Process for the preparation of dinaposoline

Details Process for the preparation of dinaposoline Process for the preparation of dinaposoline

2003-01-27

2003-11-11

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S075000, C546S048000, C514S280000

Reexamination Certificate

active

06645975

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides a process for the preparation of dinapsoline and certain derivatives thereof which are useful as dopamine receptor agonists in the treatment of movement disorders.
BACKGROUND OF THE INVENTION
Dopamine has been implicated in numerous neurological disorders. It is generally recognized that either excessive or insufficient functional dopaminergic activity in the central and/or peripheral nervous system may cause hypertension, narcolepsy, and other behavioral, neurological, physiological, and movement disorders including Parkinson's disease, a chronic, progressive disease characterized by an inability to control the voluntary motor system.
A number of ligands for the treatment of dopamine-related dysfunction of the central and peripheral nervous system are described in International Patent No. WO 97/06799, published Feb. 27, 1997, having the general tetrahydro-1H-naph[1,2,3-de]isoquinoline chemical structure described below.
In particular, the international application specifically describes the synthesis and use of (±)-8,9-dihydroxy-2,3,7,11b-tetrahydro-1H-naphtho[1,2,3-de]isoquinoline denominated as “dinapsoline” in the description. The synthesis of dinapsoline is depicted generally in FIGS. 1 and 2 as well as in the experimental section. Further description of the synthesis and pharmacological evaluation of dinapsoline is described by D. Ghosh, et al. in
J. Med. Chem
., Vol. 39, pp. 549-555 (1996).
Although the prior art process works on a small scale, the overall process is a long synthesis which involves as many as 14 steps to complete, including protection and deprotection schemes. The cyclization step near the end of the synthesis was found to be problematic and the yield not reproducible, if there is any product at all. Thus, there is a need for a simple, convenient, economical and scale-up for the preparation of dinapsoline and derivatives thereof. The present inventors have found a suitable process that avoids the problematic cyclization step which uses an isoquinoline system and a highly regloselective carbon-carbon bond forming technique to establish the entire tetracyclic framework in a few simple steps.
SUMMARY OF THE INVENTION
The present invention relates to fused isoquinoline compounds of the formula
wherein R
1
, R
2
, R
4
, R
5
, R
6
and A are as defined herein which are useful for the treatment of movement disorders. More specifically, the invention relates to a process for their preparation.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a novel process for the preparation of dinapsoline and derivatives thereof which are useful for the treatment of movement disorders, and have the formula
wherein R
1
and R
2
each are independently hydrogen or a hydroxy-protecting group; or R
1
and R
2
may be joined together to form —(CH
2
)
n
—; n is 1 to 3; A is CH
2
, CHOR
1
or C═O; and R
4
, R
5
and R
6
each are independently hydrogen, C
1-4
alkyl, C
1-4
alkoxy, hydroxy or halogen. The novel and improved process is illustrated in Reaction Scheme 4.
The present invention also provides certain dinapsoline derivatives of Formula IX which are useful for the treatment of movement disorders.
The term “C
1-4
alkyl” as used herein and in the claims (unless the context indicates otherwise) means straight or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and t-butyl. The term “C
1-4
alkoxy” as used herein and in the claims means straight or branched chain alkoxy groups such as methoxy, ethoxy, propoxy and butoxy. Preferably, these groups contain from 1 to 2 carbon atoms. Unless otherwise specified, the term “halogen” as used herein and in the claims is intended to include bromine, chlorine, iodine and fluorine while the term “halide” is intended to include bromine, chloride and iodide anion. The term “A” as used herein and in the claims is independently selected from a methylene (—CH
2
—) group, a hydroxy or hydroxy-protected methylene (—CHOR
1
) group or a carbonyl (C═O) group.
The term “hydroxy-protecting group” refers to those groups well known to those skilled in the art which can be employed in the present invention to block or protect the hydroxyl group. Preferably, said groups can be removed, if desired, by methods which do not result in any appreciable destruction of the remaining portion of the molecule, for example, by chemical or enzymatic hydrolysis, treatment with chemical reducing agents under mild conditions, irradiation with ultraviolet light or catalytic hydrogenation.
Suitable hydroxy-protecting groups include acyl groups such as acetyl, propionyl, butyryl, chloroacetyl, dichloroacetyl and trichloroacetyl, phenoxycarbonyl, benzyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, p-nitro-benzyloxycarbonyl and 2,2,2-trichloroethoxy-carbonyl; aroyl groups such as benzoyl and substituted benzoyl, for example, methoxybenzoyl, nitrobenzoyl, methylbenzoyl and the like; alkyl groups such as methoxymethyl, benzyloxymethyl, alkyl; aralkyl groups such as benzyl, benzhydryl, trityl or p-nitrobenzyl; or triorganosilyl groups such as tri(C
1
-C
6
)alkylsilyl (e.g. trimethylsilyl, triethylsilyl, triisopropylsilyl, isopropyidimethylsilyl, t-butyidimethylsilyl, methyldlisopropyisilyl or methyldi-t-butylsilyl), triarylsilyl (e.g. triphenyl-silyl, tri-p-xylsilyl) or triaralkylsilyl (e.g. tribenzysilyl). Examples of these and other suitable hydroxy-protecting groups and methods for their formation and removal are known in the art, e.g. see
Protective Groups in Organic Synthesis
, T. W. Greene, John Wiley & Sons, New York, 1991, Chapter 2, and references therein.
Preferred hydroxy-protecting groups are acyl groups such as acetyl, propionyl and chloroacetyl; aroyl groups such as benzoyl and substituted benzoyl and aryl groups such as benzyl and substituted benzyl. Most preferably, the hydroxy-protecting group is achieved when R
1
and R
2
are joined together to form a methylene (—CH
2
—) group.
It should be appreciated by those skilled in the art that the final deblocking step will naturally vary depending on the protecting groups present in substituents R
1
and R
2
. The deblocking step such as illustrated in Reaction Scheme 4, step (g), to produce compounds of Formula IX wherein R1 and R
2
are hydrogen is accomplished by conventional procedures such as hydrolysis, chemical reduction, hydrogenation and the like, and includes the method illustrated for the removal of the hydroxy-protecting group wherein R
1
and R
2
are joined together to form —CH
2
—.
The compounds of Formula IX may be prepared by various procedures such as those illustrated herein in the examples, in the Reaction Schemes and variations thereof which would be evident to those skilled in the art. The fused isoquinolines of Formula IX may advantageously be prepared by reduction methods from benzo benzoisoquinoline compounds of Formula VII followed by removal of the hydroxy-protecting groups as illustrated in Reaction Scheme 4. The various benzo benzoisoquinolines of Formula VII may advantageously be prepared using free radical carbon-carbon bond formation from aryl isoquinolines of Formula VI as illustrated in Reaction Scheme 3 while the aryl isoquinolines of Formula V may be prepared from isoquinolines of Formula I and appropriately substituted phenyl derivatives by the method illustrated in Reaction Scheme I and the alternative method illustrated in Reaction Scheme 2.
As illustrated in Reaction 1, the compounds of Formula V may be prepared from substituted or unsubstituted isoquinolines of the Formula I which are generally known to undergo electrophilic substitution preferentially at the 5-position to give 5-bromo-isoquinolines of the Formula II. The bromination reaction (a) can be done in neat form and in the presence of a Lewis Acid catalyst such as anhydrous aluminum chloride, or alternatively, the bromination can be carried out in an inert organic solvent such as methylene chloride. In both cases, the overall yields are comparable to e

Affiliated with

Also associated with

Rating

Process for the preparation of dinaposoline does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for the preparation of dinaposoline, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of dinaposoline will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3167917