Title of Invention

"INDAZOLES, BENZISOXAZOLES AND BENZIOSOTHIAZOLES"

Abstract The present invention relates to compounds of formula (I) O in which R1 R2, R3, X, Y and A are as defined in the specification.The compounds are modulators of the estrogen receptors.
Full Text Indazoles. benzisoxazoles and benzisothiazoles. process for preparing
them. pharmaceutical compositions and use as estroqenic agents
Field of the invention
The present invention relates to non steroidal compounds with affinity for
estrogen receptors. More specifically, the invention relates to indazole,
benzisoxazole and benzisothiazole compounds as estrogen receptor subtype
modulators and/or selective estrogen receptor modulators (SERM). The present
invention also relates to pharmaceutical compositions containing these
compounds, and to the use of these compounds in the treatment of
estrogen-related diseases.
Background of the invention
The end of the reproductive years of a person's life can often be accompanied by
uncomfortable and disruptive symptoms, one of the most common of which is
hoţ flushes. Perimenopause, or premenopause, is the period of years in which
normal ovulatory cycles give way to cessation of menses. This time is marked by
irregular menstrual cycles. Cycle length begins to increase, and ovulation and
fertility decrease. Menopause is typically defmed as the point, after the loss of
ovarian activity, when permanent cessation of menstruation occurs. In addition,
estrogens are involved in various other physiological processes such as the
modulation of the immune response and development of cancer (breast,
endometrium, colon, prostate). ERa has been proven to be implicated in several
diseases, such as breast cancer, and osteoporosis.
It is well established that estrogens play an important role in the development
and homeostasis of the reproductive, central nervous, skeletal and cardiovascular
systems in both males and females. To date, a plethora of estrogen receptors
have been discovered in the brain, involved in various processes such as mood,
temperatura regulation, sleep, susceptibility to seizure, pain mechanism, and
cognitive functions (Toran-Allerand, Endocrinology, 2004,145, 1069-1074).
Currently, the estrogen receptor (ER) is a nuclear receptor with two known
different subtypes. A new subtype ERp, different from the known ERoc subtype
(Green, Nature, 1986, 320, 134-139), was recently discovered (Mosselman et al,
FEBS Letters, 1996, 392, 49-53). These subtypes have different biologica! roles
and may have selective and effective clinical uses (Harris H. A., Endocrinology,
2002, 143, 11, 4172-4177). ER subtypes share about 50% identity in the ligandbinding
domain (Kuiper et al, Endocrinology, 1998, 139(10), 4252-4263), they
have similar Estradiol (E2) binding affinities and can hetero- or homodimerize
(Cowley, J Biol Chem, 1997, 272, 19858-19862) to form a signalling complex
(Kuiper et al, Endocrinology, 1997, 138(10), 863-870; Kuiper, Proc. Natl. Acad.
Sci. USA, 1996, 93, 5925-5930). ERp is strongly expressed in a number of tissues
including prostate epithelium (Weihua Z, Proc. Natl. Acad. Sci. USA, 2001, 98,
6330-6335), sympathetic ganglia (Zoubina E. V., J. Urol., 2003, 169, 382-385),
colon (Witte D., Hum. Pathol., 2001, 32, 940-944), bladder, ovarian granulosa
cells (Nilsson S., Physiol. Rev., 2001, 81, 1535-1565), bone marrow (Shim G. J.,
Proc. Natl. Acad. Sci. USA, 2003, 100, 6694-6699), breast stroma (Cunha G. R.,
J. Mammary Gland Biol. Neoplasia, 1997, 2, 393-402), lung, intestine, vascular
endothelium, dorsal raphe, parts of the brain (Mitra S. W., Endocrinology, 2003,
144, 2055-2067, Krel W., Proc. Natl. Acad. Sci. USA, 2001, 98, 12278-12282).
ERa is expressed in breast epithelium (Palmieri C., Endocr. Reiat. Cancer, 2002,
9, 1-13), uterus, bone, ovary theca cells (Couse J., Endocr. Rev., 1999, 20,
358-417), prostate stroma (Chu S., Mol. Cell Endocrinei., 1997, 132, 195-199),
liver, testis. The finding of compounds with a specific affinity for one or the other
subtypes could provide a selective treatment of estrogen-related diseases such
as Alzheimer's disease, menopausal complaints (e.g. hoţ flushes, vaginal dryness,
atrophy), cognitive functions (e.g. anxiety, depression, dementia), osteoporosis,
estrogen dependant tumours (uterine, breast, colon, or prostate cancers), benign
prostatic hyperplasia, bladder control, hearing disorders, stroke, leukaemia,
hypertension, obesity, irritable bowel syndrome, or reproductive aspecte such as
contraception or infertility. ERp-selective ligands may be therapeutically useful
agente to treat chronic intestinal and joint inflammation (Harris et coli.,
Endocrinology, 2003, 144, 4241-4249).
According to Warembourg M and Leroy D (Brain Res., 2004, 26; 55-66), ER|3 was
only detected within the rât dorsal raphe nucleus. In contrast, only
ERoc-immunoreactivity was seen in the septum, and in the magnocellular
supraoptic, paraventricular, arcuate, and premammillary nuclei. These
observations provide evidence of a distinct neuroanatomical pattern for the two
subtypes of the ERs. Localisation of ERp in serotonin cells show the link between
ERp and the serotoninergic pathway. Finally, Cyr M et al. described (J Psychiatry
Neurosci., 2002, 27, 12-27) the effect of a selective estrogen receptor modulator
(SERM) such as raloxifen on 5-HT2a receptor.
In conclusion it seems to be relevant to develop ERp modulators as compounds
of interest in the field of schizophrenia, neurodegenerative diseases such a
Alzheimer's disease or Parkinson's disease. For the same reasons, ERp
modulators should be of interest as neuroprotective, antidepressant or anxiolytic
agents.
However, the two receptors which act as ligand activated transcription factors,
were found in a variety of tissues, and differed in their binding pocket only by
two amino acids: Leu and Met in ERoc, Met and Ile in ERp. Those similarities
could explain that the control of the subtype alpha or beta led to the same
pharmacological effect, as it is the case in preclinical model of hoţ flush
phenomena. While ERa modulator decreased the occurrence of hoţ flushes in a
rât preclinical model (Harris et al., Endocrinology, 2002, 143, 4172-4177),
selective estrogen receptor modulators such as spiroindene compounds, which
were affine for both subtypes, hâd the same effect on hoţ flushes (Watanabe et
al., J Med Chem, 2003, 46, 3961-3964).
It has also been shown that estrogen receptors can suppress NFKB-mediated
transcription in both a ligand-dependent and independent manner (Quaedackers,
et al., Endocrinology 2001,142: 1156-1166; Bhat, et al., Journal of Steroid
Biochemistry & Molecular Biology 1998, 67: 233-240; Peizer, et al., Biochemical &
Biophysical Research Communications 2001, 286: 1153-7). These data show the
link between selective estrogen receptor modulators and NFKB which is
implicated in apoptosis and immune/inflammatory response.
Many compounds nave been described as estrogen receptor agonists or
antagonists as they respectively hâd a similar activity or blocked the activity of
estradiol. Such agonist compounds could be used as contraceptive agents in
premenopausal women. Antagonists are widely used therapeutic agents in the
treatment of breast cancer (Vogel, Anticancer Drugs, 2003, 14, 265-273)
whereas agonists are used in HRT (Mormone Replacement Therapy) in post
menauposal women (Burkman, Minerva Ginecol, 2003, 55, 107-116) to treat hoţ
flushes, vaginal atrophy. SERMs are compounds that present mixed activities
depending on the tissue (McDonnell, J Soc Gynecol Invest, 2000, 7, S10-S15).
SERMs might have utility for the treatment of osteoporosis, cardiovascular
diseases and related estrogen receptor diseases.
Estrogen receptors adopt different conformations when binding ligands.
Three-dimensional structures of ERoc and ER|3 have been solved by cocrystallisation
with various ligands (Pike A. C. W., EMBO J, 1999, 18, 4608-4618;
Shiau A. K., Cell, 1998, 95, 927-937). Each ligand influences receptor ERoc or ERp
conformations, leading to distinct biological activities.
Various compounds presented as estrogenic agents have been described in US
2003/0207927 Al and US 2003/0171412 Al. Indazole derivatives presented as
potassium channel blockers are described in WO 2004/043354 and
WO 2004/043933. The synthesis of various isoxazoles is described in Ind J Chem
1980, 19B: 571-575. Benzisoxazole intermediates used in the preparation of
diuretic compounds are described in Chem Pharm Bull 1991, 39(7): 1760-1772.
The synthesis of various benzisothiazoles is described in Tetrahedron 1988,
44(10): 2985-2992.
Summary of the invention
One aspect of this invention is to provide indazole, benzisoxazole and
benzisothiazole compounds, which have an affinity for the estrogen receptors.
Another aspect of this invention is to provide a pharmaceutical composition
containing an indazole, benzisoxazole or benzisothiazole compound as mentioned
above.
A further aspect of this invention is to provide the use of an indazole,
benzisoxazole, or benzisothiazole compound in the manufacture of a medicament
for treating or preventing various diseases mediated by estrogen receptors.
The indazole, benzisoxazole or benzisothiazole compounds of this invention can
be represented by the following general formula (I):
(Figure Remove)
wherein:
hydrogen or alkyl; (C3-C6)cycloalkyl, trifluoromethyl, -N=CR5R6,
-S02NR7R8, phenyl, phenyl(d-C3)alkyl or (d-C3)alkyl substituted by a
saturated heterocyclic radical, wherein the phenyl is unsubstituted or
substituted by at least one substituent selected from the group consisting of a
hydroxyl, a halogen, a nitro, a cyano, a (d-C3)alkyl, a (Ci-C3)alkoxy and a
trifluoromethyl; RI can also be a salt;
- R2 and R3 are each independently hydrogen or a hydroxyl, halogen, nitro,
cyano, (d-C6)alkyl, (C3-C6)cycloalkyl, (d-C6)alkoxy, trifluoromethyl, -NR7Re,
-CONRyRs, -COR9 or -C02R9 group; R2 can also be a phenyl or a saturated or
unsaturated heterocycle, wherein the phenyl is unsubstituted or substituted by
at least one substituent selected from the group consisting of a hydroxyl, a
halogen, a nitro, a cyano, a (d-C3)alkyl, a (d-C3)alkoxy, a trifluoromethyl and
a saturated heterocyclic radical;
- X is O, S, SO, S02 or NRi;
- R4 is hydrogen or a (d-C6)alkyl, (C3-C6)cycloalkyl, phenyl, phenyl(d-C3)alkyl,
(d-C3)alkyl substituted by a saturated heterocyclic radical, -COR7, -C02R7 or
-S02NR7R8 group, wherein the phenyl is unsubstituted or substituted by at
least one substituent selected from the group consisting of a hydroxyl, a
halogen, a nitro, a cyano, a (d-C3)alkyl, a (d-C3)alkoxy, a trifluoromethyl, a
phenyl(d-C3)alkyl and a phenyl(d-C3)alkoxy;
- Y is direct bond, O, S, SO, S02/ NFU, CO, -(CR10Rn)n- or -Ri0C=CRn-;
- R5, Re, R7 and R8 are each independently hydrogen or a (d-C6)alkyl or
(C3-C6)cycloalkyl group;
- R9 is hydrogen, a (d-C6)alkyl, a phenyl or a saturated or unsaturated
heterocyclic radical, wherein the phenyl is unsubstituted or substituted by at
least one substituent selected from the group consisting of a hydroxyl, a
halogen, a nitro, a cyano, a (d-C3)alkyl, a (CrC3)alkoxy, a trifluoromethyl and
a saturated heterocyclic radical;
- RIQ and RH are each independently hydrogen or a cyano, (C1-C6)alkyl,
-CO-phenyl, -C0(unsaturated heterocyclic radical) or -CONRyRs group,
wherein the phenyl is unsubstituted or substituted by at least one substituent
selected from the group consisting of a hydroxyl, a halogen, a nitro, a cyano,
a (Ci-C3)alkyl, a (Ci-C3)alkoxy and a trifluoromethyl;
- n is l or 2;
- A is a (C3-Ci5)cycloalkyl, a (C3-C15)cycloalkene, a phenyl or a naphthyl,
wherein the cycloalkyl or the cycloalkene is unsubstituted or substituted by at
least one (d-C6)alkyl, and wherein the phenyl or the naphthyl is unsubstituted
or substituted by at least one substituent selected from the group consisting
of a hydroxyl, a halogen, a nitro, a cyano, a (Ci-C3)alkyl, a (Ci-C3)alkoxy and a
trifluoromethyl;
- when X is NR«, Y and R2 together with the indazole ring bearing them can also
form a lH-pyrano[4,3,2-cd]indazole.
The compounds of formula (I) are claimed as such except that:
l/ when X is O, S or NRt, RI is hydrogen or a (Q-CfOalkyl, (C3-C6)cycloalkyl or
trifluoromethyl, and Y is a direct bond, then A is not optionally substituted phenyl
or optionally substituted naphthyl;
2/ when X is NR4 where R4 is H or (C1-C6)alkyl and RiO is 6-OCH3, then Y is not
3/ when X is O, RjO is 6-OH or 6-OCH3/ Y is a direct bond and A is cyclopentyl,
then (R2,R3) or (R3,R2) is different from (H, CI) in position 4,5;
4/ when X is O, R^O is 6-OH , R2 and R3 are H and Y is CH=CH, then A is not
phenyl or 4-methoxyphenyl;
5/ When X is S02, A is phenyl and RiO is 5- or 6-OCH3, then (R2,R3) or (R3/R2) is
different from (H, OCH3) in position 6- or 5-.
In the description and claims, the term "(CrC6)alkyl" is understood as meaning a
linear or branched hydrocarbon chain having l to 6 carbon atoms. A (d-QOalkyl
radical is for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,
pentyl, isopentyl or hexyl radical. Preferred alkyl radicals are those having l, 2 or
3 carbon atoms.
The term "halogen" is understood as meaning a chlorine, bromine, iodine or
fluorine atom.
The term w(C3-Ci5)cycloalkyl" is understood as meaning a saturated, fused or
bridged, mono-, bi- or tricyclic hydrocarbon having 3 to 15 carbon atoms. A
monocyclic radical is for example a cyclopropyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl or cyclododecyl radical. A fused, bridged or spiranic,
dicyclic or tricyclic radical is for example a norbornyl, bornyl, isobornyl,
noradamantyl, adamantyl or spiro[5,5]undecanyl radical. Preferred cycloalkyls are
those having 5 to 12 carbon atoms, the cyclopentyl, cyclohexyl, cycloheptyl and
adamantyl radicals being especially preferred. A (C3-C6)cycloalkyl radical is for
example a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical.
The term "(C3-Ci5)cycloalkene" is understood as meaning an unsaturated
(C3-Ci5)cydoalkyl, the latter term being as defined above.
The term "(CrCeîalkoxy" is understood as meaning a group OR in which R is a
(Ci-C6)alkyl as defined above. A (Ci-C6)alkoxy radical is for example a methoxy,
ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, n-pentyloxy or
isopentyloxy radical. Preferred alkoxy radicals are those having l, 2 or 3 carbon
atoms.
In the definition of RI, a "salt" is understood as meaning an alkali metal salt or
alkaline earth metal salt, such as a sodium, potassium, magnesium or calcium
salt, or a salt with an ammonium or with an organic amine such as triethylamine,
ethanolamine or tris-(2-hydroxyethyl)amine.
The term "heterocycle" or "heterocyclic", is understood as meaning a saturated
or unsaturated 5- to 8-membered monocyclic radical containing one or two
heteroatoms chosen from O, N and S.
Examples of unsaturated heterocyclic radicals include, but are not limited to, the
furyl, imidazolinyl, imidazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl,
pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl, thiazolyl, thienyl benzimidazolyl,
benzoxazolyl, benzothiazolyl, indolyl and indazolyl radicals.
Examples of saturated heterocyclic radicals include, but are not limited to, the
imidazolidinyl, morpholinyl, thiomorpholinyl, piperidyl, piperazinyl, pyrrolidinyl,
pyrazolidinyl, tetrahydrofuryl, 2-oxopiperazinyl, 2-oxopiperidyl and
2-oxopyrrolidinyl radicals, the morpholinyl and piperidyl radicals being preferred.
Needless to say, when X is NF*4 and Y and R2together form with the indazole ring
bearing form a lH-pyrano[4,3,2-cd]-indazole, one of the carbon atom of the
"pyrano moiety" bears substituent A as defined above.
The compounds of formula (I) can form addition salts with acids. Such salts,
especially those which are pharmaceutically acceptable, are encompassed by the
present invention. Examples of salts include those formed, for example with
inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, or with organic carboxylic acids such as acetic acid,
propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, fumărie acid,
tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid.
The present invention also encompasses stereoisomeric forms of the compounds
of formula (I).
Preferred compounds of formula (I) include those that fulfil at least one of the
following conditions:
- R! is hydrogen, a (Ci-C6)alkyl, a phenyl(d-C3)alkyl, a (Q^alkyl substituted
by a saturated heterocyclic radical or a -S02NR7R8 group;
- R2 is hydrogen, hydroxyl, (d-C6)alkyl or halogen;
- R3 is hydrogen;
- Y is direct bond;
- A is a (C3-C15)cycloalkyl optionally substituted by at least one (d-Ce)alkyl;
- RiO is in position 6- of the ring.
Particularly preferred compounds are those wherein:
- RI is hydrogen or a -S02NR7R8 group in which R7 and RS are each
independently hydrogen or a (d-C6)alkyl;
- R2 is hydrogen;
- A is a (C3-Ci2)cycloalkyl optionally substituted by l to 4 (Ci-C6)alkyls.
The following compounds are also preferred:
a) Compounds where X is NR, and
- R! is hydrogen or a (d-Ce)alkyl, phenyl(Ci-C3)alkyl or -S02NR7R8 group;
- R2 and R3 are each hydrogen;
- R4 is hydrogen or a (Ci-C6)alkyl, phenyl, phenyl(Q-C3)alkyl, (d-C3)alkyl
substituted by a saturated heterocyclic radical, -S02NR7R8 or -COR9 group,
where the phenyl is optionally substituted by at least one substituent selected
from the group consisiting of a hydroxyl, a halogen and a phenyl(Ci-C3)alkoxy;
- Y is a direct bond, -(CRioRnV or -R10C=CRU;
- R7 and Rg are each independently hydrogen or a (d-C6)alkyl;
- R9 is hydrogen or a (Ci-C6)alkyl;
- RIO and RH are each indepently hydrogen, cyano or a -CONRyRs group;
- n is l or 2;
- A is a (C3-CiS)cycloalkyl optionally substituted by at least one (Ci-C6)alkyl or a
phenyl optionally substituted by a hydroxyl or a (d-C3)alkoxy;
- Y and R2 together with the indazole ring bearing them can also form a
!H-pyrano[4,3,2-cd]indazole;
provided that when RI is H or (d-C6)alkyl and Y is a direct bond, then A is not
optionally substituted phenyl.
b) Compounds where X is O and
- RI is hydrogen or a (Ci-C6)alkyl, phenyl(Ci-C3)alkyl, (CrC3)alkyl substituted by
a saturated heterocyclic radical or -S02NR7R8 group;
- R2 is hydrogen, halogen, hydroxyl or (d-C6)alkoxy;
- R3 is hydrogen;
- Y is a direct bond, -(CRioRii)n or -CR10 = CRn-;
- R7 and RS are each independently hydrogen or (d-C6)alkyl;
- RIO and Ru are each indepently hydrogen or cyano;
- A is a (C3-d5)cycloalkyl optionally substituted by at least one (d-C6)alkyl or a
phenyl optionally substituted by at least one substituent selected from
(d-C3)alkoxy, hydroxyl, (d-C3)alkyl and halogen;
provided that
bl/ when R! is H or (d-C6)alkyl and Y is a direct bond, then A is not optionally
substituted phenyl;
b2/ when RiO is 6-OH or 6-OCH3, Y is a direct bond and A is cydopentyl, then
(R2,R3) is different from (CI, H) in position 4,5;
b3/ when X is O, RiO is 6-OH , R2 and R3 are H and Y is CH=CH, then A is not
phenyl or 4-methoxyphenyl;
c) Compounds where X is S(0)m and
d - Ri is hydrogen or a phenyl(CrC3)alkyl or -S02NR7R8 group;
- R2 and R3 are each hydrogen, hydroxyl or halogen;
- Y is a direct bond, -(CRioRn)n or -CRio = CRn-;
- R7 and RS are each indepently hydrogen or a (d-C6)alkyl;
- RIO and RII are each indepently hydrogen or cyano;
- A is a (C3-Ci5)cycloalkyl optionally substituted by at least one (d-C6)alkyl;
In view of their capability to act as agonists or antagonist for estrogen receptors
(in other words as SERMs), the compounds of the invention can be used alone or
in combination with other active ingredients for the treatment or the prevention
of any estrogen-dependent disorder or for the management of estrogenregulated
reproductive functions, in humans (Njar VC and Brodie AM, Drugs,
1999, 58: 233-255) as well as in wild or domestic animals.
The breasts being sensitive targets of estrogen-stimulated proliferation and/or
differentiation, SERMs are especially useful in the treatment or prevention of
benign breast diseases in women, gynecomastia in men and in benign or
malignant breast tumors with or without metastasis both in men and women
(A. M. Brodie and V. C. Njar, Steroids, 2000, 65: 171-179 ; K.I. Pritchard, Cancer,
2000, 85, suppl 12: 3065-3072), or in male or female domestic animals.
Due to the involvement of estrogens in the mechanisms of ovulation,
implantation and pregnancy, SERMs according to the invention can be used,
respectively, for contraceptive, contragestive or abortive purposes in women
(A. M. Brodie and V. C. Njar, Drugs, 1999, 58: 233-255) as well as in females of
wild or domestic animal species.
The uterus is another reproductive organ responsive to estrogenic stimulation.
SERMs are therefore useful to treat or prevent endometriosis, benign uterine
diseases or benign or malignant uterine tumors with or without metastasis in
women (A. M. Brodie and V. C. Njar, Drugs, 1999, 58: 233-255) or in female
domestic animals.
The ovary being the physiological source of estrogen, SERMs can be used to
treat abnormal or untimely ovarian estrogen production such as polycystic ovary
syndrome or precocious puberty, respectively (Bulun et al., J Steroid Biochem
Mol Biol, 1997, 61: 133-139). Ovarian as well as non-ovarian but estrogen
producing benign or malignant tumors with or without metastasis (Sasano H and
Harada N, Endocrine Reviews, 1998, 19: 593-607) may also benefit from
treatment with SERMs according to the invention.
In males, prostate and testicular tissues are also responsive to estrogenic
stimulation (Abney TO, Steroids, 1999, 64: 610-617; Carreau S et al., Int J
Androl, 1999, 22: 133-138). Therefore, SERMs can be used to treat or to prevent
benign (Sciarra F and Toscano V, Archiv Androl, 2000, 44: 213-220) or malignant
prostate tumors with or without metastasis (Auclerc G et al., Oncologist, 2000, 5:
36-44) or to treat, prevent or control spermatogenesis functions or malfunctions,
in men as well as in male wild or domestic animals.
Estrogens are also known to be implicated in the regulation of bone turnover;
therefore, SERMs may be useful, alone or in combination with other
antiresorbtive or proosteogenic agents, in the treatment or prevention of bone
disorders according to appropriate therapeutic sequences or regimens.
In addition, estrogens are involved in the regulation of the balance between Thi
and Th2 predominant immune functions and may therefore be useful in the
treatment or prevention of gender-dependent auto-immune diseases such as
lupus, multiple sclerosis, rheumatoid arthritis.
Another aspect of the invention thus consists in a method for the treatment or
prevention of the above-mentioned diseases or disorders, wherein a
therapeutically effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof is administered to a patient or animal in
need of such treatment or prevention. Co-administration with one or more active
substances suitable for the treatment or prevention of said diseases or disorders
is also encompassed by the present invention.
The compounds of the invention can in particular be used in the following
indications:
• treatment of cognitive dysfunction, for instance as neuroprotective,
antidepressant or anxiolytic agents.
• treatment of schizophrenia or neurodegenerative diseases such as
Alzheimer's disease or Parkinson's disease.
• prevention or treatment of estrogen-dependent disorders, for example
hoţ flushes, osteoporosis, perimenopausal mood, perimenstrual syndromes,
vasomotor related syndromes, vaginal atrophy or dryness, sexual dysfunction
such as libido decrease, urinary incontinence, pruritus, local infections of the
genital tract In this case, said compounds can be combined with a sexual
endocrine therapeutic agent.
• control or management of reproductive functions, such as male or female
fertility, pregnancy, abortion, contraception, delivery, or estrogen-related skin
diseases. In this case, said compounds can be combined with a LH-RH agonist or
antagonist, an estroprogestative contraceptive, a progestin, an antiprogestin or a
prostaglandin.
• prevention or treatment of benign or malignant diseases of the breast,
the uterus or the ovary, or of polycystic ovary syndrome. In this case, said
compounds can be combined with an antiestrogen, a progestin or a LH-RH
agonist or antagonist.
• prevention or treatment of benign or malignant diseases of the prostate
or the testis. In this case, said compounds can be combined with an
antiandrogen, a progestin, a lyase inhibitor or a LH-RH agonist. If necessary, the
compounds of the invention can also be combined with a radiotherapeutic agent;
a chemiotherapeutic agent such as a nitrogenated mustard analogue like
cyclophosphamide, melphalan, iphosphamide, or trophosphamide; an
ethylenimine like thiotepa; a nitrosourea like carmustine; a lysed agent like
temozolomide or dacarbazine; an antimetabolite of folie acid like methotrexate or
raltitrexed; a purine analogue like thioguanine, cladribine or fludarabine; a
pyrimidine analogue like fluorouracil, tegafur or gemcitabine; an alkaloid of vinca
or analogue like vinblastine, vincristine or vinorelbine; a podophyllotoxin
derivative like etoposide, taxanes, docetaxel or paclitaxel; an anthracydine or
analogue like doxorubicin, epirubicin, idarubicin or mitoxantrone; a cytotoxic
antibiotic like bleomycin or mitomycin; a platinum compound like cisplatin,
carboplatin or oxaliplatin; a monoclonal antibody like rituximab; an antineoplastic
agent like pentostatin, miltefosine, estramustine, topotecan, irinotecan or
bicalutamide; or with a prostaglandin inhibitor (COX 2/COX l inhibitor).
• prevention or treatment of irritable bowel syndrome, Crohn's disease,
ulcerative proctitis, colitis or arthritis.
• prevention or treatment of cardiovascular diseases, atherosclerosis,
hypertension, restenosis (e.g. for lowering cholesterol, triglycerides, Lp(a), or
LDL levels, or modulating HDL level).
As used herein, the term "combined" or "combination" refers to any protocol for
the co-administration of a compound of formula (I) and one or more other
pharmaceutical substances, irrespective of the nature of the time of
administration and the variation of dose over time of any of the substances. The
co-administration can for example be parallel, sequential or over an extended
period of time.
The compounds of formula (I) or their pharmaceutically acceptable salts may be
administered, for example, orally, topically, parenterally, in dosage unit
formulations containing convenţional non-toxic pharmaceutically acceptable
carriers, adjuvants and/or vehicles. These dosage forms are given as examples,
but other dosage forms may be developed by those skilled in the art of
formulation, for the administration of the compounds of formula (I). The term
parenteral as used herein includes subcutaneous injections, intravenous,
intramuscular or intrasternal injections or infusion techniques. In addition to the
treatment of warm-blooded animals such as mice, rats, horses, cattle sheep,
dogs, cats, etc., the compounds of the invention are effective in the treatment of
humans.
The pharmaceutical compositions containing the active ingredient may be in a
form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or
oily suspensions, dispersible powders or granules, emulsions, hard or soft
capsules, or syrups or elixirs. Compositions intended for oral use may be
prepared according to any method known in the art for the manufacture of
pharmaceutical compositions and such compositions may contain one or more
agents selected from the group consisting of sweetening agents, flavoring
agents, coloring agents and preserving agents in order to provide
pharmaceutically elegant and palatable preparations. Tablets contain the active
ingredient in admixture with non-toxic pharmaceutically acceptable excipients,
which are suitable for the manufacture of tablets. These excipients may be for
example, inert diluents, such as calcium carbonate, sodium carbonate, lactose,
calcium phosphate or sodium phosphate; granulating and disintegrating agents,
for example, corn starch, or alginic acid; binding agents, for example starch,
gelatin or acacia, and lubricating agents, for example, magnesium stearate,
stearic acid or talc. The tablete may be uncoated or they may be coated by
known techniques to delay disintegration and absorption in the gastrointestinal
tract and thereby provide a sustained action over a longer period. For example, a
time delay material such as glyceryl monostearate or glyceryl distearate may be
employed. They may also be coated by the technique described in U.S. Patente
N° 4,256,108, 4,166,452 and 4,265,874 to form osmotic therapeutic tablete for
control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein
the active ingredient is mixed with an inert solid diluent, for example, calcium
carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules wherein the
active ingredient is mixed with water or an oii medium, for example peanut oii,
liquid paraffin, or olive oii.
Aqueous suspensions contain the active ingredient in admixture with excipients
suitable for the manufacture of aqueous suspensions. Such excipients are
suspending agents, for example sodium carboxymethylcellulose, methylcellulose,
hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum
tragacanth and gum acacia; dispersing or wetting agente such as a naturallyoccurring
phosphatide, for example lecithin, or condensation producte of an
alkylene oxide with fatty acids, for example polyoxyethylene stearate, or
condensation products of ethylene oxide with long chain aliphatic alcohols, for
example heptadecaethyleneoxycetanol, or condensation products of ethylene
oxide with parţial esters derived from fatty acids and a hexitol such as
polyoxyethylene sorbitol monooleate, or condensation producte of ethylene oxide
with parţial esters derived from fatty acids and hexitol anhydrides, for example
polyethylene sorbitan monooleate. The aqueous suspensions may also contain
one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate,
one or more coloring agente, one or more flavoring agente, and one or more
sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a
vegetable oii, for example arachis oii, olive oii, sesame oii or coconut oii, or in a
mineral oii such as liquid paraffin. The oily suspensions may contain a thickening
agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those mentioned above, and flavoring agents may be added to provide a
palatable oral preparation. These compositions may be preserved by trie addition
of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous
suspension by the addition of water provide the active ingredient in admixture
with a dispersing or wetting agent, suspending agent and one or more
preservatives. Suitable dispersing or wetting agents and suspending agents are
exemplified by those already mentioned above. Additional excipients, for example
sweetening, flavoring and coloring agents, may also be present. The
pharmaceutical compositions of the invention may also be in the form of an oilin-
water emulsion. The oily phase may be a vegetable oii, for example olive oii or
arachis oii, or a mineral oii, for example liquid paraffin or mixtures of these.
Suitable emulsifying agents include naturally-occuring phosphatides, for example
soy bean, lecithin, and esters or parţial esters derived from fatty acids and
hexitol anhydrides, for example sorbitan monooleate, and condensation products
of the said parţial esters with ethylene oxide, for example polyoxyethylene
sorbitan monooleate. The emulsions may also contain sweetening and flavouring
agents.
The pharmaceutical compositions may be in the form of a sterile injectable
aqueous or oleagenous suspension. This suspension may be formulated
according to the known art using those suitable dispersing or wetting agents and
suspending agents which have been mentioned above. The sterile injectable
preparation may also be a sterile injectable solution or suspension in a non-toxic
parenterally-acceptable diluent or solvent, for example as a solution in
l, 3-butane diol. Acceptable vehicles and solvents that may be employed include
water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile,
fixed oils are conventionally employed as a solvent or suspending medium. For
this purpose any blând fixed oii may be employed including synthetic mono- or
diglycerides. In addition, fatty acids such as oleic acid find use in the preparation
of injectables.
Dosage levels of the order of from about 0.001 mg to about 10 mg/kg of body
weight per day are useful in the treatment or prevention of the above-mentioned
diseases or disorders, or alternatively about 0.1 mg to about 100 mg per patient
per day.
The amount of active ingredient that may be combined with the carrier materials
to produce a single dosage form will vary depending upon the host treated and
the particular mode of administration.
It will be understood, however, that the specific dose level for any particular
patient will depend upon a variety of factors including the age, body weight,
general health, sex, diet, time of administration, route of administration, rate of
excretion, drug combination and the severity of the particular disease undergoing
therapy.
The indazole derivatives of formula (I) can be prepared according to general
schemes Ia, Ib, Ic.
(Figure Remove)
According to scheme Ia fluoroanisole derivative (1) is reacted with a suitable acid
chloride of formula (2) by Friedel-Craft reaction following the procedure
described by K L Kees (J Med Chem, 29, 11, 1986, 2329-2334) to give ketone
(5). This ketone (5) can also be obtained by condensation of alkylmagnesium (4)
on fluorobenzonitrile derivative (3) according to H. Shaffer (J Am Chem Soc,
1939, 61, 2175). The ketone (5) is then refluxed in EtOH in the presence of
substituted hydrazine or in hydrazine hydrate to afford respectively the cyclised
indazoles (6) and (7). The compound (7) can also be prepared by selective
N-alkylation of indazole (6) using the conditions described by U. Lerch and
18
J. Konig (Synthesis, 1983, 2, 157-8) or the conditions described by J Chung and
all (Tetrahedron Letters, 1992, 33, 4717-20).
Demethylation of compounds (6) and (7) (if RI is methyl) with either
tribromoborane using the conditions described by J.F.W. McOmie (Tetrahedron,
1968, 24, 2289-92) or HBr/ AcOH or pyridinium hydrochioride or debenzylation of
compounds (6) and (7) (if RI is benzyl) with Pd/C with or without Pt02 using the
conditions described by W. H. Hartung (Org. React., VII, 1953, 263) give
respectively the hydroxy indazole compounds (8) and (12). Indazole (6) can be
directly N-sulfamoylated to give (10) by treatment with sodium hydride and
sulfamoyl chioride as described by P. Nussbaumer (J. Med. Chem., 2002, 45,
4310-20), or by reaction with sulfamoyl chioride in dimethylacetamide (DMAc) as
described by O. Makoto (Tetrahedron Letters, 2000, 41, 7047-51), then
deprotected to obtain sulfamate compound (11). Deprotected indazole (8) can be
disulfamoylated to give (9). In the same way, indazole (12) can be reacted with
sulfamoyl chioride to give O-sulfamate compound (13) and then deprotected to
give (14).
19
Scheme Ib
R
21
According to scheme Ib, the 3-methyl indazole compound (15) prepared using
the conditions described by F. Dennler (Tetrahedron, 22, 1966, 3131) was
reacted with BOC20, TEA and DMAP (T. Ishizuki, Tetrahedron Lett., 28, 1987,
4185) to afford (16). Compound (16) was brominated by Wohl-Ziegler reaction in
presence of NBS and benzoyl peroxide following B. R. Henke (J. Med. Chem.,
1997, 40, 17, 2706-2725) to give (17). Compound (18) was obtained by reaction
of (17) with KCN using the conditions described by Ainsworth (J. Am. Chem.
Soc., 1957, 79, 5242-5243). (18) was then reacted with aldehyde (19) in NaH/
DMF or KOH/EtOH to give (20) following the procedure described by M. J.
Meyers (X Med. Chem., 44, 24, 2001, 4230) (BOC deprotection was performed
during this reaction). Compound (20) was then reacted with NaBH4 in EtOH to
give (21). Demethylation of compound (21) (if R: is methyl) with either
tribromoborane using the conditions described by J.F.W. McOmie (Tetrahedron,
968, 24, 2289-92) or HBr/AcOH or pyridinium hydrochloride or debenzylation of
compound (21) (if RI is benzyl) with Pd/C with or without Pt02 using the
conditions described by W. H. Hartung (Org. React, VII, 1953, 263) gave nitrile
compound (22). Demethylation with HBr/ AcOH gave amide compound (23).
R4N N
According to scheme Ic, compound (24), prepared using the conditions described
by M. Kitagawa (Chem. Pharm. Bull., 39, 10, 1991, 2681), was reacted with
hydrazine hydrate or alkyl or aryl hydrazine under reflux to give compound (25).
Compound (25) was demethylated in the presence of BBr3 in CH2CI2 using the
conditions described by McOmie J.F.W (Tetrahedron, 1968, 24, 2289-92) to give
compounds (26) and (27).
The benzisoxazole derivatives of formula (I) can be prepared according to
general schemes Ha , Ilb, IIc.
Scheme Ila
According to scheme Ha, the already described ketone (5) or ketone (29)
obtained by Friedel-Craft procedure described by K L Kees (J Med Chem, 29, 11,
1986, 2329-2334) are refluxed in hydroxylamine hydrochioride using the
conditions described by Y. Yamanaka (Pestic. Sci., 1998, 54, 3, 223-229) to
afford respectively uncyclised oxime (28) and (30). Compound (28) is then
cyclised in refluxing NaOH/EtOH solution and compound (30) is cyclised using an
intramolecular Mitsunobu reaction (Synthesis, 1981, 1) to afford the
corresponding benzisoxazole (31).
Demethylation of compound (31) (if RI is methyl) with either tribromoborane
using the conditions described by J.F.W. McOmie (Tetrahedron, 1968, 24, 2289-
92) or HBr/ AcOH or pyridinium hydrochioride or debenzylation of compounds
(31) (if RI is benzyl) with Pd/C using conditions described by A. M. Felix (J. Org.
Chem., 43, 1978, 4194) give the hydroxy benzisoxazole compound (32). This
compound (32) can be transformed into the corresponding sulfamate (33) by
treatment with sodium hydride and sulfamoyl chioride (P. Nussbaumer., J. Med.
Chem., 2002, 45, 4310-20), or by reaction with sulfamoyl chioride in
dimethylacetamide (DMAc) (O. Makoto, Tetrahedron letters, 2000, 41, 7047-51).
Compound (32) can also be transformed into ether compound (34) by reaction
with l-(2-chloroethyl)piperidine using conditions described by M. R. Tremblay
(Bioorg. Med. Chem., 1999, 7, 6, 1013-1024).
Scheme Ilb
According to scheme Ilb the benzisoxazole (35) prepared using the conditions
described by H. Uno (Chem. Pharm. Bull., 24, 1976, 632) was reacted with
aldehyde (19) in NaH/ DMF or KOH/EtOH to give (36). Compound (36) was
reacted with NaBH4 in EtOH to give (37).
Demethylation of compound (37) with either tribromoborane using the conditions
described by J.F.W. McOmie (Tetrahedron, 1968, 24, 2289-92) or HBr/AcOH or
pyridinium hydrochloride gave the hydroxy benzisoxazole compound (38).
(Figure Remove)
According to scheme IIc the benzisoxazole (39) prepared using the conditions
described by M. A. Elkasaby (Indian J. Chem. Sect B, 1980, 19, 571) was
protected with tert-butyldimethylsilylchloride in imidazole/DMF (P. M. Kendall,
J. Org. Chem., 44, 1979,1421) and the compound (40) obtained was brominated
in the presence of NBS and benzoyl peroxide to give (41). Compound (41) was
reacted with LDA and substituted phenylacetonitrile to give (42) using the
procedure described by E. Teodori (Bioorg. Med. Chem., 7, 9, 1999, 1873-1880).
Deprotection of the hydroxyl group in presence of nBu4F using the conditions
described by E. l Corey (J. Am. Chem. Soc., 94, 1972, 6190) gave compound
(43).
The benzisothiazole derivatives of formula (I) can be prepared according to
general scheme III.
(Figure Remove)
According to scheme III, ketone (5) was reacted with phenylmethanethiol to give
(44). The obtained compound (44) was refluxed in sulfuryl chioride followed by
ammoniac treatment to afford cyclised benzisothiazole (45) according to the
procedure described by D. M. Fink (Tetrahedron Letters, 1993, 34, 41, 6525-
6528). Demethylation of compounds (45) with either tribromoborane using the
conditions described by J.F.W McOmie (Tetrahedron, 1968, 24, 2289-92) or
HBr/AcOH or pyridinium hydrochloride gave the hydroxy benzisothiazole
compounds (46). These compounds (46) can be transformed into the
corresponding sulfamates (47) by treatment with sodium hydride and sulfamoyl
chioride (P. Nussbaumer, J. Med. Chem., 2002, 45, 4310-20), or by reaction with
sulfamoyl chioride in dimethylacetamide (DMAc) (O. Makoto. Tetrahedron letters,
2000, 41, 7047-51).
Oxidation of these compounds (46) and (47) by hydrogen peroxide in
trifluoroacetic acid, foilowing the conditions described by S. Grivas and E. Ronne
(Acta Chemica Scandinavia, 1995, 49, 225-229), gave respectively the mono
and/or dioxidised benzisothiazoles (49) and (48). Compound (49) can be
sulfamoylated to give (48).
General schemes I, II and III illustrate the synthesis of compounds (I) in which
the substituent RiO is in position 6- of the heterocyclic ring. It will however be
appreciated that compounds (I) where the substituent RiO is in position 4-, 5- or
7- of the heterocyclic ring can be prepared using the procedures described
above.
The following examples are intended to illustrate and not to limit the scope of the
invention.
PREPARATION OF ACETOPHENONES (5)
EXAMPLE 1: 4-benzyloxy-2-fluorobenzonitrile
To a mixture of 2-fluoro-4-hydroxy-benzonitrile (98 g, 0.68 mol) and K2C03
(94 g, 0.68 mol) in acetonitrile was added benzyl chloride (86.6 g, 0.68 mol). The
mixture was stirred overnight at room temperature and the reaction followed by
TLC (toluene/AcOEt 8/2). The mixture was filtered, concentrated under vacuum
and crystallized from pentane to give 147 g of solid (95 %).
^-NMR (DMSO d6): 5.25 (s,2H), 7.05 (dd,lH), 7.25 (dd,lH), 7.30-7.60 (m,5H),
7.75 (t,lH).
Using the same procedure but replacing 2-fluoro-4-hydroxy-benzonitrile by:
cycloheptyl (2-fluoro-4-hydroxyphenyl) methanone
1-adamantyl (2-fluoro-4-hydroxyphenyl) methanone
the following compounds were respectively obtained:
EXAMPLE 2: cycloheptyl (4-benzyloxy-2-fluorophenyl) methanone
(71 %).
^-RMN (CDCI3): 1.10-2.00 (m, 12H), 3.50 (m, 1H), 5.17 (s, 2H), 6,85 (dt, 1H),
7.20 (dd, 1H), 7.30-7.60 (m, 6H).
EXAMPLE 3: 1-adamantyl (4-benzyloxy-2-fluorophenyl) methanone
(38%)
NMR (DMSO d6): 1.30-2.30 (m, 15H), 5.20 (s, 2H), 6.85 (dt, 1H), 7.12
(dd, 1H), 7.20-7.60 (m, 6H).
EXAMPLE 4: cyclopentyl (4-benzyloxy-2-fluorophenyl) methanone
A suspension of magnesium (19 g, 0.79 mol) and iodine (catalytic amount) in
THF (20 ml) was refluxed under N2. A solution of cyclopentylbromide
(110 g, 0.738 mol) in THF (400 ml) was added slowly. The mixture was refluxed
26
until all the magnesium was consumed, then cooled to 30°C and added to a
solution of 4-benzyloxy-2-fluorobenzonitrile (129 g, 0.56 mol) in THF (600 ml).
The reaction was stirred at 50°C overnight then quenched by aqueous NH4CI and
ice, extracted with ethyl acetate, and washed with brine. The mixture was dried
over Na2S04, filtered and concentrated under vacuum. Purification by flash
chromatography (heptane/EtOAc 9/1) gave 60 g of product (35 %, as solid).
'H-NMR (DMSO d6): 1.40-2.00 (m, 8H), 3.58 (m, 1H), 5.20 (s, 2H), 6.85-7.20
(m, 2H), 7.25-7.55 (m, 5H), 7.80 (t, 1H).
Using the same procedure but replacing cyclopentylbromide by
cyclohexylchloride, the following compound was obtained:
EXAMPLE 5: cyclohexyl (4-benzyloxy-2-fluorophenyl) methanone
(35%). mp 78°C.
NMR (DMSO d6): 1.00 to 2.00 (m, 10H), 3.05 (m, 1H), 5.20 (s, 2H), 6.90-7.10
(m, 2H), 7.20-7.60 (m, 5H), 7.75 (t, 1H).
EXAMPLE 6:1-adamantyl (2-fluoro-4-hydroxyphenyl) methanone
To a mixture of AICI3 (45 g, 0.337 mol) in 1,2-dichloroethane (DCE, 250 ml) at
0°C was added 1-adamantyl carbonyl chloride (36.6 g, 0.228 mol) in DCE
(150 ml). 3-fluorophenol (21 g, 0.183 mol) in DCE (100 ml) was added slowly at
0°C. The reaction was followed by TLC (heptane/toluene 50/50). The mixture
was poured onto HCI 2N, extracted with AcOEt, washed with NaHCO3 and brine,
dried over Na2S04, filtered and concentrated under vacuum. Purification by flash
chromatography (heptane/toluene 8/2) gave 27 g of 1-adamantyl (2-fluoro-4
-hydroxyphenyl) methanone (48% as solid).
'H-NMR (DMSO, d6): 1.30 (m, 15H), 5.97 (s, 1H), 6.70 (d,!H), 6.94 (dd, 1H),
7.64 (d, 1H).
Using the same procedure but replacing 1-adamantyl carbonyl chloride by
cycloheptane carbonyl chloride, the following compound was obtained:
EXAMPLE 7: cycloheptyl (2-fluoro-4-hydroxyphenyl) methanone
(60 %).
'H-RMN (CDCI3): 1.20-2.00 (m, 12H), 3.58 (m, 1H), 6.70-6.90 (m, 2H), 7.90-8.10
(m, 1H), 12.45 (s, 1H).
Using the same procedura but replacing 1-adamantyl carbonyl chloride by
cycloheptane carbonyl chloride and 3-fluorophenol by 3-fluoroanisole, the
following compound was obtained:
EXAMPLE 8: cycloheptyl (4-methoxy-2-fluorophenyl) methanone
(45 %).
'H-NMR (CDCI3): 1.40-2.00 (m, 12H), 1.9 (3, 2H), 3.25 (m, 1H), 3.80 (s, 3H),
6.50 (dd, 1H), 6.65 (dd, 1H), 7.75 (t, 1H).
Using the same procedure but replacing 3-fluorophenol by:
3-fluoroanisole
3,5-dimethoxy-chlorobenzene
the following compounds were respectively obtained:
EXAMPLE 9:1-adamantyl (4-methoxy-2-fluorophenyl) methanone
(15 %).
HH-NMR (CDCI3): 1.50-2.30 (m, 15H), 3.85 (s, 3H), 6.60 (2d, 1H), 6.70 (2d, 1H),
7.70 (t, 1H).
EXAMPLE 10: 1-adamantyl (2-chloro-4,6-dimethoxyphenyl) methanone
(22 %).
'H-NMR (CDCI3, dx): 1.60-2.10 (m, 15H), 3.75 (s, 3H), 3.80 (s, 3H), 6.35 (s, 1H),
6.50 (s, 1H).
Using the same procedure but replacing 3-fluorophenol by 3,4-dimethoxy
-fluorobenzene and 1-adamantyl carbonyl chloride by cyclohexane carbonyl
chloride, the following compound was obtained:
EXAMPLE 11: cyclohexyl (2-fluoro-4-hydroxy-5-methoxyphenyl)
methanone
'H-NMR (DMSO, d6): 1.00-2.00 (m, 10H), 3.05 (m, 1H), 3.80 (s, 3H), 6.65
(d, 1H), 7.23 (d, 1H), 10.50 (s, 1H).
PREPARATION OF INDAZOLES (6), (7), (8) and (12)
EXAMPLE 12: 6-benzyloxy-3-cyclopentyl-lH-indazole
A mixture of cyclopentyl (4-benzyloxy-2-fluorophenyl) methanone (40 g, 0.13
mol) in hydrazine hydrate (50 ml) was refluxed overnight. After cooling to room
temperature, the solid was filtered, dissolved in EtOAc, then washed with
aqueous NH4C1 and brine. The solution was dried over Na2S04, filtered and
concentrated under vacuum. Purification by flash chromatography
(toluene/EtOAc 9/1) gave the expected product (13 g , 45 % as solid).
'H-NMR (DMSO d6): 1.40-2.20 (m, 8H), 3.34 (m, 1H), 5.13 (s, 2H), 6.75
(dd, 1H), 6.90 (d, 1H), 7.20-7.53 (m, 5H), 7.57 (d, 1H), 9.40 (s, 1H).
Using the same procedure but replacing cyclopentyl (4-benzyloxy-2-fluorophenyl)
methanone by:
cydohexyl (4-benzyloxy-2-fluorophenyl) methanone
cycloheptyl (4-benzyloxy-2-fluorophenyl) methanone
1-adamantyl (4-methoxy-2-fluorophenyl) methanone
cycloheptyl (4-methoxy-2-fluorophenyl) methanone
the following compounds were respectively obtained:
EXAMPLE 13: 6-benzyloxy-3-cyclohexyl-lH-indazole
(58 %).
RMN (CDCI3): 1.10-2.10 (m, 10H), 2.95 (m, 1H), 5.15 (s, 2H), 6.75 (dd, 1H),
6.90 (d, 1H), 7.20-7.55 (m, 5H), 7.65 (d, 1H), 12.32 (s, 1H).
EXAMPLE 14: 6-benzyloxy-3-cycloheptyl-lH-indazole
(85 %).
iH-RMN (CDCI3): 1.20-2.10 (m, 12H), 2.55 (m, 1H), 5.07 (s, 2H), 6.45 (dd, 1H),
6.55 (d, 1H), 6.95 (d, 1H), 7,20-7.50 (m, 5H).
EXAMPLE 15 : 3-(l-adamantyl)-6-methoxy-lH-indazole
(30 %).
^-NMR (CDCI3): 1.50-2,70 (m, 15 H), 3.85 (s, 3H), 6.78 (dd, 1H), 6.88 (d, 1H),
7.57 (d, 1H).
EXAMPLE 16: 3-cycloheptyl-6-methoxy-lH-indazole
(45 %).
-NMR (CDCI3): 1.40-2.30 (m, 12H), 3.22 (m, 1H), 3.83 (s, 3H), 6.35 (s, 1H),
6.65-6.90 (m, 2H), 7.58 (d, 1H).
Using the same procedure but replacing hydrazine hydrate by
l-(4-benzyloxyphenyl)hydrazine (prepared following K.J. Duffy, J Med Chem
2001, 44, 22, 3730-3745), the following compound was obtained:
29
EXAMPLE 17: 6-benzyloxy-3-cyclopentyl-l-(4-benzyloxyphenyl)-lHindazole
(66%).
'H-RMN (DMSO d6): 1.15-2.05 (m, 10H), 2.95 (dt, 1H), 3.88 (s, 3H), 5.15
(s, 2H), 6.75 (dd, 1H), 7.12 (d, 1H), 7.25-7.58 (m, 5H), 7.65 (d, 1H).
Using the same procedura but replacing cyclopentyl (4-benzyloxy-2-fluorophenyl)
methanone by cyclohexyl (4-benzyloxy-2-fluorophenyl) methanone and hydrazine
hydrate by methylhydrazine or benzylhydrazine, the following compound were
respectively obtained:
EXAMPLE 18: 6-benzyloxy-3-cyclohexyl-l-methyl-lH-indazole
(66%).
'H-RMN (DMSO d6): 1.15-2.05 (m, 10H), 2.95 (dt, 1H), 3.88 (s, 3H), 5.15
(s, 2H), 6.75 (dd, 1H), 7.12 (d, 1H), 7.25-7.58 (m, 5H), 7.65 (d, 1H).
EXAMPLE 19: l-benzyl-6-benzyloxy-3-cyclohexyl-lH-indazole
(76%).
^-RMN (DMSO ds): 1.15-2.05 (m, 10H), 2.95 (dt, 1H), 5.10 (s, 2H), 5.15
(s, 2H), 6.75 (dd, 1H), 7.12 (d, 1H), 7.15-7.65 (m, 10H), 7.65 (d, 1H).
EXAMPLE 20: Tertio-butyl-6-benzyloxy-3-cyclohexyl-lH-indazole-lcarboxylate
At 0°C di-tert-butyldicarbonate (36.38 g, 0.166 mol) in acetonitrile (340 ml) was
added on a mixture of 6-benzyloxy-3-cyclohexyl-lH-indazole (42.50 g, 0.138
mol), TEA (22 ml, 0.152 mol), acetonitrile (460 ml) and DMAP (3.40 g, 0.027
mol).
The mixture was stirred at room temperature overnight, then concentred under
vacuum, diluted with ethyl acetate and washed with water acidified with HCI 2N
to pH 2. The mixture was dried over Na2S04, filtered and diluted in diisopropyl
ether, the expected product crystallized (44.50 g, yield 79 %).
'H-NMR (DMSO d6) : 1.15-2.05 (m, 19H), 3.00 (m, 1H), 5.19 (s, 2H), 7.03
(dd, 1H), 7.25-7.45 (m, 5H), 7.69 (d, 1H), 7.78 (d, 2H).
EXAMPLE 21: 6-benzyloxy-3-cyclopentyl-l-(2-piperidin-l-yl-ethyl)-lHindazole
6-benzyloxy-3-cyclopentyl-lH-indazole was heated for l hour with NaOH
(1.64g, 41 mmol) and l-(2-chloroethyl)piperidine in EtOH (60 ml) at 40°C. The
30
reaction was followed by TLC (toluene/dioxane: 7/3), and when completed, the
mixture was cooled to room temperatura. The mixture was quenched by NH4CI,
extracted with AcOEt, dried over Na2S04, filtered and concentrated under
vacuum. Purification by flash chromatography (toluene/ 1,4-dioxane 7/3) gave
the expected product (600 mg, 8% as solid).
*H-RMN (DMSO d6): 1.40-2.40 (m, 14H), 2.50-2.80 (m, 2H), 3.10-3.60 (m, 5H),
4.30 (t, 2H), 5.15 (s, 2H), 6.70 (dd, 1H), 7.10 (d, 1H), 7.40 (m, 5H), 7.60
(d, 1H).
Using the same procedure but replacing l-(2-chloroethyl)piperidine by
4-bromobenzylbromide, the following compound was obtained:
EXAMPLE 22: 6-benzyloxy-l-(4-bromobenzyl)- 3-cyclopentyl-lHindazole
'H-RMN (DMSO d6): 1.50-2.20 (m, 8H), 3.38 (m, 1H), 5.15 (s, 2H), 5.50 (s, 2H),
6.78 (dd, 1H), 7.05-7.55 (m, 10H), 7.60 (d, 1H).
EXAMPLE 23: 3-cyclopentyl-lH-indazol-6-ol
A mixture of 6-benzyloxy-3-cyclopentyl-lH-indazole (13 g, 0.102 mol), Pd/C
(5%, 0.65 g) and Pt02 (catalytic amount) in ethanol (130 ml) was stirred at room
temperature under hydrogen. The reaction was followed by TLC (heptane/EtOAc
50/50). When completed, the mixture was filtered on Celite® and concentrated
under vacuum. Crystallization from CH2Cl2/pentane gave 7.2 g of white crystals
(85 %). mp 175°C.
^-NMR (DMSO, d6): 1.40-2.20 (m, 8H), 3.35 (m, 1H), 6.55 (dd, 1H), 6.68
(d, 1H), 7.50 (d, 1H), 9.45 (s, 1H), 12.05 (s,lH).
Using the same procedure but replacing 6-benzyloxy-3-cyclopentyl-lH-indazole
by:
6-benzyloxy-3-cyclohexyl-lH-indazole
6-benzyloxy-3-cyclohexyl-l-methyl-lH-indazole
6-benzyloxy-3-cyclopentyl-l-(4-benzyloxyphenyl)-lH-indazole
6-benzyloxy-3-cyclopentyl-l-(2-piperidin-l-yl-ethyl)-lH-indazole
6-benzyloxy-l-(4-bromobenzyl)-3-cyclopentyl-lH-indazole
l-benzyl-6-benzyloxy-3-cyclopentyl-lH-indazole
Tertio-butyl-6-benzyloxy-3-cyclohexyI-lH-indazole-l-carboxylate
the following compounds were respectively obtained:
EXAMPLE 24: 3-cyclohexyl-lH-indazol-6-ol
(85%). mp 147°C.
'H-RMN (DMSO d6): 1.10-2.10 (m, 10H), 2.90 (m, 1H), 6.55 (dd, 1H), 6.65
(s, 1H), 7.50 (d, 1H), 9.45 (s, 1H), 12.05 (s, 1H).
EXAMPLE 25: 3-cyclohexyl-l-methyl-lH-indazol-6-ol
(75%). mp 205°C.
XH-RMN (DMSO ds): 1.20-2.00 (m, 10H), 2.92 (dt, 1H), 3.80 (s, 3H), 6.60
(dd, 1H), 6.68 (d, 1H), 7.55 (d, 1H), 9.58 (s, 1H).
EXAMPLE 26: 3-cyclopentyl-l-(4-hydroxyphenyl)-lH-indazol-6-ol
(54%). mp 178°C.
'H-RMN (DMSO d6): 1.50-2.20 (m, 8H), 3.40 (t, 1H), 6.68 (dd, 1H), 6.83 (d, 1H),
6.90 (d, 2H), 7.38 (d, 2H), 7.59 (d, 1H), 9.60 (s, 1H), 9.68 (s, 1H).
EXAMPLE 27: 3-cyclopentyl-l-(2-piperidin-l-yl-ethyl)-lH-indazol-6-ol,
hydrochloride
(90%). mp 120°C.
'H-NMR (DMSO d6): 1.15-2.30 (m, 14H), 2.90 (m, 2H), 3.20-3.60 (m, 5H), 4.68
(t, 2H), 6.70 (dd, 1H), 6.88 (d, 1H), 7.52 (d, 1H), 10.80 (s, 1H).
EXAMPLE 28: l-(4-bromobenzyl)-3-cyclopentyl-lH-indazol-6-ol
(90%). mp 147°C.
'H-RMN (DMSO d6): 1.45-2.30 (m, 8H), 3.35 (m, 1H), 5.40 (s, 2H), 6.60 (d, 1H),
7.00-7.40 (m, 4H), 7.50 (d, 1H), 7.70 (s, 1H).
EXAMPLE 29:.l-benzyl-3-cyclohexyl-lH-indazol-6-ol
(40%) mp 154°C
'H-NMR (CDCI3) : 1.10-2.40 (m, 10H), 3.03 (m, 1H), 5.40 (s, 2H), 5.70 (s, 1H),
6.53 (d, 1H), 6.76 (dd, 1H), 7.00-7.35 (m, 5H), 7.60 (d, 1H).
EXAMPLE 30: Jertio-butyl-3-cyclohexyl-6-hydroxy-lH-indazole-lcarboxylate
(87%) mp 124°C
^-NMR (DMSO d6) : 1.20-2.05 (m, 19H), 2.95 (m, 1H), 6.80 (dd, 1H), 7.40
(d, 1H), 7.65 (d, 1H).
EXAMPLE 31: 3-(l-adamantyl)-lH-indazol-6-ol, hydrochloride
A mixture of 3-(l-adamantyl)-6-methoxy-lH-indazole (210 mg, 0.75 mol) in
40 % HBr in acetic acid (10 ml) was heated overnight at 70°C. The mixture was
32
poured onto ice and neutralised with a solution of NaHC03, then extracted with
AcOEt, dried over Na2SO4, filtered and concentrated under vacuum. Purification
by flash chromatography (heptane/EtOAc 50/50) gave 200 mg of product. The
solid was crystallised as HCI salt from Et20. The crystals were filtered, washed
with ether, and dried to give 160 mg of salt (80 %). mp 140°C.
'H-NMR (DMSO d6): 1.00-2.60 (m, 15H), 6.65 (d, 1H), 6.75 (s; 1H), 7.55 (d, 1H).
Using the same procedure but replacing 3-(l-adamantyl)-6-methoxy-lH-indazole
by 3-cycloheptyl-6-methoxy-lH-indazole, the following compound was obtained:
EXAMPLE 32: 3-cycloheptyl-lH-indazol-6-ol, hydrochloride
(60 %). mp 95°C.
^-NMR (DMSO d6): 1.20-2.00 (m, 12H), 3.1 (m, 1H), 6.62 (d, 1H), 6.64 (s, 1H),
7.60 (d, 1H).
PREPARATION OF 1H-INDAZOLE SULFONAMIDES (9), (10), (11), (13)
and (14)
EXAMPLE 33: 6-benzyloxy-3-cycloheptyl-lH-indazole-l-sulfonamide
Sulfamoyl chloride (2.9 g, 25 mmol) was added to a solution of 6-benzyloxy-3-
cydoheptyl-lH-indazole (6) (4 g, 1.75 mmol) in N,N-dimethylacetamide (40 ml)
at 0°C. The mixture was stirred for 3h at 0°C. After extraction with EtOAc, the
organic layer was washed with NH4CI solution and brine. It was dried over
Na2S04, filtered and concentrated under vacuum. Purification by flash
chromatography followed by crystallisation from EtOH gave 1.2 g of yellow
crystals (24 %).
-NMR (DMSO d6): 1.20-2.00 (m, 12H), 2.58 (m, 1H), 5.05 (s, 2H), 6.65-7.00
(m, 1H), 7.20-7.50 (m, 6H), 7.92 (s, 1H), 8.55 (s, 2H).
Using the same procedure but replacing 6-benzyloxy-3-cycloheptyl-lH-indazole
by:
6-benzyloxy-3-cyclohexyl-lH-indazole
3-cyclohexyl-lH-indazol-6-ol
3-cyclohexyl-l-methyl-lH-indazol-6-ol
l-benzyl-3-cydohexyl-lH-indazol-6-ol
Tertio-butyl-6-benzyloxy-3-cydohexyl-lH-indazole-l-carboxylate
the following compounds were respectively obtained:
33
EXAMPLE 34: 6-benzyloxy-3-cycIohexyl-lH-indazole-l-sulfonamide
(100%).
^-NMR (DMSO d6): 1.10 to 2.10 (m, 10 H), 3.05 (m, 1H), 5.15 (s, 2H), 7.00
(dd, 1H), 7.25-7.60 (m, 6H), 7.80 (d, 1H), 8.35 (s, 2H).
EXAMPLE 35: l-(aminosulfonyl)-3-cyclohexyl-lH-indazol-6-ylsulfamate
(40%). mp 213°C.
XH-NMR (DMSO d6): 1.20-2.10 (m, 10H), 3.13 (d, 1H), 7.25 (dd, 1H), 7.80
(d, 1H), 8.00 (d, 1H), 8.10 (s, 2H), 8.50 (s, 2H).
EXAMPLE 36: 3-cyclohexyl-l-methyl-lH-indazole-6-sulfonamide
(84%). mp 188°C.
NMR (DMSO d6): 1.20-2.10 (m, 10H), 3.03 (m, 1H), 3.95 (s, 3H), 6.98
(d, 1H), 7.45 (s, 1H), 7.85 (d, 1H), 8.00 (s, 2H).
EXAMPLE 37: l-benzyl-3-cyclohexyl-lH-indazol-6-yl-sulfamate
(85%) mp 188°C
'H-NMR (DMSO d6) : 1.10-2.10 (m, 10H), 3.04 (m, 1H), 5.55 (s, 2H), 7.05
(d, 1H), 7.10 (m, 5H), 5.53 (s, 1H), 7.88 (d, 1H), 8.00 (s, 2H).
EXAMPLE 38: Tertio-butyl-6-[(aminosulfonyl)oxy]-3-cyclohexyl-lHindazole-
1-carboxylate
(46%) mp 128°C
'H-NMR (DMSO d6) : 1.20-2.10 (m, 19H), 3.10 (m, 1H), 7.23 (dd, 1H), 7.90-8.05
(m, 2H), 8.11 (s, 2H).
Using the same procedure as in Example 21 but replacing 6-benzyloxy-3-
cyclopentyl-lH-indazole by:
6-benzyloxy-3-cycloheptyl-lH-indazol-l-sulfonamide
6-benzyloxy-3-cyclohexyl-lH-indazol-l-sulfonamide
the following compounds were respectively obtained:
EXAMPLE 39: 3-cycloheptyl-6-hydroxy-lH-indazole-l-sulfonamide
mp 155°C.
'H-NMR (DMSO d5): 1.20-2.00 (m, 12H), 2.60 (m, 1H), 6.70 (m, 2H), 6.90
(s, 2H), 7.05 (m, 1H), 7.80 (s, 1H).
34
EXAMPLE 40: 3-cyclohexyl-6-hydroxy-lH-indazole-l-sulfonamide
mp 162°C.
'H-NMR (DMSO d6): 1.10-2.10 (m, 10H), 3.00 (m, 1H), 6,78 (dd, 1H), 7.25
(d, 1H), 7.68 (d, 1H), 8.22 (s, 2H), 10.05 (s, 1H).
EXAMPLE 41: 3-cyclohexyl-lH-indazol-6-yl-sulfamate
A mixture of tertio-butyl-6-[(aminosulfonyl)oxy]-3-cyclohexyl-lH-indazole-
1-carboxylate (4.00g, 10.12 mmol), water (10 ml), dioxan (30 ml) and few drops
of HCI concentred (30%) was stirred overnight and poured into water. The
precipitate was collected by filtration to give the expected product. Crystallisation
from toluene gave white crystals (1.25 g, 48 %)
H-NMR (DMSO d6) : 1.10-2.10 (m, 10H), 3.04 (m, 1H), 6.95 (dd, 1H), 7.35
(d, 1H), 7.83 (d, 1H), 7.96 (s, 2H).
PREPARATION OF 3-BROMOMETHYL-1H-INDAZOLES (16), (17) and
(18)
EXAMPLE 42: l-[(tert-butoxycarbonyl)oxy]-6-methoxy-3-methyl-lHindazole
Di-tert-butyl-dicarbonate in acetonitrile was mixed at 0°C with 6-methoxy-3-
methyl-lH-indazole (prepared following the procedure described by F. Dennler,
Tetrahedron, 22, 1966, 3131-3139) (26.27 g, 0.162 mol), acetonitrile (200 ml),
triethylamine (25 ml, 0.178 mol), DMAP (3.96 g, 0.0324 mol). The mixture was
stirred at room temperature overnight. Acetonitrile was concentrated under
vacuum. The mixture was extracted with ethylacetate and acidified at pH = 2
with a solution of concentrated HCI, dried over Na2S04, filtered and put in
diisopropylether. 23.9 g of the expected product were obtained (as solid, 59 %).
'H-NMR (DMSO d6): 1.60 (s, 9H), 2.44 (s, 3H), 3.85 (s, 3H), 6.95 (dd, 1H), 7.50
(d, 1H), 7.65 (d, 1H).
EXAMPLE 43: l-[(tert-butoxycarbonyl)oxy]-6-methoxy-3-bromomethyl-
lH-indazole
l-[(tert-butoxycarbonyl)oxy]-6-methoxy-3-methyl-lH-indazole (25.2 g, 0.096
mol) was dissolved in CCI4 and mixed with benzoyl peroxide (2.33 g, 9.6 mmol).
N-bromosuccinimide (NBS, 18.8 g, 0.109 mol) was slowly added to this mixture
and heated under reflux overnight. The mixture was cooled at room temperature,
concentrated under vacuum and flashed with
toluene. 10.5 g of the expected product were obtained (32 %, as oii).
'H-NMR (DMSO d6): 1.65 (s, 9H), 3.85 (s, 3H), 4.95 (s, 2H), 7.05 (dd, 1H), 7.55
(s, 1H), 7.80 (d, 1H)
EXAMPLE 44: {l-[(tert-butoxycarbonyl)oxy]-6-methoxy-lH-indazol-3-
yl> acetonitrile
KCN (5.73 g, 88 mmol) in 23 ml of H20 was added dropwise at 0°C to l-[(tertbutoxycarbonyl)
oxy]-6-methoxy-3-bromomethyl-lH-indazole (10.5 g, 30.08
mmol) in 80 ml of ethanol and stirred at room temperature for Ih30. The mixture
was poured into water, and extracted with ethyl acetate. The organic layer was
dried over Na2SO4. Concentration and precipitation in diisopropyl ether gave the
expected product (4.42 g, 50 % as solid).
'H-NMR (DMSO d6): 1.65 (s, 9H), 3.85 (s, 3H), 4.42 (s, 2H), 7.00 (d, 1H), 7.50
(d, 1H), 7.75 (d, 1H).
PREPARATION OF (lH-INDAZOLE-3-YL)ACETONITRILE (20), (21) and
(22)
EXAMPLE 45: 2-(Z/E)-2-(6-methoxy-lH-indazol-3-yl)-3-(4-
methoxyphenyl) prop-2-ene nitrile
A solution of KOH at 40 % in 3.5 ml of water and 7.1 ml ethanol was added
dropwise to p-anisaldehyde (2.06 ml, 16.9 mmol) and {l-[(tertbutoxycarbonyl)
oxy]-6-methoxy-lH-indazol-3-yl}acetonitrile in ethanol. When the
reaction was complete, the mixture was filtered to obtain 3.53 g of the expected
product (77 % as solid).
^-NMR (DMSO d6): 3.35 (s, 1H), 3.85 (s, 3H), 3.90 (s, 3H), 6.70-7.20 (m, 4H),
7.85-8.15 (m, 4H).
Using the same procedure but replacing p-anisaldehyde by cyclohexane
carboxaldehyde, the following compound was obtained:
EXAMPLE 46: 2-(Z/E)-3-cyclohexyl-2(6-methoxy-lH-indazol-3-yl)
prop-2-enenitrile
(55.4%).
NMR (DMSO d6): 1.20-1.80 (m, 10H), 2.60-2.75 (m, 1H), 3.80 (s, 3H), 6.85
(dd, 1H), 6.95 (d, 1H), 7.15 (d, 1H), 7.85 (d, 1H), 13.20 (s, 1H).
EXAMPLE 47: 2-(6-methoxy-lH-indazol-3-yl)-3-(4-methoxyphenyl)
propanenitrile
To 2-(6-methoxy-lH-indazol-3-yl)-3-(4-methoxyphenyl)prop-2-enenitrile
(3.53 g, 11.56 mmol) dissolved in ethanol was added portionwise NaBH4
(0.66 g, 17 mmol). The mixture was stirred at 70°C overnight, then poured into
water, acidified with concentrated HCI, extracted with ethyl acetate. The organic
layer was dried over Na2SO4, filtered and concentrated. The oii was precipitated
in ethanol and diisopropyl ether to give the expected product (3.18 g, as a white
powder 85.3 %).
XH-NMR (DMSO d6): 3.56 (s, 3H), 3.60-3.80 (m, 2H), 3.85 (s, 3H), 4.26 (t, 1H),
6.90-7.30 (m, 6H), 7.97 (d, 1H), 11.13 (s, 1H).
Using the same procedure but replacing 2-(Z/E)-2-(6-methoxy-lH-indazol-3-yl)-
3-(4-methoxyphenyl)prop-2-enenitrile by 2-(Z/E)-3-cyclohexyl-2-(6-methoxy-lHindazol-
3-yl)prop-2-ene nitrile, the following compound was obtained:
EXAMPLE 48: 3-cyclohexyl-2-(6-methoxy-lH-indazol-3-yl)
propanenitrile
(97.5 %).
HH-NMR (DMSO d6): 0.85-2.45 (m, 13H), 3.80 (s, 3H), 4.65 (t, 1H), 6.75
(dd, 1H), 6.90 (d, 1H), 7.65 (d, 1H), 12.85 (s, 1H).
EXAMPLE 49: 3-cyclohexyl-2-(6-hydroxy-lH-indazol-3-yl)
propanenitrile
3-cyclohexyl-2-(6-methoxy-lH-indazol-3-yl) propanenitrile (1.61 g, 5.68 mmol)
was dissolved in CH2CI2 and cooled with an ice bath. BBr3 / CH2CI2 IM
(8.6 ml, 8.52 mmol) was added to this mixture, which was stirred at 50°C, then
poured onto saturated NaHC03 solution, extracted with ethylacetate, dried over
Na2S04, filtered, concentrated under vacuum and purified by flash
chromatography (CH^MeOH 98/2). Crystallisation from EtOH gave 780 mg of
white crystals (51 %). mp 175°C.
'H-NMR (DMSO d6): 0.80-2.05 (m, 13H), 4.65 (t, 1H), 6.70 (dd, 1H), 6.78
(d, 1H), 7.60 (d, 1H), 9.70 (s, 1H), 12.60 (s, 1H).
PREPARATION OF PROPANAMIDES (23)
Using the same procedura as in Example 27 but replacing 3-(l-adamantyl)-6-
methoxy-lH-indazole by:
2-(6-methoxy-lH-indazol-3-yl)-3-(4-methoxyphenyl) propanenitrile
3-cyclohexyl-2-(6-methoxy-lH-indazol-3-yl) propanenitrile
the following compounds were respectively obtained:
EXAMPLE 50: 2-(l-acetyl-6-hydroxy-lH-indazol-3-yl)-3-(4-
methoxyphenyl) propanamide
(7.7 %). mp = 152°C.
'H-NMR (DMSO d6): 2.22 (s, 3H), 3.15 (q, 2H), 3.80 (s, 3H), 4.15 (m, 1H), 6.68
(dd, 1H), 6.80 (d, 1H), 6.85-7.05 (m, 3H), 7.20 (d, 2H), 7.52 (s, 1H), 7.80
(d, 1H), 12.53 (s, 1H).
EXAMPLE 51: 3-cyclohexyl-2-(6-hydroxy-lH-indazol-3-yl) propanamide
(34 %). mp = 199°C.
iR-NMR (DMSO d6):0.70 -2.10 (m, 13H), 3.90 (t, 1H), 6.55 (d, 1H), 6.75 (s, 1H),
6.83 (s, 1H), 7.45 (s, 1H), 7.65 (d, 1H), 9.50 (s, 1H), 12.20 (s, 1H).
PREPARATION OF THE !H-PYRANO[4,3,2-cd]INDAZOLES (25), (26)
and (27)
EXAMPLE 52: 7-methoxy-3-(4-methoxyphenyl)-lH-pyrano[4,3,2-cd]
indazole
Using the same procedure as in Example 12 but replacing cyclopentyl
(4-benzyloxy-2-fluorophenyl) methanone by 5-chloro-7-methoxy-3-
(4-methoxyphenyl)-4H-chromen-4-one (prepared following Kitagawa Chem
Pharm Bull, 39, 1991, 2681), the expected product was obtained (as a solid, 84
%).
'H-NMR (DMSO, d6): 3.60 (s, 3H), 3.80 (s, 3H), 6.60 (d, 2H), 6.80 (d, 2H), 7.10
(d, 1H), 7.30 (d, 1H), 7.80 (s, 1H).
Using the same procedure as in Example 49 but replacing 3-cyclohexyl-2-
(6-methoxy-lH-indazol-3-yl) propanenitrile by 7-methoxy-3-(4-methoxyphenyl)
-lH-pyrano[4,3,2-cd] indazole, the following compounds were obtained:
EXAMPLE 53: 3-(4-methoxy-phenyl)-lH-pyrano[4,3,2-cd]indazol-7-ol,
hydrochloride
(26 %). mp 255°C.
XH-NMR (DMSO d6): 3.55 (s, 3H), 6.63 (m, 4H), 7.05 (d, 2H), 8.05 (s, 1H), 10.00
EXAMPLE 54: 3-(4-hydroxy-phenyl)-lH-pyrano[4,3,2-cd]indazol-7-ol,
hydrochloride
(15 %). mp 111°C.
'H-NMR (DMSO d6): 6.45 (s, 2H), 6.65 (d, 2H), 7.10 (d, 2H), 8.00 (s, 1H), 10.00
(s, 1H).
PREPARATION OF OXIMES (28) and (30)
EXAMPLE 55: l-adamantyl(2-chloro-4,6-dihydroxyphenyl)methanone
Boron tribromide IM in CH2CI2 was added to a solution of l-adamantyl-(2-chloro-
4,6-dimethoxyphenyl) methanone (7 g, 21.0 mmoles) and CH2CI2 (30 ml). The
mixture was warmed overnight and then poured into water, extracted with ethyl
acetate, dried over Na2S04 and concentrated under vacuum to give the expected
product (1.9 g, 30 %).
^-NMR (DMSO d6): 1.00-1.90 (m, 15H), 6.25 (s, 1H), 6.30 (s, 1H), 10.00
EXAMPLE 56: l-adamantyl(2-chloro-4,6-dihydroxyphenyl) methanone
oxime
l-adamantyl-(2-chloro-4,6-dihydroxyphenyl) methanone (1.9 g, 6.2 mmoles),
hydroxylamine hydrochloride (100 g) and pyridine (50 ml) were refluxed for 4 h.
The mixture was concentrated under vacuum, poured into water, extracted with
ethyl acetate, washed with HCI IN, dried over Na2S04 and concentrated under
vacuum to give the crude product. Flash chromatography (AcOEt/toluene 3/7)
gave the pure oxime (l g as a solid, 50%).
'H-NMR (DMSO d6): 1.50-2.00 (m, 15H), 6.24 (s, 1H), 6.28 (s, 1H).
Using the same procedure but replacing l-adamantyl-(2-chloro-4,6-
dihydroxyphenyl) methanone by:
l-adamantyl-(4-benzyloxy-2-fluorophenyl) methanone
cycloheptyl (4-benzyloxy-2-fluorophenyl) methanone
the following compounds were respectively obtained:
EXAMPLE 57: l-adamantyl-(4-benzyloxy-2-fluorophenyl) methanone
'H-NMR (DMSO d6): 1.20-2.20 (m, 15H), 5.10 (s, 2H), 6.80 (dt, 1H), 6.90-7.17
(m, 2H), 7.20-7.60 (m, 5H), 10.55 (s, 1H).
EXAMPLE 58: cycloheptyl (4-benzyloxy-2-fluorophenyl) methanone
oxime
(60%).
'H-NMR (DMSO d6): 1.10-2.00 (m, 12H), 2.10-2.20 (m, 1H), 5.10 (s, 2H),
6.67-6.85 (m, 1H), 6.90-7.15 (m, 2H), 7.25-7.50 (m, 5H), 10.47 (s, 1H).
PREPARATION OF BENZISOXAZOLES (31), (32) and (34)
EXAMPLE 59: 6-benzyloxy-3-cyclohexyl-l,2-benzîsoxazole
A solution of hydroxylamine hydrochloride (11.7 g) in warm water (100 ml) was
poured into a mixture of cyclohexyl (4-benzyloxy-2-fluorophenyl) methanone
(20.22 g, 64.7 mmol) and EtOH (54 ml). A solution of sodium hydroxide
(11.13 g, 0.278 mol) in water (54 ml) was then added as rapidly as the reflux
permitted. The reaction mixture was heated for 12h and then most of the EtOH
was removed by distillation. To the residue was added a solution of potassium
hydroxide (8.7 g, 0.155 mol) in water (54 ml). The mixture was refluxed for 2
days, then cooled to about 6°C and stirred vigorously. A white solid was
obtained, which was thoroughly washed with water and triturated with
diisopropyl ether. The benzisoxazole was obtained as a white powder (12.26 g,
62 %) after filtration. mp 110°C.
MH-NMR (DMSO d6): 1.00-2.10 (m, 10H), 3.05 (m, 1H), 5.20 (s, 2H), 7.00
(dd, 1H), 7.25-7.55 (m, 6H), 7.75 (d, 1H).
Using the same procedure but replacing cyclohexyl (4-benzyloxy-2-
fluorophenyl)methanone by cyclohexyl-(2-fluoro-4-hydroxy-5-methoxyphenyl)
methanone, the following compound was obtained:
EXAMPLE 60: 3-cyclohexyl-6-hydroxy-5-methoxybenzisoxazole
(50.5 %).
'H-NMR (DMSO d6): 1.20-2.10 (m, 10H), 3.05 (m, 1H), 3.85 (s, 3H), 6.95
(s, 1H), 7.23 (s, 1H), 9.94 (s, 1H).
EXAMPLE 61: 3-(l-adamantyl)-4-chloro-l,2-benzisoxazol-6-ol
Diethylazodicarboxylate (0.92 g, 1.7 eq) in THF (20 ml) was added to a mixture
of 1-adamantyl (2-chloro-4,6-dihydroxyphenyl) methanone oxime (l g, 3.1
mmoles), triphenyl phosphine (1.4 g, 1.7 eq) in THF (20 ml) at 0°C. The mixture
was stirred 2 h at 0°C, poured into water, extracted with ethylacetate, dried over
Na2SO4 and concentrated under vacuum to give the crude product. Flash
chromatography (AcOEt/toluene 1/9) and crystallisation from EtOH yielded the
expected product (230 mg, 23 %). mp 215°C.
'H-NMR (CDCI3): 1.50-2.10 (m, 15H), 6.23 (d, 1H), 6.32 (d, 1H).
EXAMPLE 62: 3-(l-adamantyl)-6-benzyloxy-l,2-benzisoxazole
l-adamantyl-(4-benzyloxy-2-fluorophenyl) methanone oxime (2.3 mg, 6 mM) in
DMF (30 ml) was added at 0°C dropwise under N2, to a stirred suspension of
NaH (0.61 g, 18 mM, 60 % oii dispersion) in DMF (10 ml). After the complete
addition, the reaction mixture was ailowed to warm to room temperature and
poured into H2O. The precipitate was collected by filtration to give the expected
product (2.06 g, 95 %). mp 132°C.
'H-NMR (DMSO d6): 1.20-2.45 (m, 15H), 5.22 (s, 2H), 7.00 (d, 1H), 7.30-7.60
(m, 6H), 7.72 (d, 1H).
Using the same procedare but replacing l-adamantyl-(4-benzyloxy-2-
fluorophenyl) methanone oxime by cycloheptyl (4-benzyloxy-2-fluorophenyl)
methanone oxime, the following compound was obtained
EXAMPLE 63: 6-benzyloxy-3-cycloheptyl-l,2-benzisoxazole
(90 %). mp 80°C.
-NMR (DMSO d6): 1.30-2.20 (m, 12H), 3.25 (m, 1H), 5.21 (s, 2H), 7.00
(dd, 1H), 7.25-7.60 (m, 6H), 7.75 (d, 1H).
Using the same procedure as in Example 23 but replacing 6-benzyloxy-3-
cyclopentyl-lH-indazole by:
3-(l-adamantyl)-6-benzyloxy-l,2-benzisoxazole
6-benzyloxy-3-cycloheptyl-l,2-benzisoxazole
6-benzyloxy-3-cyclohexyl-l,2-benzisoxazole
the following compounds were respectively obtained:
EXAMPLE 64: 3-(l-adamantyl)-l,2-benzisoxazol-6-ol
(47.5 %). mp 215°C.
'H-NMR (DMSO d6): 1.40-2.20 (m, 13H), 2.35 (s, 2H), 6.80 (dd, 1H), 6.92
(d, 1H), 7.58 (d, 1H), 10.28 (s, 1H).
EXAMPLE 65: 3-cycloheptyl-l,2-benzisoxazol-6-ol
(48 %). mp 156°C.
^-NMR (DMSO d6): 1.20-2.20 (m, 12H), 3.18 (m, 1H), 6.80 (d, 1H), 6.90
(s, 1H), 7.65 (d, 1H), 10.25 (s, 1H).
EXAMPLE 66: 3-cyclohexyl-l,2-benzisoxazol-6-ol
(37%). mp 181°C.
-NMR (DMSO d6): 1.10-2.10 (m, 10H), 3.02 (dt, 1H), 6.80 (dd, 1H), 6.90
(s, 1H), 7.68 (d, 1H), 10.25 (s7 1H).
EXAMPLE 67: 3-cyclohexyl-l,2-benzisoxazol-5,6-diol
Using the same procedare as in Example 49 but replacing 3-cyclohexyl-2-
(6-methoxy-lH-indazol-3-yl) propanenitrile by 3-cyclohexyl-6-hydroxy-5-
methoxybenzisoxazole, the expected product was obtained (48.4 %). mp 177°C.
NMR (DMSO d6): 1.20-2.05 (m, 10H), 3.05 (dt, 1H), 6.92 (s, 1H), 7.05
(s, 1H), 9.55 (br s , 2H).
EXAMPLE 68: 3-cyclohexyl-6-(2-piperidin-l-yl-ethoxy)-l,2-
benzisoxazole
A mixture of 3-cyclohexyl-l,2-benzisoxazol-6-ol (2.69 g, 12 mmol), 1-
(2-chloroethyl)-piperidine hydrochioride (2.39 g, 13 mmol) and K2C03 (3.59 g, 26
mmol) in CH3CN (30 ml) was heated at reflux for 3h and stirred at room
temperature overnight. The reaction mixture was poured into H20 and extracted
with EtOAc. The organic extract was washed with brine, dried (Na2S04) and
concentrated to give a residue (3.78 g). This residue was purified by flash
chromatography (toluene/l,4-dioxane 8/2). Crystallisation from EtOH gave white
crystals (0.53 g, 13.4 %). mp 69°C.
^-NMR (DMSO de): 1.20-2.10 (m, 16H), 2.30-2.50 (m, 4H), 2.70 (t, 2H),
2.95-3.05 (dt, 1H), 4.15 (t, 2H), 6.95 (dd, 1H), 7.25 (d, 1H), 7.75 (d, 1H).
42
EXAMPLE 69: Trihydroxybenzoin
Resorcinol (100 g, 0.91 mol) and 4-hydroxyphenylacetic acid (138.4 g, 0.91 mol)
were dissolved into BF3Et20 (346 ml, 2.73 mol) under N2. The mixture was stirred
and heated at 50-60°C. After complete reaction, the mixture was cooled to room
temperature and poured into a large volume of iced water. The crude product
was filtered off and dried to yield trihydroxybenzoin (70 %). mp 211°C.
'H-NMR (Acetone d6): 4.12 (s, 2H), 6.78 (d, 2H), 6.91 (d, IH), 7.13 (d, 2H),
7.54-7.6 (m, 2H), 8.21 (s, 1H), 8.35 (s, IH), 8.70 (s, IH).
EXAMPLE 70: l-[2-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2-
[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]ethanone
To a cooled (0-5°C) suspension of trihydroxybenzoin (100 g, 0.41 mol) and, as a
catalyst, TsOH (0.062 g) in toluene (350 ml), a solution of dihydropyran (DHP)
(150 ml, 1.64 mol) was slowly added. The reaction mixture became homogenous
and was stirred at room temperature for In. Triethylamine was added and the
solvent was evaporated under reduced pressure. The brown oii crystallized upon
trituration with hoţ isopropanol (1.2 I) and a white solid was collected (182 g, 90
(CDCI3): 1.40-2.05 (m, 12H), 3.40-3.60 (m, 2H), 3.65-3.90 (m, 2H), 4.05
(s, 2H), 5.30 (t, IH), 5.40 (t, IH), 6.46 (dd, IH), 6.54 (d, IH), 6.94 (d, 2H), 7.10
(d, 2H), 7.68 (d, IH), 12.52 (s, IH).
EXAMPLE 71: l-[2-hydroxy-4-tetrahydro-2H-pyran-2-yloxy)phenyl]-2-
[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]ethanoneoxime
A mixture of l-[2-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)]-2-[4-(tetrahydro-2Hpyran-
2-yloxy) phenyl]ethanone (5 g, 12 mmol) and H2NOH, HCI (8.59 g, 12.3
mmol) was stirred for 24h in pyridine (65 ml) at room temperature. The reaction
mixture was poured into a large volume of 99/1 H20/triethylamine and was then
extracted with EtOAc. The organic solution was washed with brine. After drying
over Na2S04, EtOAc was evaporated. The residue was purified by flash column
chromatography (toluene/l,4-dioxane 90/1 + TEA l %) to provide a colorless oii
(5.05 g, 97 %).
:H-NMR (DMSO d6): 1.30-2.00 (m, 12H), 3.40-3.60 (m, 2H), 3.60-3.80 (m, 2H),
4.12 (s, 2H), 5.38 (t, IH), 5.45 (t, IH), 6.48 (d, IH), 6.50 (s, IH), 6.93 (d, 2H),
7.05-7.30 (m, 3H), 7.40 (d, IH), 11.63 (s, IH), 11.85 (s, IH).
EXAMPLE 72: 6-(tetrahydro-2H-pyran-2-yloxy)-3-[4-(tetrahydro-2Hpyran-
2-yloxy) benzyl]-l,2-benzisoxazole
Using the same procedura as in Example 61 but replacing l-adamantyl-(2-chloro-
4,6-dihydroxyphenyl) methanone oxime by l-[2-hydroxy-4-(tetrahydro-2H-pyran-
2-yloxy)phenyl]-2-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]ethanone oxime, the
expected product was obtained (25 %).
MH-NMR (DMSO d6): 1.40-2.10 (m, 12H), 3.40 -3.85 (m, 4H), 4.25 (s, 2H), 5.39
(s, 1H), 5.61 (s, 1H), 6.90-7.10 (m, 3H), 7.20-7.35 (m, 3H), 7.55 (d, 1H)
EXAMPLE 73: 3-(4-hydroxybenzyl)-l,2-benzisoxazol-6~ol
6-(tetrahydro-2H-pyran-2-yloxy)-3-[4-(tetrahydro-2H-pyran-2-yloxy)benzyl]-l,
2-benzisoxazole (3.85 mmol) and paratoluenesulfonic acid (APTS, catalytic
amount) were dissolved in methanol (20 ml). After reaction at 60-70°C for 3h,
the reaction mixture was cooled to room temperature and poured into satured
NaHC03 and extracted with EtOAc. After washing (H20) and drying (MgS04), the
extract was concentrated. The crude product was purified by flash
chromatography (toluene/l,4-dioxane 8/2) and crystallised to give an off-white
crystal (0.58 g, 31%). mp 178°C.
NMR (DMSO d6): 4.11 (s, 2H), 6.69 (d, 2H), 6.75 (dd, 1H), 6.90 (d, 1H), 7.13
(d, 2H), 7.48 (d, 1H), 9.80 (s, 2H).
PREPARATION OF BENZISOXAZOLE SULFAMATE (33)
Using the same procedure as in Example 33 but replacing 6-benzyloxy-3-
cycloheptyl-lH-indazole by:
3-(l-adamantyl)-l,2-benzisoxazol-6-ol
3-cycloheptyl-l,2-benzisoxazol-6-ol
3-cyclohexyl-l,2-benzisoxazol-6-ol
the following compounds were respectively obtained:
EXAMPLE 74: 3-(l-adamantyl)-l,2-benzisoxazol-6-yl sulfamate
(82 %). mp 87°C.
NMR (DMSO d5): 1.50-2.45 (m, 15H), 7.28 (dd, 1H), 7.63 (d, 1H), 7.96
(d, 1H), 8.15 (s, 2H).
EXAMPLE 75: 3-cycloheptyl-l,2-benzisoxazol-6-yl sulfamate
(54 %). mp 82°C.
NMR (DMSO de): 1.40-2.10 (m, 12H), 3.32 (m, 1H), 7.30 (d, 1H), 7.60
(d, 1H), 8.05 (d, 1H), 8.15 (s, 2H).
EXAMPLE 76: 3-cyclohexyl-l,2-benzisoxazol-6-yl sulfamate
(46 %). mp 145°C.
'H-NMR (DMSO d6): 1.20-2.20 (m, 10H), 3.15 (dt, 1H), 7.25 (dd, 1H), 7.62
(d, 1H), 8.05 (d, 1H), 8.15 (s, 2H).
PREPARATION OF BENZISOXAZOLES (36) (37) and (38)
EXAMPLE 77: 2-(Z/E)-(6-methoxy-l,2-benzisoxazol-3-yl)-3-(4-
methoxyphenyl)prop-2-enenitrile
A solution of 40 % KOH/H2O (3 ml) and EtOH (4,8 ml) was added slowly to a
heterogenous mixture of (6-methoxy-l,2-benzisoxazol-3-yl)acetonitrile
(2.4 g, 12.7 mmoles), prepared following H. Uno (Chem. Pharm. BulL, 24 (4),
632-643, 1976), 4-methoxybenzaldehyde (1.1 eq, 14 mmoles, 1.8 g) and EtOH
(24 ml) at room temperatura. The mixture was stirred at room temperature for
Ih and the precipitate was filtered under vacuum, washed with water and EtOH,
to give pure 2-(Z/E)-(6-methoxy-l,2-benzisoxazol-2-yl)-3-(4-methoxy-phenyl)-
prop-2-enenitrile (3.15 g, 81 %).
XH-NMR (acetone d6) = 3.94 (s, 3H), 3.97 (s, 3H), 7.08 (dd, IH), 7.15 (d, 2H),
8.05-8.30 (m, 4H).
Using the same procedure but replacing 4-methoxybenzaldehyde by
4-hydroxybenzaldehyde the following compound was obtained:
EXAMPLE 78: 2-(Z/E)-3-(4-hydroxyphenyl)-2-(6-methoxy-l,2-
benzisoxazol-3-yl)prop-2-enenitrile
(86 %). mp > 380°C.
NMR (DMSO d6): 3.85 (s, 3H), 6.15 (d, 2H), 7.00 (d, IH), 7.25 (s, IH), 7.70
(s, 3H), 8.00 (d, IH).
EXAMPLE 79: 2-(6-methoxy-l,2-benzisoxazol-3-yl)-3-(4-
methoxyphenyl) propanenitrile
NaBH4 (1.05 eq, 0.2 g, 5.15 mmoles) was added to an heterogenous solution of
2-(Z/E)-(6-methoxy-l,2-benzisoxazol-3-yl)-3-(4-methoxy-phenyl)prop-2-enenitrile
(1.5 g, 4.9 mmoles) and EtOH (20 ml). The mixture was heated at 50°C for l h,
and acidified at pH l with HCI IN, extracted with AcOEt, dried over Na2S04 and
concentrated under vacuum to give pure 2-(6-methoxy-l,2-benzisoxazol-3-yl)-3-
(4-methoxyphenyl) propanenitrile (1.5 g, 100 %).
'H-NMR (CDCI3) = 3.35 (d, 2H), 3.80 (s, 3H), 3.90 (s, 3H), 4.45 (t, 1H), 6.84
(d, 2H), 6.93 (dd, 1H), 7.02 (d, 1H), 7.04 (d, 2H), 7.50 (d, 1H).
EXAMPLE 80: 2-(6-hydroxy-l,2-benzisoxazol-3-yl)-3-(4-
hydroxyphenyl) propanenitrile
To a solution of 2-(6-methoxy-l,2-benzisoxazol-3-yl)-3-
(4-methoxyphenyl)propanenitrile (1.5 g, 4.9 mmoles) in CH2CI2 (100 ml) under
N2, was added BBr3 IM in CH2CI2 (4 eq, 20 ml). The mixture was refluxed for 2h,
poured into water and extracted with EtOAc, dried over Na2S04, filtered and
concentrated under vacuum to give the crude product. Purification by flash
chromatography (CH^Iz/MeOH 98/2) and crystallisation from EtOH yielded the
expected crystals (850 mg, 62 %). mp 214°C.
'H-NMR (DMSO d6): 3.25 (m, 2H), 5.10 (t, 1H), 6.65 (d, 2H), 6.90 (d, 1H), 7.00
(d, 2H), 7.06 (s, 1H), 7.70 (d, 1H), 9.35 (s, 1H), 10.50 (s, 1H).
Using the same procedure as in Example 77 but replacing
4-methoxybenzaldehyde by:
3-fluoro-4-methoxybenzaldehyde
4-methoxy-2-methyl-benzaldehyde
3-methoxy-benzaldehyde
4-fluorobenzaldehyde
cyclohexanal
3,4-dimethoxybenzaldehyde
and then using the same procedures as described in Examples 79 and 80, the
following compounds were respectively obtained:
EXAMPLE 81: 2-(6-hydroxy-l,2-benzisoxazol-3-yl)-3-(3-fluoro-4-
hydroxyphenyl)- propanenitrile
(56 %). mp 201°C.
NMR (DMSO d6) : 3.25 (m, 2H), 5.15 (t, 1H), 6.70-7.20 (m, 5H), 7.72 (d, 1H),
9.82 (s, 1H), 10.55 (s, 1H).
46
EXAMPLE 82: 2-(6-methoxy-l,2-benzisoxazol-3-yl)-3-(4-hydroxy-2-
methylphenyl)- propanenitrile
(15 %). mp 131°C.
NMR (acetone d6): 2.11 (s, 3H), 3.28 (d, 2H), 3.80 (s, 3H), 4.72 (t, 1H),
6.40-6.60 (m, 2H), 6.85 (dd, 1H), 7.00 (d, 1H), 7.10 (d, 1H), 8.09 (s, 1H).
EXAMPLE 83: 2-(6-hydroxy-l,2-benzisoxazol-3-yl)-3-(3-
hydroxyphenyl) propanenitrile
(20%).
'H-NMR (acetone d6): 3.25-3.60 (m, 2H), 4.90 (t, 1H), 6.60-7.25 (m, 6H), 7.70
(d, 1H), 8.80 (br s,lH).
EXAMPLE 84: 2-(6-hydroxy-l,2-benzisoxazol-3-yl)-3-(4-fluorophenyl)
propanenitrile
(35%). mp 152°C.
XH-NMR (DMSO d6): 2.40-2.70 (m, 2H), 3.95 (t, 1H), 4.25 (s, 1H); 5.90-6.50
(m, 6H), 6.70 (d, 1H).
EXAMPLE 85: 2-(6-hydroxy-2-benzisoxazol-3-yl)-3-cyclohexylpropanenitrile
(63 %). mp 111°C.
'H-NMR (acetone d6): 0.80-2.10 (m, 13H), 4.56 (dd, 1H), 6.90 (dd, 2H), 7.02
(d, 1H), 7.67 (d, 1H), 9.38 (s, 1H).
EXAMPLE 86: 2-(6-hydroxy-l/2-benzisoxazol-3-yl)-3-(3,
4-dihydroxyphenyl) propanenitrile
(56 %). mp 154°C.
HH-NMR (DMSO d6): 3.00-3.35 (m, 2H), 5.06 (t, 1H), 6.50 (dd, 1H), 6.55-6.75
(m, 2H), 6.90 (dd, 1H), 7.00 (dd, 1H), 7.70 (d, 1H), 8.90 (br s, 1H).
PREPARATION OF BENZISOXAZOLES (40) (41) (42) and (43)
EXAMPLE 87: 3-methyl-6-[(tert-butyl(dimethyl)silyl)oxy]-l,
2-benzisoxazole
3-methyl-l,2-benzisoxazol-6-ol (10 g, 67 mmoles) (prepared following M.A.
Elkasaby, Indian J. Chem., 1987, 26, 620) and DMF (50 ml) were added to a
mixture of tert-butyldimethylsilyl chloride (1.05 eq, 10.6 g), imidazole (2.5 eq,
11.4 g) and DMF (100 ml) under N2. The mixture was then stirred at room
47
temperature for Ih, poured into water and extracted with ethyl acetate, dried
over Na2S04/ filtered and concentrated under vacuum to give a crude product.
Flash chromatography (AcOEt/Toluene 18/85 with 0.1 % TEA) gave
6-[(tert-butyl(dimethyl)silyl) oxy]-3-methyl-l,2-benzisoxazole (17.1 g, 97 %).
NMR (CDCI3 di): 0.20 (s, 6H), 1.00 (s, 9H), 2.60 (s, 3H), 6.80 (dd, IH), 6.95
(d, 1H), 7.45 (d, IH).
EXAMPLE 88: 3-(bromomethyl)-6-[(tert-butyl(dimethyl)silyl)oxy]-l,
2-benzisoxazole
NBS (12.7 g, 71.5 mmoles) and benzyl peroxide (1.6 g, 6.5 mmoles) were added
to a mixture of 3-methyl-6-[(tert-butyl(dimethyl)silyl)oxy]-l,2-benzisoxazole
(17.1 g, 65 mmoles) and CCI4 (200 ml). The mixture was refluxed overnight and
the precipitate was filtered, washed with CCI4 and purified by flash
chromatography (AcOEt/Toluene 1/9 with 0.1 % TEA) to give
3-(bromomethyl)-6-[(tert-butyl(dimethyl)silyl)oxy]-l,2-benzisoxazole (15.1 g,
68 %).
^-NMR (CDCI3 di): 0.25 (s, 6H), 1.00 (s, 9H), 4.57 (s, 2H), 6.88 (dd, IH), 7.02
(d, 1H), 7.55 (d, IH).
EXAMPLE 89: 3-(6-[(tert-butyl)silyl)oxy]-l,2-benzisoxazol-3-yl)-2-
(4-methoxyphenyl) propanenitrile
A solution of n-BuLi 2.0M in THF (9.7 mmoles) was slowly added to a solution of
diisopropylamine (1.3 ml, 1.05 eq) and dry THF (10 ml) at -20°C under N2. The
mixture was stirred for 30 min at -20°C, then 4-methoxybenzonitrile (1.3 g, 8.8
mmoles) and dry THF (10 ml) were slowly added at -78°C. The mixture was
stirred for 30 min at -78°C, then 3-(bromomethyl)-6-[(tertbutyl(
dimethyl)silyl)oxy]-l,2-benzisoxazole (3 g, 8.8 mmoles) and dry THF
(10 ml) were slowly added. The mixture was then stirred for 30 min at room
temperature, poured into water, extracted with AcOEt, dried over Na2S04, and
purified by flash chromatography (AcOEt/Heptane 2/8 with 0.1 % TEA) to give
3-(6-[(tert-butyl)dimethylsilyl)oxy]-l,2-benzisoxazol-3-yl)-2-(4-methoxyphenyl)
propanenitrile (l g, 28 %).
NMR (CDCI3 di): 0.20 (s, 6H), 1.00 (s, 9H), 3.25-3.65 (m, 2H), 3.70-4.48
(t, IH), 6.80-7.60 (m, 7H).
EXAMPLE 90: 3-(6-hydroxy-l,2-benzisoxazol-3-yl)-2-
(4-methoxyphenyl)propanenitrile
A solution of nBu4F IN in THF was added to a mixture of 3-(6-[(tertbutyl)
silyl)oxy]-l,2-benzisoxazol-3-yl)-2-(4-methoxyphenyl)propanenitrile
(1.0 g, 2.45 mmoles) in dry THF (20 ml) at room temperature. The mixture was
then stirred at room temperature for 2h and then poured into water and
extracted with ethyl acetate, dried over Na2SCX,, filtered, and concentrated under
vacuum. The crude product was purified by flash chromatography
(AcOEt/Toluene 2/8) and crystallisation from MeOH/cyclohexane yielded the
expected product (210 mg, 30 %).
XH-NMR (DMSO d6) = 3.00-3.50 (m, 2H), 5.05 (t, 1H), 6.60 (d, 2H), 6.90
(dd, 1H), 7.00 (d,2H), 7.05 (s, 1H), 7.70 (d, 1H), 9.40 (s, 1H), 10.50 (s, 1H).
PREPARATION OF BENZISOTHIAZOLES (45) and (46)
EXAMPLE 91: cyclohexyl (4-benzyloxy-2-benzylthiophenyl) methanone
A solution of phenylmethanethiol (2.35 ml, 20 mmoles) in THF (10 ml) was
slowly added to a mixture of potassium tert-butoxide (2.24 g, 20 mmoles) in THF
(80 ml) under N2 at room temperature. The mixture was stirred for 15 min at
room temperature and cyclohexyl (4-benzyloxy-2-fluorophenyl) methanone
(6.5 g, 20 mmoles) in THF (10 ml) was slowly added. The mixture was heated
for 2h at 50°C and poured into an aqueous solution of NH4CI, extracted with
ethyl acetate, dried over Na2SO4 and concentrated under vacuum. The crude
product was purified by flash chromatography (Heptane/AcOEt 90/10 with 0.1 %
TEA) to give cyclohexyl (4-benzyloxy-2-benzylthiophenyl) methanone (8.3 g,
100 %).
^-RMN (DMSO d6): 1.00-1.85 (m, 10H), 3.10-3.30 (m, 1H), 4.15 (s, 2H), 5.19
(s, 1H), 6.85 (dd, 1H), 7.05 (d, 1H), 7.15-7.60 (m, 10H), 7.90 (d, 1H).
EXAMPLE 92: 6-benzyloxy-3-cyclohexyl-l,2-benzisothiazole
Sulfuryl chloride (1.77 ml, 2.2 mmoles) was slowly added to a solution of
cyclohexyl (4-benzyloxy-2-benzylthiophenyl) methanone (8.77 g, 21 mmoles) in
CH2CI2 (80 ml) at 0°C. The mixture was stirred for 2h at room temperature and
then concentrated under vacuum. THF (80 ml) was added to the mixture and
then EtOH (80 ml) saturated with ammoniac was slowly added at 0°C. The
mixture was stirred overnight at room temperatura, poured into water, extracted
with ethyl acetate, dried over Na2S04, filtered and concentrated under vacuum to
give a crude product. Flash chromatography (heptane/AcOEt 98/2) gave
6-benzyloxy-3-cyclohexyl-l,2-benzisothiazole (3.55 g, 52 %).
'H-NMR (DMSO d6): 1.10 to 2.00 (m, 10H), 3.25 (dt, 1H), 5.20 (s, 2H), 7.12
(dd, 1H), 7.25 to 7.55 (m, 5H), 7.75 (d, 1H), 8.02 (d, 1H).
EXAMPLE 93: 3-cyclohexyl-l,2-benzisothiazol-6-ol
A solution of boron tribromide IM in CH2CI2 (11.9 ml, 11.9 mmoles) was slowly
added to a solution of 6-benzyloxy-3-cyclohexyl-l,2-benzisothiazole (3.5 g, 10
mmoles) in CH2CI2 (50 ml) at 0°C. The mixture was stirred at room temperature
for 15 min and poured into water. The precipitate was filtered, dried and
crystallised from EtOH to give pure 3-cyclohexyl-l,2-benzisothiazol-6-ol (940 mg,
40.3 %). mp 190°C.
MR (DMSO d6): 1.10 to 2.10 (m, 10H), 3.20 (dt, 1H), 6.95 (dd, 1H), 7.40
(d, 1H), 7.93 (d, 1H), 10.18 (s, 1H).
Using the same procedures as in Examples 91 to 93 but replacing cyclohexyl
(4-benzyloxy-2-fluorophenyl) methanone by cyclopentyl (4-benzyloxy-2-
fluorophenyl) methanone, the following compound was obtained:
EXAMPLE 94: 3-cyclopentyl-l,2-benzisothiazol-6-ol
mp 130°C.
'H-NMR (DMSO d6): 1.50 to 2.20 (m, 8H), 3.62 (m, 1H), 6.95 (dd, 1H), 7.35
(d, 1H), 7.92 (d, 1H), 10.18 (s, 1H).
PREPARATION OF BENZISOTHIAZOLE SULF A M AŢE S (47) and (48)
EXAMPLE 95: 3-cyclohexyl-l,2-benzisothiazol-6-yl sulfamate
Sulfamoyl chloride (780 mg, 6.76 mmol) was added by portions to a mixture of
3-cyclohexyl-l,2-benzisothiazol-6-ol (790 mg, 3.38 mmoles) and
dimethylacetamide (15 ml) at 0°C. The mixture was stirred for 30 min at 0°C and
then at room temperature overnight, poured into water and extracted with ethyl
acetate, dried over Na2S04and concentrated under vacuum.
The crude product was purified by flash chromatography (Toluene/l,4-dioxan
9/1) and crystallised from EtOH/pentane to give the expected product (620 mg,
59 %). mp 150°C.
'H-INMR (DMSO d6): 1-20 to 2.05 (m, 10H), 3.30 (m, 1H), 7.40 (dd, 1H), 8.10
(d, 1H), 8.15 (s, 2H), 8.25 (d, 1H).
Using the same procedure but replacing 3-cyclohexyl-l,2-benzisothiazol-6-ol by
3-cyclopentyl-l,2-benzisothiazol-6-ol, the following compound was obtained:
EXAMPLE 96: 3-cyclopentyl-l,2-benzisothiazol-6-yl sulfamate
mp 132°C.
NMR (DMSO d6): 1.55 to 2.25 (m, 8H), 3.65-3.85 (m, 1H), 7.4 (dd, 1H), 8.10
(s, 1H), 8.15 (s, 2H), 8.23 (d, 1H).
EXAMPLE 97: 3-cyclohexyl-l,l-dioxido-l,2-benzisothiazol-6-yl
sulfamate
Hydrogen peroxide (0.6 ml) was slowly added to a mixture of sulfamic acid,
3-cyclohexyl-l,2-benzisothiazol-6-yl-ester (l g, 3.2 mmoles), trifluoroacetic acid
(2 ml) and dichioromethane (20 ml) at room temperature. The mixture was then
stirred for 2h and then poured into water. The precipitate was filtered and
purified by flash chromatography (Toluene/l,4-dioxan 85/15) to give after
crystallisation a solid (70 mg, 6 %). mp 170°C.
'H-NMR (DMSO d6): 1.10 to 2.20 (m, 10H), 7.25 (dd, 1H), 8.07 (d, 1H), 8.25
(s, 1H), 8.43 (s, 1H).
PHARMACOLOGICAL TEST RESULTS
SUBTYPE ESTROGEN RECEPTOR BINDING IN VITRO
The method was derived from those described for rât uterus (Botella J. et al,
J Endocrinei Invest, 1990, 13: 905-910) and human Ishikawa cell (Botella J.,
J Steroid Biochem Molec Biol, 1995, 55: 77-84) estrogen receptors. Relative
binding affinities (RBA) were determined by competitive radiometric binding
assays, using purified full-length recombinant human ERoc and ER(3 (PanVera,
Madison, WI). Receptors were incubated in Tris buffer (lOmM Tris, 2 mM DTT,
l mg/BSA, 10 % Glycerol, pH 7.5 with HCI) at 4 °C for 18-20 hours with 2 nM of
[3H]-E2 with or without increasing concentrations of test compound from l nM to
10 uM. Non-specific binding was measured in the presence of a 500-fold excess
of unlabeled E2. Separation of bound and free 3H-E2 fractions was achieved with
dextran (0.25 %) coated charcoal (2.5 %) in Tris-EDTA buffer. After shaking for
a few seconds and centrifugation at 1500 g and 4°C for 10 minutes, 150 ul/well
51
of Optiphase 'Super Mix' scintillation liquid was mixed with 50 |jl of supernatant
of each sample and the radioactivity was measured in a MicroBeta counter
(Wallac, Turku, Finland). Data were evaluated by a sigmoidal dose-response
curve (Prism, GraphPad Software Inc.) to estimate the concentration of
competitor at half-maximal specific binding (IC5o). RBA of each competitor was
calculated as the ratio of IC50s of E2 and competitor, and the RBA value for E2
was arbitrarily set at 100 %. The selectivity for ERa and ERfJ was obtained from
the ratio R of the IC50 for ERoc to the IC50 for ER(3 for each test compound.
(Table Remove)
ESTROGENIC AND ANTI-ESTROGENIC ACTIVITIES IN VITRO
The estrogenic and anti-estrogenic potentials of new compounds were evaluated
using the induction of alkaline phosphatase (APase) activity, an estrogen specific
response in human endometrial adenocarcinoma Ishikawa cells (Botella X,
J Steroid Biochem Molec Biol, 1995, 55: 77-84; Littlefield et al., Endocrinology,
1990, 127: 2757-2762).
Ishikawa cells were routinely grown as monolayers in Dulbecco's Modified Eagle's
medium (DMEM) containing 4 mM Glutamax I and supplemented with 10 % of
decomplemented fetal calf serum (dFCS) and antibiotics. They were maintained
in a humidified atmosphere of 5 % C02 and 95 % air, at 37 ± 0.1° C. Stocks
were performed once a week to maintain continuous exponenţial growth.
For studies, Ishikawa cells were plated into 96-well microplates. The next day,
the medium was changed to a phenol red-free DMEM containing 5 % dFCS
stripped of endogenous estrogens by dextran coated charcoal treatment.
Twenty-four hours later, the medium was renewed and the relevant controls and
test compounds, diluted appropriately in estrogen-free DMEM, were added either
alone (estrogenic effect) or with IO'8 M E2 (anti-estrogenic effect) to the plated
cells and incubated for four days. For each compound, the tested concentrations
ranged from IO"12 M to IO"5 M, and the final vehicle concentration did not exceed
0.1 %.
At the end of the incubation period, APase activity was assayed by a method
involving the hydrolysis of p-nitrophenyl phosphate to p-nitrophenol at pH 9.8
and spectrophotometric deterrnination of the product at 405 nm.
In brief, the microplates were first rinsed twice with cold phosphate buffered
solution and then placed at -80° C for at least 15 minutes. After thawing at room
temperature for 5-10 minutes, the plates were put on ice and 50 pi ice-cold
solution containing 5 mM p-nitrophenyl phosphate was added to each well. The
plates were warmed to room temperature to allow for the development of the
enzymatic reaction (to). After a 15 to 60 minute incubation period, the intensity
of the yellow color generated by the production of p-nitrophenol was measured
into each well at 405 nm using a microplate reader (Wallac, model 1420 Victor2).
For each tested concentration, APase activity, reflected by absorbance, was first
expressed as fold increase over control (FI) and then as percentage of E2 activity
(IO"8 M) chosen equal to 100 %. Sigmoidal dose-response curves were plotted
and EC50 (estrogenic effect) and IC50 (anti-estrogenic effect) values were
calculated for each compound.
(Table Remove)
PROLIFERATIVE ACTIVITY IN VITRO
The proliferative effect of the compounds of the invention was evaluated on
human breast cancer cell line MCF-7 by measuring the number of viable cells
after 6 days of treatment.
MCF-7 cells were routinely cultured as monolayers in Dulbecco's modified Eagle's
medium (DMEM) containing 4 mM Glutamax and 4.5 g/l glucose and
supplemented with 5 % (v/v) decomplemented fetal calf serum (dFCS) and
antibiotics.
Cells were plated at 2. IO6 cells/75 cm2 flasks and incubated at 37° C in a
humidified atmosphere containing 5 % C02. They were passaged once weekly to
maintain continuous exponenţial growth. Forty eight hours before the start of an
experiment, near-confluent cells were changed to a phenol red free DMEM
containing 5 % steroid-stripped dFCS by dextran coated charcoal treatment
(DCC-DMEM). On the day of the experiment, cells were harvested by brief
exposure to trypsin and plated in DCC-DMEM in 96-well microplates at a density
of 4.103 cells/well. The next day, the medium was renewed and test compounds,
diluted appropriately in estrogen-free DMEM, were added and incubated for six
days. For each compound, the tested concentrations ranged from IO"12 M to IO"5
M and the final vehicle concentration did not exceed 0.1 % (v/v). At the end of
the incubation period, cell proliferation was evaluated by quantitation of the
cellular ATP content which signals the presence of metabolically active cells.
ATP assay
The assay, based on the ATP-dependent luciferase reaction, enables generation
of a luminescent signal proporţional to the amount of ATP present. As there is a
linear relationship between the amount of ATP and the number of viable cells
present in culture, the luminescent signal allowed to precisely evaluate cell
proliferation (Crouch, S.P.M. et al. J. Immunol. Meth., 1993, 160, 81; Kangas,
L. et al. Med. Biol. 1984, 62, 338; Petty, R.D. et al. J. Biolum. Chemilum. 1995,
10, 29).
In brief, the microplates were inverted to discard the culture medium and 100 ui
of fresh medium was added into each well. The microplates were equilibrated at
room temperature for approximately 30 minutes. 100 ui of luciferase reagent was
added into each well and contents were mixed for 2 minutes to induce cell lysis.
The plates were incubated at room temperature for 10 minutes to stabilize
luminescence signal.
Luminescence was recorded using a microplate reader (Wallac, model 1420
Victor2) and results were expressed as percentage of the control luminescence.
Sigmoidal dose-response curves were plotted and EC50 values were calculated for
each compound in order to evaluate their proliferative potency.
(Table Remove)
ESTROGENIC ACTIVITY IN VIVO
Prepubescent female rats were orally treated at 3 mg/rat/day for 3 days. On the
day following the last treatment, uteri were removed and wet weights were
recorded.
The results are expressed as % of stimulation of uterus weight in comparison
with vehicles.
The compounds of examples 23, 31, 35, 66, 73, 84, 86 and 93 exhibited a
marked selectivity for the human recombinant estrogen receptor (3 and a weak
estrogenic effect in alkaline phosphatase activity in the Ishikawa cell model.
These compounds were accordingly selected to check their in vitro estrogenicity.
The aim of this study was to test these compounds in comparison with tamoxifen
(TAM), with an ER|3 selective standard agonist: DPN or 2,3-bis-(4
-hydroxyphenyl)propionitrile (Meyers M J, J Med Chem 2001, 44; 24, 4230-4251)
and with an ERa selective standard agonist: PPT or l,3,5-tris-(4-hydroxyphenyl)
-4-propyl-lH-pyrazole (Stauffer S R, J Med Chem 2000, 43; 4934-4947), when
17p-estradiol (E2) at 3 mg/rat/day p.o. is taken as the standard reference.
(Table Remove)
The compound of example 23 has been selected as a potenţial good candidate
for treating estrogenic dependent diseases because of the lack of uterotrophicity
up to a 3 mg/animal/day dosage, after oral administration.
EFFECT OF COMPOUNDS ON HOŢ FLUSH MODEL IN VIVO
According to Berendsen et al. (Eur. J. Pharmacol., 2003, 482; 329-33), tail skin
temperature of ovariectomized rats may serve as a useful tool for selection of
compounds that are of potenţial use in the treatment of hoţ flushes in
postmenopausal women. The aim of this study was to evaluate the effect of the
compound of Example 23 over 4 days on tail skin temperature in ovariectomized
rats. 17(3-estradiol, the standard reference, was administered by oral route at
l mg/rat/day over 13 consecutive days (Watanabe N. et al, 2003). Twenty IOPS
Wistar female rats from Charles River France, weighing 176 to 200 g on arrival,
were used for the study. Rats were accommodated in groups of four in stainless
steel mesh cages. After implantation of telemetrie transmitters (TA10TA-F40,
Data Sciences International) until the end of the study, they were housed in
groups of two in macrolon cages and maintained on a 14-10 hours light/dark
cycle. Standard environmental conditions for this species were regularly
controlled. Animals were allowed free access to a specific estrogen-free diet of
Harlan Teklad 2016 pellets from HARLAN. They were allowed free access to
filtered and softened ţap water. Water was dispensed ad libitum via automatic
deliveries in metallic cages and in plastic bottles in macrolon cages. Rats were
then ovariectomized and left undisturbed for at least 2 weeks. After this
hormonal rest period, tail skin temperature was monitored during the same
period and animals were randomized into 3 groups based on mean temperature.
The first group was "ovariectomy control group", the second group was "estradiol
group" to confirm the estrogen activity on tail temperature and the third group
was "Ex 23 group" to test the activity of this product on temperature. Body
weights were then recorded on the first day of treatment and at the end of
study.
The Results are expressed as % of stimulation of uterus weight in comparison
with vehicles. 17|5-estradiol (E2) at 3 mg/rat/day is taken as the standard
reference.
(Table Remove)
The compound of example 23 decreased tail skin temperature of ovariectomized
rât, without deleterious side-effects on uteri, unlike estradiol activity on body
weight or uteri (as seen below).
EFFECT OF COMPOUNDS ON BONE AND CARDIOVASCULAR
PARAMETERS IN VIVO
The ovariectomized rât is a mandatory model for preclinical evaluation of new
compounds used for the prevention of bone loss (osteoporosis). Female Wistar -
derived OFA străin rats from IFFA CREDO (France) were ovariectomized or sham
operated as intact control. Upon arrival, they were housed in metal hanging
cages in groups of 3 or 4 per cage and hâd ad libitum access to food and water
for one week. After a one week acclimation period, daily dosing was carried out
with the compound of interest or 17p-estradiol.
During the study, plasma samples were taken to allow lipid parameter assay:
triglycerides, free cholesterol, total cholesterol, HDL, LDL, VLDL, apoliporotein A
and B100; bone metabolism parameters such as: DPD, Ca2+, collagen type I and
II C-telopeptide fragments; and urinary bone markers such as Ca2+, and
inorganic phosphate. AII assays were carried out following the manufacturer's
recommendations.
To allow bone mineral density measurement of individual lumbar segments,
lumbar high resolution or whole body dual energy X-ray absorptiometry
procedures were carried out during the study on isoflurane anesthetized animals.
ANTIDEPRESSANT ACTIVITY OF COMPOUNDS
Antidepressant effect of estradiol was recently reported in studies using
ER (3 KO mice model. In addition, ER (5 localization in dorsal raphe nuc/eusarea
in rât has been described. The gold standard test for antidepressant potency of
compound consist in the forced swimming test, in this experiment
antidepressants could be distinguished from psychostimulants which decreased
immobility at doses which increased general activity. In order to investigate the
putative antidepressant potency of the compounds reported here, the forced
swimming test was performed according to the following design. The animals
were housed six per cage under standard colony conditions, with a 12 h
light/dark cycle and ad libitum food and water. They were allowed to acclimatize
to the colony for at least 7 days prior to any experimentation. For subcutaneous
administration, the compound of Example 23 was dissolved in olive oii and
diluted to the desired concentration on the day of administration. For positive
control, intraperitoneal (i.p.) injection of desipramine was done. Desipramine was
dissolved in double-distilled water (10 mg/kg). The experiments were conducted
30 min after the positive control drug treatment (only for desipramine
treatment). Other compounds, ie: estradiol and the compound of Example 23
were daily injected subcutaneously in rats, during a 7 days period. Acquisition
were performed on day 8 (24 h after the last administration of items) and day 9
(48h after estradiol or compound 23 administration), respectively. Data aquired
24 hours after the last administration consisted in the "naive animal group",
these animals hâd never been previousiy tested in the device. Data aquired 48
hours after a last administration of compounds consisted in "trained animal
(Table Remove)
On the 8th, the forced swim test was performed. This study was carried out in
rats according to the methods described by Porsolt (Eur. J. Pharm., 1978).
Briefly, rats were placed individually in glass cylinders (height: 40 cm, diameter:
18 cm) containing 25 cm of water at 25 °C. Ten minutes later, rats were
removed and dried before being returned to their home cages. The animals were
replaced in the cylinders 24 h later, and the procedure was repeated, and a
10-min observation period was recorded.
The model was validated by desipramine activity found in the test. Results shown
the confirmation of the antidepressor potency of estradiol, 24h and 48h after
administration. the compound of Example 23 exhibited a antidepressor activity
when animals were first-in-the-test 24h after administration, while in trained
animal group 48h after administration, the antidepressor potency of the
compound of Example 23 disappeared.


. A compound of formula (I)
or an aC1d addition salt or a stereoisomeric form thereof,
(Figure Remove)
wherein:
- R1 is hydrogen or a (C1-C6)alkyl, (C3-C6)cycloalkyl, trifluoromethyl, -N=CR5R6,
-S02NR7R8, phenyl, phenyl(C1C3)alkyl or (C1-C3)alkyl substituted by a
saturated heterocyclic radical, wherein the phenyl is unsubstituted or
substituted by at least one substituent selected from the group consisting of a
hydroxyl, a halogen, a nitro, a cyano, a (C1-C3)alkyl, a (C1-C3)alkoxy and a
trifluoromethyl; R1 can also be a salt;
- R2 and R3 are each independently hydrogen or a hydroxyl, halogen, nitro,
cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, trifluoromethyl, -NR7Rg,
-CONR7R8, -COR9 or -C02R9 group; R2 can also be a phenyl or a saturated or
unsaturated heterocycle, wherein the phenyl is unsubstituted or substituted by
at least one substituent selected from the group consisting of a hydroxyl, a
halogen, a nitro, a cyano, a (C1-C3)alkyl, a (C1-C3)alkoxy, a trifluoromethyl and
a saturated heterocyclic radical;
- X is O, S, SO, S02 or NR4;
- R4 is hydrogen or a (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, phenyl(C1C3)alkyl,
(C1-C3)alkyl substituted by a saturated heterocyclic radical, -COR7/ -C02R7 or
-S02NR7Rs group, wherein the phenyl is unsubstituted or substituted by at
least one substituent selected from the group consisting of a hydroxyl, a
halogen, a nitro, a cyano, a (C1-C3)alkyl, a (C1-C3)alkoxy, a trifluoromethyl, a
phenyl(C1-C3)alkyl and a phenyl(C1-C3)alkoxy;
- Y is direct bond, O, S, SO, S02, NR-,, CO, - or -Ri0C=CRn-;
- R5, R6 R7 and RS are each independently hydrogen or a (C1-C6)alkyl or
(C3-C6)cycloalkyl group;
- R9 is hydrogen, a (C1-C6)alkyl, a phenyl or a saturated or unsaturated
heterocyclic radical, wherein the phenyl is unsubstituted or substituted by at
least one substituent selected from the group consisting of a hydroxyl, a
halogen, a nitro, a cyano, a (C1-C3)alkyl; a (C1-C3)alkoxy, a trifluoromethyl and
a saturated heterocyclic radical;
- R10 and RH are each independently hydrogen or a cyano, (C1-C6)alkyl,
-CO-phenyl, -CO(unsaturated heterocyclic radical) or -CONR7R8 group,
wherein the phenyl is unsubstituted or substituted by at least one substituent
selected from the group consisting of a hydroxyl, a halogen, a nitro, a cyano,
a (C1-C3)alkyl, a (C1-C3)alkoxy and a trifluoromethyl;
- n is l or 2;
- A is a (Crds)cycloalkyl, a (C3-C5)cycloalkene, a phenyl or a naphthyl,
wherein the cycloalkyl or the cycloalkene is unsubstituted or substituted by at
least one (C1-C6)alkyl, and wherein the phenyl or the naphthyl is unsubstituted
or substituted by at least one substituent selected from the group consisting
of a hydroxyl, a halogen, a nitro, a cyano, a (C1-C3)alkyl, a (C1-C3)alkoxy and a
trifluoromethyl;
- when X is NR4, Y and R2 together with the indazole ring bearing them can also
form a lH-pyrano[4,3,2-cd]indazole;
provided that:
l/ when X is O, S or NR4, RI is hydrogen or a (C1-C6)alkyl, (C3-C6)cycloalkyl or
trifluoromethyl, and Y is a direct bond, then A is not optionally substituted phenyl
or optionally substituted naphthyl;
2/ when X is NR, where R4, is H or (C1C6)alkyl and RiO is 6-OCH3, then Y is not
CO;
3/ when X is O, R1O is 6-OH or 6-OCH3, Y is a direct bond and A is cyclopentyl,
then (R2,R3) or (R3,R2) is different from (H, C1) in position 4,5;
4/ when X is O, RiO is 6-OH , R2 and R3 are H and Y is CH=CH, then A is not
phenyl or 4-methoxyphenyl;
5/ When X is S02, A is phenyl and R10 is 5- or 6-OCH3, then (R2,R3) or (R3,R2) is
different from (H, OCH3) in position 6- or 5-.
2. A compound according to claim l, wherein RI is hydrogen, a alkyl,
a phenyl(C1-C3)alkyl, a (C1C3)alkyl substituted by a saturated heterocyclic radical
or a -S02NR7R8 group.
3. A compound according to claim l or 2, wherein R2 is hydrogen, hydroxyl,
(CrC6)alkyl or halogen.
4. A compound according to one of claims l to 3, wherein R3 is hydrogen.
5. A compound according to one of claims l to 4, wherein Y is a direct bond.
6. A compound according to one of claims l to 5, wherein A is a
(C3-C15)cycloalkyl optionally substituted by at least one (d-C6)alkyl.
7. A compound according to one of claims l to 6, wherein RiO is in position
6- of the ring.
8. A compound according to one of claims l to 7 or a pharmaceutically
acceptable salt thereof for use as an active therapeutic substance.
9. A compound according to one of claims l to 7 or a pharmaceutically
acceptable salt thereof for use as an active substance modulating estrogen
receptors.
10. A pharmaceutical composition comprising (i) a compound according to
one of claims l to 7 or a pharmaceutically acceptable salt thereof and (ii) a
pharmaceutically acceptable exC1pient.
11. Use of a compound of formula (I) or a pharmaceutically acceptable salt
thereof in the manufacture of a medicament for the treatment of cognitive
dysfunction:

(Figure Remove)wherein:
- Ri is hydrogen or a (CrC6)alkyl; (C3-C6)cycloalkyl, trifluoromethyl, -N=CR5R6,
-S02NR7R8, phenyl, phenyl(CrC3)alkyl or (CrC3)alkyl substituted by a
saturated heterocyclic radical, wherein the phenyl is unsubstituted or
substituted by at least one substituent selected from the group consisting of a
hydroxyl, a halogen, a nitro, a cyano, a (C1-C3)alkyl, a (C1-C3)alkoxy and a
trifluoromethyl; RI can also be a salt;
- R2 and R3 are each independently hydrogen or a hydroxyl, halogen, nitro,
cyano, (d-C6)alkyl, (C3-C6)cycloalkyl, (C1-QOalkoxy, trifluoromethyl, -NR7R8,
-CONRyRs, -COR9 or -C02R9 group; R2 can also be a phenyl or a saturated or
unsaturated heterocycle, wherein the phenyl is unsubstituted or substituted by
at least one substituent selected from the group consisting of a hydroxyl, a
halogen, a nitro, a cyano, a (C1-C3)alkyl, a alkoxy, a trifluoromethyl and
a saturated heterocyclic radical;
- X is O, S, SO, S02 or NR;
- R is hydrogen or a (C1-C5)alkyl, (C3-C6)cycloalkyl, phenyl, phenyl(d-C3)alkyl,
(C1-C3)alkyl substituted by a saturated heterocyclic radical, -COR7, -C02R7 or
-S02NR7Ra group, wherein the phenyl is unsubstituted or substituted by at
least one substituent selected from the group consisting of a hydroxyl, a
halogen, a nitro, a cyano, a (C1-C3)alkyl, a (C1-C3)alkoxy, a trifluoromethyl, a
phenyl(CrC3)alkyl and a phenyl(C1-C3)alkoxy;
- Y is direct bond, O, S, SO, S02, NR, CO, -(CR10Rn)n- or -R10C=CRn-;
- R5, Re, R7 and RQ are each independently hydrogen or a (C1-C6)alkyl or
(C3-C6)cycloalkyl group;
- R9 is hydrogen, a (CrC6)alkyl, a phenyl or a saturated or unsaturated
heterocyclic radical, wherein the phenyl is unsubstituted or substituted by at
least one substitutent selected from the group consisting of a hydroxyl, a
halogen, a nitro, a cyano, a (CrC3)alkyl, a (C1-C3)alkoxy; a trifluoromethyl and a saturated heterocyclic radical;
- R10 and Ru are each independently hydrogen or a cyano, (d-C6)alkyl,
-CO-phenyl, -C0(unsaturated heterocyclic radical) or -CONR7Rs group,
wherein the phenyl is unsubstituted or substituted by at least one substituent
selected from the group consisting of a hydroxyl, a halogen, a nitro, a cyano,
a (C1-C3)alkyl, a (C1-C3)alkoxy and a trifluoromethyl;
- n is l or 2;
- A is a (C1-C6)alkyl, a (C3-C15)cycloalkyl, a (C3-C15)cycloalkene, a phenyl or a
naphthyl, wherein the cycloalkyl or the cycloalkene is unsubstituted or
substituted by at least one (C1-C6)alkyl, and wherein the phenyl or the
naphthyl is unsubstituted or substituted by at least one substituent selected
from the group consisting of a hydroxyl, a halogen, a nitro, a cyano, a
(C1-C3)alkyl, a (C1-C3)alkoxy and a trifluoromethyl;
- when X is NR, Y and R2 together with the indazole ring bearing them can also
form a lH-pyrano[4,3,2-cd]indazole;
provided that when X is O, S or NR4, RI is hydrogen or a (d-C6)alkyl, (C3-C6)cycloalkyl or trifluoromethyl, and Y is a direct bond, then A is not optionally substituted phenyl or optionally substituted naphthyl.
12. Use of a compound of formula (I) as defined in claim 11, or a
pharmaceutically acceptable salt thereof, in the manufacture of a medicament forthe treatment of schizophrenia or neurodegenerative diseases.
13. Use of a compound of formula (I) as defined in claim 11, or a
pharmaceutically acceptable salt thereof, in the manufacture of a medicament for
the prevention or treatment of estrogen-dependent disorders, wherein said
compound can be used in combination with a sexual endocrine therapeutic
agent.
14. Use of a compound of formula (I) as defined in claim 11, or a
pharmaceutically acceptable salt thereof in the manufacture of a medicament for
the control or management of reproductive functions, wherein said compound
can be used in combination with a LH-RH agonist or antagonist, an estroprogestative contraceptive, a progestin, an antiprogestin or a prostaglandin.
15. Use of a compound of formula (I) as defined in claim 11, or a
pharmaceutically acceptable salt thereof, in the manufacture of a medicament for
the prevention or treatment of benign or malignant diseases of the breast, the
uterus or the ovary, or of polycystic ovary syndrome, wherein said compound can
be used in combination with an antiestrogen, a progestin or a LH-RH agonist or
antagonist.
16. Use of a compound of formula (I) as defined in claim 11, or a
pharmaceutically acceptable salt thereof, in the manufacture of a medicament for
the prevention or treatment of benign or malignant diseases of the prostate or
the testis, wherein said compound can be used in combination with an
antiandrogen, a progestin, a lyase inhibitor or a LH-RH agonist or antagonist.
17. Use of a compound of formula (I) as defined in claim 11, or a
pharmaceutically acceptable salt thereof, in the manufacture of a medicament for
the prevention or treatment of irritable bowel syndrome, Crbhn's disease,
ulcerative proctitis, colitis or arthritis.
18. Use of a compound of formula (I) as defined in claim 11, or a
pharmaceutically acceptable salt thereof, in the manufacture of a medicament for
the prevention or treatment of cardiovascular diseases, atherosclerosis,
hypertension or restenosis.
19. A method of preventing or treating a disease where modulation of
estrogen receptors is required, which comprises administering to a subject in
need thereof a therapeutically effective amount of a compound of formula (I) as
defined in claim 11, or a pharmaceutically acceptable salt thereof.
20. Use or method according to one of claims 11 to 19, wherein the
compound of formula (I) fulfils at least one of the following conditions:
R! is hydrogen, a (C1-C6)alkyl, a phenyl(C1C3)alkyl, a a!kyl substituted
by a saturated heterocyclic radical or a -S02NR7R8 group;
R2 is hydrogen, hydroxyl, (C!-C6)alkyl or halogen;
R3 is hydrogen;
Y is direct bond;
A is a (C3-C15)cycloalkyl optionally substituted by at least one (C1-C6)alkyl;
RiO is in position 6- of the ring.

Documents:

2412-delnp-2007-Abstract-(19-03-2013).pdf

2412-delnp-2007-abstract.pdf

2412-delnp-2007-Claims-(19-03-2013).pdf

2412-delnp-2007-claims.pdf

2412-delnp-2007-Correspondence Others-(06-12-2012).pdf

2412-delnp-2007-Correspondence Others-(10-09-2008).pdf

2412-delnp-2007-Correspondence-Others-(19-03-2013).pdf

2412-delnp-2007-Correspondence-Others-(22-10-2012).pdf

2412-delnp-2007-correspondence-others.pdf

2412-delnp-2007-description (complete).pdf

2412-delnp-2007-form-1.pdf

2412-delnp-2007-Form-18-(10-09-2008).pdf

2412-delnp-2007-Form-2-(19-03-2013).pdf

2412-delnp-2007-form-2.pdf

2412-delnp-2007-Form-3-(06-12-2012).pdf

2412-delnp-2007-form-3.pdf

2412-delnp-2007-form-5.pdf

2412-delnp-2007-GPA-(19-03-2013).pdf

2412-delnp-2007-pct-210.pdf

2412-delnp-2007-pct-220.pdf

2412-delnp-2007-pct-237.pdf

2412-delnp-2007-pct-301.pdf

2412-delnp-2007-pct-304.pdf

2412-delnp-2007-pct-306.pdf

2412-delnp-2007-pct-308.pdf

2412-delnp-2007-pct-311.pdf

2412-delnp-2007-Petition-137-(19-03-2013).pdf

abstract.jpg


Patent Number 258993
Indian Patent Application Number 2412/DELNP/2007
PG Journal Number 08/2014
Publication Date 21-Feb-2014
Grant Date 19-Feb-2014
Date of Filing 30-Mar-2007
Name of Patentee LABORATOIRE THERAMEX
Applicant Address 6 AVENUE ALBERT II, 98000 MONACO, (M C)
Inventors:
# Inventor's Name Inventor's Address
1 BENOIT RONDOT PARC DE MONTFORT, LOT 8 CHEMIN DU CAMINON, F-06480 LA COLLE SUR LOUP, FRANCE
2 JEAN LAFAY 1 AVENUS CLEMENT ADER, F-06100 NICE, FRANC
3 PAULE BONNET VILLA LES ROCAILLES GLENA 37 ROUTE DE SOSPEL , F-06500 MENTON, FRANCE
4 THIERRY CLERC VILLA VALMONT CHEMIN DE LA BORDINA F, 06320 LA TURBIE FRANCE
5 IGOR DUG VILLA CASIMIR 26 RUE BORNIOL F-06400 CANNES FRANCE
6 ERIC DURANTI, 258 AVENUE DES FILAGNES F-06700 SAINT LAURENT DU VAR FRANCE
7 JACQUELINE SHIELDS 6 AVENUE GEORGE SAND , F-06100 NICE FRANCE
8 FRANCOIS PUCCIO 74 AVENUE DU MONT ALBAN, F06300 NICE ,FRANCE
9 CHRISTIAN BLOT 1582 ROUTE DE CAGNES, F-06480 LA COLLE SUR LOUP FRANCE
10 PHILIPPE MAILLOS 38 CHEMIN DE LA BOURDETTE, F-81500 LABASTIDE SAINT GEORGES, FRANCE
PCT International Classification Number CO7D 231/56
PCT International Application Number PCT/EP2005/055262
PCT International Filing date 2005-10-14
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 04292439.9 2004-10-14 EUROPEAN UNION