Title of Invention

NOVEL VERBENONE DERIVATIVES PROCESS FOR THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITION

Abstract The invention discloses the compound having the formula I wherein X, Y and Z are as defined in the specification with the proviso that when when X = O and Y = H, Z is other than H; and, when X = dimethylamino, diethylamino, pyrrolidino, piperidino or morpholino: Y = H; Z = H, CONHAr, CONHR; Ar = aryl, preferably phenyl; R = H, C1-C4 alkyl, C4-C6 cycloalkyl; with the proviso that when when Z = H, X is other than pyrrolidino. The invention is also for process preparation of compounds of the invention, novel intermediates and pharmaceutical composition comprising the compounds of the invention.
Full Text NOVEL VERBENONE DERIVATIVES PROCESS FOR THEIR
PRODUCTION AND PHARMACEUTICAL COMPOSITION
COMPRISING THEM
(i) Verbenone derivatives
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 a- and ß-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 (OZOTHINE®) 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 a-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).
GB A-1585 831 and Masataka Watanabe et al. J. Org. Chem; vol. 58, no. 15 (1993) p.
3923-3927 both disclose the compound verbenone which is not in the ambit of the
compounds claimed by the present invention.
Y. Chretien-Bessiere et al., Comptes Rendus Hebdomadaires des Seances de
l'Academie des Sciences, Serie C: Sciences Chimiques, vol.264, no. 8 (1967), p. 710-713)
though discloses compounds wherein X in the compounds of the formulae I of the
present invention represents pyrrolidino and Y and Z represent H, this possibility has
been excluded from the scope of the present invention. Further, the document is silent
about the activity or use of the compounds disclosed therein.
The present invention solves the problem of oily nature, instability and water-
insolubility of (-)- verbenone by preparing derivatives in a solid, water-soluble form
while maintaining anti-inflammatory activity in respect of respiratory tract which is
typical of (-) verbenone. There is no hint in the prior art that (-) - verbenone derivatives
as disclosed in the present invention could solve the problem posed.
(-)-verbenone is an oily substance having a characteristic odour and a boiling point of
227-228° C, d= 0.975, no20 = 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, NH2, NH3-X1-, NHCOAr. NHCOR, NHCONHR,
NHCONHAr;
X1- = pharmaceutically acceptable anion;
Ar = aryl or heteroaryl, preferably phenyl, 4-chlorophenyl, 2-furyl,
2-thienyl, 2-hydroxypbenyl, 2-acetoxyphenyl;
with the proviso that when X = 0 and Y = H, Z is other than H;
ylth the proviso that when Z = H, X is other than pyrrolidino
3.
R = H, C1-C4 alkyl, C4-C6 cycloalkyl, CH2COOH, CH2COOEt,
CH2COCH3, CH2CN, CH2COCH,COOEt, CH2C6H5;
and, when X = dimethylamino, diethylamino, pyrrolidino, piperidino or morpholino:
Y = H;
Z = H, CONHAr, CONHR;
Ar = aryl, preferably phenyl;
R=H, C1-C4 alkyl, C4-C6 cycloalkyl
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
siroup and the C-10 are joined by a double bond); or, alternatively,
when Z = H, preferably Y = NH2, NH3+X1-, NHCOAr, NHCOR, NHCONHR;
and wherein:
X1- = 5-sulphosalicylate, tartrate, 10-camphosulphonate;
A? = phenyl, 4-chlorophenyl, 2-furyl, 2-thienyl, 2-hydroxyphenyl, 2-
acetoxyphenyl;
The invention discloses the compound having the formula I
wherein X, Y and Z are as defined in the specification with the proviso that when when X
= O and Y = H, Z is other than H; and, when X = dimethylamino, diethylamino,
pyrrolidino, piperidino or morpholino:
Y = H;
Z = H, CONHAr, CONHR;
Ar = aryl, preferably phenyl;
R = H, C1-C4 alkyl, C4-C6 cycloalkyl;
with the proviso that when when Z = H, X is other than pyrrolidino.
The invention is also for process preparation of compounds of the invention, novel
intermediates and pharmaceutical composition comprising the compounds of the
invention.

Documents:


Patent Number 225233
Indian Patent Application Number IN/PCT/2001/01026/KOL
PG Journal Number 45/2008
Publication Date 07-Nov-2008
Grant Date 05-Nov-2008
Date of Filing 03-Oct-2001
Name of Patentee EUPHAR GROUP SRL
Applicant Address VIA SETTALA, 3, I-20124 MILANO
Inventors:
# Inventor's Name Inventor's Address
1 CORVI MORA PAOLO VIA SCALABRINI, 49, I-29100, PIACENZA
2 RANISE ANGELO VIA BORZONE, 21, INTERNO 13, I-16132 GENOVA
PCT International Classification Number C07C 235/62
PCT International Application Number PCT/EP00/03339
PCT International Filing date 2000-04-13
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 MI99A000799 1999-04-16 Italy