Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-12
2002-05-28
Fan, Jane (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06395902
ABSTRACT:
The present invention relates to a process for the preparation of N-[heteroaryl]hydroxyalkylamines, novel N-[heteroaryl]hydroxyamines obtainable by the process and processes for preparing piperazine derivatives using the N-[heteroaryl]hydroxyalkylamines.
GB 2 255 337A discloses piperazine derivatives having the general formula I
and their pharmaceutically acceptable acid addition salts as 5-HT
1A
binding agents, particularly 5-HT
1A
antagonists and, in particular, their use in the treatment of CNS disorders, for example, anxiolytics. They may also be used as anti-depressants, hypertensives and as agents for regulating the sleep/wake cycle, feeding behaviour and/or sexual function.
In formula I above A is C
2-4
alkylene optionally substituted by one or more lower alkyl groups, Z is oxygen or sulphur, R is hydrogen or lower alkyl, R
1
is an optionally substituted monocyclic or bicyclic aryl or heteroaryl radical, R
2
represents an optionally substituted monocyclic or bicyclic heteroaryl and R
3
represents inter alia hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl (lower) alkyl, aryl, aryl (lower) alkyl and heteroaryl (lower) alkyl.
GB 2 255 337A also discloses piperazine derivatives having the general formula II
where R, R
1
, R
2
and A are as defined above as chemical intermediates for the preparation of the piperazine derivatives having the general formula I. The chemical intermediates are reacted with an acid having the formula R
3
—CZ—OH where R
3
and Z are as defined above or a reactive derivative of such an acid to prepare the compounds having formula I. The chemical intermediates were prepared by the following process:
(where R, R
1
, R
2
and A are as defined above, Hal is halo, particularly chloro or bromo and A′ is an alkylene chain of 1 to 3 carbon atoms optionally substituted by one or more lower alkyl groups)
The reduction may be carried out with, for example, a boron reducing agent eg boranedimethyl sulphide or a complex metal hydride, e.g. lithium aluminium hydride.
The present invention is based upon the discovery that the aforesaid chemical intermediates having formula II can be prepared by means of a process involving a novel rearrangement reaction. The rearrangement reaction has the advantages that it can be performed in high yields and that it can be carried out as an asymmetric synthesis for the preparation of particular stereosomeric forms.
The present invention provides novel compounds having formula V
R
5
O—A—NR
4
—R
2
(V)
and the salts thereof in which A is as defined above; R
2
represents a group having the formula R
6
—N═CR
7
— where R
6
and R
7
, together with carbon atom and nitrogen atom to which they are attached, complete an optionally substituted monocyclic or bicyclic heteroaryl radical and R
4
and R
5
each represent a hydrogen atom or together represent —SO— or —SO
2
—. Thus the compounds having formula V include the compounds having formula Va
HO—A—NH—R
2
(Va)
and compounds having formula Vb
and compounds having the formula Vc
The term “heteroaryl” refers to an aromatic radical containing one or more hetero atoms (eg oxygen, nitrogen, sulphur) and which may be optionally substituted by one or more substituents. Examples of such substituents include lower alkyl (for example, methyl, ethyl and propyl), lower alkoxy (for example, methoxy and ethoxy), halogen, trifluoromethyl, nitro, cyano, di(lower alkyl)amino and (lower) alkoxycarbonyl. The heteroaryl radical may, for example, contain up to 10 ring atoms. Preferably the heteroaryl radical is a monocyclic radical containing 5 to 7 ring atoms. The hetero ring of R
2
must contain a nitrogen hetero atom and may also contain one or more further hetero atoms.
When R
2
is a bicyclic heteroaryl radical both rings of the radical may contain hetero ring atoms or only one ring may contain a hetero atom or atoms. In the latter instance the radical R
2
is connected to the rest of the molecule of formula (I) via the ring containing the hetero atom(s).
Examples of the heteroaryl radical R
2
include monocyclic radicals containing one hetero atom, eg optionally substituted 2-pyridyl, particularly 2-pyridyl, monocyclic radicals containing two hetero atoms, eg 2- or 4-thiazolyl (particularly 2-thiazoyl) and bicyclic radicals containing one or two hetero atoms eg 2-quinolinyl or 1- or 3-isoquinolinyl (particularly 2-quinolinyl).
The term “lower” as appplied to alkyl and alkoxy groups herein means that the alkyl or alkoxy group contains 1 to 6 carbon atoms preferably 1 to 4 carbon atoms. The term “(lower)” alkoxy carbonyl” means alkoxycarbonyl in which the alkoxy group is “lower”. Examples of lower alkyl include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, isopentyl and hexyl.
The group A may represent dimethylene, trimethylene, tetramethylene or a lower alkyl-substitution product thereof, for instance, —CH(CH
3
)—CH
2
—. Where one or more lower alkyl substituents are present, the group A may contain an asymetric carbon atom. Thus the new compounds having formula V may exists in different steroisomeric forms. Different stereoisomers are preferably prepared by using a starting material of formula VII (see below) in a particular stereoisomeric form.
The invention provides a process for the preparation of a compound having formula Va
HO—A—NH—R
2
(Va)
or a salt thereof where R
2
and A are as defined above, which comprises subjecting a compound having the formula VI
R
2
O—A—NH
2
(V)
where R
2
and A are as defined above, to rearrangement. The rearrangement can be carried out by heating the compound having formula VI in the presence of a suitable solvent, optionally in the presence of an acidic catalyst. The rearrangement reaction has the advantage that it can be carried out in very high yields.
The compounds having the formula VI can be prepared by ether formation in known manner from alcohols having the formula VII
HO—A—NH
2
(VII)
where A is as defined above. In particular the alcohol may be converted into an alkali metal salt thereof, particularly the sodium, potassium or lithium salt, in solution in a suitable solvent prior to reaction with a compound having the formula R
2
—X where X is a leaving group, preferably, chloro, bromo or fluoro. The salt formation is preferably carried out by treating the alcohol (VII) with potassium t-butoxide in tetrahydrofuran to form the potassium salt of the alcohol.
The aminoalcohols having formula Va are useful for the preparation of alkylating agents for the introduction of a substituted alkyl group having the formula X
—A—NH—R
2
(X)
Such alkylating agents are reacted with a piperazine derivative having the formula IIIa
where R
1
is as defined above to form the aforesaid chemical intermediates having formula II which in turn can be used to prepare the pharmaceutically useful piperazine derivatives having formula I.
We have found that conventional alkylating agents, namely, those of the formula RY where R is the alkyl or substituted alkyl group and Y is a leaving group such as a chlorine or bromine atom or tosyloxy group, are not generally suitable for use in the aforeside reaction with the piperazine derivative having formula IIa to prepare the compund having formula II. However, we have surprisingly found that the reaction is possible by using a compound having the formula Vb or Vc, preferably Vc as reactant. The compounds having the formulae Vb and Vc may be prepared by a process which comprises reacting a compound having the formula Va with a compund having the formula SO
n
X
2
where n is 1 or 2 and X is a leaving group. X may be halogen particularly chlorine or a residue from imidazole. When n is 1 then the product of the process is of formula Vb. When n is 2 the product of the proces is of formula Vc. The compounds having formula Vc may also be prepared by oxidation of a compound having formula Vb. The oxidation may be carried out according to known methods.
The invention also includes a process for the preparation
Brightwell Christopher Ian
Shepherd Robin Gerald
Barrett Rebecca R.
Fan Jane
John Wyeth & Brother Limited
LandOfFree
Oxathiazolidinyl pyridines does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Oxathiazolidinyl pyridines, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Oxathiazolidinyl pyridines will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2897437