(−)-Verbenone derivatives

Details (−)-Verbenone derivatives (−)-Verbenone derivatives

2001-10-15

2003-11-18

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C514S661000, C514S429000, C514S277000, C514S231200, C564S253000, C564S460000, C548S560000, C546S001000, C544S106000

Reexamination Certificate

active

06649658

ABSTRACT:

This application is a 371 of PCT/EP00/03339 Apr. 13, 2000.
The present invention relates to novel derivatives of (1S,5S)-4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-one), which is more commonly known as (−)-verbenone.
The oxidation of &agr;- and &bgr;-pinene leads to complex mixtures of monoterpenoid compounds, which are predominantly characterized by alcohol and carbonyl functions; these mixtures have been used for some time, for example in Italy (OZOPULMIN®), France (OZOTHENE®) and Germany (OZOTHIN®), in the therapy of respiratory disorders, owing to their recognised balsamic, bronchosecretolytic and antiseptic properties.
Among the above-mentioned monoterpene derivatives of the carbonyl type (−)-verbenone, a ketone derivative having an &agr;-pinane structure whose structural formula is given below, is of particular interest.
(−)-verbenone is characterized by its particular pulmonary tropism, its anti-inflammatory action on the respiratory tract and by its good muco-regulatory capacity.
The anti-inflammatory activity on the respiratory apparatus has been investigated in a series of classical experimental pharmacology tests: carrageenan- and dextran-induced oedema, adjuvant arthritis (rat), passive cutaneous anaphylaxis (rabbit), turpentine- and carrageenin-induced pleurisy (rat) and acrolein-induced aerosol (guinea pig).
(−)-verbenone is an oily substance having a characteristic odour and a boiling point of 227-228° C. d=0.975, n
D
20
=1.497 and a specific rotatory power which varies according to the respective suppliers (ACROS catalogue, purity 94%: −193°, c=10, ethanol; FLUKA catalogue, purity ≧99%: 180±2°, c=10, ethanol).
However, the oily nature, the instability over time and the water-insolubility of (−)-verbenone make it difficult to administer in water-soluble dosage forms. Therefore, the object of the present invention is to synthesize (−)-verbenone derivatives that are in a solid, water-soluble form or which can in any case be readily converted into water-soluble compounds, while maintaining and possibly increasing the anti-inflammatory characteristics in respect of the respiratory tract which are typical of (−)-verbenone.
Novel pharmacologically active derivatives of (−)-verbenone having the general formula I given below:
wherein, when X=O
Z=H, ═CHAR, ═C(OH)COOEt, ═NOR;
Y=H, NH
2
, NH
3
+
X,
1
−
, NHCOAr, NHCOR, NHCONHR, NHCONHAr,
X
1
−
=pharmaceutically acceptable anion;
Ar=aryl or heteroaryl, preferably phenyl, 4chlorophenyl, 2-furyl, 2-thienyl, 2-hydroxyphenyl, 2-acetoxyphenyl;
R=H, C
1
-C
4
alkyl, C
4
-C
6
cycloalkyl, CH
2
COOH, CH
2
COOEt, CH
2
COCH
3
, CH
2
CN, CH
2
COCH
2
COOEt, CH
2
C
6
H
5
;
with the proviso that when X=O and Y=H, Z is other than H;
and, when X=dimethylamino, diethylamino, pyrrolidino, piperidino or morpholino:
Y=H;
Z=H, CONAr, CONHR;
Ar=aryl, preferably phenyl;
R=H, C
1
-C
4
alkyl, C
4
-C
6
Cyclalkyl
with the proviso that when Z=H, X is other than pyrrolidino have now been found, and form subject-matter of the present invention.
The broken line given in the general formula I is thus intended to indicate two distinct structures resulting from the different positioning of the two conjugated double bonds of (−)-verbenone, as is demonstrated more clearly by the general formulae II and III given below:
wherein:
when Y=H, preferably Z=═CHAr, ═C(OH)COOEt, ═NOR (that is to say, the Z group and the C-10 are joined by a double bond); or, alternatively,
when Z=H, preferably Y=NH
2
, NH
3
+
X
1
−
, NHCOAr, NHCOR, NHCONH; and wherein:
X
1
−
=5-sulphosalicylate, tare, 10camphosulphonate;
Ar=phenyl, 4chlorophenyl, 2-furyl, 2-thienyl, 2-hydroxyphenyl, 2-acetoxyphenyl;
R=H, C
1
-C
4
alkyl, C
4
-C
6
cycloalkyl, CH
2
COOH, CH
2
COOEt, CH
2
COCH
3
, CH
2
CN, CH
2
COCH
2
COOEt, CH
2
C
6
H
5
;
 wherein:
X=dimethylamino, diethylamino, pyrrolidino, piperidino or morpholino;
Z=H, CONHAr, CONHR;
Ar=phenyl;
R=H, methyl, cyclohexyl.
The structure II preserves the &agr;-&bgr;-unsaturated carbonyl system typical of verbenone, while III is structurally related to the non-isolatable dienol form of verbenone A
which may, however, constitute the reactive intermediate in some reactions described here.
As will be appreciated from the accompanying Examples, the novel derivatives of (−)-verbenone according to the present invention are nearly all solid and stable at room temperature and thus can be readily used for the preparation of pharmaceutical compositions which are easy to use, preserve and administer, some of them also have an anti-inflammatory activity which is comparable to, if not higher than, that of (−)-verbenone.
The present invention therefore relates secondly to the pharmaceutical compositions containing at least one of the novel derivatives according to the present invention as active ingredient together with the excipients and/or co-adjuvants known in the art; these formulations are preferably administrable orally, parentally and topically. Among the novel (−)-verbenone derivatives of formula I, those of greatest interest are represented by formula IV, given below,
wherein X
1
−
represents, as described above, a pharmaceutically acceptable anion and, preferably, 5-sulphosalicylate, tartrate, 10-camphosulphonate. These derivatives, in addition to being completely soluble in water, have a pharmacological activity which is surprisingly higher than that of (−)-verbenone; they therefore constitute the aspect of the present invention of greatest interest.
The novel derivatives according to the present invention are readily synthesised from (−)-verbenone which, in turn, can be readily prepared firm (−)-&agr;-pinene; in particular, it has been observed that the best pharmacological results are obtained by using as starting material (−)-verbenone having a high degree of optical purity, preferably of at least −180°, even more preferably of at least −193°; the (−)-verbenone most preferred has an optical purity of −217° (c=10, ethanol).
The synthesis processes in question, in addition to being described individually in the Examples are also summarised in the accompanying scheme 1. As will be appreciates the majority of the novel derivatives according to the present invention can be prepared by way of the novel intermediates of formulae V, VI and VII, given below to which the invention therefore also relates.
(wherein X=dimethylamino, diethylamino, pyrrolidino, piperidino and morpholino). Because (−)-verbenone constitutes a key intermediate in the synthesis of the novel derivatives of formula I, the present invention relates also to its use as an intermediate in the preparation thereof. The present invention relates also to the processes for the preparation of the compounds in question.
Those and other aspects of the present invention will be demonstrated more clearly by the following Examples, which are to be regarded purely as non-limiting illustrations thereof.


REFERENCES:
patent: 4157451 (1979-06-01), Ohloff et al.
patent: 4190675 (1980-02-01), Vegezzi
patent: 4876276 (1989-10-01), Mechoulam et al.
patent: 5478821 (1995-12-01), Bloy et al.
patent: 5532277 (1996-07-01), Janzen et al.
CA 125:58781, Toda, Fumio, 1996.*
CA 120:134874, Oprean, Ioan et al, 1994.*
CA: 118: 197831, Kizlink, Juraj et al, 1993.

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