Benzofurane derivatives

Details Benzofurane derivatives Benzofurane derivatives

2002-01-09

2003-03-11

Owens, Amelia (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S252130, C514S254100, C514S469000, C549S469000, C548S525000, C544S357000, C544S359000

Reexamination Certificate

active

06531503

ABSTRACT:

The invention relates to benzofuran derivatives of the formula I.
in which
R is 1-piperazinyl, 4-R
1
-piperazinyl or L,
R′ is 2-R
2
-5-R
3
-pyrrol-1-ylcarbonyl, 4-R
4
-piperazinyl-1-ylcarbonyl, N,N-di(tert-butyloxy-carbonyl)aminocarbonyl, —CH═C(R
5
R
6
), benzofuran-2-yl-C≡C—, —C(Hal)
3
, —CO—C (Hal)
3
, 1,4-dihydrobenzo[d][1,2]oxazin-3-ylcarbonyl or 3,4-dihydrobenzo-1H-phthalazin-2-ylcarbonyl,
L is Cl, Br, I or a free or reactive functionally modified OH group,
R
1
, R
4
in each case independently of one another are H, benzyl or another amino protective group,
R
2
, R
3
in each independently of one another are H or alkyl having 1-6 C atoms,
R
5
, R
6
in each case independently of one another are alkyl having 1-6 C atoms,
Hal is F, Cl, Br or I,
and their salts.
Similar compounds are disclosed in DE 43 33 254 and DE 195 14 567.
The invention was based on the object of finding novel compounds which can be used, in particular, as intermediates in the synthesis of medicaments, but can also be used directly for the production of medicaments.
It has been found that the compounds of the formula I and their salts are important intermediates for the production of medicaments and at the same time have pharmacological properties. Thus, they show, for example, effects on the central nervous system.
The invention relates to the benzofuran derivatives of the formula I and their salts.
Above and below, the radicals R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R, R′, L, Q and Q′ have the meanings indicated in the formulae I to V, if not expressly stated otherwise. In the above formulae, A has 1 to 4, preferably 1, 2 or 3, C atoms. A is preferably methyl or ethyl, furthermore propyl or isopropyl, and additionally also butyl, isobutyl, sec-butyl or tert-butyl. The radical Ph is phenyl.
In the compounds of the formula [sic] I, II, V, VI and VII, L, Q and Q′ are preferably Cl, Br, I or a reactive modified OH group such as, for example, an activated ester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy) or arysulfonyloxy having 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy).
The expression “amino protective group” is generally known and relates to groups which are suitable for protecting (for blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other positions in the molecule. Typical of such groups are, in particular, unsubstituted acyl, aryl, aralkoxymethyl or aralkyl groups. As the amino protective groups are removed after the desired reaction (or reaction sequence), their nature and size is otherwise uncritical; preferred groups, however, are those having 1-20, in particular 1-8 C atoms. The expression “acyl group” is to be interpreted in the widest sense in connection with the present process and the present compounds. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and also, in particular, alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of acyl groups of this type are alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as phenoxyacetyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl), 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as CBZ (carbobenzoxycarbonyl, also called “Z”), 4-methoxybenzyloxycarbonyl, FMOC (9-fluorenylmethoxycarbonyl); arylsulfonyl such as Mtr (4-methoxy-2,3,6-trimethylphenylsulfonyl). Preferred amino protective groups are BOC and Mtr, and additionally CBZ or FMOC.
The compounds of the formula I can have one or more chiral centres and therefore occur in various stereoisomeric forms. The formula I includes all these forms.
The invention further relates to a process for the preparation of benzofuran derivatives of the formula I according to claim 1 and of their salts, characterized in that
a) for the preparation of compounds of the formula I in which
R is Cl, Br, I, 1-piperazinyl or 4-R
1
-piperazinyl and
R′ is 2-R
2
-5-R
3
-pyrrol-1-ylcarbonyl, 4-R
4
-piperazin-1-yl carbonyl, 1,4-dihydrobenzo[d] [1,2]-oxazin-3-ylcarbonyl or 3,4-dihydrobenzo-1H-phthalazin-2-ylcarbonyl,
a compound of the formula II
 in which
R is Cl, Br, I, 1-piperazinyl or 4-R
1
-piperazinyl and
Q is Cl, Br, I or a free or reactive functionally modified OH group,
and R
1
has the meaning indicated in claim 1
is reacted with a compound of the formula III
R′—H  III
 in which
R′ is 2-R
2
-5-R
3
-pyrrol-1-yl, 4-R
4
-piperazin-1-yl, 1,4-dihydrobenzo[d][1,2]oxazin-3-yl or 3,4-dihydrobenzo-1H-phthalazin-2-yl,
and R
2
, R
3
and R
4
have the meanings indicated in claim 1, or
b) for the preparation of compounds of the formula I in which
R is Cl, Br, I, 1-piperazinyl or 4-R
1
-piperazinyl and
R′ is —CH═C(R
5
R
6
), benzofuran-2-yl-C≡C—, —C(Hal)
3
or —CO—C(Hal)
3
,
and R
1
, R
5
and R
6
have the meanings indicated in claim 1,
i) a compound of the formula IV
 in which
R is Cl, Br, I, 1-piperazinyl or 4-R
1
-piperazinyl, is reacted with a compound of the formula V
Q′—CH
2
—CO—R′  V
 in which R′ is —CH═C(R
5
R
6
), benzofuran-2-yl-C-≡C—, —C(Hal)
3
or —CO—C(Hal)
3
,
and Q′ is Cl, Br, I or a free or reactive functionally modified OH group,
and R
5
and R
6
have the meanings indicated in claim 1, or
ii) a compound of the formula Va
 in which R and R′ have the meanings indicated under i) is cyclized, or
c) a compound of the formula I,
 in which R is a 1-piperazinyl radical, is converted by introduction of an amino protective group into another compound of the formula I in which R is the 4-R
1
-piperazinyl radical,
in which R
1
is an amino protective group, or
d) a compound of the formula I,
 in which R is a 4-R
1
-piperazinyl group, in which R
1
is benzyl or another amino protective group, is converted by removal of the benzyl or amino protective group into a compound of the formula I in which R
1
is 1-piperazinyl, or
e) in a compound of the formula I a radical R is converted into another radical R
by, for example,
i) replacing a Br atom by OH,
ii) esterifying an OH group or
iii) replacing a Br atom by a 4-R
1
-piperazinyl group, in which R
1
is benzyl or an amino protective group,
and/or a base of the formula I is converted into one of its salts by treatment with an acid.
The compounds of the formula I′ and also the starting substances for their preparation are otherwise prepared by methods known per se, such as are described in the literature (e.g. in the standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), namely under reaction conditions which are known and suitable for the reactions mentioned. In this case, use can also be made of variants which are known per se but not mentioned here in greater detail.
If desired, the starting substances can also be formed in situ such that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I.
In the compounds of the formula II, the radical Q is preferably Cl or Br; however, it can also be I, OH or a reactive modified OH group such as alkylsulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy) or arylsulfonyloxy having 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy, 1- or 2-naphthalenesulfonyloxy). In the compounds of the formula II, the radical R is preferably Br or 4-benzylpiperazinyl. The compounds of the formula II are known in some cases; the unknown compounds can easily be prepared analogously to the known compounds.
The reaction of the compounds of the formula II with compounds of the formula III proceeds according to methods such as are known from the literature for the alkylation of a

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