical values of X and Y are chosen from halides, oxygen, oxygen-comprising ligands, organic radicals and organic anions.
The oxygen-comprising ligands comprise, for example, oxygen or alkoxy, phenoxy, carboxylate, &bgr;-ketocarboxylate, sulphate, sulphonate, phosphate, phosphonate and equivalent radicals.
The organic radicals comprise, for example, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, phenylalkyl and (substituted phenyl)alkyl radicals.
The organic anions comprise cyclopentadienyl and substituted cyclopentadienyl anions.
The Lewis acids preferably comprise at least one oxygen-comprising ligand, for example an alkoxy radical or a sulphonate radical. The preferred weak Lew
Benson Gregg C.
Kifle Bruck
Richardson Peter C.
Ronau Robert T.
Warner-Lambert LLC
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