Title of Invention

"[3R,4R] - TRANS-3,4-DIARYLCHROMAN DERIVATIVES AND A PROCESS FOR THE PREPARATION THEREOF"

Abstract The present invention relates to compounds of the formula I in which substituents R2 and R3 are arranged in trans-configuration (1) wherein: R1 is H or C1-C6 alkyl; C3-C7 cycloalkyl; R2 is phenyl, optionally substituted with 1 to 5 substituents independently selected from the group comprising OH, C1-C6 -alkyl, halogen, nitro, cyano, SH, SR4, trihalo-Cl-C6-alkyl, C1-C6 -alkoxy and phenyl, wherein R4 is C1-C6 alkyl; R3 is phenyl substituted with OR5 wherein R5 has the formula (II), wherein Y is chosen from NHR4, NR42, NHCOR4, NHSO2R4, CONHR4, CONR4, CONR42, COOH, COOR4, SO2R4, SOR4, SONHR4, SONR42, a C3-C7 heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of O, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group comprising H, OH, halogen, nitro, cyano, SH, SR4, trihalo-C 1-C6- alkyl, C1-C6-alkyl and C1-C6 -alkoxy, preferably NHR4, NR24, or a nitrogen heterocycle, wherein R4 is as defined above, and the esters, ethers, and salts of the compounds of formula I, optionally along pharmaceutically acceptable excipients, a process for the preparation of the same, and a method of preventing and/or treating estrogen-related disease conditions in a subject using compounds of formula 1, or its salts, optionally along with pharmaceutically acceptable excipients. 55
Full Text (3R,4R)-trans-3,4-diarylchroman derivatives and a method for the prevention
and/or treatment of estrogen dependent diseases
Field of the present Invention
The present invention relates to compounds of the formula I in which substituents R2 and
R3 are arranged in trans-configuration:
wherein:
R1 is H or C1-C6 alkyl; C3-C7 cycloalkyl;
R2 is phenyl, optionally substituted with 1 to 5 substituents independently selected
from the group comprising OH, C1-C6 -alkyl, halogen, nitro, cyano, SH, SR4'
trihalo-Cl-C6-alkyl, C1-C6 -alkoxy and phenyl, wherein R4 is C1-C6 alkyl;
R3 is phenyl substituted with OR5 wherein R5 has the formula (II), (III) or (IV)
OH OH
(II) (III) (IV)
wherein Y is chosen from NHR4, NR4
2, NHCOR4, NHSO2R4, CONHR4, CONR4,
CONR4
2, COOH, COOR4, SO2R4, SOR4, SONHR4, SONR4
2, a C3-C7 heterocyclic ring,
saturated or unsaturated, containing one or two heteroatoms independently selected from
the group consisting of O, S and N, optionally being substituted with 1 to 3 substituents
independently selected from the group comprising H, OH, halogen, nitro, cyano, SH,
SR4, trihalo-Cl-C6- alkyl, Cl-C6-alkyl and C1-C6 -alkoxy, preferably NHR4, NR2
4, or
a nitrogen heterocycle, wherein R4 is as defined above, and the esters, ethers, and salts of
the compounds of formula I, optionally along with pharmaceutically acceptable
excipients, a process for the preparation of the same, and a method of preventing and/or
treating estrogen-related disease conditions in a subject using compounds of formula 1, or
its salts, optionally along with pharmaceutically acceptable excipients.
Background of the present Invention
Menopause in women's life is the most critical stage of the life when she undergoes
dramatic physiological changes and is defined as the transition in women from
reproductive to non-reproductive stage of life, which is due to the cessation of
menstruation and occurs at an average age of fifty years. More particularly, the postmenopausal
stage is characterized by the changes in the levels of circulating sex
hormones, the most dramatic of which is the reduction in plasma levels of 17-betaestradiol
to less than ten percent of pre-menopausal values, which results in a number of
chronic disorders and is often referred to as Post Menopausal Syndrome. In view of the
fact that the current life span of women is about eighty years, women spend
approximately one-third of their lives in the post-menopausal state. This means that the
potential for chronic effects of the post-menopausal state on women's health is far greater
today than at the turn of the century when life expectancy was considerably shorter.
Estrogen deficiency is the most important risk factor associated with Post Menopausal
Syndrome. Some of the major effects of the Post Menopausal Syndrome that are source
of greatest long-term medical concern include osteoporosis, bone loss, bone formation,
cardiovascular effects more particularly hyperlipidaemia, thrombosis and vasomotor
disorders, neurodegenerative effects such as stroke, senile dementia-Alzheimer type and
Parkinson disease, menopausal symptoms including hot flushes, urogenital atrophy,
depression, mania, schizophrenia, urinary incontinence, relief of dysmenorrhea; relief of
dysfunctional uterine bleeding, an aid in ovarian development, treatment of acne,
hirsutism.
Osteoporosis can be defined as a reduction in bone mass per unit volume with an
alteration in bone microarchitecture that results in an increased susceptibility to fractures.
It is not surprising that the most common fractures are those associated with bones, which
are highly dependent on trabecular support, for example the vertebrae, the neck, and the
weight bearing bone such as the femur, and the fore arm. Indeed the hip fracture, collies
fractures and vertebrae crush fractures are hallmarks of post-menopausal osteoporosis. In
most cases, bone loss occurs as a result of increased bone destruction (resorption) relative
to bone formation and most women lose from about 20% to 60% of the bone mass in the
trabecular compartment of the bone within 3 to 6 years after the menopause.
Osteoporosis, more particularly the post-menopausal osteoporosis represents a major
problem in women health care and poses a risk to quality of life during old age. Efforts
to reduce this risk factor and incidence of fractures have resulted in the development of
compounds that conserve skeletal mass by inhibiting bone resorption and/or by
enhancing bone formation (Dwivedi I, Ray S, 1995 "Recent developments in the
chemotherapy of osteoporosis" Progress in Drug Research 45, 289-338, Editor E Jucker,
Birkhauser Vela; Marshall DH, Horsmann A, Nordin BEC, 1977, "The prevention and
management of post-menopausal osteoporosis" Acta Obstet Gynecol Scand (Suppl)
65:49-56; Hutchinson TA, Polansky SM, Feinstein AR, 1979, "Postmenopausal estrogen
protect against fractures of hip and distal radius: A care-control study" Lancet 2:705-709.
Estrogen replacement therapy also has positive effect on CVS & CNS related disorders
(Lobo RA, 1990, "Cardiovascular implication of estrogen replacement therapy"
Obstetrics & Gynaecology 75:185-245; Mendelson ME, Karas RH, 1994, "Estrogen and
the blood vessel wall" Current opinion in Cardiology 1994:619-626; Stampfer MJ,
Colditz GA, 1991, "Estrogen replacement therapy and coronary heart disease: a
quantitative assessment of the epidemiological evidence" Preventive Medicine 20:47-63).
Cardiovascular disease is another leading cause of morbidity and mortality in older
women. Menopause and ageing increase risk of atherosclerosis and coronary artery
disease. An altered lipid profile is thought to be associated with this increased risk.
Compared to men, pre-menopausal women are relatively more protected from
cardiovascular diseases. This protection is gradually lost following menopause. This loss
of protection has been linked to the loss of estrogen and in particular to the loss of
estrogen's stationary phase ability to regulate the level of serum lipids. The nature of
estrogens ability to reduce serum lipids is not well understood, but evidences indicate that
estrogen can up-regulate LDL receptors in the liver which act to remove excess
cholesterol.
Additionally, estrogen appears to have some effects on the biosynthesis of cholesterol
and other beneficial effects on cardiovascular health. Estrogen is also believed to directly
influence vessel wall compliance, reduce peripheral resistance and prevent
atherosclerosis. It is also reported that serum lipids in post-menopausal women having
estrogen replacement therapy (ERT) return to concentrations found in the premenopausal
state (Gruber CJ, Tschugguel W, Schneeberger C, Huber JC, 2002,
"Production and actions of estrogens" The New England Journal of Medicine 346:340-
352; Bellino FL, Wise PM, 2003 "Nonhuman primate models of menopause workshop"
Biology of Reproduction 68:10-18; Lobo RA 1990, "Cardiovascular implication of
estrogen replacement therapy", Obstetrics and Gynaecology 75:18S-24S; Medelson ME,
Karas RD 1994, "Estrogen and the blood vessel wall", Current opinion in Cardiology,
1994 (9):619-626).
Based on available epidemiological data, the overall impact of these physiological and
pharmacological actions of estrogen is an age independent reduction in cardiovascular
mortality and morbidity in women (Knnel WH, Hjortland M, McNamara PM, 1976
"Menopause and risk of cardiovascular disease: The Framingham Study", Ann Int Med
8:5447-5552). Furthermore, a more recent analysis has concluded that post-menopausal
estrogen replacement therapy reduces the risk of cardiovascular disease by approximately
50 percent (Stampfer MJ, Colditz GA, 1991, "Estrogen replacement therapy and coronary
heart disease: a quantitative assessment of the epidemiological evidence", Preventive
Medicine 20:47-63).
There is growing interest in recent years on neuroprotective effects of estrogens for
neurodegenerative conditions such as stroke, Alzheimer disease and Parkinson disease.
Reports of greater brain damage in males than in females and in ovariectomized than
intact female animals in ischemic stroke models ^re available. Estrogen is also known to
increase density of N-methyl-D-aspartate receptors and increase neuronal sensitivity to
input mediated by these receptors in neurons of hippocampus, the area involved in
memory. The estradiol-depleted state in post-menopausal women has been correlated
with increased incidence of stroke, cognitive defects, hot flashes, mood changes, and
early onset and severity of Alzheimer disease. Some epidemiological data suggests that
in post-menopausal women, estrogen deficiency is associated with decline in cognitive
function and increased risk of Alzheimer's disease (Gruber CJ, Tschugguel W,
Schneeberger C, Huber JC, 2002 "Production and actions of estrogens", The New
England Journal of Medicine 346:340-352; Dhandapani KM, Brann DW, 2002,
"Protective effects of estrogen and Selective Estrogen Receptor Modulators in the brain"
Biology of Reproduction 67:1379-1385).
Short-term studies in human subjects have shown that increased levels of estrogen are
associated with higher memory scores in post-menopausal women (Kampen DL, Sherwin
BB, 1994 "Estrogen use and verbal memory in healthy postmenopausal women",
Obstetrics & Gynaecology 83:979-983; Ohkura T, Isse K, Akazawa K, Hamanioto M,
Yoshimasa Y, Hagino N, 1995, "Long-term estrogen replacement therapy in female
patients with dementia of the Alzheimer Type: 7 Case reports", Dementia 6:99-107).
Furthermore, the administration of exogenous estrogen to surgically post-menopausal
women specially enhances short-term memory. Moreover, the effects as epidemiological
findings indicate that estrogen treatment significantly decreases the risk of senile
dementia-Alzheimer type in women (Paganini-Hill A, Henderson VW, 1994, "Estrogen
deficiency and risk of Alzheimer's disease in women", Am J Epidemiol 140:256-261;
Ohkura T, Isse K, Akazawa K, Hamamoto M, Yoshimasa Y, Hagino N, 1995, "Longterm
estrogen replacement therapy in female patients with dementia of the Alzheimer
Type: 7 case reports", Dementia 6:99-107).
While the mechanism whereby estrogens enhance cognitive function is unknown, it is
possible to speculate that the direct effects of estrogen on cerebral blood flow (Goldman
H, Skelley Eb, Sandman CA, Kastin AJ, Murphy S, 1976, "Hormones and regional brain
blood flow", Pharnacik Biochem Rev 5 (suppl 1): 165-169; Ohkura T, Teshima Y, Isse K,
Mastuda H, Inoue T, Sakai Y, Iwasaki N, Yaoi Y, 1995, "Estrogen increases cerebral and
cerebellar blood flows in postmenopausal women", Menopause: J North Am Menopause
Soc 2:13-18) and neuronal cell activities (Singh M, Meyer EM, Simpkins JW, 1995, "The
effect of ovariectomy and estradiol replacement on brain-derived neurotrophic factor
messenger ribonucleic acid expression in cortical and hippocampal brain regions of
female Sprague-Dawley rats", Endocrinology 136:2320-2324; McMillan PJ, Singer CA,
Dorsa DM, 1996, "The effects of ovariectomy and estrogen replacement on trkA and
choline acetyltransferase mRNA expression in the basal forebrain of the adult female
Sprague-Dawley rat", Neurosci 16:1860-1865).
Even though the beneficial effects of estrogen replacement on a wide variety of organ
systems and tissues appear indisputable, the dose and duration of estrogen therapy is also
associated with an increased risk of endometrial hyperplasia and carcinoma. The use of
concomitant cyclic progestins does reduce the risk of endometrial pathology, but this is
achieved at the expense of the return of regular uterine bleeding, a result that is
objectionable to many patients. In addition to estrogen's stimulatory effect on the
endometrium, there remains considerable controversy regarding reports of an association
between long-term estrogen replacement and an increased risk of breast cancer
(Bergkvist L, Adami HO, Persson I, Hoover R, Schairer C, 1989, "The risk of breast
cancer after estrogen and estrogen-progestin replacement", N Eng J Med, 321:293-297;
Coiditz GA, Hankinson SE, Hunter DJ, Willett WX, Manson JE, Stampfer MJ,
Hennekens C, Rosner B, Speizer FE, 1995, "The use of estrogens and progestins and the
risk of breast cancer in postmenopausal women", N Eng J Med 332:1593). Furthermore,
there are other side effects of estrogen replacements, which, while might not be life
threatening, contraindicate estrogen's use and reduce patient compliance.
Breast cancer is by far the most common malignant disease in women (22% of all new
cancer cases). Concerted efforts are being made worldwide to develop new and safer
drugs for the treatment of breast cancer. Tamoxifen ("Nolvadex'), a selective estrogen
receptor modulator (SERM), is currently the most widely used drug for the treatment of
estrogen receptor positive (ER+ve) breast cancer. Tamoxifen inhibits the estrogendependent
growth of cancer cells by competitive binding to estrogen receptors of the
cells. However, as tamoxifen has also estrogen-like effects, it induces, among other
adverse effects, endometrial cancer, deep vein thrombosis and pulmonary embolism in
women undergoing the therapy. In addition, tamoxifen is known to induce DNA adduct
formation and produced liver tumors in rodent life-term bioassays. Thus there is an
urgent need for developing safer SERMs for the treatment of breast cancer (Baum M,
Odling-Smee W, Houghton J, Riley D, Taylor H, 1994, "Endometrial cancer during
tamoxifen treatment", Lancet 343:1291; demons M, Danson S, Howell A, 2002,
"Tamoxifen ('Nolvadex'): Antitumour treatment. A review", Cancer Treatment Reviews
28:165-180; Muggins, C, Yang NC, 1962, "Induction and extinction of mammary
cancer", Science 137:257-262; Williams GM, Latropoulos,' MJ, Djordjevic MV,
Kaltenberg OP, 1993, "The triphenylethylene drug tamoxifen is a strong liver carcinogen
in the rat", Carcinogenesis 14:315-317; Meier CR, Jick H, 1998, "Tamoxifen and risk of
idiopathic venous thromboembolism", Br J Clin Pharmacol 45:608-612).
Egg-implantation in most mammals is dependent on a sequential action of estrogen and
progesterone on the uterus and is considered as a preferential peripheral site for
contraception. Development of hormone antagonists (both antiestrogens and
antiprogestins) which inhibit action of endogenous hormones at the receptor level
resulting in inhibition of implantation is one of the promising approaches for control or
regulation of fertility in humans and other animals. Previous studies have revealed that
administration of estrogen antagonists, recently termed as Selective Estrogen Receptor
Modulators (SERMs), due to their tissue selective action) to cyclic or mated females
prevents implantation.
Studies also reveal their uterine specific action, inhibiting endometrial receptivity to
embryonic signal(s) for decidualisation, without affecting pre-implantation development
of embryos up to the blastocyst stage (Singh MM, 2001, "Centchroman, a selective
estrogen receptor modulator, as contraceptive and in the management of hormone related
clinical disorders", Medicinal Research Reviews 21:302-347; Nityanand S, Chandravati,
Singh L, Srivastava JS, Kamboj VP, 1988, "Clinical evaluation of centchroman: A new
oral contraceptive", In: Hormone Antagonists for Fertility Regulation, Eds Puri CP, Van
Look PFA, Indian Society for the Study of Reproduction and Fertility, Bombay, India,
223-230; Puri V, Kamboj VP, Chandra H, Ray S, Kole PL, Dhawan BN, Anand N, 1988,
"Results of multicentric trial of centchroman", In: Pharmacology for Health in Asia, Eds
Dhawan BN, Agarwal KK, Arora RB, Parmar SS, Allied Publishers, New Delhi, 439-
447; Nityanand S, Kamboj VP, Chandravati, Das K, Gupta K, Rohtagi P, Baveja R, Jina
R, Mitra R, Sharma U, 1994, "Contraceptive efficacy and safety of centchroman with
biweekly-cum-weekly schedule", In: Current Concepts in Fertility Regulation and
Reproduction, Eds Puri CP, Van Look PFA, Wiley Eastern Ltd., New Delhi, 61-68;
Nityanand S, Gupta RC, Kamboj VP, Srivastava PK, Berry M, 1995, "Centchroman:
Current Status as a contraceptive", Indian Progress in Family Welfare 10:26-31;
Nityanand S, Anand N, 1996, "Centchroman: A nonsteroidal antifertility agent", FOGSI
FOCUS, March issue: 8-10).
Such SERMs have also been successfully used for induction of ovulation in amenorrhic
women under the assisted reproduction programmes (Roy SN, Kumari GL, Modoiya K,
Prakash V, Ray S, 1976, "Induction of ovulation in human with Centchroman, a
preliminary report", Fertility and Sterility 27:1108-1110) and suppression of postpartum
lactation (Goodman and Gilman, The Pharmacological Basis of Therapeutics
(Seventh Edition) Macmillan Publishing Company, 1985, pages 1321-1423).
From the foregoing discussion it would appear that the availability of therapies which
possess the ideal pharmacological profile and could mimic the beneficial actions of
estrogen on the bone, cardiovascular system and central nervous system without the
undesirable side effects on uterus and breast, would essentially provide a "safe estrogen"
which could dramatically influence the number of patients that would be able to benefit
from estrogen replacement therapy. Therefore, in recognition of estrogen's beneficial
effects on a number of body systems and disease conditions, there is a continuing need
for the development of potent estrogen agonists which can selectively target different
body tissues. Accordingly, the present invention provides new compounds,
pharmaceutically acceptable salts and compositions thereof and methods of using such
compounds for the prevention or treatment of:
(a) estrogen deficient or deprivation state in a mammal, in particular osteoporosis,
bone loss, bone formation, cardiovascular effects more particularly
hyperlipidaemia, thrombosis and vasomotor system, neurodegenerative effects
such as stroke, senile dementia-Alzheimer type and Parkinson disease,
menopausal symptoms including hot flushes, urogenital atrophy, depression,
mania, schizophrenia and the like, urinary incontinence, relief of dysmenorrhea;
relief of dysfunctional uterine bleeding, an aid in ovarian development, treatment
of acne and hirsutism;
(b) estrogen dependent or estrogen independent cancers such as prostatic carcinoma,
cancer of breast, cancer of uterus, cancer of the cervix and cancer of the colon;
(c) an aid in ovarian development or function;
(d) control or regulation of fertility in humans and in other animals;
(e) prevention of threatened or habitual abortion;
(f) suppression of post-partunrlactation;
(g) physiological disorders such as obesity, depression etc.;
(h) regulation of glucose metabolism in non-insulin dependent diabetes mellitus
Objects of the present Invention
The main object of the present invention is to develop compounds of the formula I in
which substituents R2 and R3 are arranged in trans-configuration:
(1)
wherein:
R1 is H or C1-C6 alkyl; C3-C7 cycloalkyl;
R2 is phenyl, optionally substituted with 1 to 5 substituents independently selected
from the group comprising OH, C1-C6 -alkyl, halogen, nitro, cyano, SH, SR4'
trihalo-Cl-C6-alkyl, C1-C6 -alkoxy and phenyl, wherein R4 is C1-C6 alkyl;
R3 is phenyl substituted with OR5 wherein R5 has the formula (II), (III) or (IV)
' OH OH OH
(II) (III) (IV)
wherein Y is chosen from NHR4, NR4
2, NHCOR4, NHSO2R4, CONHR4, CONR4,
CONR4
2, COOH, COOR4, S02R4, SOR4, SONHR4, SONR4
2, a C3-C7
heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms
independently selected from the group consisting of O, S and N, optionally being
substituted with 1 to 3 substituents independently selected from the group
comprising H, OH, halogen, nitro, cyano, SH, SR4, trihalo-C 1-C6- alkyl, C1-C6-
alkyl and C1-C6 -alkoxy, preferably NHR4, NR2
4, or a nitrogen heterocycle,
wherein R4 is as defined above, and the esters, ethers, and salts of the compounds
of formula I, optionally along pharmaceutically acceptable excipients.
Another main object of the present invention is to develop a process for the preparation
of compounds of formula I.
Yet another object of the present invention is to develop a method of preventing and/or
treating estrogen-related disease conditions in a subject in need thereof, said method
comprising step of administering to the subject, a phannaceuticallv effective amount of
compounds of formula 1 , or its salts, optionally along with pharmaceutically acceptable
excipients.
Still another object of the present invention is to develop a method of prevention and/or
treatment as claimed in claim 14, wherein said method helps in preferably diseases or
syndromes caused by an estrogen-deficient state, with Relative Binding affinity (RBA) to
estrogen receptors ranging between 5 to 7.
Still another object of the present invention is to develop A method of prevention and/or
treatment as claimed in claim 14, wherein said method helps in disease conditions caused
by osteoporosis, bone loss, and bone formation, with T/C ratio of Still another object of the present invention is to develop A method of prevention and/or
treatment as claimed in claim 14, wherein said method helps in disease conditions
affecting cardiovascular systems, more particularly hyperlipidaemia, thrombosis and
vasomotor system.
Still another object of the present invention is to develop a method to help in disease
conditions showing neurodegenerative effects, more particularly, stroke, senile dementia-
Alzheimer type and Parkinson disease.
Still another object of the present invention is to develop a method to help in disease
conditions showing menopausal symptoms, more particularly, hot flushes, urogenital
atrophy, depression, mania, schizophrenia, urinary incontinence, dysmenorrhea,
dysfunctional uterine bleeding, acne, hirsutism, improper ovarian development.
Still another object of the present invention is to develop a method to help in disease
conditions showing cancers, more particularly, prostatic carcinoma, breast cancer, cancer
of uterus, cancer of the cervix and colon cancer, with LCso ranging between 17 to 20
Still another object of the present invention is to develop a method wherein the volume of
the tumor decreases by about 25%.
Still another object of the present invention is to develop method to help regulate fertility
in humans and in other animals.
Still another object of the present invention is to develop a method to help in threatened
or habitual abortion.
Still another object of the present invention is to develop a method to help in suppression
of post-partum lactation.
Still another object of the present invention is to develop a method to help in the
management of certain physiological disorders, more particularly, obesity and depression.
Still another object of the present invention is to develop a method to help regulate of
glucose metabolism in non-insulin dependent diabetes mellitus.
Summary of the present invention
The present invention relates to compounds of the formula I in which substituents R2 and
R3 are arranged in trans-configuration:
0)
wherein:
R1 is H or C1-C6 alkyl; C3-C7 cycloalkyl;
R2 is phenyl, optionally substituted with 1 to 5 substituents independently selected
from the group comprising OH, C1-C6 -alkyl, halogen, nitro, cyano, SH, SR4'
trihalo-Cl-C6-alkyl, C1-C6 -alkoxy and phenyl, wherein R4 is C1-C6 alkyl;
R3 is phenyl substituted with OR5 wherein R5 has the formula (II), (III) or (IV)
(II) (III) (IV)
wherein Y is chosen from NHR4, NR4
2, NHCOR4, NHSO2R4, CONHR4, CONR4,
CONR4
2, COOH, COOR4, S02R4, SOR4, SONHR4, SONR4
2, a C3-C7
heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms
independently selected from the group consisting of O, S and N, optionally being
substituted with 1 to 3 substituents independently selected from the group
comprising H, OH, halogen, nitro, cyano, SH, SR4, trihalo-C 1-C6- alkyl, C1-C6-
alkyl and C1-C6 -alkoxy, preferably NHR4, NR2
4, or a nitrogen heterocycle,
wherein R4 is as defined above, and the esters, ethers, and salts of the compounds
of formula I, optionally along with pharmaceutically acceptable excipients, a
process for the preparation of the same, and a method of preventing and/or
treating estrogen-related disease conditions in a subject using compounds of
formula 1, or its salts, optionally along with pharmaceutically acceptable
excipients.
Detailed Description of the present invention
Accordingly, the present invention relates to compounds of the formula I in which
substituents R2 and R3 are arranged in trans-configuration:
R3
wherein:
R1 is H or C1-C6 alkyl; C3-C7 cycloalkyl;
R2 is phenyl, optionally substituted with 1 to 5 substituents independently selected
from the group comprising OH, C1-C6 -alkyl, halogen, nitro, cyano, SH, SR4'
trihalo-Cl-C6-alkyl, C1-C6 -alkoxy and phenyl, wherein R4 is C1-C6 alkyl;
R3 is phenyl substituted with OR5 wherein R5 has the formula (II), (III) or (IV)
OH
OH
(Figure Removed)
wherein Y is chosen from NHR4, NR4
2, NHCOR4, NHSO2R4, CONHR4, CONR4,
CONR4
2, COOH, COOR4, SO2R4, SOR4, SONHR4, SONR4
2, a C3-C7
heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms
independently selected from the group consisting of O, S and N, optionally being
substituted with 1 to 3 substituents independently selected from the group
comprising H, OH, halogen, nitro, cyano, SH, SR4, trihalo-Cl-C6~ alkyl, C1-C6-
alkyl and C1-C6 -alkoxy, preferably NHR4, NR2
4, or a nitrogen heterocycle,
wherein R4 is as defined above, and the esters, ethers, and salts of the compounds
of formula I, optionally along with pharmaceutically acceptable excipients, a
process for the preparation of the same, and a method of preventing and/or
treating estrogen-related disease conditions in a subject using compounds of
formula 1, or its salts, optionally along with pharmaceutically acceptable
excipients.
In the main embodiment of the present invention, the substituents R2 and R3 are arranged
in trans-configuration in compounds of formula I, wherein compounds of the formula I in
which substituents R2 and R3 are arranged in trans-configuration:
(Figure Removed)
wherein:
R1 is H or C1-C6 alkyl; C3-C7 cycloalkyl;
R2 is phenyl, optionally substituted with 1 to 5 substituents independently selected
from the group comprising OH, C1-C6 -alkyl, halogen, nitro, cyano, SH, SR4'trihalo-
Cl-C6-alkyl, C1-C6 -alkoxy and phenyl, wherein R4 is C1-C6 alkyl;
R3 is phenyl substituted with OR5 wherein R5 has the formula (II), (III) or (IV)
Y
OH OH OH
(II) (III) (IV)
wherein Y is chosen from NHR4, NR4
2, NHCOR4, NHSO2R4, CONHR4, CONR4,
CONR4
2, COOH, COOR4, SO2R4, SOR4, SONHR4, SONR4
2, a C3-C7 heterocyclic
ring, saturated or unsaturated, containing one or two heteroatoms independently
selected from the group consisting of O, S and N, optionally being substituted with 1
to 3 substituents independently selected from the group comprising H, OH, halogen,
nitro, cyano, SH, SR4, trihalo-Cl-C6- alkyl, Cl-C6-alkyl and C1-C6 -alkoxy,
preferably NHR4, NR2
4, or a nitrogen heterocycle, wherein R4 is as defined above,
and the esters, ethers, and salts of the compounds of formula I, optionally along
pharmaceutically acceptable excipients.
In another main embodiment of the present invention, wherein R3 is phenyl
substituted with -OR5 wherein R5 has the formula II and wherein Y is a C3-C7
heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms
independently selected from the group comprising O, S and N, optionally being
substituted with 1 to 3 substituents independently selected from the group
comprising H, OH, halogen, nitro, cyano, SH, SR4, trihalo-Ci-C6 - alkyl, C1-C6-
alkyl, Cl-C6-alkyl and C1-C6-alkoxy.
In yet another main embodiment of the present invention, wherein R3 is phenyl
substituted with -OR5 wherein R5 has the formula III and wherein Y is a C3-C7
heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms
independently selected from the group comprising O, S and N, optionally being
substituted with 1 to 3 substituents independently selected from the group
comprising H, OH, halogen, nitro, cyano, SH, SR4, trihalo-Cl-C6- alkyl, C1-C6-
alkyl, Cl-C6-alkyl and C1-C6-alkoxy.
In still another main embodiment of the present invention, wherein R3 is phenyl
substituted with -OR5 wherein R5 has the formula IV and wherein Y is a C3-C7
heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms
independently selected from the group comprising O, S and N, optionally being
substituted with 1 to 3 substituents independently selected from the group
comprising H, OH, halogen, nitro, cyano, SH, SR4, trihalo-Cl-C6- alkyl, C1-C6-
alkyl, Cl-C6-alkyl and Cl-C6-alkoxy.
In still another main embodiment of the present invention, wherein R1 is preferably
methyl.
In still another main embodiment of the present invention, wherein R2 is preferably
phenyl.
In still another main embodiment of the present invention, wherein R4 is preferably
butyl.
In still another main embodiment of the present invention, wherein the preferred
compounds are:
a. (3R,4R)-2,2-Dimethyl-7-methoxy-4-(4-[{2R)-3-methylamino-2-
hydroxy} propyloxy] phenyl)-3 -phenyIchroman.
b. (3R,4R)-2,2-Dimethyl-7-methoxy-4-(4-[{2R)-3-ethylamino-2-
hydroxy} propyloxy] phenyl)-3 -phenylchroman.
c. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{2R)-3-propylamino-2-
hydroxy} propyloxy] phenyl)chroman.
d. (3R,4R)-4-(4-[{2R)-3-Butylamino-2-hydroxy}propyloxy]phenyl)-2,2-
dimethyl-7-methoxy-3 -phenylchroman.
e. (3R,4R)-2,2-Dimethyl-7-methoxy-4-(4-[{2R)-3-pentylamino-2-
hydroxy} propyloxy] phenyl)-3 -phenylchroman.
f. (3R,4R)-2,2-Dimethyl-4-(4-[{2R)-3-dimethylamino-2-
hydroxy}propyloxy]phenyl)-7-methoxy-3-phenylchroman.
g. (3R,4R)-4-(4-[{2R)-3-Diethylamino-2-hydroxy}propyloxy]phenyl)-2,2-
dimemyl-7-memoxy-3-phenylchroman.
h. (3R,4R)-2,2-Dimethyl-4-(4-[{2R)-3-dipropylamino-2-
hydroxy}propyloxy]phenyl)-7-methoxy-3-phenylchroman.
i. (3R,4R)-4-(4-[{2R)-3-Dibutylamino-2-hydroxy}propyloxy]phenyl)-2,2-
dimethoxy-3 -phenylchroman.
j. (3R,4R)-2,2-Dimethyl-4-(4-[{2R)-3-dipentylamino-2-
hydroxy}propyloxy]phenyl)-7-methoxy-3-phenylchroman.
k. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{2R)-3-pyrrolidino-2-
hydroxy} propyloxy] phenyl)-chroman.
1. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{2R)-3-piperidino-2-
hydroxy} propyloxy]phenyl)-chroman.
m. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{2R)-3-morpholino-2-
hydroxy} propyloxy]phenyl)-chroman.
n. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{2R)-3-piperazino-2-
hydroxy} propyloxy]phenyl)-chroman.
o. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{2R)-3-
cyclohexylamino-2-hydroxy} propyloxy]phenyl)-chroman.
p. (3R,4R)-2,2-Dimethyl-7-methoxy-4-(4-[{2S)-3-methylamino-2-
hydroxy} propyloxy] phenyl)-3 -phenylchroman.
q. (3R,4R)-2,2-Dimethyl-7-methoxy-4-(4-[{2S)-3-ethylamino-2-hydroxy}
propyloxy]phenyl)-3-phenylchroman.
r. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{2S)-3-propylamino-2-
hydroxy} propyloxy]phenyl)-chroman.
s. (3R,4R)-4-4-(4-[{2S)-3-Butylamino-2-hydroxy}propyloxy]phenyl)-2,2-
dimethyl-7-methoxy-3 -phenylchroman.
t. (3R,4R)-2,2-Dimethyl-7-methoxy-4-(4-[{2S)-3-pentylamino-2-
hydroxy}propyloxy] phenyl)-3-phenylchroman.
u. (3R,4R)-2,2-Dimethyl-4-(4-[{2S)-3-dimethylamino-2-
hydroxy} propyloxy]phenyl)-7-methoxy-3 -phenylchroman.
v. (3R,4R)-4-(4-[{2S)-3-Diethylamino-2-hydroxy}propyloxy]phenyl)-2,2-
dimethyl-7-methoxy-3-phenylchroman.
w. (3R,4R)-2,2-Dimethyl-4-(4-[{2S)-3-dipropylamino-2-
hydroxy}propyloxy]phenyl)-7-methoxy-3-phenylchroman.
x. (3R,4R)-4-(4-[{2S)-3-Dibutylamino-2-hydroxy}propyloxy]phenyl)-3-
phenyl)-2,2-dimethoxy-3-phenylchroman.
y. (3R,4R)-2,2-Dimethyl-4-(4-[{2S)-3-dipentylamino-2-
hydroxy}propyloxy]phenyl)-7-methoxy-3-phenylchroman.
z. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{2S)-3-pyrrolidino-2-
hydroxy} propyloxy]phenyl)-chroman.
aa. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{2S)-3-piperidino-2-
hydroxy} propyloxy]phenyl)-chroman.
bb. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{2S)-3-morpholoino-2-
hydroxy} propyloxy]phenyl)-chroman.
cc. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{2S)-3-piperazino-2-
hydroxy} propyloxy]phenyl)-chroman.
dd. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{2S)-3-
cyclohexylamino-2-hydroxy} propyloxy]phenyl)-chroman.
ee. (3R,4R)-2,2-Dimethyl-7-methoxy-4-(4-[{3-methylamino-2-
hydroxy}propyloxy] phenyl)- 3-phenylchroman.
ff. (3R,4R)-2,2-Dimethyl-7-methoxy-4-(4-[{3-ethylamino-2-
hydroxy} propyloxy]phenyl)-3 -phenylchroman.
gg. (3R,4R)-2,2-Dimethyl-7-methoxy-4-(4-[{3-propylamino-2-
hydroxy} propyloxy]phenyl)-3 -phenylchroman.
hh. (3R,4R)-4-(4-[{3-butylamino-2-hydroxy}propyloxy]phenyl)-2,2-
dimethyl-7-methoxy-3-phenylchroman.
ii. (3R,4R)-2,2-Dimethyl-7-methoxy-4-(4-[{3-pentylamino-2-
hydroxy}propyloxy]phenyl)-3-phenylchroman.
jj. (3R,4R)-2,2-Dimethyl-4-(4-[{3-dimethylamino-2-
hydroxy}propyloxy]phenyl)-7-methoxyphenyl)-3-phenylchroman.
kk. (3R,4R)-4-(4-[{3-Diethylamino-2-hydroxy}propyloxy]phenyl)-2,2-
dimethyl-7-methoxy-3-phenylchroman.
11. (3R,4R)-2,2-Dimethyl-4-(4-[{3-dipropylamino-2-
hydroxy} propyloxy]phenyl-7-methoxy phenyl)-3 -phenylchroman.
mm. (3R,4R)-4-(4-[{3-Dibutylamino-2-hydroxy}propyloxy]phenyl)-
2,2-dimethoxy-3 -phenylchroman.
nn. (3R,4R)-2,2-Dimethyl-4-(4-[ {3 -dipentylamino-2-
hydroxy} propyloxy]phenyl-7-methoxy phenyl)-3-phenylchroman.
oo. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{3-pyrrolidino-2-
hydroxy}propyloxy] phenyl)-chroman.
pp. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{3-piperidino-2-
hydroxy}propyloxy] phenyl)-chroman.
qq. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{3-morpholino-2-
hydroxy}propyloxy] phenyl)-chroman.
rr. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{3-piperazino-2-
hydroxy}propyloxy] phenyl)-chroman.
ss. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{3-cyclohexylamino-2-
hydroxy} propyloxy]phenyl)-chroman.
In still another main embodiment of the present invention, wherein the salts are
selected from a group comprising acid addition salts consisting of formate, acetate,
phenyl acetate, trifluroacetate, acrylate, ascorbate, benzoate, chlorobenzoates,
bromobezoates, iodobenzoates, nitrobenzoates, hydroxybenzoates, alkylbenzoates,
alkyloxybenzoates, alkoxycarbonylbenzoates, naphthalene-2 benzoate, butyrates,
phenylbutyrates, hydroxybutyrates, caprate, caprylate, cinnamate, mandelate,
mesylate, citrate, tartarate, fumarate, heptanoate, hippurate, lactate, malate, maleate,
malonate, nicotinate, isonicotinate, oxalate, phthalate, terephthalate, phosphate,
monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate,
propiolate, propionate, phenylpropionate, salicylate, sebacte, succinate, suberate,
sulphate, bisulphate, pyrosulphate, sulphite, bisulphate, sulphonate, benzene
sulphonate, bromobenzene sulphonates, chlorobenzene sulphonates, ethane
sulphonates, methane sulphonates, naphthalene sulphonates, toluene sulphonates, and
the likes. Additionally, the invention includes alkyl or aryl halides addtion salts of
the compounds of this invention, wherein the alkyl halide is selected from a group
comprising C\ to Cig alkyl halide, and aryl halide is selected from a group comprising
benzyl halide and substituted benzyl halide.
In still another main embodiment of the present invention, wherein most preferred
salts are fumerate, ascorbate, hydrochloride, and methyl iodide.
In still another main embodiment of the present invention, wherein the compounds or
its salts are in the physical forms of the gelatin capsules or compressed into the tablets
or pills or may be formulated in the form of lozenges, inclusion complexes with
cyclodextrin derivatives, injectable depo formulations, aerosols, granules, powders,
oral liquids, mucosal adhesive formulations, gel formulations, troches, elixirs,
suspensions, syrups, wafers, liposomal delivery systems, implants, suppository,
pessary, microemulsions, nanoemulsion, microparticles, nanoparticles, controlled
release delivery systems, transdermal delivery systems, and targeted delivery systems
such as conjugates with monoclonal antibodies or with other suitable carrier moieties.
In still another main embodiment of the present invention, wherein the
phannaceutically acceptable excipients are selected from a group comprising:
i. diluent such as lactose, mannitol, sorbitol, microcrystalline
cellulose, sucrose, sodium citrate, dicalcium phosphate, or any
other ingredient of the similar nature alone or in a suitable
combination thereof;
ii. a binder such as gum tragacanth, gum acacia, methyl cellulose,
gelatin, polyvinyl pyrrolidone, starch or any other ingredient of
the similar nature alone or in a suitable combination thereof;
iii. a disintegrating agent such as agar-agar, calcium carbonate,
sodium carbonate, silicates, alginic acid, corn starch, potato tapioca
starch, primogel or any other ingredient of the similar nature alone
or in a suitable combination thereof;
iv. a lubricant such as magnesium stearate, calcium stearate or
steorotes, talc, solid polyethylene glycols, sodium lauryl sulphate
or any other ingredient of the similar nature alone or in a suitable
combination thereof;
v. a glidant such as colloidal silicon dioxide or any other ingredient
of the similar nature alone or in a suitable combination thereof;
vi. a sweetening agent such as sucrose, saccharin or any other
ingredient of the similar nature alone or in a suitable combination
thereof;
vii. a flavoring agent such as peppermint, methyl salicylate, orange
flavor, vanilla flavor, or any other phannaceutically acceptable
flavor alone or in a suitable combination thereof;
viii. a wetting agents such as cetyl alcohol, glyceryl monostearate or
any other pharmaceutically acceptable flavor alone or in a suitable
combination thereof;
ix. a absorbents such as kaolin, bentonite clay or any other
pharmaceutically acceptable flavor alone or in a suitable
combination thereof; and
x. a solution retarding agents such as wax, paraffin or any other
pharmaceutically acceptable flavor alone or in a suitable
combination thereof.
In another main embodiment of the present invention, wherein a process for the
preparation of compounds of formula I, said process comprising steps of:
a. reacting a compound of formula V in which substituents R2 and R6 are
arranged in the (3R,4R) configuration: wherein R1 and R2 are as defined in
formula 1 and R6 is phenyl substituted with a hydroxy substituents at C2,
C3 or C4, preferably at C4 with a compound of formula VI, VII, VIII, neat
or in an aprotic solvent which includes dimethylsulphoxide,
dimethylformamide in the presence of a base such as K^COa at
temperature ranging between 50 to 120°C,
b. obtaining compounds of structure IX (a-c) wherein R1 and R2 are as
R'O
defined in formula 1,
(Figure Removed)
c. reacting compound of formula IX a-c with a nucleophile preferably an
amine of formula X wherein R7 and R8 are individually hydrogen, C1-C6-
alkyl which includes straight chain as well as branched alkyl groups such
as methyl, ethyl, propyl, isopropyl, butyl, isobutyl Cl-C6-cycloalkyl
which includes cyclopropane, cyclobutane, cyclopentane, cyclohexane or
form a C3-C7 heterocyclic ring, saturated or unsaturated, containing one
d.
or two heteroatoms independently selected from the group comprising O,
S and N, optionally being substituted with 1,2,3 substituents independently
selected from the group comprising H, OH, halogen, nitro, cyano, SH,
SR4, trihalo-Cl-C6-alkyl, Cl-C6-alkyl and Cl-C6-alkoxy, wherein R4 is
defined above, either neat or in the presence of organic solvent such as
benzene, dimethylsulphoxide, dimethylformamide, and
obtaining compounds of formula XI a-c, optionally converting the amino
derivative into their corresponding salts such as HCL, fumerate, citrate by
treating the free base with the corresponding acid.
(Figure Removed)
e. wherein Y, R and R are as defined above.
In still another main embodiment of the present invention, wherein a method of
preventing and/or treating estrogen-related disease conditions in a subject in need thereof,
said method comprising step of administering to the subject, a pharmaceutically effective
amount of compounds of formula 1, or its salts, optionally along with pharmaceutically
acceptable excipients.
In still another main embodiment of the present invention, wherein the salts are
selected from a group comprising acid addition salts consisting of formate, acetate,
phenyl acetate, trifluroacetate, acrylate, ascorbate, benzoate, chlorobenzoates,
bromobezoates, iodobenzoates, nitrobenzoates, hydroxybenzoates, alkylbenzoates,
alkyloxybenzoates, alkoxycarbonylbenzoates, naphthalene-2 benzoate, butyrates,
phenylbutyrates, hydroxybutyrates, caprate, caprylate, cinnamate, mandelate,
mesylate, citrate, tartarate, fumarate, heptanoate, hippurate, lactate, malate, maleate,
malonate, nicotinate, isonicotinate, oxalate, phthalate, terephthalate, phosphate,
monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate,
propiolate, propionate, phenylpropionate, salicylate, sebacte, succinate, suberate,
sulphate, bisulphate, pyrosulphate, sulphite, bisulphate, sulphonate, benzene
sulphonate, bromobenzene sulphonates, chlorobenzene sulphonates, ethane
sulphonates, methane sulphonates, naphthalene sulphonates, toluene sulphonates, and
the likes. Additionally, the invention includes alkyl or aryl halides addtion salts of the
compounds of this invention, wherein the alkyl halide is selected from a group
comprising C\ to Cig alkyl halide, and aryl halide is selected from a group comprising
benzyl halide and substituted benzyl halide.
In still another main embodiment of the present invention, wherein most preferred salts
are fumerate, ascorbate, hydrochloride, and methyl iodide.
In still another main embodiment of the present invention, wherein the administration is
through various routes selected from a group comprising oral, systemic, local, and topical
delivery selected from a group consisting of intravenous, intra-arterial, intra-muscular,
subcutaneous, intra-peritoneal, intra-dermal, buccal, intranasal, inhalation, vaginal, rectal,
and transdermal.
In still another main embodiment of the present invention, wherein the preferred route of
administration is oral route.
In still another main embodiment of the present invention, wherein the physical forms of
the compound of formula 1 and its salts could be gelatin capsules or compressed into the
tablets or pills or may be formulated in the form of lozenges, inclusion complexes with
cyclodextrin derivatives, injectable depo formulations, aerosols, granules, powders, oral
liquids, mucosal adhesive formulations, gel formulations, troches, elixirs, suspensions,
syrups, wafers, liposomal delivery systems, implants, suppository, pessary,
microemulsions, nanoemulsion, microparticles, nanoparticles, controlled release delivery
systems, transdermal delivery systems, and targeted delivery systems such as conjugates
with monoclonal antibodies or with other suitable carrier moieties.
In still another main embodiment of the present invention, wherein the pharmaceutically
acceptable excipients are selected from a group comprising:
i. diluent such as lactose, mannitol, sorbitol, microcrystalline
cellulose, sucrose, sodium citrate, dicalcium phosphate, or
any other ingredient of the similar nature alone or in a
suitable combination thereof;
ii. a binder such as gum tragacanth, gum acacia, methyl
cellulose, gelatin, polyvinyl pyrrolidone, starch or any other
ingredient of the similar nature alone or in a suitable
combination thereof;
iii. a disintegrating agent such as agar-agar, calcium carbonate,
sodium carbonate, silicates, alginic acid, corn starch, potato
tapioca starch, primogel or any other ingredient of the
similar nature alone or in a suitable combination thereof;
iv. a lubricant such as magnesium stearate, calcium stearate or
steorotes, talc, solid polyethylene glycols, sodium lauryl
sulphate or any other ingredient of the similar nature alone
or in a suitable combination thereof;
v. a glidant such as colloidal silicon dioxide or any other
ingredient of the similar nature alone or in a suitable
combination thereof;
vi. a sweetening agent such as sucrose, saccharin or any other
ingredient of the similar nature alone or in a suitable
combination thereof;
vii. a flavoring agent such as peppermint, methyl salicylate,
orange flavor, vanilla flavor, or any other pharmaceutically
acceptable flavor alone or in a suitable combination
thereof;
viii. a wetting agents such as cetyl alcohol, glyceryl
monostearate or any other pharmaceutically acceptable
flavor alone or in a suitable combination thereof;
ix. a absorbents such as kaolin, bentonite clay or any other
pharmaceutically acceptable flavor alone or in a suitable
combination thereof; and
x. a solution retarding agents such as wax, paraffin or any
other pharmaceutically acceptable flavor alone or in a
suitable combination thereof.
In still another main embodiment of the present invention, wherein said method helps in
preferably diseases or syndromes caused by an estrogen-deficient state, with Relative
Binding affinity (RBA) to estrogen receptors ranging between 5 to 7.
In still another main embodiment of the present invention, wherein said method helps in
disease conditions caused by osteoporosis, bone loss, and bone formation, with T/C ratio
of 0.6.
In still another main embodiment of the present invention, wherein said method helps in
disease conditions affecting cardiovascular systems, more particularly hyperlipidaemia,
thrombosis and vasomotor system.
In still another main embodiment of the present invention, wherein said method helps in
disease conditions showing neurodegenerative effects, more particularly, stroke, senile
dementia-Alzheimer type and Parkinson disease.
In still another main embodiment of the present invention, wherein said method helps in
disease conditions showing menopausal symptoms, more particularly, hot flushes,
urogenital atrophy, depression, mania, schizophrenia, urinary incontinence,
dysmenorrhea, dysfunctional uterine bleeding, acne, hirsutism, improper ovarian
development.
In still another main embodiment of the present invention, wherein said method helps in
disease conditions showing cancers, more particularly, prostatic carcinoma, breast cancer,
cancer of uterus, cancer of the cervix and colon cancer, with LCso ranging between 17 to
20 uM.
In still another main embodiment of the present invention, wherein the volume of the
tumor decreases by about 25%.
In still another main embodiment of the present invention, wherein said method helps
regulate fertility in humans and in other animals.
In still another main embodiment of the present invention, wherein said method helps in
threatened or habitual abortion.
In still another main embodiment of the present invention, wherein said method helps in
suppression of post-partum lactation.
In still another main embodiment of the present invention, wherein said method helps in
the management of certain physiological disorders, more particularly, obesity and
depression.
In still another main embodiment of the present invention, wherein said method helps
regulate of glucose metabolism in non-insulin dependent diabetes mellitus.
In accordance with the principal embodiment, the present invention provides a class of
novel (3R,4R)-trans-3,4-diarylchroman derivatives of the formula (1) or
pharmaceutically acceptable salts or pharmaceutically acceptable compositions thereof in
which substituents R2 and R3 are arranged in the (3R,4R)-trans-configuration wherein:
R'isHorCl-C6alkyl; (1)
R2 is phenyl, optionally substituted with 1 to 5 substituents independently selected from
the group consisting of OH, Cl-C6-alkyl, halogen, nitro, cyano, SH, SR4'trihalo-Cl-C6-
alkyl, Cl-C6-alkoxy and phenyl, wherein R4 is C1-C6 alkyl; C3-C7 cycloalkyl;
R3 is phenyl substituted with O-R5 wherein R5 has the formula (II), (III) or (IV)
OH OH
wherein Y is chosen^from NHR4, NR1? NHCOR4, NHSO2R^)CONHR4, CONR4,
CONR4
2, COOH, COOR4, SO2R4, SOR4, SONHR4, SONR4
2, a C3-C7 heterocyclic ring,
saturated or unsaturated, containing one or two heteroatoms independently selected from
the group consisting of O, S and N, optionally being substituted with 1 to 3 substituents
independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH,
SR4, trihalo-Cl-C6- alkyl, C1-C6 -alkyl and Cl-C6-alkoxy, wherein R4 is as defined
above, and pharmaceutically acceptable esters, ethers and salts thereof.
The general chemical terms used in the above formula have their usual meanings.
For example the term Cl-C6-alkyl includes straight chain as well as branched alkyl
groups such as methyl as ethyl, propyl, isopropyl, butyl and isobutyl.
The term halogen means chloro, bromo, iodo and fluoro.
The term C3-C7-heterocyclic ring include groups such as pyrrolidinyl, pyrrolinyl,
imidazolyl, imidazolidinyl, pyrazolyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl,
pyrrol, 2H-pyrrol, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholino,
thiomorpholino, isothiazolyl, isozazolyl, oxazolyl, oxadiazolyl, thiadiazolyl and thiazolyl.
In an important embodiment, the present invention provides a pharmaceutical
composition comprising a therapeutically effective amount of a compound of formula 1
or a pharmaceutically acceptable salt thereof, alone or in a combination of an estrogen or
a progestin or both and one or more pharmaceutically acceptable carrier or excipients.
In another embodiment, the present invention provides a medical method of employing
the compounds of the present invention or pharmaceutically acceptable salts and
compositions thereof and methods of using such compounds for the prevention or
treatment of symptoms of estrogen deficiency or deprivation including estrogen deficient
or deprivation states in mammals, in particular osteoporosis, bone loss, bone formation,
cardiovascular effects more particularly hyperlipidaemia.
In another embodiment of the medical methods of the present invention, the compounds
of the present invention or pharmaceutically acceptable salts and compositions thereof
are employed in the prevention or the treatment of estrogen dependent cancers such as
cancer of breast.
In yet another alternative embodiment of the medical methods of the present invention,
the compounds of the present invention are employed in the prevention or the treatment
of disease conditions or disorders associated with an aberrant physiological response to
endogenous estrogen including regulation of fertility in humans and in other animals.
The present invention relates to the field of Pharmaceuticals and organic chemistry and
provides new (3R,4R)-trans-3,4-diarylchroman derivatives, their pharmaceutically
acceptable salts and compositions that are useful for the prevention or treatment of
various medical indications associated with estrogen dependent or independent diseases
or syndromes, preferably in prevention or treatment of diseases and syndromes caused
by:
(a) estrogen deficient or deprivation state in a mammal, in particular osteoporosis,
bone loss, bone formation, cardiovascular effects more particularly
hyperlipidaemia, thrombosis and vasomotor system, neurodegenerative effects
such as stroke, senile dementia-Alzheimer type and Parkinson disease,
menopausal symptoms including hot flushes, urogenital atrophy, depression,
mania, schizophrenia and the like, urinary incontinence, relief of dysmenorrhea;
relief of dysfunctional uterine bleeding, an aid in ovarian development, treatment
of acne and hirsutism;
(b) estrogen dependent or estrogen independent cancers such as prostatic carcinoma,
cancer of breast, cancer of uterus, cancer of the cervix and cancer of the colon;
(c) an aid in ovarian development or function;
(d) control or regulation of fertility in humans and in other animals;
(e) prevention of threatened or habitual abortion;
(f) suppression of post-partum lactation;
(g) physiological disorders such as obesity, depression etc.;
(h) regulation of glucose metabolism in non-insulin dependent diabetes mellitus
The present invention further relates to the processes for the preparation of
pharmaceutically active compounds, their pharmaceutically acceptable salts and
compositions of the principal aspect of the present invention.
The present invention provides novel (3R,4R)-trans-3,4-diarylchroman derivatives of the
formula (1) or pharmaceutically acceptable salts or pharmaceutically acceptable
compositions thereof in which substituents R2 and R3 are arranged in the (3R,4R)-transconfiguration
wherein:
(Figure Removed)
R'isHorCl-C6alkyl; d)
R2 is phenyl, optionally substituted with 1 to 5 substituents independently selected from
the group consisting of OH, Cl-C6-alkyl, halogen, nitro, cyano, SH, SR4'trihalo-Cl-C6-
alkyl, Cl-C6-alkoxy and phenyl, wherein R4 is C1-C6 alkyl; C3-C7 cycloalkyl;
R3 is phenyl substituted with 0-R5 wherein R5 has the formula (II), (III) or (IV)
OH OH OH
(II) (III) (IV)
wherein Y is chosen from NHR4, NR4
2, NHCOR4, NHSO2R4, CONHR4, CONR4,
CONR4
2, COOH, COOR4, SO2R4, SOR4, SONHR4, SONR4
2, a C3-C7 heterocyclic ring,
saturated or unsaturated, containing one or two heteroatoms independently selected from
the group consisting of O, S and N, optionally being substituted with 1 to 3 substituents
independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH,
SR4, trihalo-Cl-C6- alkyl, C1-C6 -alkyl and Cl-C6-alkoxy, wherein R4 is as defined
above, and pharmaceutically acceptable esters, ethers and salts thereof.
The general chemical terms used in the above formula have their usual meanings.
For example the term Cl-C6-alkyl includes straight chain as well as branched alkyl
groups such as methyl as ethyl, propyl, isopropyl, butyl and isobutyl.
The term halogen means chlofo, bromo, iodo and fluoro.
The term C3-C7-heterocyclic ring include groups such as pyrrolidinyl, pyrrolinyl,
imidazolyl, imidazolidinyl, pyrazolyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl,
pyrrol, 2H-pyrrol, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholino,
thiomorpholino, isothiazolyl, isozazolyl, oxazolyl, oxadiazolyl, thiadiazolyl and thiazolyl.
The compounds of this invention or pharmaceutically acceptable salts and compositions
thereof are novel Select--e Estrogen Receptor Modulators and provide methods of using
such compounds for the prevention or treatment of symptoms of estrogen deficiency or
deprivation including estrogen deficient or deprivation state in mammals, in particular
osteoporosis, bone loss, bone formation, cardiovascular effects more particularly
hyperlipidaemia, prevention or the treatment of estrogen dependent or estrogen
independent cancers such as cancer of breast and control or regulation of fertility in
humans and in other animals.
The term "estrogen deficiency or deprivation" is meant to imply the conditions where the
optimal level of estrogen is absent. This level varies from one tissue to another depending
on the function of the tissue. Thus, in some cases, estrogen deficiency or deprivation may
be total absence of estrogen, whereas in other cases, deficiency or deprivation may
involve estrogen levels, which are too low for proper tissue function. In women, the two
most common causes of estrogen deprivation are menopause and ovariectomy, although
other conditions may be causative.
The term "pharmaceutically acceptable salts" as used through out this specification and
the appended claims denotes salts of the types disclosed in the article by Berge et al. (J.
Phramaceutical Sciences, 66 (1), 1-19, 1977). Suitable pharmaceutically acceptable salts
include salts formed by in-organic acids such as hydrochloric acid, hydrobromic acid,
hydroiodic acid, nitric acid, sulphuric acid, phosphoric acid, hypophosphoric acid, and
the like, as well as the salts derived from organic acids such as aliphatic mono and
dicarboxylic acids, phenyl substituted alkanoic acids, aromatic acids, aliphatic and
aromatic sulphonic acids. Also, the salts derived from alkyl halides (preferably, methyl
iodide) and aryl halides.
Such pharmaceutically acceptable acid addition salts include formate, acetate, phenyl
acetate, trifluroacetate, acrylate, ascorbate, benzoate, chlorobenzoates,
bromobezoates, iodobenzoates, nitrobenzoates, hydroxybenzoates, alkylbenzoates,
alkyloxybenzoates, alkoxycarbonylbenzoates, naphthalene-2 benzoate, butyrates,
phenylbutyrates, hydroxybutyrates, caprate, caprylate, cinnamate. mandelate,
mesylate, citrate, tartarate, fumarate, heptanoate, hippurate, lactate, malate, maleate,
malonate, nicotinate, isonicotinate, oxalate, phthalate, terephthalate, phosphate,
monohydrogen phosphate, dihydrogen phosphate, metaphosphate. pyrophosphate,
propiolate, propionate, phenylpropionate, salicylate, sebacte, succinate, suberate,
sulphate, bisulphate, pyrosulphate, sulphite, bisulphate, sulphonate, benzene
sulphonate, bromobenzene sulphonates, chlorobenzene sulphonates, ethane
sulphonates, methane sulphonates, naphthalene sulphonates, toluene sulphonates,
and the like. Additionally, the invention includes alkyl or aryl halides addtion salts of
the compounds of this invention, wherein the alkyl halide is selected from a group
comprising d to Cis alkyl halide, and aryl halide is selected from a group comprising
benzyl halide and substituted benzyl halide.
Most preferred salts are fumarate or ascorbate or hydrochloride.
Pharmaceutical compositions of the compound of the present invention or a
pharmaceutically acceptable salt thereof may be prepared by procedures known in the art
using pharmaceutically acceptable excipients known in the art.
Methods of preventing or treating disorders or disease conditions mentioned herein
comprise administering, to an individual human being or any other mammal or any other
animal in need of such treatment, a therapeutically effective amount of one or more of the
compounds of this invention or a pharmaceutically acceptable salt or a pharmaceutically
acceptable composition thereof with one or more of the pharmaceutically acceptable
carriers, excipients etc.
The dosage regimen and the mode of administration of the compound of this invention or
a pharmaceutically acceptable salt or a pharmaceutically acceptable composition thereof
with one or more of the pharmaceutically acceptable carriers, excipients etc. will vary
according to the type of disorder or disease conditions described herein and will be
subject to the judgment of the medical practitioner involved.
The compound of this invention or a pharmaceutically acceptable salt or a
pharmaceutically acceptable composition thereof with one or more of the
pharmaceutically acceptable carriers, excipients etc. may be effectively administered in
doses ranging from 0.1 mg to 1000 mg, more preferably in doses ranging from 0.5 to 500
or still more preferably in the doses ranging from 1 mg to 100 mg weekly or bi-weekly or
daily or twice a day or three times a day or in still more divided doses.
Therapeutically effective amounts of a compound of the present invention or a
pharmaceutically acceptable salt thereof may be enclosed in gelatin capsules or
compressed into the tablets or pills or may be formulated in the form of lozenges,
inclusion complexes with cyclodextrin derivatives, injectable depo formulations,
aerosols, granules, powders, oral liquids, mucosal adhesive formulations, gel
formulations, troches, elixirs, suspensions, syrups, wafers, liposomal delivery systems,
implants, suppository, pessary, microemulsions, nanoemulsion, microparticles,
nanoparticles, controlled release delivery systems, transdermal delivery systems, targeted
delivery systems such as conjugates with monoclonal antibodies or with other suitable
carrier moieties.
Such doses may be administered by any appropriate route for example, oral, systemic,
local or topical delivery for example, intravenous, intra-arterial, intra-muscular,
subcutaneous, intra-peritoneal, intra-dermal, buccal, intranasal, inhalation, vaginal, rectal,
transdermal or any other suitable means in any conventional liquid or solid dosage form
to achieve, conventional delivery, controlled delivery or targeted delivery of the
compounds of this invention or a pharmaceutically acceptable salt or a pharmaceutically
acceptable composition thereof with one or more of the pharmaceutically acceptable
carriers, excipients etc.
A preferred mode of administration of a compound of the present invention or a
pharmaceutically acceptable salt or a pharmaceutically acceptable composition thereof is
oral.
Oral compositions will generally comprise of a compound of the present invention or a
pharmaceutically acceptable salt thereof and one or more of the pharmaceutically
acceptable excipients.
The oral compositions such as tablets, pills, capsules, powders, granules, and the like may
contain any of the following pharmaceutically acceptable excipients:
1. a diluent such as lactose, mannitol, sorbitol, microcrystalline cellulose, sucrose,
sodium citrate, dicalcium phosphate, or any other ingredient of the similar nature
alone or in a suitable combination thereof;
2. a binder such as gum tragacanth, gum acacia, methyl cellulose, gelatin, polyvinyl
pyrrolidone, starch or any other ingredient of the similar nature alone or in a
suitable combination thereof;
3. a disintegrating agent such as agar-agar, calcium carbonate, sodium carbonate,
silicates, alginic acid, corn starch, potato tapioca starch, primogel or any other
ingredient of the similar nature alone or in a suitable combination thereof;
4. a lubricant such as magnesium stearate, calcium stearate or steorotes, talc, solid
polyethylene glycols, sodium lauryl sulphate or any other ingredient of the similar
nature alone or in a suitable combination thereof;
5. a glidant such as colloidal silicon dioxide or any other ingredient of the similar
nature alone or in a suitable combination thereof;
6. a sweetening agent such as sucrose, saccharin or any other ingredient of the
similar nature alone or in a suitable combination thereof;
7. a flavoring agent such as peppermint, methyl salicylate, orange flavor, vanilla
flavor, or any other pharmaceutically acceptable flavor alone or in a suitable
combination thereof;
8. wetting agents such as cetyl alcohol, glyceryl monostearate or any other
pharmaceutically acceptable flavor alone or in a suitable combination thereof;
9. absorbents such as kaolin, bentonite clay or any other pharmaceutically
acceptable flavor alone or in a suitable combination thereof;
10. solution retarding agents such as wax, paraffin or any other pharmaceutically
acceptable flavor alone or in a suitable combination thereof.
In a preferred embodiment, the present invention is concerned with compounds where R3
is phenyl substituted with OR5 wherein R5 has the formula II.
In another preferred embodiment, the present invention is concerned with compounds
wherein R3 is phenyl substituted with -OR5 wherein R5 has the formula III and wherein Y
is chosen from NHR4, NR4
2, NHCOR4, NHSO2R4, CONHR4, CONR4
2, COOH, COOR4,
SO2R4, SOR4, SONHR4, or SONR4
In another preferred embodiment, the present invention is concerned with compounds
wherein R3 is phenyl substituted with - OR5 wherein R5 has the formula III and wherein
Y is a C3-C7 heterocyclic ring, saturated or unsaturated, containing one or two
heteroatoms independently selected from the group consisting of O, S and N, optionally
being substituted with 1 to 3 substituents independently selected from the group
consisting of H, OH, halogen, nitro, cyano, SH, SR4, trihalo-Cl-C6 -alkyl and C1-C6-
alkoxy.
In another preferred embodiment, the present invention is concerned with compounds
wherein R3 is phenyl substituted with -OR5 wherein R5 has the formula IV.
In another preferred embodiment, the present invention is concerned with compounds
wherein R3 is phenyl substituted with -OR5 wherein R5 has the formula IV and wherein Y
is chosen from NHR4, NR4
2, NHCOR4, NHS02R4, CONR, CONR4
COOH, COOR4,
SO2R4, SOR4, SONHR4, SONR4
In another preferred embodiment, the present invention is concerned with compounds
wherein R3 is phenyl substituted with -OR5 wherein R5 has the formula IV and wherein Y
is a C3-C7 heterocyclic ring, saturated or containing one or two heteroatoms
independently selected from the group consisting of O, S and N, optionally being
substituted with 1 to 3 substituents independently selected from the group consisting of H,
OH, halogen, nitro, cyano, SH, SR4, trihalo-Cl-C6 - alkyl and C1-C6 -alkoxy.
In another preferred embodiment, the present invention is concerned with compounds in
which OR1 is substituted at C5, C6, C7, or C8 position. In another preferred embodiment,
the present invention is concerned with compounds in which OR1 is placed at C7 position.
In another preferred embodiment, the present invention is concerned with compounds in
which R1 is H, methyl or ethyl, preferably methyl.
In another preferred embodiment, the present invention is concerned with compounds in
which R2 is phenyl optionally substituted with 1 to 5 substituents independently selected
from the group consisting of OH, Cl-C6-alkyl halogen, cyano, trihalo-Cl-C6 -alkyl and
Cl-C6-alkoxy, preferably R2 is phenyl.
In another preferred embodiment, the present invention is concerned with compounds in
which R4 is methyl, ethyl, propyl, isopropyl, butyl, n-butyl, isobutyl, phenyl, hexyl,
preferably butyl.
The compounds of the invention may be prepared by resorting to the chroman chemistry
which is well-known in the art, for example in PK Arora, PL Kole and S Ray, Indian J
Chem 20 B, 41-5, 1981; S Ray, PK Grover and N Anand, Indian J Chem 9, 727-8, 1971;
S Ray, PK Grover, VP Kamboj, BS Setty, AB Kar and N Anand, J Med Chem 19, 276-9,
1976; M Salman, S Ray, AK Agarwal, S Durani, BS Setty, VP Kamboj and N Anand, J
Med Chem 26, 592-5, 1983; C Teo, K Sim, Bull Singapore Natl Inst Chem 22, 69-74,
1994; M Salman, PK Arora, S Ray, RC Srimal, Indian J Pharm Sci 49, 43-47, 1987.
However, the invention is further more concerned with a general method of preparation of
compounds of formula 1 comprising the steps:
a), reacting a compound of formula V in which substituents R2 and R6 are arranged in the
(3R,4R) configuration: wherein R1 and R2 are as defined in formula 1 and R6 is phenyl
substituted with a hydroxy substituent at C2, C3 or C4, preferably at C4 with a
compound of formula VI, VII, VIII, neat or in an aprotic solvent which includes
dimethylsulphoxide, dimethylformamide in the presence of a base such as ^COs at
elevated temperature (50-120°C) to form a compound of structure IX (a-c) wherein R1
and R2 are as defined above.
(Figure Removed)
b). reacting compound of formula (IX a-c) with a nucleophile preferably an amine of
formula X wherein R7 and R8 are individually hydrogen, Cl-C6-alkyl which includes
straight chain as well as branched alkyl groups such as methyl, ethyl, propyl,
isopropyl, butyl, isobutyl C3-C7-cycloalkyl which includes cyclopropane,
cyclobutane, cyclopentane, cyclohexane, cycloheptane or form a C3-C7 heterocyclic
ring, saturated or unsaturated, containing one or two heteroatoms independently
selected from the group consisting of O, S and N, optionally being substituted with
1,2,3 substituents independently selected from the group consisting of H, OH,
halogen, nitro, cyano, SH, SR4, trihalo-Cl-C6-alkyl, Cl-C6-alkyl and Cl-C6-alkoxy,
wherein R4 is defined above, either neat or in the presence of organic solvent such as
benzene, dimethylsulphoxide, dimethylformamide, to form a compound structure (XI
a-c), optionally converting the amino derivative into their corresponding salts such as
HCL, fumerate, citrate by treating the free base with the corresponding acid.
(Figure Removed)
wherein Y, R1 and R2 are as defined above.
Further, formula 1 compounds may then be formed as desired. Specific preparations of
the compounds of the present invention are described below. Modifications to the above
methods may be necessary to accommodate reactive functionalities of particular
substituents. Such modification would be both apparent to, and readily ascertained by,
those skilled in the art.
Although the free base form of the compounds of the formula 1 can be used in the
methods of the present invention, it is preferred to prepare and use a pharmaceutically
acceptable salt form. Thus, the compounds used in the methods of this invention
primarily form pharmaceutically acceptable acid addition salts with a wide variety of
organic and inorganic acids, and include the physiologically acceptable salts which
are often used in the pharmaceutical chemistry. Such salts are also part of this
invention. Typical inorganic acids used to form such salts include hydrochloric,
hydrobromic, hydroiodic, nitric, sulphuric, phosphoric, hypophosphoric, and the like.
Salts derived from the organic acids, such as aliphatic mono and dicarboxylic acids,
phenyl substituted alkanoic acids, hydroxyl alkanoic acids, and hydroxyl alkandioic
acids, aromatic acids, aliphatic and aromatic sulphonic acids, may also be used. Such
pharmaceutically acceptable salts thus include acetate, phenyl acetate,
triflurocacetate, acrylate, ascorbate, benzoate, chlorobenzoate, nitrobenzoate,
dinitrobenzoate, hydroxyl benzoate, methoxy benzoate, methyl benzoate, acetoxy
benzoate, hydrochloride, hydrobromide, hydroiodide, butyrate, phenyl butyrate,
hydroxyl butyrate, caprate, caprylate, cinnamate, citrate, formate, succinate, fumarate,
glycolate, heptanoate, hippurate, maleate, lactate, malate, hydroxyl maleate,
malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate,
terephthalate, phosphate, monohydrogen phosphate, dihydrogen phosphate,
metaphosphate, pyrpphosphate, propioplate, propionate, phenylpropionate, salicylate,
sebacate, sulphate, bisulphate, sulphite, bisulphate, sulphonate, benzene sulphonate,
p-bromobenzenesulphonate, p-chlorobenzenesulphonate, ethane sulphonate, methane
sulphonate, tartarate and the like. Additionally, the invention includes alkyl or aryl
halides addtion salts of the compounds of this invention, wherein the alkyl halide is
selected from a group comprising Ci to C|g alkyl halide, and aryl halide is selected
from a group comprising benzyl halide and substituted benzyl halide.
A preferred salts are fumerate, ascorbate, methyl iodide, and hydrochloride salt.
Following examples are presented to further illustrate the preparation of the compounds
of the present invention. It is not intended that the invention be limited in scope by
reason of any of the following examples:
Example 1
3R,4R-/raif5-2-dimethyl-3-phenyl-4-(4-[{2R)-(2,3-epoxy-propyloxy)-phenyl]-7-
methoxychroman: (IX a: R\ = Me, R2 = phenyl):
A mixture of 3R,4R-/rans-2,2-dimethyl-3-phenyl-4-[4-hydroxy phenyl]-7-
methoxychroman (0.7g, 1.94 mmol), anhydrous potassium carbonate (2.5 g, 18 mmol),
R (-) epichlorohydrin (0.4 ml, 5.11 mmol) in dry DMSO (10 ml) was stirred at 65°C for
10 hrs. Reaction mixture was poured onto ice-cold water and extracted with ethylacetate,
washed with water, dried over anhydrous sodium sulphate and concentrated to give an
oil, which was crystallized from benzene-hexane to give the desired product.
Yield: 0.6 g (74.18 %), m.p.: 120°C, [a]D
20 (C = 1, MeOH): -201.96.
IR (KBr, cm'1): 1454, 1506, 1585, 1616 (ArH), 1217 (OMe), 2933 (CH), 1382 (gemdimethyl),
758 (C-0).
'H NMR (5, CDC13): 1.2 (s, 3H, gem-dimethyl), 1.3 (s, 3H, gem-dimethyl), 3.1 (d, 1H,
monobenzylic H, J=12 Hz), 4.2 (d, 1H, dibenzylic H, J=12 Hz), 6.3-7.3 (m, 12H, ArH),
2.8 (d, 2H, r^nQ), 4.0 (d, 2H, OCH2), 3.3 (m, 1H, iH-cH2 { j ) Analysis:
(C27H2804) Calculated (Cald): C,77.88%; H,6.73%, Observed (Obsd): C,77.85%;
H,6.75%,Mass:m/z416.
Example 2
3R,4R-/rart$-2,2-dimethyl-3-phenyl-4-(4-[{2R)-(3-n-butyIamino-2-hydroxy}
propyloxy]-phenyl)-7-methoxychroman (HC1 salt): (XI a: RI = Me, R2 = phenyl, Y =
butylamine):
A mixture of 3R,4R-frara'-2,2-dimemyl-3-phenyl-4-(4-[{2R)-(2,3-epoxy- propyloxy)-
phenyl]-7-methoxychroman (0.2 g, 0.48 mmol), n-butylamine (0.5 ml, 5.06 mmol) and
ethanol (15 ml) was refluxed for 3 hrs. Ethanol was distilled off. The obtained residue
was purified by passing through basic alumina column using hexane-benzene as eluant.
The free base thus obtained was converted into its hydrochloride by treating with
ethanolic HC1 and crystallized from anhydrous ethanol-diethylether to give the desired
product.
Yield: 0.160 g, (63.33%) m.p.: 193°C [a]D
20 (C = 1, MeOH): -160.
IR (KBr, cm'1): 1506, 1585, 1614 (ArH), 1215 (OMe), 2935 (CH), 3417 (OH), 3719
(amine) 1380 (gem-dimethyl).
'H NMR (8, CDC13): 1.2 (s, 3H, gem-dimethyl), 1.3 (s, 3H, gem-dimethyl), 3.1 (d, 1H,
monobenzylic H, J=12 Hz), 4.2 (d, 1H, dibenzylic H, 3=12 Hz), 3.76 (s, 3H, OMe), 3.83
(d, 2H, OCH2), 4.0 (m, 1H, CHOH), 2.77 (d, 2H, CH2N), 0.87-0.94 (t, 3H, NCH2), 1.20-
1.27 (q, 3H, CH2CH3), 2.59-2.71 (m, 4H, 2 x (CH2)2).
Analysis: (C3iH39O4N) Cald: C,76.07%; H,7.98%; N,2.86%, Obsd: C,76.02%; H,7.95%;
N,2.88%, Mass: m/z 489 [M+-37].
Add here
Example 3
3R,4R-fr propyloxy]-phenyl)-7-methoxychroman (citric acid salt): (XI a: RI = Me, R2 = phenyl,
Y = butylamine):
A mixture of 3R,4R-/r phenyl]-7-methoxychroman (0.2 g, 0.48 mmol), n-butylamine (0.5 ml, 5.06 mmol) and
ethanol (15 ml) was refluxed for 3 hrs. Ethanol was distilled off. The obtained residue
was purified by passing through basic alumina column using hexane-benzene as eluant.
The free base thus obtained was converted into its citrate and crystallized from anhydrous
ethanol-diethylether to give the desired product.
Yield: 0.165 g, (63.5%) m.p.: 142°C [oc]D
20 (C = 1, MeOH): -136.
IR (KBr, cm'1): 1437, 1506, 1589, 1614 (ArH), 1240 (OMe), 2966 (CH), 3429 (OH),
3758 (amine) 1380 (gem-dimethyl).
'H NMR (5, CDC13): 1.2 (s, 3H, gem-dimethyl), 1.3 (s, 3H, gem-dimethyl), 3.1 (d, 1H,
monobenzylic H, J=12 Hz), 4.2 (d, 1H, dibenzylic H, J=12 Hz), 3.72 (s, 3H, OMe), 3.89-
3.93 (d, 2H, OCH2), 4.18 (m, 1H, CHOH), 2.77 (d, 2H, CH2N), 0.79-0.82 (t, 3H, NCH2),
1.22-1.35 (q, 3H, CH2CH3), 2.62-2.85 (m, 4H, 2 x (CH2)2).
Mass: m/z 489 [M+-192].
Example 4
3R,4R-a/is-2,2-dimethyl-3-phenyl-4-(4-[{2R)-3-pyrrolidino-2-hydroxy} propyloxy]
phenyl)-7-methoxychroman (HC1 salt): (XI a: RI = Me, R2= phenyl, Y = pyrrolidine):
A mixture of 3R,4R-/raHs-2,2-dimethyl-3-phenyl-4-(4-[{2R)-(2,3-epoxy-propyloxy)-
phenyl]-7-methoxychroman (0.2 g, 0.48 mmol), pyrrolidine (0.5 ml, 5.99 mmol) in
absolute alcohol (15 ml) was refluxed for 3 hrs. Ethanol was distilled off and the residue
purified by passing through basic alumina column using hexane-benzene as eluent. The
free base thus obtained was converted into its hydrochloride by treating with ethanolic
HC1 and crystallized from anhydrous ethanol-diethylether to give the desired product.
Yield: 0.136 g (54.04%), m.p.: 135°C, [a]D
20 (C = 1, MeOH): -167.64.
IR (KBr, cm'1): 1508, 1585, 1610 (ArH), 1245 (OMe), 2927 (CH), 3415 (OH), 3715
(amine) 1370 (gem-dimethyl).
'H NMR (5, CDC13): 6.3-7.2 (m, 12H, ArH), 3.1 (d, 1H, monobenzylic H, J=12 Hz), 4.2
(d, 1H, dibenzylic H, J=12 Hz), 1.2 (s, 3H, gem-dimethyl), 1.3 (s, 3H, gem-dimethyl),
3.76 (s, 3H, MeO), 1.7-1.8 (m, 4H, 2 x CH2 of pyrrolidine), 2.41-2.49 (m, 4H, 2 x NCH2),
3.96 (m, 1H, CHOH), 3.8 (d, 2H, OCH2), 2.75 (d, 2H, CH2N).
Analysis: (C3iH37O4N), Cald: C,76.39%; H,7.59%; N,2.87%, Obsd: C,76.42%; H,7.57%;
N,2.83%, Mass: m/z 487 [M+-37].
Example 5
3R,4R-rra/i5-2^-dimethyl-3-phenyl-4-(4-[{2R)-3-piperidino-2-hydroxy} propyloxy]
phenyl)-7-methoxychroman (HC1 salt): (XI a: RI = Me, R2 = phenyl, Y = piperidine):
A mixture of 3R,4R-/m«5'-2,2-dimethyl-3-phenyl-4-(4-[{2R)-(2,3-epoxy-propyloxy)-
phenyl]-7-methoxychroman (0.160 g, 0.38 mmol), piperidine (0.28 ml, 2.8 mmol) in
absolute alcohol (15 ml) was refluxed for 4 hrs. Ethanol was distilled off and the residue
purified by passing through basic alumina column using hexane-benzene as eluent. The
free base thus obtained was converted into its hydrochloride by treating with ethanolic
HC1 and crystallized from anhydrous ethanol-diethylether to give the desired product.
Yield: 0.140 g (67.72%), m.p.: 130°C, [oc]D
20 (C = 1, MeOH): -101.50.
IR (KBr, cm'1): 1444, 1506, 1584, 1616 (ArH), 1217 (OMe), 2935 (CH), 3396 (OH),
3677 (amine), 1384 (gem-dimethyl).
'H NMR (8, CDC13): 1.2 (s, 3H, gem-dimethyl), 1.3 (s, 3H, gem-dimethyl), 3.76 (s, 3H,
MeO), 3.1 (d, 1H, monobenzylic H, J=12 Hz), 4.2 (d, 1H, dibenzylic H, J=12 Hz), 3.87
(d, 2H, OCH2), 3.9 (m, 1H, CHOH), 2.7 (d, 2H, CH2N) 6.3-7.2 (m, 12H, ArH), 1.5-1.67
(m, 6H, 3 x CH2 piperidine ring), 2.5-2.6 (m, 4H, 2 x NCH2).
Analysis: (C32H39O4N), Cald: C,76.65%; H,7.78%; N,2.79%, Obsd: C,76.62%; H,7.77%;
N,2.83%, Mass: m/z 501 [M+-37].
Example 6
3R,4R-/ra«5-2,2-dimethyl-3-phenyl-4-(4-[{2S)-(2,3-epoxy-propyloxy)-phenyl]-7-
methoxychroman: (IX b: RI = Me, R2= phenyl):
A mixture of 3R,4R-fra/w-2,2-dimethyl-3-phenyl-4-[4-hydroxy phenyl]-7-
methoxychroman (0.7 g, 1.94 mmol), anhydrous potassium carbonate (2.5 g, 18.0 mmol),
S (+) epichlorohydrin (0.4 ml, 5.11 mmol) in dry DMSO (10 ml) was stirred at 70°C for
10 hrs. Reaction mixture was poured onto ice-cold water and extracted with ethylacetate,
washed with water, dried over anhydrous sodium sulphate and concentrated to give an
oil, which was crystallized from benzene-hexane to give the desired product.
Yield:0.7 g (86.53%), m.p.: 118°C, [a]D
(C = 1, MeOH):-266.04.
IR (KBr, cm"1): 1454, 1506, 1583, 1616 (ArH), 1217 (OMe), 2931(CH), 1382 (gemdimethyl),
759 (C-0).
'H NMR (5, CDC13): 1.2 (s, 3H, gem-dimethyl), 1.3 (s, 3H, gem-dimethyl), 3.1 (d, 1H,
monobenzylic H, J=12 Hz), 4.2 (d, 1H, dibenzylic H, J=12 Hz), 6.3-7.2 (m, 12H, ArH),
2.8 (d, 2H,i H - c H ,) 4.0 (d, 2H, OCH2), 3.4 (m, 1H, i H - c H 2 i ).
Analysis: (C27H28O4), Cald: C,77.88%; H,6.73%, Obsd: C,77.85%; H,6.72%, Mass: m/z
416.
Example 7
3R,4R-rra«5-2^-dimethyl-3-phenyl-4-(4-{2S)-3-n-butylamino-2-
hydroxy}propy!oxy]-phenyl)-7-methoxychroman (HC1 salt): (XI b: RI = Me, R2 =
phenyl, Y = butylamine):
A mixture of 3R,4R-/ra«j-2,2-dimethyl-3-phenyl-4-(4-[{2S)-(2,3-epoxy-propyloxy)-
phenyl]-7-methoxychroman (0.2 g, 0.48 mmol), n-butylamine (0.4 ml, 4.04 mmol) in
absolute alcohol (15 ml) was refluxed for 3 hrs. Ethanol was distilled off and the residue
obtained was purified by passing through basic alumina column using hexane-benzene as
eluent. The free base thus obtained was converted into its hydrochloride by treating with
ethanolic HC1 and crystallized from anhydrous ethanol-diethylether to give the desired
product.
Yield: 0.130 g, (51.46%) m.p.: 140 °C, [oc]D
20 (C = 1, MeOH): -151.49.
IR (KBr, cm'1): 1465, 1494, 1593, 1614 (ArH), 1215 (OMe), 2943 (CH), 3398 (OH),
3683 (amine), 1340 (gem-dimethyl).
'H NMR (5, CDC13): 1.2 (s, 3H, gem-dimethyl), 1.3 (s, 3H, gem-dimethyl), 3.1 (d, 1H,
monobenzylic H, J=12 Hz), 4.2 (d, 1H, dibenzylic H, J=12 Hz), 3.76 (s, 3H, OMe), 3.8
(d, 2H, OCH2), 3.96 (m, 1H, CHOH), 0.86-0.94 (t, 3H, CH2CH3), 1.3 (q, 2H, NCH2),
2.58-2.74 (m, 4H, 2 x (CH2)2), 2.76 (d, 2H, CH2N).
Analysis: (C3iH39O4N), Cald: C,76.07%; H,7.98%; N,2.86%, Obsd: C,76.10%; H,7.98%;
N,2.85%, Mass: m/z 489 [M+-37].
Example 8
3R,4R-rrc/i5-2,2-dimethyl-3-phenyl-4-(4-[{2S)-3-pyrrolidino-2-hydroxy}propyloxy]
phenyl)-7-methoxychroman (HC1 salt): (XI b: RI = Me, R2= phenyl, Y = pyrrolidine)
A mixture of 3R,4R-Jrara-2,2-dimethyl-3-phenyl-4-(4-[{2S)-(2,3-epoxy-propyloxy)-
phenyl]-7-methoxychroman (0.2 g, 0.48 mmol), pyrrolidine (0.4 ml, 4.79 mmol) in
absolute alcohol (15 ml) was refluxed for 3 hrs. Ethanol was distilled off and the residue
thus obtained was purified by passing through basic alumina column using hexanebenzene
as eluent. The free base thus obtained was converted into its hydrochloride by
treating with ethanolic HC1 and crystallized from anhydrous ethanol and diethylether to
give the desired product.
Yield: 0.210 g (83.44%), m.p.: 140°C, [a]D
20 (C = 1, MeOH): -133.94
IR (KBr, cm'1): 1458, 1506, 1614 (ArH), 1217 (OMe), 2927 (CH), 3408 (OH), 3681
(amine), 13 80 (gem-dimethyl).
'H NMR (6, CDC13): 6.26-7.18 (m, 12H, ArH), 3.1 (d, 1H, monobenzylic H, J=12 Hz),
4.2 (d, 1H, dibenzylic H, J=12 Hz), 1.2 (s, 3H, gem-dimethyl), 1.3 (s, 3H, gem-dimethyl),
3.69 (s, 3H, MeO), 1.5-1.9 (m, 4H, 2 x CH2 pyrrolidine), 2.2-2.3 (m, 4H, 2 x NCH2), 4.0
(m, 1H, CHOH), 3.7 (d, 2H, OCH2), 2.75 (d, 2H, CH2N).
Analysis: (C3iH37O4N), Cald: C,76.39%; H,7.59%; N,2.87%, Obsd: C,76.33%; H,7.56%;
N,2.85%, Mass: m/z 487 [M+-37].
Example 9
3R,4R-7>a«5-2^-dimethyl-3-phenyl-4-(4-[{2S)-3-piperidino-2-hydroxy}propyloxy]
phenyl)-7-methoxychroman (HC1 salt): (XI b: RI = Me, R2 = phenyl, Y = piperidine):
A mixture of 3R,4R-/raws-2,2-dimethyl-3-phenyl-4-(4-[{2S)-(2,3-epoxy-propyloxy)-
phenyl]-7-methoxychroman (0.2 g, 0.48 mmol), piperidine (0.4 ml, 4.04 mmol) in
absolute alcohol (15 ml) was refluxed for 4 hrs. Ethanol was distilled off and the residue
thus obtained was purified by passing through basic alumina column using hexanebenzene
as eluent. The free base thus obtained was converted into its hydrochloride by
treating with ethanoiic HC1 and crystallized from anhydrous ethanol-dry ether to give the
desired product.
Yield:0.140 g (54.18%), m.p.: 168°C, [cc]D
(C - 1, MeOH): -148.84.
IR (KBr, cm-'): 1444, 1506, 1584, 1616 (ArH), 1217 (OMe), 2935 (CH), 3396 (OH),
3677 (amine), 1384 (gem-dimethyl).
'H NMR (5, CDC13): 1.2 (s, 3H, gem-dimethyl), 1.3 (s, 3H, gem-dimethyl), 3.76 (s, 3H,
MeO), 3.1 (d, 1H, monobenzylic H, J=12 Hz), 4.2 (d, 1H, dibenzylic H, J=12 Hz), 3.87
(d, 2H, OCH2), 3.9 (m, 1H, CHOH), 2.7 (d, 2H, CH2N) 6.3-7.2 (m, 12H, ArH), 1.5-1.67
(m, 6H, 3 x CH2 piperidine ring), 2.5-2.6 (m, 4H, 2 x NCH2).
Analysis: (C32H39O4N), Cald: C,76.65%; H,7.78%; N,2.79%, Obsd: C,76.58%; H,7.74%;
N,2.84%. Mass: m/z 501 [M+-37].
Example 10
3R,4R-7raws-2,2-dimethyl-3-phenyl-4-(4-(2,3-epoxypropyloxy)-phenyl)-7-methoxy
chroman : (IX c: R\ = Me, R2 = phenyl):
A mixture of 3R,4R-/ramc-2,2-dimethyl-3-phenyl-4-(4-hydroxy phenyl)-7-methoxy
chroman (0.5 g, 1.39 mmol), potassium carbonate (2 g, 14.4 mmol) in racemic
epichlorohydrin (10 ml, 127.8 mmol) was refluxed for 12 hrs. at 120°C. Potassium
carbonate was filtered off. Reaction mixture was extracted with ethyl acetate, washed
with water, dried over anhydrous sodium sulphate and concentrated to give an oil, which
was crystallized from methanol to give the desired product.
Yield: 0.454 g (78.58 %), m.p.: 113-115°C, [a]D
2° (C = 1, MeOH): -159.78.
IR (KBr, cm'1): 1431, 1506, 1575, 1614 (ArH), 1217 (OMe), 2927 (CH), 1379 (gemdimethyl),
767(C-O).
'H NMR (5, CDC13): 1.2 (s, 3H, gem-dimethyl), 1.3 (s, 3H, gem-dimethyl), 3.3 (d, 1H,
monobenzylic H, J=12 Hz), 4.6 (d, 1H, dibenzylic H, J=12 Hz), 6.4-7.3 (m, 12H, ArH),
3.77 (s, 3H, OMe), 2.8 (d, 2H, ) 4.10 (d, 2H OCH2), 3.1 (m, 1H,
Analysis: (C27H28O4), Cal£ Cf,77.88%; H,6.73%, Obsd: C,77.86%; H,6.72^,°Mass: m/z
416.
Example 11
3R,4R-7ra/i5-2^-dimethyl-3-phenyl-4-(4-(2-hydroxy-3n-butylaminopropyloxy)-
phenyl)-7-methoxychroman (HC1 salt): (XI c: R\ = Me, R2 = phenyl, Y = butylamine):
A mixture of 3R,4R-fr-am'-2,2-dimethyl-3-phenyl-4-[4-(2,3 epoxypropyloxy)-phenyl]-7-
methoxychroman (0.3 g, 0.72 mmol), n-butylamine (0.4 ml, 4.05 mmol) and absolute
alcohol (10 ml) was refluxed for 3 hrs. Ethanol was distilled off and residue purified by
passing through basic alumina column using hexane-benzene as eluent. The free base
thus obtained was converted into its hydrochloride by treating with ethanolic HC1 and
crystallized from anhydrous ethanol-diethylether to give the desired product.
Yield: 0.14 g (36.94 %), m.p.: 210°C, [cc]D
20 (C = 1, MeOH) :-170.23.
IR (KBr, cm'1): 1458, 1508, 1550, 1614 (ArH), 1232 (OMe), 2935 (CH), 3246 (OH),
3411 (amine), 1358 (gem-dimethyl).
'H NMR (8, CDC13):1.2 (s, 3H, gem-dimethyl), 1.3 (s, 3H, gem-dimethyl), 3.1 (d, 1H,
monobenzylic H, J=12 Hz), 4.2 (d, 1H, dibenzylic H, J=12 Hz), 3.77 (s, 3H, OMe), 1.4-
2.3 (m, 9H, NCH2C3H7), 2.7 (d, 2H, NCH2), 3.98 (d, 2H, OCH2), 4.0 (m, 1H, CHOH).
Analysis: (C3iH39O4N) Cald: C,76.07%; H,7.98%; N,2.86%; Obsd: C,76.1%; H,6.97%;
N,2.83%, Mass: m/z 489 [M+-37].
Example 12
3R,4R-rrans-2,2-dimethyl-3-phenyl-4-(4-(2-hydroxy-3-pyrrolidinopropyloxy)-
phenyl)-7-methoxy chroman (HC1 salt): (XI c: RI = Me, R2 = phenyl, Y = pyrrolidine)
A mixture of 3R,4R-/ran^-2,2-dimethyl-3-phenyl-4-(4(2,3 epoxypropyloxy)-phenyl)-7-
methoxychroman (0.9g, 2.16 mmol), pyrrolidine (5ml, 5.99mmol) in absolute alcohol (15
ml) was refluxed for 4 hrs. Ethanol was distilled off and passing through basic alumina
column using benzene-hexane as eluent purified the residue thus obtained. The free base
thus obtained was converted into its hydrochloride by treating with ethanolic HC1 and
crystallized from dry ethanol-diethylether to give the desired compound.
Yield: 0.9 g (79.46 %), m.p.: 180°C, [a]D
20 (C = 1, MeOH): -174.25.
IR (KBr, cm'1): 1456, 1506, 1556, 1612 (ArH), 1232 (OMe), 2945 (CH), 3258 (OH),
3506 (amine), 1370 (gem-dimethyl).
'H NMR (6, CDC13): 6.3-7.2 (m, 12H, ArH), 3.1 (d, 1H, monobenzylic H, J=12 Hz), 4.2
(d, 1H, dibenzylic H, J=12 Hz), 1.2 (s, 3H, gem-dimethyl), 1.3 (s, 3H, gem-dimethyl),
3.76 (s, 3H, MeO), 1.7-1.8 (m, 4H, 2 x CH2 of pyrrolidine), 2.41-2.49 (m, 4H, 2x NCH2),
3.96 (m, 1H, CHOH), 3.8 (d, 2H, OCH2), 2.75 (d, 2H, CH2N).
Analysis: (C3iH37O4N), Cald: C,76.39%; H,7.59%; N,2.87%, Obsd: C,76.42%; H,7.57%;
N,2.83%, Mass: m/z 487 [M+-37].
Example 13
3R,4R-r/-flws-2,2-dimethyl-3-phenyl-4-(4-(2-hydroxy-3-piperidinopropyloxy)-
phenyl)-7-methoxychroman (HC1 salt): (XI c: RI = Me, R2 = phenyl, Y = piperidine):
A mixture of 3R,4R-/ra«s-2,2-dimemyl-3-phenyl-4-[4-(2,3-epoxypropyloxy)-phenyl]-7-
methoxychroman (0.2 g, 0.48 mmol), piperidine (0.4 ml, 4.04 mmol) and absolute
alcohol (10 ml) was refluxed for 4 hrs. Ethanol was distilled off and residue purified by
passing through basic alumina column using hexane-benzene as eluant. The free base
thus obtained was converted into its hydrochloride by treating with ethanolic HC1 and
crystallized from anhydrous ethanol-diethylether to give the desired product.
Yield: 0.25g (96.74%), m.p.: 125-130°C, [a]D
20 (C = 1, MeOH): -143.14
IR (KBr, cm'1): 1444, 1505, 1584, 1615 (ArH), 1242 (OMe), 1383 (gem-dimethyl), 2934
(CH), 3403 (OH), 3647, 3785(amine).
'H NMR (8, CDC13): 1.2 (s, 3H, gem-dimethyl), 1.3 (s, 3H, gem-dimethyl), 3.76 (s, 3H,
MeO), 3.1 (d, 1H, monobenzylic H, J=12 Hz), 4.2 (d, 1H, dibenzylic H, J=12 Hz), 3.87
(d, 2H, OCH2), 3.9 (m, 1H, CHOH), 2.7 (d, 2H, CH2N) 6.3-7.2 (m, 12H, ArH), 1.5-1.67
(m, 6H, 3 x CH2 of piperidine ring), 2.5-2.6 (m, 4H, 2 x NCH2).
Analysis: (C32H39O4N), Cald: C,76.65%; H,7.78%; N,2.79%, Obsd: C,76.61%; H,7.77%;
N,2.81%, Mass: m/z 501 [M+-37].
Biological evaluation
The compounds of the present invention were evaluated for use for the prevention or
treatment of symptoms of estrogen deficiency or deprivation including estrogen deficient
or deprivation state in mammals, in particular osteoporosis, bone loss, bone formation,
cardiovascular effects more particularly hyperlipidaemia, prevention or the treatment of
estrogen dependent or estrogen independent cancers such as cancer of breast and control
or regulation of fertility in humans and in other animals. Detailed procedures for the
evaluation of the compounds of the present invention or pharmaceutically acceptable
salts or compositions thereof are described hereunder:
Test procedure for evaluation of antiosteoporosis (antiresorptive) activity in vitro
Test solutions of the compounds of the present invention are prepared in appropriate
solvents in concentration range of 5 millimolar to 400 millimolar, most preferably in
concentrations of 20 millimolar. 5 ul of each concentration are used for evaluation of
antiresorptive activity in vitro. In control experiments, 5 ul of appropriate solvent is used
in lieu of test compound. Femur bones are isolated from chick embryos on day 11 postovulation.
The adhering soft connective tissue is completely removed. Each femur bone
is then placed in a drop of phosphate buffered saline (PBS) and is transferred to BGJb
culture medium containing 45CaCl2 and incubated for 2 h. Labeled femur bones are
washed 2-3 times with PBS and transferred to BGJb medium containing parathyroid
hormone and cultured for 96 h in the presence or absence of the compound of invention
or the vehicle in BGJb medium. Contralateral femur of each fetus serves as
corresponding control. Culture medium with the respective treatment in each well is
changed after 48 h. On termination of the culture at 96 h, bones are transferred to 0.1 N
HC1 for 24 h. Radioactivity due to 45Ca in the spent medium collected at 48 and 96 h of
culture and HC1 extract at 96 h of culture is quantified by Liquid Scintillation
Spectrophotometer in 10 ml of the scintillation fluid. Bone resorbing activity is
expressed as percentage of 45Ca released into the culture medium and the effect of the
compound of invention as percent of the corresponding contra-lateral control or T/C ratio
as shown below:
45Ca resorption in presence of PTH + test agent
T/C ratio =
45Ca resorption in presence of PTH + vehicle
Appropriate solvents are selected from solvents like water, normal (physiological) saline,
phosphate buffered saline, phosphate buffer, DMSO alone or in a suitable combinations
thereof.
In accordance with the above test procedure, the compounds of the present invention, on
employing or administering their effective amounts, exhibit positive response by
inhibiting the PTH induced resorption of 45Ca from chick fetal bones in culture. The
compounds showing T/C ratio of considered active (Table 1). Activity in the above test procedure indicates that the
compounds of the present invention are useful as antiresorptive agents in the treatment of
post-menopausal osteoporosis.
Table 1: Inhibition in PTH-induced resorption of 45Ca from chick fetal bones in
culture
Compound
Example number 1
Example number 7
Example number 10
Example number 12
Concentration in ^M
100
100
100
100
T/C ratio
0.59
0.41
0.79
0.77
Test procedure for evaluation of antiosteoporosis activity in vivo
The in vivo antiosteoporosis activity is evaluated in colony-bred adult (3-4 month
old) female Sprague-Dawley rats or female retired breeder Sprague-Dawley rats (12-14
months old; parity >3). Animals are bilaterally ovariectomized (OVX) under light ether
anesthesia and treated with the compound of the present invention, 17-alfaethynylestradiol
(EE) or the vehicle once daily on days 1-30 post-ovariectomy (day 1:
day of bilateral ovariectomy) by the oral route. One group of females is sham operated
and treated similarly with the vehicle. Animals of all the groups are autopsied 24 h after
the last treatment. Before autopsy, 24 h fasting urine samples are collected in fresh
containers using all-glass metabolic cages and stored at -20°C until analyzed for calcium,
phosphorus and creatinine. At autopsy, about 5 ml blood samples are collected by
cardiac puncture from each rat under light ether anesthesia and serum is isolated and
stored at -20°C until analyzed for total and bone specific alkaline phosphatase,
osteocalcin and calcium.
Uterus of each rat is carefully excised, gently blotted, weighed and fixed for histology.
Representative sections (5 |Lim) from each uterus are stained with haematoxylin and eosin.
Femur and tibia of each rat are then dissected free of adhering tissue, fixed in 70%
ethanol in physiological saline and stored at -20°C until Bone Mineral Density (BMD)
measurement. Before autopsy, whole body scan of each rat for measurement of BMD is
performed on an Hologic QDR-4500A fan-beam densitometer, calibrated daily with
Hologic hydroxyapatite anthropomorphic spine phantom using manufacturer provided
software for small animals. BMD measurement of isolated bones is performed using
identical regions of interest. Serum total alkaline phosphatase, osteocalcin, calcium ion
content and urinary calcium and creatinine are estimated colorimetrically using
commercial kits.
Test procedure for evaluation of anti-hyperlipidaemic activity
The in vivo anti-hyperlipidaemic activity is evaluated in colony-bred adult (3-4 month
old) female Sprague-Dawley rats or female retired breeder Sprague-Dawley rats (12-14
months old; parity >3). Animals are bilaterally ovariectomized (OVX) under light ether
anesthesia and treated with the compound of the present invention, 17-alfaethynylestradiol
(EE) or the vehicle once daily on days 1-30 post-ovariectomy (day 1:
day of bilateral ovariectomy) by the oral route. One group of females is sham operated
and treated similarly with the vehicle. Animals of all the groups are autopsied 24 h after
the last treatment. At autopsy, about 5 ml blood samples are collected by cardiac
puncture from each rat under light ether anesthesia and serum is isolated and stored at 20°C until analyzed for total cholesterol. The total cholesterol concentration is measured
by a timed-end point method using a Beckman Synchron CX autoanalyser. In the
reaction, cholesterol estrase hydrolyses cholesterol esters to free cholesterol and fatty
acids. Free cholesterol is oxidized to cholestene-3-one and FbC^ by cholesterol oxidase.
Peroxidase catalyses :ie reaction of H^Oa with 4-amino antipyrine and phenol to produce
a colored quinoneimine product. Absorbance is recorded at 520 nm.
Test procedure for evaluation of antiproliferative/cvtotoxic activity in vitro
The procedure is based on the following methods: New colorimetric assay for anticancer
drug screening, Skehan et al., J Natn Cancer Inst, 82,1107, 1990 and Feasibility of a
high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines
83,757, 1991.
A fully confluent flask of MCF-7 cells in trypsinized and 104 cells/well are plated in a 96
welled flat bottomed plate in 200 ul Minimum Essential Medium (MEM), pH 7.4 and
allowed to attach for 24 h at 37°C in a humidified CC>2 incubator. Subsequently, the
compound of invention dissolved in DMSO or ethanol is added at a specified
concentration and further incubated for 48 h as before. The cells are then fixed in 50 ul
cold 50% TCA and incubated for 1 h at 4°C. The supernatant is discarded and the plate is
washed five times with deionized water and air dried. 100 ul of 0.4% (w/v)
Sulforhodamine B (SRB) in 1% acetic acid is added to each well and incubated at room
temperature for 30 minutes. Unbound SRB is removed by five washes with chilled 1%
acetic acid and the plate is air dried. 200ul of unbuffered 10 mM Tris base is added to
solublize the bound stain for 5 minutes at room temperature and O.D. is read at 560 nm in
a plate reader. The graph is plotted between O.D. and concentration and LCso is
calculated with respect to tamoxifen, which is used as a positive control.
Table 2; Antiproliferative/cytotoxic activity in cultured MCF-7 cells
Compound
Tamoxifen
LC50 (nM)
14.20
(Figure Removed)
Test procedure for evaluation of anti-cancer breast activity in vivo.
Compound(s) of invention identified on the basis of the above test are evaluated in vivo
for anticancer breast activity using the well established and widely used rodent model of
hormone responsive breast cancer namely, 7,12-dimethylbenz (a) anthracene (DMBA)
induced rat mammary tumor model. Healthy female Sprague-Dawley rats (50-60 days of
age) are given a single oral administration of DMBA (180 mg/kg) and the mammary
tumor development is monitored by weekly palpation of the mammary tracks. Body
weight of the animals is recorded weekly. All animals are used and handled adhering to
the Animal Ethics Committee guidelines for humane treatment of animals. The animals
have free access to standard rodent pellet diet and safe drinking water and are housed in
temperature and photoperiod-controlled animal quarters throughout the experimental
period. When palpable mammary tumors develop and reach approximately 0.5 cm in
diameter, the tumor bearing rats are grouped and receive oral administration of the test
compound at a daily dose of 10 mg/kg body weight for 4 weeks. Tumor incidence,
number and area/volume are recorded at the commencement of the treatment and at
weekly intervals. The diameter of tumors is measured using calipers and the tumor
volume is derived using the formula for sphere volume. The compound is considered
active against mammary tumor if, by the end of treatment period, the tumor volume
decreases by more than 25% or remains static or when the volume shows less than 25%
increase over the pre-treatment volume.
Test procedure for evaluation of post-coital antifertilitv activity
Adult female rats are caged overnight with coeval males of proven fertility and their
vaginal smears are checked on the following morning. The day of presence of
spermatozoa in the vaginal smear is taken as day 1 of pregnancy. Mated rats are isolated
and randomized into various treatment groups and treated orally with the compound of
invention or the vehicle on days 1-7/1-5 post-coitum. Animals of all the groups are
autopsied on day 10 post-coitum and number and status of corpora lutea and implantation
sites in each rat are recorded. The compounds of the present invention are considered
active if there is complete absence of implantations in the uterus of all rats, in comparison
to presence of normal implantations in the uterus of rats of vehicle control group.
Table 3; Post-coital antifertility efficacy in adult female rats
Compound
Vehicle
Example number 2
Example number 7
(Table Removed)
Test procedure for evaluation of estrogen agonistic activity
Twenty-one-day-old immature female rats are bilaterally ovariectomized under light
ether anaesthesia and, after post-operative rest for 7 days, are randomized into different
treatment groups. Each rat receives the compound of the invention once daily for 3
consecutive days on days 28-30 of age. A separate group of animals receiving only the
vehicle for similar duration serves as control. At autopsy 24 h after the last treatment on
day 31 of age, vaginal smear of each rat is taken and uterus is carefully excised, gently
blotted, weighed and fixed for histology and histomorphometry using image analysis.
Premature opening of vagina, cornification of vaginal epithelium, increase in uterine
fresh weight, total uterine and endometrial area and uterine luminal epithelial cell height
are taken as parameters for evaluation of estrogen agonistic activity in comparison to rats
of vehicle control group.
Table 4: Increase in uterine weight in immature ovariectomized rats:
Percent of OVX+vehicIe treatment group
Compound
1 7-alfa-Ethynylestradiol
Example number 2
Example number 7
Example number 8
Example number 12
(Table Removed)
For image analysis in estrogen agonistic activity evaluation studies, paraffin sections (6
um thick) of the uterus stained with haematoxylin and eosin were analysed
microscopically. To determine changes in uterine tissue components, areas of whole
uterus and endometrium and the thickness of uterine epithelium were measured using a
computer-image analysis system (BioVis, Expert Vision, India). Briefly, microscopic
images of uterus acquired through a CCD camera were loaded in to the image analysis
program and spatially calibrated against a stage micrometer image taken at the same
magnification. Using thresholding and line tools, the regions for measurements were
selected and the area (mm2) of whole uterine transection excluding the luminal space, the
area (mm2) of the endometrium only, and the thickness (um) of luminal epithelial lining
were measured. Luminal epithelial thickness data was the Average of measurements
made at 6 randomly selected sites are taken as parameters for evaluation.
Table 5; Estrogen agonistic activity in immature ovariectomized rats: Effect on
uterine morphometry
Compound
Vehicle
1 7-alfa-Ethynylestradiol
Example number 2
Example number 7
Example number 8
Example number 1 2
Daily
(Table Removed)
Endometrium
(Table Removed)
Test procedure for evaluation of estrogen antagonistic activity
Twenty-one-day-old immature female rats are bilaterally ovariectomized under light
ether anaesthesia and after post-operative rest for 7 days, are randomized into different
treatment groups. Each rat receives the compounds of the invention and 0.02 mg/kg dose
of 17-alfa-ethynylestradiol in 10% ethanol-distilled water once daily for 3 consecutive
days on days 28-30 of age. A separate group of animals receiving only 17-alfaethynylestradiol
(0.02 mg/kg) in 10% ethanol-distilled water for similar duration are used
for comparison. At autopsy on day 31 of age, vaginal smear of each rat is taken and
uterus is carefully excised, gently blotted, weighed and fixed for histology and
histomorphometry using image analysis. Inhibition in 17-alfa-ethynylestradiol-induced
premature opening of vagina, cornification of vaginal epithelium, increase in uterine
fresh weight, total uterine and endometrial area and uterine luminal epithelial cell height
are taken as parameters .for evaluation of estrogen antagonistic activity.
Table 6; Percent inhibition in EE induced uterine weight gain in immature
ovariectomized rats
Compound
Example number 2
Example number 7
Example number 8
Example number 12
Daily dose
(mg/kg)
Test procedure for evaluation of relative binding affinity (RBA) to estrogen
receptors
The relative binding affinity (RBA) of the compounds for estrogen receptor was
determined by competition assay, employing 3H-estradiol (3H-E2) as the radioligand. The
test ligands and 3H-E2 were incubated at 4°C with cytosol estrogen receptors obtained
from uteri of immature estradiol-primed (1 ug/rat 24 h before autopsy) 20-21 days old
rats. Aliquot of uterine cytosol (200 ul; 2 uteri per ml) prepared in TEA buffer (10 mM
Tris, 1.5 mM EDTA, 0.02% sodium azide, pH 7.4) were incubated in duplicate with a
fixed concentration of 3H-E2 in the absence or presence of various concentrations of the
competitor substance dissolved in 30 ul of the TEA buffer containing DMF as co-solvent
(final concentration of DMF in the incubation mixture never exceeded 5%) for 18 hrs at
4°C. At the end of this period, dextran coated charcoal (5% Norit 0.5% dextran)
suspension in 100 ul of TEA buffer was added to each tube, which were briefly vortexed
and allowed to stand for 15 minutes at 4°C. The mixture was centrifuged at 800 g for 10
minutes and the supernatants counted for radioactivity in 10 ml of a dioxane-based
scintillation fluid. RBA of the text compound was computed from a graph plotted
between percent bound radioactivity verses log concentration of the test substance. At
50% inhibition, log of the competitor concentration relative to that of 17-beta-estradiol,
gave the affinity of the test compound to estrogen receptor relative to estradiol. This
when multiplied with 100 gave the percentage value designated as RBA.
Table 7: Relative binding affinity (RBA) to estrogen receptors
Compound
1 7-beta-Estradiol
Example number 2
Example number 8
RBA
The derivates of the instant application are novel in nature and are found to have the
aforementioned activities. These activities are absent in the basic structure of the
compound of formula I. Thus, the invention of the instant Application is both novel and
non-obvious.



Claims
1. Compounds of the formula I in which substituents R2 and R3 are arranged in
trans-configuration:
wherein:
R1 is H or C1-C6 alkyl; C3-C7 cycloalkyl;
R2 is phenyl, optionally substituted with 1 to 5 substituents independently selected
from the group comprising OH, C1-C6 -alkyl, halogen, nitro, cyano, SH, SR4'
trihalo-Cl-C6-alkyl, C1-C6 -alkoxy and phenyl, wherein R4 is C1-C6 alkyl;
R3 is phenyl substituted with OR5 wherein R5 has the formula (II), (III) or (IV)
wherein Y is chosen from NHR4, NR4
2, NHCOR4, NHSO2R4, CONHR4. CONR4,
CONR4
2, COOH, COOR4, S02R4, SOR4, SONHR4, SONR4
2. a C3-C7
heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms
independently selected from the group consisting of 0, S and N, optionally being
substituted with 1 to 3 substituents independently selected from the group
comprising H, OH, halogen, nitro, cyano, SH, SR4, trihalo-Cl-C6- alkyl, C1-C6-
alkyl and C1-C6 -alkoxy, preferably NHR4, NR2
4, or a nitrogen heterocycle,
wherein R4 is as defined above, and the esters, ethers, and salts of the compounds
of formula I, optionally along pharmaceutically acceptable excipients.
2. Compounds as claimed in claim 1, wherein R3 is phenyl substituted with -OR5
wherein R5 has the formula II and wherein Y is a C3-C7 heterocyclic ring,
saturated or unsaturated, containing one or two heteroatoms independently
selected from the group comprising O, S and N, optionally being substituted with
1 to 3 substituents independently selected from the group comprising H, OH,
halogen, nitro, cyano, SH, SR4, trihalo-Ci-C6 - alkyl, Cl-C6-alkyl, Cl-C6-alkyl
and Cl-C6-alkoxy.
3. Compounds as claimed in claim 1, wherein R3 is phenyl substituted with -OR5
wherein R5 has the formula III and wherein Y is a C3-C7 heterocyclic ring,
saturated or unsaturated, containing one or two heteroatoms independently
selected from the group comprising O, S and N, optionally being substituted with
1 to 3 substituents independently selected from the group comprising H, OH,
halogen, nitro, cyano, SH, SR4, trihalo-Cl-C6- alkyl, Cl-C6-alkyl, Cl-C6-alkyl
andCl-C6-alkoxy.
4. Compounds as claimed in claim 1, wherein R3 is phenyl substituted with -OR5
wherein R5 has the formula IV and wherein Y is a C3-C7 heterocyclic ring,
saturated or unsaturated, containing one or two heteroatoms independently
selected from the group comprising O, S and N, optionally being substituted with
1 to 3 substituents independently selected from the group comprising H, OH,
halogen, nitro, cyano, SH, SR4, trihalo-Cl-C6- alkyl, Cl-C6-alkyl, Cl-C6-alkyl
and Cl-C6-alkoxy.
5. Compounds as claimed in claim 1, wherein R1 is preferably methyl.
6. Compounds as claimed in claim 1, wherein R2 is preferably phenyl.
7. Compounds as claimed in claim 1, wherein R4 is preferably butyl.
8. Compounds as claimed in claim 1, wherein the preferred compounds are:
I. (3R,4R)-2,2-Dimethyl-7-methoxy-4-(4-[{2R)-3-methylamino-2-
hydroxy}propyloxy] phenyl)-3-phenylchroman.
II. (3R,4R)-2,2-Dimethyl-7-methoxy-4-(4-[{2R)-3-ethylamino-2-
hydroxy} propyloxy] phenyl)-3 -phenylchroman.
III. (3R,4R)-2,2-Dimemyl-7-memoxy-3-phenyl-4-(4-[{2R)-3-propylamino-2-
hydroxy} propyloxy] phenyl)chroman.
IV. (3R,4R)-4-(4-[{2R)-3-Butylamino-2-hydroxy}propyloxy]phenyl)-2,2-
dimethyl-7-methoxy-3-phenylchroman.
V. (3R,4R)-2,2-Dimethyl-7-methoxy-4-(4-[{2R)-3-pentylamino-2-
hydroxy} propyloxy] phenyl)-3-phenylchroman.
VI. (3R,4R)-2,2-Dimethyl-4-(4-[{2R)-3-dimethylarnino-2-
hydroxy}propyloxy]phenyl)-7-methoxy-3-phenylchroman.
VII. (3R,4R)-4-(4-[{2R)-3-Diethylamino-2-hydroxy}propyloxy]phenyl)-2,2-
dimethyl-7-methoxy-3-phenylchroman.
VIII. (3R,4R)-2,2-Dimethyl-4-(4-[{2R)-3-dipropylamino-2-
hydroxy}propyloxy]phenyl)-7-methoxy-3-phenylchroman.
IX. (3R,4R)-4-(4-[{2R)-3-Dibutylamino-2-hydroxy}propyloxy]phenyl)-2,2-
dimethoxy-3 -phenylchroman.
X. (3R,4R)-2,2-Dimethyl-4-(4-[{2R)-3-dipentylamino-2-
hydroxy}propyloxy]phenyl)-7-methoxy-3-phenylchroman.
XI. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{2R)-3-pyrrolidino-2-
hydroxy} propyloxy] phenyl)-chroman.
XII. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{2R)-3-piperidino-2-
hydroxy} propyloxy]phenyl)-chroman.
XIII. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{2R)-3-morpholino-2-
hydroxy} propyloxy]phenyl)-chroman.
XIV. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{2R)-3-piperazino-2-
hydroxy} propyloxy]phenyl)-chroman.
XV. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{2R)-3-cyclohexylamino-
2-hydroxy} propyloxy]phenyl)-chroman.
XVI. (3R,4R)-2,2-Dimethyl-7-methoxy-4-(4-[{2S)-3-methylamino-2-
hydroxy}propyloxy]phenyl)-3-phenylchroman.
XVII. (3R,4R)-2,2-Dimethyl-7-methoxy-4-(4-[{2S)-3-ethylamino-2-hydroxy}
propyloxy]phenyl)-3-phenylchroman.
XVIII. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{2S)-3-propylainino-2-
hydroxy} propyloxy]phenyl)-chroman.
XIX. (3R,4R)-4-4-(4-[{2S)-3-Butylamino-2-hydroxy}propyloxy]phenyl)-2,2-
dimethyl-7-methoxy-3-phenylchroman.
XX. (3R,4R)-2,2-Dimethyl-7-methoxy-4-(4-[{2S)-3-pentylamino-2-
hydroxy} propyloxy] phenyl)-3-phenylchroman.
XXI. (3R,4R)-2,2-Dimethyl-4-(4-[{2S)-3-dimethylamino-2-
hydroxy} propyloxy]phenyl)-7-methoxy-3 -phenylchroman.
XXII. (3R,4R)-4-(4-[{2S)-3-Diethylamino-2-hydroxy}propyloxy]phenyl)-2,2-
dimethyl-7-methoxy-3-phenylchroman.
XXIII. (3R,4R)-2,2-Dimethyl-4-(4-[{2S)-3-dipropylamino-2-
hydroxy } propyloxy]phenyl)-7-methoxy-3 -phenylchroman.
XXIV. (3R,4R)-4-(4-[{2S)-3-Dibutylamino-2-hydroxy}propyloxy]phenyl)-3-
phenyl)-2,2-dimethoxy-3-phenylchroman.
XXV. (3R,4R)-2,2-Dimethyl-4-(4-[{2S)-3-dipentylamino-2-
hydroxy}propyloxy]phenyl)-7-methoxy-3-phenylcnroman.
XXVI. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{2S)-3-pyrrolidino-2-
hydroxy} propyloxy] phenyl)-chroman.
XXVII. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{2S)-3-piperidino-2-
hydroxy} propyloxy]phenyl)-chroman.
XXVIII. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{2S)-3-morpholoino-2-
hydroxy} propyloxy]phenyl)-chroman.
XXIX. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{2S)-3-piperazino-2-
hydroxy} propyloxy]phenyl)-chroman.
XXX. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{2S)-3-cyclohexylamino-
2-hydroxy} propyloxy]phenyl)-chroman.
XXXI. (3R,4R)-2,2-Dimethyl-7-methoxy-4-(4-[{3-methylamino-2-
hydroxy}propyloxy] phenyl)- 3-phenylchroman.
XXXII. (3R,4R)-2,2-Dimethyl-7-methoxy-4-(4-[{3-ethylamino-2-
hydroxy}propyloxy]phenyl)-3-phenylchroman.
XXXIII. (3R,4R)-2,2-Dimethyl-7-methoxy-4-(4-[{3-propylamino-2-
hydroxy} propyloxy]phenyl)-3 -phenylchroman.
XXXIV. (3R,4R)-4-(4-[{3-butylamino-2-hydroxy}propyloxy]phenyl)-2,2-dimethyl-
7-methoxy-3-phenylchroman.
XXXV. (3R,4R)-2,2-Dimethyl-7-methoxy-4-(4-[{3-pentylamino-2-
hydroxy}propyloxy]phenyl)-3-phenylchroman.
XXXVI. (3R,4R)-2,2-Dimethyl-4-(4-[{3-dimethylamino-2-
hydroxy}propyloxy]phenyl)-7-methoxyphenyl)-3-phenylchroman.
XXXVII. (3R,4R)-4-(4-[{3-Diethylamino-2-hydroxy}propyloxy]phenyl)-2,2-
dimethyl-7-methoxy-3 -phenylchroman.
XXXVIII. (3R,4R)-2,2-Dimethyl-4-(4-[{3-dipropylamino-2-
hydroxy}propyloxy]phenyl-7-methoxy phenyl)-3-phenylchroman.
XXXIX. (3R,4R)-4-(4-[{3-Dibutylamino-2-hydroxy}propyloxy]phenyl)-2,2-
dimethoxy-3-phenylchroman.
XL. (3R,4R)-2,2-Dimethyl-4-(4-[{3-dipentylamino-2-
hydroxy} propyloxy]phenyl-7-methoxy phenyl)-3 -phenylchroman.
XLI. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{3-pyrrolidino-2-
hydroxy}propyloxy] phenyl)-chroman.
XLH. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{3-piperidino-2-
hydroxy}propyloxy] phenyl)-chroman.
XLIII. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{3-morpholino-2-
hydroxy}propyloxy] phenyl)-chroman.
XLIV. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{3-piperazino-2-
hydroxy}propyloxy] phenyl)-chroman.
XLV. (3R,4R)-2,2-Dimethyl-7-methoxy-3-phenyl-4-(4-[{3-cyclohexylamino-2-
hydroxy} propyloxy]phenyl)-chroman.
9. Compounds as claimed in claim 1, wherein the salts are selected from a group
comprising acid addition salts consisting of formate, acetate, phenyl acetate,
trifluroacetate, acrylate, ascorbate, benzoate, chlorobenzoates, bromobezoates,
iodobenzoates, nitrobenzoates, hydroxybenzoates, alkylbenzoates,
alkyloxybenzoates, alkoxycarbonylbenzoates, naphthalene-2 benzoate, butyrates,
phenylbutyrates, hydroxybutyrates, caprate, caprylate, cinnamate, mandelate,
mesylate, citrate, tartarate, fumarate, heptanoate, hippurate, lactate, malate,
maleate, malonate, nicotinate, isonicotinate, oxalate, phthalate, terephthalate,
phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate,
pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacte,
succinate, suberate, sulphate, bisulphate, pyrosulphate, sulphite, bisulphate,
sulphonate, benzene sulphonate, bromobenzene sulphonates, chlorobenzene
sulphonates, ethane sulphonates, methane sulphonates, naphthalene sulphonates,
toluene sulphonates, and the likes.
10. Compounds as claimed in claim 1, wherein most preferred salts are methyl iodide,
fumerate, ascorbate, and hydrochloride.
11. Compounds as claimed in claim 1, wherein the compounds or its salts are in the
physical forms of the gelatin capsules or compressed into the tablets or pills or
may be formulated in the form of lozenges, inclusion complexes with
cyclodextrin derivatives, injectable depo formulations, aerosols, granules,
powders, oral liquids, mucosal adhesive formulations, gel formulations, troches,
elixirs, suspensions, syrups, wafers, liposomal delivery systems, implants,
suppository, pessary, microemulsions, nanoemulsion, microparticles,
nanoparticles, controlled release delivery systems, transdermal delivery systems,
and targeted delivery systems such as conjugates with monoclonal antibodies or
with other suitable carrier moieties.
12. Compounds as claimed in claim 1, wherein the pharmaceutically acceptable
excipients are selected from a group comprising:
a) diluent such as lactose, mannitol, sorbitol, microcrystalline cellulose,
sucrose, sodium citrate, dicalcium phosphate, or any other ingredient of the
similar nature alone or in a suitable combination thereof;
b) a binder such as gum tragacanth, gum acacia, methyl cellulose, gelatin,
polyvinyl pyrrolidone, starch or any other ingredient of the similar nature
alone or in a suitable combination thereof;
c) a disintegrating agent such as agar-agar, calcium carbonate, sodium
carbonate, silicates, alginic acid, corn starch, potato tapioca starch, primogel
or any other ingredient of the similar nature alone or in a suitable
combination thereof;
d) a lubricant such as magnesium stearate, calcium stearate or steorotes, talc,
solid polyethylene glycols, sodium lauryl sulphate or any other ingredient of
the similar nature alone or in a suitable combination thereof;
e) a glidant such as colloidal silicon dioxide or any other ingredient of the
similar nature alone or in a suitable combination thereof;
f) a sweetening agent such as sucrose, saccharin or any other ingredient of
the similar nature alone or in a suitable combination thereof;
g) a flavoring agent such as peppermint, methyl salicylate, orange flavor,
vanilla flavor, or any other pharmaceutically acceptable flavor alone or in a
suitable combination thereof;
h) a wetting agents such as cetyl alcohol, glyceryl monostearate or any other
pharmaceutically acceptable flavor alone or in a suitable combination thereof;
i) a absorbents such as kaolin, bentonite clay or any other pharmaceutically
acceptable flavor alone or in a suitable combination thereof; and
j) a solution retarding agents such as wax, paraffin or any other
pharmaceutically acceptable flavor alone or in a suitable combination thereof.
13. A process for the preparation of compounds of formula I, said process comprising
steps of:
I. reacting a compound of formula V in which substituents R2 and R6 are
arranged in the (3R,4R) configuration: wherein R1 and R2 are as defined in
formula 1 and R6 is phenyl substituted with a hydroxy substituents at C2, C3
or C4, preferably at C4 with a compound of formula VI, VII, VIII, neat or in
art aprotic solvent which includes dimethylsulphoxide, dimethylformamide
in the presence of a base such as KiCOs at temperature ranging between 50
to 120°C,
II. obtaining compounds of structure IX (a-c) wherein R1 and R2 are as defined
(Figure removed)
III. reacting compound of formula IX a-c with a nucleophile preferably an
amine of formula X wherein R7 and R8 are individually hydrogen, C1-C6-
alkyl which includes straight chain as well as branched alkyl groups such as
methyl, ethyl, propyl, isopropyl, butyl, isobutyl Cl-C6-cycloalkyl which
includes cyclopropane, cyclobutane, cyclopentane, cyclohexane or form a
C3-C7 heterocyclic ring, saturated or unsaturated, containing one or two
heteroatoms independently selected from the group comprising O, S and N,
optionally being substituted with 1,2,3 substituents independently selected
from the group comprising H, OH, halogen, nitro, cyano, SH, SR4, trihalo-
Cl-C6-alkyl, Cl-C6-alkyl and Cl-C6-alkoxy, wherein R4 is defined above,
either neat or in the presence of organic solvent such as benzene,
dimethylsulphoxide, dimethylformamide, and
IV. obtaining compounds of formula XI a-c, optionally converting the amino
derivative into their corresponding salts such as HCL, fumerate, citrate by
treating the free base with the corresponding acid.
(Figure removed)wherein Y, R1 and R2 are as defined above.
14. A method of preventing and/or treating estrogen-related disease conditions in a
subject in need thereof, said method comprising step of administering to the
subject, a pharmaceutically effective amount of compounds of formula 1, or its
salts, optionally along with pharmaceutically acceptable excipients.
15. A method of treatment as claimed in claim 14, wherein the salts are selected from
a group comprising acid addition salts consisting of formate, acetate, phenyl
acetate, trifluroacetate, acrylate, ascorbate, benzoate, chlorobenzoates,
bromobezoates, iodobenzoates, nitrobenzoates, hydroxybenzoates,
alkylbenzoates, alkyloxybenzoates, alkoxycarbonylbenzoates, naphthalene-2
benzoate, butyrates, phenylbutyrates, hydroxybutyrates, caprate, caprylate,
cinnamate, mandelate, mesylate, citrate, tartarate, fumarate, heptanoate, hippurate,
lactate, malate, maleate, malonate, nicotinate, isonicotinate, oxalate, phthalate,
terephthalate, phosphate, monohydrogen phosphate, dihydrogen phosphate,
metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate,
salicylate, sebacte, succinate, suberate, sulphate, bisulphate, pyrosulphate,
sulphite, bisulphate, sulphonate, benzene sulphonate, bromobenzene sulphonates,
chlorobenzene sulphonates, ethane sulphonates, methane sulphonates,
naphthalene sulphonates, toluene sulphonates, and alkyl or aryl halides addtion
salts of the compounds of this invention, wherein the alkyl halide is selected from
a group comprising Q to Cig alkyl halide, and aryl halide is selected from a group
comprising benzyl halide and substituted benzyl halide.
16. A method of treatment as claimed in claim 14, wherein most preferred salts are
methyl iodide, fumerate, ascorbate, and hydrochloride.
17. A method of treatment as claimed in claim 14, wherein the administration is
through various routes selected from a group comprising oral, systemic, local, and
topical delivery selected from a group consisting of intravenous, intra-arterial,
intra-muscular, subcutaneous, intra-peritoneal, intra-dermal, buccal, intranasal,
inhalation, vaginal, rectal, and transdermal.
18. A method of treatment as claimed in claim 14, wherein the preferred route of
administration is oral route.
19. A method of treatment as claimed in claim 14, wherein the physical forms of the
compound of formula 1 and its salts could be gelatin capsules or compressed into
the tablets or pills or may be formulated in the form of lozenges, inclusion
complexes with cyclodextrin derivatives, injectable depo formulations, aerosols,
granules, powders, oral liquids, mucosal adhesive formulations, gel formulations,
troches, elixirs, suspensions, syrups, wafers, liposomal delivery systems,
implants, suppository, pessary, microemulsions, nanoemulsion, microparticles,
nanoparticles, controlled release delivery systems, transdermal delivery systems,
and targeted delivery systems such as conjugates with monoclonal antibodies or
with other suitable carrier moieties.
20. A method of treatment as claimed in claim 14, wherein the pharmaceutically
acceptable excipients are selected from a group comprising:
a) diluent such as lactose, mannitol, sorbitol, microcrystalline cellulose,
sucrose, sodium citrate, dicalcium phosphate, or any other ingredient of the
similar nature alone or in a suitable combination thereof;
b) a binder such as gum tragacanth, gum acacia, methyl cellulose, gelatin,
polyvinyl pyrrolidone, starch or any other ingredient of the similar nature
alone or in a suitable combination thereof;
c) a disintegrating agent such as agar-agar, calcium carbonate, sodium
carbonate, silicates, alginic acid, corn starch, potato tapioca starch, primogel
or any other ingredient of the similar nature alone or in a suitable
combination thereof;
d) a lubricant such as magnesium stearate, calcium stearate or steorotes, talc,
solid polyethylene glycols, sodium lauryl sulphate or any other ingredient of
the similar nature alone or in a suitable combination thereof;
e) a glidant such as colloidal silicon dioxide or any other ingredient of the
similar nature alone or in a suitable combination thereof;
f) a sweetening agent such as sucrose, saccharin or any other ingredient of
the similar nature alone or in a suitable combination thereof;
g) a flavoring agent such as peppermint, methyl salicylate, orange flavor,
vanilla flavor, or any other pharmaceutically acceptable flavor alone or in a
suitable combination thereof;
h) a wetting agents such as cetyl alcohol, glyceryl monostearate or any other
pharmaceutically acceptable flavor alone or in a suitable combination thereof;
i) an absorbents such as kaolin, bentonite clay or any other pharmaceutically
acceptable flavor alone or in a suitable combination thereof; and
j) a solution retarding agents such as wax, paraffin or any other
pharmaceutically acceptable flavor alone or in a suitable combination thereof.
21. A method of prevention and/or treatment as claimed in claim 14, wherein said
method helps in preferably diseases or syndromes caused by an estrogen-deficient
state, with Relative Binding affinity (RBA) to estrogen receptors ranging between
5 to 7.
22. A method of prevention and/or treatment as claimed in claim 14, wherein said
method helps in disease conditions caused by osteoporosis, bone loss, and bone
formation, with T/C ratio of 23. A method of prevention and/or treatment as claimed in claim 14, wherein said
method helps in disease conditions affecting cardiovascular systems, more
particularly hyperlipidaemia, thrombosis and vasomotor system.
24. A method of prevention and/or treatment as claimed in claim 14, wherein said
method helps in disease conditions showing neurodegenerative effects, more
particularly, stroke, senile dementia-Alzheimer type and Parkinson disease.
25. A method of prevention and/or treatment as claimed in claim 14, wherein said
method helps in disease conditions showing menopausal symptoms, more
particularly, hot flushes, urogenital atrophy, depression, mania, schizophrenia,
urinary incontinence, dysmenorrhea, dysfunctional uterine bleeding, acne,
hirsutism, improper ovarian development.
26. A method of prevention and/or treatment as claimed in claim 14, wherein said
method helps in disease conditions showing cancers, more particularly, prostatic
carcinoma, breast cancer, cancer of uterus, cancer of the cervix and colon cancer,
with LCso ranging between 17 to 20 uM.
27. A method as claimed in claim 26, wherein the volume of the tumor decreases by
about 25%.
28. A method of prevention and/or treatment as claimed in claim 14, wherein said
method helps regulate fertility in humans and in other animals.
29. A method of prevention and/or treatment as claimed in claim 14, wherein said
method helps in threatened or habitual abortion.
30. A method of prevention and/or treatment as claimed in claim 14, wherein said
method helps in suppression of post-partum lactation.
31. A method of prevention and/or treatment as claimed in claim 14, wherein said
method helps in the management of certain physiological disorders, more
particularly, obesity and depression.
32. A method of prevention and/or treatment as claimed in claim 14, wherein said
method helps regulate of glucose metabolism in non-insulin dependent diabetes
mellitus.
33. (3R,4R)-trans-3,4-diarylchroman derivatives and a method for the prevention
and/or treatment of estrogen dependent diseases substantially as herin described
with reference to the examples.

Documents:

1367-DEL-2003-Abstract-(14-07-2008).pdf

1367-del-2003-abstract.pdf

1367-del-2003-claims.pdf

1367-DEL-2003-Correspondence-Others-(14-07-2008).pdf

1367-del-2003-correspondence-others.pdf

1367-del-2003-correspondence-po.pdf

1367-del-2003-description (complete).pdf

1367-DEL-2003-Form-1-(14-07-2008).pdf

1367-del-2003-form-1.pdf

1367-del-2003-form-18.pdf

1367-DEL-2003-Form-2-(14-07-2008).pdf

1367-del-2003-form-2.pdf

1367-DEL-2003-Form-3-(14-07-2008).pdf

1367-del-2003-form-3.pdf

1367-DEL-2003-Petition-137-(14-07-2008).pdf

abstract.jpg


Patent Number 223231
Indian Patent Application Number 1367/DEL/2003
PG Journal Number 29/2008
Publication Date 26-Sep-2008
Grant Date 08-Sep-2008
Date of Filing 06-Nov-2003
Name of Patentee COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH
Applicant Address RAFI MARG, NEW DELHI-110 001, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 SANGITA, ATUL KUMAR CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW - 226 001(U.P.)INDIA.
2 M.M. SINGH CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW - 226 001(U.P.)INDIA.
3 SUPRABHAT RAY CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW - 226 001(U.P.)INDIA.
4 G.K. JAIN CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW - 226 001(U.P.)INDIA.
PCT International Classification Number A61K 31/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA