PYRROLIDINE- SUBSTITUTED FLAVONE DERIVATIVES FOR PREVENTION OR TREATMENT OF ORAL MUCOSITIS
FIELD OF THE INVENTION
The present invention relates to pyrrolidine substituted with flavone derivatives,
represented by the compounds of Formula (I) (as described herein) or
pharmaceutically acceptable salts, solvates, stereoisomers or diastereoisomers
thereof or pharmaceutical compositions containing the compounds of Formula (I) for
use in the prevention or treatment of oral mucositis.
BACKGROUND OF THE INVENTION
Oral mucositis is the most common debilitating complication of cancer treatment
(e.g. chemotherapy, radiation therapyor a combination thereof), including bone
marrow transplantation or stem cell transplantation. Oral mucositis causes
considerable pain and morbidity and is often the dose-limiting toxicity of cancer
treatment. Oral mucositis may also limit the patient's ability to tolerate either
chemotherapy or radiotherapy or both. Oral mucositis is associated with
odynophagia (painful swallowing), dysphagia (difficulty in swallowing) including
feeding tube dependency and dysgeusia (distortion and/or decrease of the sense of
taste). This suppresses the appetite and further adds to diminishing adequate
nutrition and caloric intake. Reduction of caloric intake can lead to weight loss,
malnutrition, loss in muscle mass strength and other complications including
decrease in immunity. Oral mucositis is also associated with dehydration, and
potential life threatening aspiration. Patients with high grade mucositis (grade 3 or 4)
and reduced immunity are prone to opportunistic mouth infections. The damaged
oral mucosa serves as portals of entry for endogenous oral microorganisms and
therefore is a significant risk factor for life-threatening systemic infections as well.
Oral mucositis frequently occur in patients with squamous cell carcinoma of the head
and neck (SCCHN) who are treated with radiation therapy directed at the oral and
pharyngeal regions. According to Trotti et al. (Radiother. Oncol., 2003; 66, 253-262)
the overall incidence of mucositis in this patient population of 6,000 patients with
SCCHN was 80%, with 39% of cases being grade 3/4, which limited or prevented
alimentation. The said patient population received radiation therapy with or without
chemotherapy. In patients who received only chemotherapy, the incidence of
mucositis was 22%. Between 50% and 100% of patients undergoing stem cell
transplantation (SCT) experience mucositis as a result of high-dose chemotherapy or
total-body irradiation (TBI). Sonis et al. (J Clin Oncol 2001 ;19:2201-2205) reported
that a higher oral mucositis rating correlated with an increased risk of significant
5 infection, an increased number of days in the hospital, a greater use of opioids and
total parenteral nutrition (TPN), higher healthcare costs, and an elevated 100-day
mortality rate.
Oral mucositis is not only a common consequence of radiation therapy or
i o combination of chemotherapy and radiation therapy, but is also caused to patients
undergoing bone marrow transplantation (BMT). BMT has been found to be
successful in the treatment of leukemia, lymphoma and some solid mass tumours.
Prior to a BMT, intensive chemotherapy and total body irradiation (for allogenic BMT
patients) is administered to the patient in an effort to destroy all cancer cells. At this
15 stage the oral mucositis is caused to BMT patients.
Since the healthcare cost associated with oral mucositis and its treatment can be
substantial, prompt and accurate diagnosis and initiation of prophylaxis and
treatment of oral mucositis are essential.
20
The management of oral mucositis currently focuses on maintaining oral hygiene
and pain control. Good oral hygiene promotes patient comfort and helps to prevent
superimposed infection. Adequate analgesia is essential both to control pain and to
ensure maximum possible oral nutritional intake. Paracetamol in conjunction with
25 stronger analgesics such as codeine, dihydrocodiene or strong opiates such as
morphine can be used for pain relief. MASCC (Multinational Association of
Supportive Care in Cancer) guidelines recommend the use of Benzydamine
hydrochloride mouthwash for the prevention of oral mucositis in patients with head
and neck cancer receiving moderate-dose radiation therapy or chemotherapy or
30 combination thereof. Antibiotic and antifungal medication can be used for the
treatment of mouth infections post cancer therapy.
A number of targeted therapies have recently been evaluated for prevention and/or
treatment of oral mucositis, including palifermin, amifostine, glutamine, cytokines
35 growth factors, and other antioxidants.
Palifermin, a human recombinant keratinocyte growth factor produced by E.coli, is
approved for the treatment of severe oral mucositis. It is known to reduce the
incidence and duration of severe oral mucositis by binding to epithelial cell-surface
receptors and stimulating epithelial cell proliferation, differentiation, and upregulation
of cytoprotective mechanisms. However, palifermin is associated with skin toxicities
such as rash; erythema; edema; and pruritus; oral toxicities such as dysesthesia;
tongue discoloration; tongue thickening and alteration of taste, and pain arthralgias
(www.accessdata.fda.gov: "Kepivance® (palifermin)- For injection, for intravenous
use- Label Approved by the USFDA-Supplement number 0018).
Amifostine, a cytoprotective prodrug has been extensively studied for its role in
prevention of oral mucositis induced by radiation therapy or chemotherapy. It
showed statistically significant role in the reduction of severity of oral mucositis.
However, amifostine therapy is associated with several drawbacks such as
hypocalcemia, diarrhea, nausea, vomiting, sneezing, somnolence, hiccoughs, more
serious side-effects such as hypotension (found in 62% of patients), erythema
multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis, immune
hypersensitivity syndrome, erythroderma, anaphylaxis, and loss of consciousness
(rare). In addition, amifostine requires daily intravenous infusions. Due to the
inconsistent results, amifostine was not approved by US FDA for oral mucositis.
Glutamine, a nonessential amino acid reduces mucosal injury by reducing the
production of pro-inflammatory cytokines and cytokines related apoptosis. Many
malignancies are characterized by decreased glutamine levels, which can be further
exacerbated by cell damage caused by cancer therapy. Glutamine supplementation
can reverse this effect and may help to protect mucosal tissues from damage by
radiation therapy or chemotherapy and thus accelerate recovery. But many trials
using glutamine as oral or systemic supplement and as mouth washes have shown
inconsistent results. Due to which MASCC and ISOO (International Society of Oral
Oncology) did not recommend its routine use.
Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony
stimulating factor (GM-CSF) have shown protective effects against radiation induced
mucositis. The systemic and local use as topical mouth wash of G-CSF and GMCSF,
respectively, has been evaluated in different trials for the prevention and
treatment of oral mucositis. But the results of these trials favor the systemic
intervention group however no preventive effect was found for the topical
administration group. In view of inconsistent results MASCC/ISOO guidelines did not
5 recommend the routine use of GM-CSF and G-CSF in any form for the prevention or
treatment of oral mucositis.
Despite the availability of certain therapeutic options for the treatment of oral
mucositis which is debilitating complication of cancer treatment, effective prevention
i o or treatment of this severe side effect of cancer treatment still constitutes a
challenging job for medical practitioners. Therefore, newer treatment options for oral
mucositis are needed.
There are a large numbers of cancer patients particularly those undergoing radiation
15 therapy for head and neck cancers, who often receive multiple cycles of radiation
and hence, suffer from radiation related toxicity. Mucositis is arguably the most
significant radiation induced toxicity associated with head and neck cancer therapy.
Despite the availability of certain therapeutic options for the treatment of mucositis,
an effective prevention or treatment of this severe side effect still constitutes a
20 challenging job for medical practitioners. Therefore, newer treatment options are
needed.
The inventors of the present invention have now surprisingly found out that
pyrrolidine substituted with flavone derivatives can be used for the prevention or
25 treatment of oral mucositis.
The invention described herein provides pyrrolidine substituted with flavone
derivatives represented by Formula (I) (as described herein) for the prevention and
treatment of oral mucositis caused by cancer therapy.
30
SUMMARY OF THE INVENTION
According to one aspect of the invention, there is provided a compound of Formula
(I) (as described herein), a pharmaceutically acceptable salt, a solvate, or a
stereoisomer or a diastereoisomer thereof for use in the prevention, treatment or
5 reduction in severity of oral mucositis in a subject undergoing cancer therapy.
According to another aspect of the invention, there is provided a method for the
prevention, treatment or reduction in severity of oral mucositis in a subject
undergoing cancer therapy, comprising administering to the subject a therapeutically
i o effective amount of a compound of Formula (I), or a pharmaceutically acceptable
salt, a solvate, a stereoisomer or a diastereoisomer thereof.
According to another aspect of the invention, there is provided a method for
prevention, treatment or reduction in the severity of oral mucositis in a subject
undergoing cancer therapy, comprising administering the compound of Formula (I) to
15 the subject, prior to, concurrently with or after the cancer therapy.
According to another aspect of the invention, there is provided use of a compound of
Formula (I), a pharmaceutically acceptable salt, a solvate, or a stereoisomer or a
diastereoisomer thereof for the prevention, treatment or reduction in severity of oral
mucositis in a subject undergoing cancer therapy.
20 According to another aspect of the invention, there is provided use of the compound
of Formula (I), a pharmaceutically acceptable salt, a solvate, a stereoisomer or a
diastereoisomer thereof in the manufacture of a medicament for use in the treatment
of oral mucositis in a subject undergoing cancer therapy.
According to another aspect of the invention there is provided a pharmaceutical
25 composition comprising a therapeutically effective amount of a compound of Formula
(I) a pharmaceutically acceptable salt, a solvate, a stereoisomer or a
diastereoisomer thereof and a pharmaceutically acceptable carrier for use in the
treatment of oral mucositis in a subject undergoing cancer therapy.
Other aspects and further scope of applicability of the present invention will become
30 apparent from the detailed description to follow.
DETAILED DESCRIPTION OF THE INVENTION
The general terms used hereinbefore and hereinafter preferably have within the
context of this disclosure the following meanings, unless otherwise indicated. Thus,
the definitions of the general terms as used in the context of the present invention
are provided herein below:
The singular forms "a," "an," and "the" include plural reference unless the context
clearly dictates otherwise.
It will be understood that "substitution" or "substituted with" includes the implicit
proviso that such substitution is in accordance with permitted valence of the
substituted atom and the substituent, as well as represents a stable compound,
which does not readily undergo transformation such as rearrangement, cyclization,
elimination, etc.
The term "CrC 4 - alkyl" refers to the radical of saturated aliphatic groups, including
straight or branched-chain containing from 1 to 4 carbon atoms. Examples of alkyl
groups include but are not limited to methyl, ethyl, propyl, butyl, isopropyl, isobutyl,
sec-butyl, -butyl and the like.
The term "CrC 4 - alkoxy" refers to an alkyl group as defined above attached via
oxygen linkage to the rest of the molecule. Examples of alkoxy include, but are not
limited to methoxy, ethoxy, propoxy, butoxy, tert-butoxy and the like.
The term "halogen" refers to fluorine, chlorine, bromine and iodine.
The term "hydroxy" or "hydroxyl" as used herein, refers to -OH group.
The term "therapeutically effective amount", as used herein refers to the amount of a
compound represented by Formula (I), a pharmaceutically acceptable salt, a solvate,
a stereoisomer or a diastereoisomer thereof, that, when administered to a subject in
need of such treatment, is sufficient to provide therapeutic benefit, including, the
prevention, treatment or amelioration of oral mucositis; such that any toxic or
detrimental effects of the composition of compound of Formula (I) is outweighed by
its therapeutically beneficial effects. The precise desired therapeutic effect will vary
according to the disease state, the formulation to be administered, age, sex, and
weight of the individual and a variety of other factors that are appreciated by those of
ordinary skill in the art.
The term "subject" as used herein, refers to an animal, preferably a mammal, most
preferably a human, being treated. More particularly, a human suffering from solid
and/or haematological cancer. The term "mammal" as used herein is intended to
encompass humans, as well as non-human mammals which are susceptible to oral
mucositis. Non-human mammals include but are not limited to domestic animals,
such as cows, pigs, horses, dogs, cats, rabbits, rats and mice, and non-domestic
animals.
The term "prevention" as used herein refers to the prophylactic effect. The term
means preventing the complete or partial occurrence of oral mucositis.
The term "treat" or "treatment" or "treating" as used herein, includes, curative,
alleviative or prophylactic effects. The term includes (i) reduction in the progression
of oral mucositis or (ii) reduction in the severity of oral mucositis or (iii) reduction in
the frequency of development of oral mucositis or (iv) reduction in the duration of oral
mucositis or (v) amelioration and/or relief of one or more signs or symptoms
associated with oral mucositis.
The term "oral mucositis" as used herein, refers to inflammation of mucosal cells of
the oral cavity. Oral mucositis is characterized by pain, redness, inflammation,
ulceration, or combinations thereof, which results from cancer therapy such as
radiation therapy, chemotherapy or both.
The term "head and neck cancer" as used herein, refers to the cancer originating in
the head and neck area, comprising nasal cavity, sinuses, lips, mouth, salivary
glands, throat, and larynx.
The term "reduction in the severity of oral mucositis" as used herein refers to
reduction in grade 3 and above of oral mucositis, in comparison to the control group.
Grade 3 and above are as defined in Common Terminology Criteria for Adverse
Events (version 3) laid down by the National Cancer Institute.
As used herein the term "cancer therapy" encompasses within its scope radiation
therapy, chemotherapy, hematopoietic stem cell transplantation, bone marrow
transplantation or a combination thereof.
The term "subject undergoing cancer therapy" as used herein refers to an animal,
preferably a mammal, most preferably a human, who is suffering from solid or
haematological cancer, is exposed to or is going to be exposed to cancer therapy,
for the treatment of the solid or haematological cancer.
The term "about" as used herein refers to the deviation in the numerical values by
+ 10%.
As used herein the term "pharmaceutically acceptable" is meant that the carrier,
diluent, excipients, and/or salt must be compatible with the other ingredients of the
formulation, and not deleterious to the recipient thereof. "Pharmaceutically
acceptable" also means that the compositions or dosage forms are within the scope
of sound medical judgment, suitable for use for an animal or human without
excessive toxicity, irritation, allergic response, or other problem or complication,
commensurate with a reasonable benefit/risk ratio.
The present invention furthermore includes all solvates of the compounds of the
Formula (I), for example hydrates, and the solvates formed with other solvents of
crystallization, such as alcohols, ethers, ethyl acetate, dioxane, dimethylformamide
or a lower alkyl ketone, such as acetone, or mixtures thereof. Certain compounds of
the present invention can exist in unsolvated forms as well as solvated forms,
including hydrated forms. Certain compounds of the present invention may exist in
multiple crystalline or amorphous forms. In general, all physical forms are equivalent
for the uses contemplated by the present invention and are intended to be within the
scope of the present invention.
According to one aspect of the present invention, there is provided a compound of
Formula (I),
Formula (I)
wherein Ar is a phenyl group, which is unsubstituted or substituted by 1, 2, or 3
identical or different substituents selected from: halogen, nitro, cyano, C C4-alkyl,
trifluoromethyl, hydroxyl or C C4-alkoxy; or a pharmaceutically acceptable salt, a
solvate, a stereoisomer or a diastereoisomer thereof, for use in the prevention,
treatment or reduction in severity of oral mucositis in a subject undergoing cancer
therapy.
According to one embodiment of the present invention, there is provided a
compound of Formula (I), a pharmaceutically acceptable salt, a solvate, a
stereoisomer or a diastereoisomer thereof, wherein Ar is phenyl group substituted by
1, 2, or 3 identical or different substituents selected from chlorine, bromine, fluorine,
iodine, Ci-C4-alkyl or trifluoromethyl, for use in the prevention, treatment or reduction
in severity of oral mucositis in a subject undergoing cancer therapy.
According to another embodiment of the present invention, there is provided a
compound of Formula (I), a pharmaceutically acceptable salt, a solvate, a
stereoisomer or a diastereoisomer thereof, wherein Ar is phenyl group substituted by
1, 2, or 3 identical or different halogens selected from chlorine, bromine, fluorine or
iodine, for use in the prevention, treatment or reduction in severity of oral mucositis
in a subject undergoing cancer therapy.
According to another embodiment of the present invention, there is provided a
compound of Formula (I), a pharmaceutically acceptable salt, a solvate, a
stereoisomer or a diastereoisomer thereof, wherein Ar is phenyl group substituted
by chlorine, for use in the prevention, treatment or reduction in severity of oral
mucositis in a subject undergoing cancer therapy.
According to another embodiment of the present invention there is provided a
compound of Formula (I), a pharmaceutically acceptable salt, a solvate, a
stereoisomer or a diastereoisomer thereof, wherein Ar is phenyl group substituted
with two different substituents namely chlorine and trifluromethyl, for use in
prevention, treatment or reduction in severity of oral mucositis in a subject
undergoing cancer therapy.
It will be appreciated by those skilled in the art that the compounds of Formula (I)
contain at least two chiral centres and hence, exists in the form of two different
optical isomers (i.e., (+) or (-) enantiomers), two different geometric isomers (cis and
trans) and 4 different diasteroisomers. All such enantiomers, geometric isomers,
diasteroisomers and mixtures thereof including racemic mixtures are included within
the scope of the invention. The enantiomers of the compound of Formula (I) can be
obtained by methods disclosed in PCT Application Publication Nos. WO2004004632,
WO20071481 58 and WO2008007169 incorporated herein by reference or the
enantiomers of the compound of Formula (I) can also be obtained by methods well
known in the art, such as chiral HPLC and enzymatic resolution. Alternatively, the
enantiomers of the compounds of Formula (I) can be synthesized by using optically
active starting materials.
The manufacture of the compounds of Formula (I), which may be in the form of
pharmaceutically acceptable salts, and the manufacture of pharmaceutical
composition suitable for oral, topical and/or parenteral administration containing the
above compounds are generally disclosed in US Application Publication No.
US2007001 5802 which is incorporated herein by reference.
As indicated herein above the compound of Formula (I) may be used in the form of
their salts. Preferred salt of compounds of Formula (I) include acetates, alginates,
ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates,
cinnamates, citrates, ethanesulfonates, fumarates, glucuronates, glutamates,
glycolates, hydrochlorides, hydrobromides, hydrofluorides, ketoglutarates, lactates,
maleates, malonates, mesylate, nitrates, oxalates, palmoates, perchlorates,
phosphates, picrates, salicylates, succinates, sulfamate, sulfates, tartrates, tosylate,
trifluoroacetic acid salt and other acid addition salts known to the person skilled in
the art.
According to another aspect of the invention there is provided a (+)-trans isomer of
the compound of Formula (I), as indicated in Formula (IA) below,
Formula (IA)
wherein Ar is a phenyl group, which is unsubstituted or substituted by 1, 2, or 3
identical or different substituents selected from halogen, nitro, cyano, C -C4-alkyl,
trifluoromethyl, hydroxyl or C C4-alkoxy; or a pharmaceutically acceptable salt or a
solvate thereof for use in the prevention, treatment or reduction in severity of oral
mucositis in a subject undergoing cancer therapy.
Accordingly, in another aspect of the invention, the compound of Formula (IA) for
use in the prevention, treatment or reduction in severity of oral mucositis in a subject
undergoing cancer therapy is selected from (+)-frans-2-(2-Chloro-phenyl)-5,7-
dihydroxy-8-(2-hydroxy-methyl-1 -methyl-pyrrolidin-3-yl)-chromen-4-one
hydrochloride (referred to herein as compound A) or (+)-trans-3-[2[(2-Chloro-4-
trifluoromethyl-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1 -methyl-pyrrolidin-3-yl)-
chromen-4-one hydrochloride (referred to herein as compound B).
Compounds A and B are disclosed in PCT Application Publication WO20071 48158
and specifically as Example 10 and Example 44, respectively.
In an embodiment, the compound of Formula (IA) for use in the prevention ,
treatment or reduction in severity of oral mucositis in a subject undergoing cancer
therapy is (+)-irans-2-(2-Chloro-phenyl)-5,7-dihydroxy-8-(2-hydroxy-methyl-1-methylpyrrolidin-
3-yl)-chromen-4-one hydrochloride (compound A).
In another embodiment, the compound of Formula (IA) for use in the prevention,
treatment or reduction in severity of oral mucositis in a subject undergoing cancer
therapy is (+)-irans-3-[2[(2-Chloro-4-trifluoromethyl-phenyl)-5,7-dihydroxy-8-(2-
hydroxymethyl-1 -methyl-pyrrolidin-3-yl)-chromen-4-one hydrochloride (compound B).
A method for the prevention, treatment or reduction in severity of oral mucositis in a
subject undergoing cancer therapy, comprising administering to the subject a
therapeutically effective amount of a compound of Formula (I), a pharmaceutically
acceptable salt, a solvate, a stereoisomer or a diastereoisomer thereof.
A method for the prevention, treatment or reduction in severity of oral mucositis in a
subject undergoing cancer therapy, comprising administering to the subject a
therapeutically effective amount of a compound of Formula (I), a pharmaceutically
acceptable salt, a solvate, a stereoisomer or a diastereoisomer thereof, wherein the
cancer therapy is selected from radiation therapy, chemotherapy, hematopoietic
stem cell transplantation, bone marrow transplantation or a combination thereof.
According to an embodiment of the present invention, the cancer therapy is radiation
therapy, chemotherapy or a combination thereof.
According to an embodiment of the present invention, there is provided a method for
the prevention, treatment or reduction in severity of oral mucositis in a subject
undergoing cancer therapy, comprising administering to the subject a therapeutically
effective amount of a compound of Formula (I), a pharmaceutically acceptable salt, a
solvate, a stereoisomer or a diastereoisomer thereof, prior to cancer therapy,
concurrently with the cancer therapy, after the cancer therapy or in between two
cancer therapies.
According to an embodiment of the present invention, there is provided a method for
the prevention, treatment or reduction in severity of oral mucositis in a subject
undergoing cancer therapy, comprising administering to the subject a therapeutically
effective amount of a compound of Formula (I), a pharmaceutically acceptable salt, a
solvate, a stereoisomer or a diastereoisomer thereof, prior to the cancer therapy.
According to an embodiment of the present invention, there is provided a method for
the prevention, treatment or reduction in the severity of oral mucositis in a subject
undergoing cancer therapy comprising administering to the subject a therapeutically
effective amount of a compound of Formula (I), concurrently with the cancer therapy.
According to an embodiment of the present invention, there is provided a method for
the prevention, treatment or reduction in the severity of oral mucositis in a subject
undergoing cancer therapy comprising administering to the subject a therapeutically
effective amount of a compound of Formula (I), after the cancer therapy.
According to an embodiment of the present invention, there is provided a method for
the prevention, treatment or reduction in the severity of oral mucositis in a subject
undergoing cancer therapy comprising administering to the subject a therapeutically
effective amount of a compound of Formula (I), in between two cancer therapies.
According to an embodiment of the present invention, compound of formula (I) is
administered to the subject after administration of chemotherapy and before
administration of radiation therapy.
Dosage of the compound of Formula (I) depends on the mode of administration,
body weight, age of the patient and other factors that are commonly considered by a
skilled medical practitioner.
According to an embodiment of the present invention, the subject in need of the
prevention, treatment or reduction in the severity of oral mucositis is a patient
receiving therapy for the treatment of cancer, including both solid and
haematological cancer.
According to an embodiment of the present invention, the subject in need of the
prevention, treatment or reduction in the severity of oral mucositis is a patient
receiving therapy for the treatment of cancer, wherein the cancer is selected from
acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia,
Hodgkin's disease, multiple myeloma, non-Hodgkin's disease or head and neck
cancer.
According to an embodiment of the present invention, the subject in need of the
prevention, treatment or reduction in the severity of oral mucositis is a patient
receiving therapy for the treatment of cancer, wherein the cancer is head and neck
cancer.
5
According to an embodiment of the present invention there is provided a method for
the prevention, treatment or reduction in severity of oral mucositis in a subject
undergoing cancer therapy for head and neck cancer, comprising administering to
the subject a therapeutically effective amount of a compound of Formula (I), or a
i o pharmaceutically acceptable salt, a solvate, a stereoisomer or a diastereoisomer
thereof.
According to another embodiment of the present invention, there is provided a
method for the prevention, treatment or reduction in severity of oral mucositis in a
15 subject undergoing cancer therapy for head and neck cancer, comprising
administering to the subject a therapeutically effective amount of a compound of
Formula (I), or a pharmaceutically acceptable salt, a solvate, a stereoisomer or a
diastereoisomer thereof, wherein the cancer therapy includes radiation therapy,
chemotherapy or a combination thereof.
20
According to an embodiment of the present invention, there is provided a method for
the prevention, treatment or reduction in the severity of oral mucositis in a subject
undergoing radiation therapy for head and neck cancer, comprises administering a
compound of Formula (I), wherein oral mucositis includes inflammation of the
25 mucosal cells of the oral cavity. The other symptoms associated with oral mucositis
include oral pain, mouth and throat sores, dysphagia (difficulty in swallowing)
including feeding tube dependency, odynophagia (painful swallowing), lost or altered
taste (dysgeusia), ulcers, nausea and vomiting, loss of appetite, fatigue,
dehydration, weight loss, malnutrition and potential life threatening aspiration.
30
According to an embodiment of the present invention, the cumulative dose of the
radiation administered to a subject in need thereof is from about 30 Gy to about 82
Gy.
According to an embodiment of the present invention, the cumulative dose of the
radiation administered to a subject in need thereof is from about 50 Gy to about 82
Gy.
According to an embodiment of the present invention, the cumulative dose of the
radiation administered to a subject in need thereof is from about 66 Gy to about 82
Gy.
According to an embodiment of the present invention, the cumulative dose of the
radiation administered to a subject in need thereof is from about 66 Gy to about 75
Gy.
According to an embodiment of the present invention, the cumulative dose of the
radiation administered to a subject in need thereof is from about 60 Gy to about 75
Gy.
According to an embodiment of the present invention, the cumulative dose of the
radiation administered to a subject in need thereof is from about 60 Gy to about 70
Gy.
According to an embodiment of the present invention, the cumulative dose of the
radiation administered to a subject in need thereof is 66 Gy.
According to an embodiment of the present invention, the cumulative dose of the
radiation administered to a subject in need thereof is 60 Gy.
According to an embodiment of the present invention, there is provided a method for
the prevention, treatment or reduction in the severity of oral mucositis in a subject
undergoing cancer therapy for head and neck cancer, comprising administering
compound of Formula (I) to a subject in need thereof, wherein the chemotherapeutic
drug is a platinum-containing antineoplastic agent.
According to an embodiment of the present invention, the platinum-containing
antineoplastic agent is cisplatin.
According to an embodiment of the present invention, the dose of cisplatin
administered to a subject in need thereof, is from about 30 mg/m2 to about 40
mg/m2.
A method for the prevention, treatment or reduction in the severity of oral mucositis
in a subject undergoing cancer therapy for head and neck cancer comprising
administering to the subject in need thereof about 9 mg/m /day to about 259
mg/m /day of the compound A.
A method for the prevention, treatment or reduction in the severity of oral mucositis
in a subject undergoing cancer therapy for head and neck cancer comprising
administering to the subject in need thereof about 9 mg/m /day to about 185
mg/m /day of the compound A.
A method for the prevention, treatment or reduction in the severity of oral mucositis
in a subject undergoing cancer therapy for head and neck cancer comprising
administering to the subject in need thereof about 50 mg/m /day to about 100
mg/m /day of the compound A.
A method for the prevention, treatment or reduction in the severity of oral mucositis
in a subject undergoing cancer therapy for head and neck cancer comprising
administering to the subject in need thereof about 100 mg/m /day of the compound
A.
A method for the prevention, treatment or reduction in the severity of oral mucositis
in a subject undergoing radiation therapy for head and neck cancer comprises the
steps of: (a) administering compound A to the subject intravenously; and (b)
administering radiation therapy within 1.5 to 2 hours after the infusion of compound
A.
A method for the prevention, treatment or reduction in the severity of oral mucositis
in a subject undergoing radiation therapy for head and neck cancer, comprises the
steps of: (a) administering intravenously about 9 mg/m /day to about 259 mg/m /day
of compound A to the subject; and (b) administering about 60 to about 70 Grays of
cumulative radiation therapy within 1.5 to 2 hours after the infusion of compound A.
A method for the prevention, treatment or reduction in the severity of oral mucositis
in a subject undergoing radiation therapy for head and neck cancer, comprises the
steps of: (a) administering intravenously about 9 mg/m /day to about 185 mg/m /day
of compound A to the subject; and (b) administering about 60 to about 70 Grays of
cumulative radiation therapy within 1.5 to 2 hours after the infusion of compound A.
A method for the prevention, treatment or reduction in the severity of oral mucositis,
in a subject undergoing radiation therapy for head and neck cancer, comprises the
steps of: (a) administering intravenously about 100 mg/m /day of compound A to the
subject; and (b) administering about 1.8 Grays to about 2 Grays/day of radiation
therapy immediately after the infusion of compound A.
A method for the prevention, treatment or reduction in the severity of oral mucositis
in a subject undergoing radiation therapy for head and neck cancer comprises the
steps of: (a) administering cisplatin to the subject intravenously (b) administering
compound A to the subject intravenously; and (c) administering radiation therapy
within 2 hours after the end of the infusion of compound A.
A method for the prevention, treatment or reduction in the severity of oral mucositis
in a subject undergoing radiation therapy for head and neck cancer comprises the
steps of: (a) administering intravenously about 30 mg/m2 to about 40 mg/m2 of
cisplatin (b) administering intravenously about 100 mg/m /day of compound A to the
subject; and (c) administering from about 66 Grays to about 82 Grays of cumulative
radiation therapy within 2 hours after the end of the infusion of compound A.
A method for the prevention, treatment or reduction in the severity of oral mucositis,
in a subject undergoing a combination of chemotherapy and radiation therapy for
head and neck cancer, comprises the steps of: (a) administering intravenously about
30 mg/m2 to about 40 mg/m2 of cisplatin (b) administering intravenously about 100
mg/m /day of compound A to the subject on days 1 to 5 of weeks 1, 4 and 7 and (c)
administering about 1.8 Grays to about 2 Grays/day of radiation therapy within 2
hours after the infusion of compound A.
According to another aspect of the invention, there is provided use of the compound
of Formula (I), a pharmaceutically acceptable salt, a solvate, a stereoisomer or a
diastereoisomer thereof in the manufacture of a medicament for the prevention,
treatment or reduction in severity of a oral mucositis in a subject undergoing cancer
therapy.
According to an embodiment of the invention, there is provided use of the compound
of Formula (I), a pharmaceutically acceptable salt, a solvate, a stereoisomer or a
diastereoisomer thereof in the manufacture of a medicament for the prevention,
treatment or reduction in severity of a oral mucositis in a subject undergoing cancer
therapy for head and neck cancer.
According to an embodiment of the present invention, the cancer therapy for the
treatment of head and neck cancer is chemotherapy, radiation therapy or a
combination thereof.
According to the present invention, the subject in need of treatment of head and
neck cancer may be administered with radiation therapy of the type: Internal
Radiation Therapy, External Beam Radiation Therapy (EBRT), Three-dimensional
Conformal Radiation Therapy (3D-CRT) or Intensity Modulated Radiotherapy
(IMRT). EBRT involves the administration of radiation via a machine capable of
producing high-energy external beam radiation. The radiation can be either
electromagnetic (X-ray or gamma radiation) or particulate (a or b particles). Internal
radiation therapy (brachytherapy), involves implantation of a radioactive isotope as
the source of the radiation. 3D-CRT is an advanced type of external beam radiation
therapy technique that targets the prescribed radiation dose to the tumor, contouring
the spatial distribution of the dose to the precise 3D configuration of the tumor. IMRT
is an advanced type of high-precision external beam radiation therapy. It improves
the ability to conform the treatment volume to concave tumor shapes by creating a
shaped radiation beam and delivering high doses of radiation to the tumor and
significantly smaller doses of radiation to the surrounding normal tissues.
According to an embodiment of the present invention, the subject in need of
treatment for head and neck cancer may be administered with external beam
radiation therapy.
There is provided a pharmaceutical composition which comprises a therapeutically
effective amount of compound of Formula (I), a pharmaceutically acceptable salt, a
solvate, a stereoisomer, or a diastereoisomer thereof; in association with a
pharmaceutically acceptable carrier for use in the prevention, treatment or reduction
in the severity of oral mucositis.
There is provided a pharmaceutical composition which comprises a therapeutically
effective amount of compound of Formula (IA), a pharmaceutically acceptable salt, a
solvate, a stereoisomer, or a diastereoisomer thereof in association with a
pharmaceutically acceptable carrier for use in the prevention, treatment or reduction
in the severity of oral mucositis.
The pharmaceutical preparations/compositions may contain about 1% to 99%, for
example, about 5% to 70%, or from about 5% to about 30% by weight of the
compound of the Formula (I) or pharmaceutically acceptable salt thereof as the
active ingredient. The amount of the compound of the Formula (I) or
pharmaceutically acceptable salt thereof in the pharmaceutical preparations normally
is from about 1 mg to 1000 mg.
Administration of the pharmaceutical composition containing the compound of
Formula (I) disclosed herein may be via any route known to be effective to a skilled
medical practitioner. The compound of Formula (I) may be administered orally,
topically or parenterally (including intravenous, subcutaneous, intramuscular,
intravascular or infusion).
Compositions intended for pharmaceutical use may be prepared according to any
method known in the art for the manufacture of pharmaceutical compositions, e.g.
Remington - The Science and Practice of Pharmacy (21st Edition) (2005), Goodman
& Gilman's The Pharmacological Basis of Therapeutics ( 11th Edition) (2006) and
Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (9th Edition),
edited by Allen et al., Lippincott Williams & Wilkins, (201 1), Solid-State Chemistry of
Drugs (2nd Edition)^ 999), each of which is hereby incorporated by reference."
The compositions described herein may be in a form suitable for oral administration,
for example, solid dosage forms such as tablets, capsules, lozenges, or granules;
liquid dosage forms such as, emulsions, solutions, suspensions; for parenteral
injection (including intravenous, subcutaneous, intramuscular, intravascular or
infusion) for example as a sterile solution, suspension or emulsion; for topical
administration for example as an ointment, cream, gel, lotions or collodion.
Compositions for oral delivery may be in the form of tablets, lozenges, aqueous or
oily suspensions, granules, powders, cachets, emulsions, capsules, syrups, or
elixirs. Orally administered compositions may contain one or more optional agents,
for example, sweetening agents such as fructose, aspartame or saccharin; flavoring
agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and
preserving agents, to provide a pharmaceutically palatable preparation. Selectively
permeable membranes surrounding an osmotically active driving compound are also
suitable for oral administration of compounds of present invention. Oral compositions
can include standard vehicles such as mannitol, lactose, starch, corn starch,
magnesium stearate, talc, sodium saccharine, cellulose, magnesium carbonate, etc.
Such vehicles are preferably of pharmaceutical grade.
For ointments, creams, the compound of Formula (I) is formulated in oil-in-water or
water-in-oil base.
For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile
solutions of compound of Formula (I) are usually employed, and the pH of the
solutions should be suitably adjusted and buffered.
Further, the effect of the compounds of Formula (I) contained in the pharmaceutical
composition may be delayed or prolonged by proper formulation. For example, a
slowly soluble pellet of the compound may be prepared and incorporated in a tablet
or capsule. The technique may be improved by making pellets of several different
dissolution rates and filling capsules with a mixture of the pellets. Tablets or capsules
may be coated with a film which resists dissolution for a predictable period of time.
Even the parenteral preparations may be made long-acting, by dissolving or
suspending the compound in oily or emulsified vehicles which allow it to disperse
only slowly in the serum.
Effective dose of the compound of Formula (I) depends at least on the nature of the
condition being treated, the mode of delivery, and the pharmaceutical formulation,
and will be determined by the skilled medical practitioner or clinician using
conventional dose escalation studies. It can be from about 9 mg/m2 to about 259
mg/m2 per day; particularly, from about 9 mg/m2 to about 185 mg/m2 per day; more
particularly, from about 50 mg/m2 to about 100 mg/m2 per day.
Compounds of Formula (I) may be prepared according to the methods disclosed in
PCT Patent Publication No. WO2004004632 and PCT Patent Publication No.
WO20071481 58 which are incorporated herein by reference.
The general process for the preparation of compounds of Formula (I), or a
pharmaceutically acceptable salt thereof, comprises the following steps:
(a) treating the resolved enantiomerically pure (-)-trans enantiomer of the
intermediate compound of Formula VIA,
VIA
with acetic anhydride in the presence of a Lewis acid catalyst to obtain a resolved
acetylated compound of Formula VIIA,
(b) reacting the resolved acetylated compound of Formula VIIA with an acid of
Formula ArCOOH or an acid chloride of Formula ArCOCI or an acid anhydride of
Formula (ArCO)20 or an ester of Formula ArCOOCH3, wherein Ar is as defined
hereinabove in reference to the compound of Formula (I), in the presence of a base
and a solvent to obtain a resolved compound of Formula VIIIA;
(c) treating the resolved compound of Formula VIIIA with a base in a suitable solvent
to obtain the corresponding resolved b-diketone compound of Formula IXA;
IXA
wherein Ar is as defined above;
(d) treating the resolved b-diketone compound of Formula IXA with an acid such as
hydrochloric acid to obtain the corresponding cyclized compound of Formula XA,
XA
(e) subjecting the compound of Formula XA to dealkylation by heating it with a
dealkylating agent at a temperature ranging from 120-1 80 ° to obtain the {+)-trans
enantiomer of the compound of Formula (I) and, optionally, converting the subject
compound into its pharmaceutically acceptable salt.
The Lewis acid catalyst utilized in the step (a) above may be selected from: BF3,
Et20 , zinc chloride, aluminium chloride and titanium chloride.
The base utilized in the process step (b) may be selected from triethylamine, pyridine
and a DCC-DMAP combination (combination of N, N'-dicyclohexyl carbodiimide and
4-dimethylaminopyridine).
It will be apparent to those skilled in the art that the rearrangement of the compound
of Formula VINA to the corresponding b-diketone compound of Formula IXA is
known as a Baker-Venkataraman rearrangement (J. Chem. Soc, 1933, 1381 and
Curr. Sci., 1933, 4, 214).
The base used in the process step (c) may be selected from: lithium hexamethyl
disilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, sodium
hydride and potassium hydride. A preferred base is lithium hexamethyl disilazide.
The dealkylating agent used in process step (e) for the dealkylation of the compound
of Formula IXA may be selected from: pyridine hydrochloride, boron tribromide,
boron trifluoride etherate and aluminium trichloride. A preferred dealkylating agent is
pyridine hydrochloride.
Preparation of the starting compound of Formula VIA involves reacting 1-methyl-4-
piperidone with a solution of 1,3,5-trimethoxybenzene in glacial acetic acid, to yield
1-methyl-4-(2,4,6-trimethoxyphenyl)-1 ,2,3,6-tetrahydropyridine, which is reacted with
boron trifluoride diethyl etherate, sodium borohydride and tetrahydrofuran to yield 1-
methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-ol. Conversion of 1-methyl-4-(2,4,6-
trimethoxyphenyl)piperidin-3-ol to the compound of Formula VIA involves converting
the hydroxyl group present on the piperidine ring of the compound, 1-methyl-4-
5 (2,4,6-trimethoxyphenyl) piperidin-3-ol to a leaving group such as tosyl, mesyl, triflate
or halide by treatment with an appropriate reagent such as p-toluenesulfonylchloride,
methanesulfonylchloride, triflic anhydride or phosphorous pentachloride in the
presence of oxygen nucleophiles such as triethylamine, pyridine, potassium
carbonate or sodium carbonate , followed by ring contraction in the presence of
i o oxygen nucleophiles such as sodium acetate or potassium acetate in an alcoholic
solvent such as isopropanol, ethanol or propanol.
It is to be understood that the invention may assume various alternative variations
and step sequences, except where expressly specified to the contrary. Moreover,
other than in any operating examples, or where otherwise indicated, all numbers
15 expressing, for example, quantities of ingredients used in the specification and
claims are to be understood as being modified in all instances by the term "about".
Accordingly, unless indicated to the contrary, the numerical parameters set forth in
the following specification and attached claims are approximations that may vary
depending upon the desired properties to be obtained by the present invention. At
20 the very least, and not as an attempt to limit the application of the doctrine of
equivalents to the scope of the claims, each numerical parameter should at least be
construed in light of the number of reported significant digits and by applying
ordinary rounding techniques.
Those skilled in the art will recognize that several variations are possible within the
25 scope and spirit of this invention. The invention will now be described in greater
detail by reference to the following non-limiting examples. The following examples
further illustrate the invention but, of course, should not be construed as in any way
limiting its scope.
30
EXEMPLIFICATION
In the following examples and elsewhere, abbreviations have the following
meanings:
Reference example 1
A) Preparation of (+)-trans-2-(2-Chlorophenyl)-5, 7-dihydroxy-8-(2-
hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one hydrochloride
(Compound A)
Molten pyridine hydrochloride (4.1 g, 35.6 mmol) was added to (+)-trans-2-(2-chlorophenyl)-
8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one
(0.4 g, 0.9 mmol) and heated at 180 ° for 1.5 h. The reaction mixture was cooled to
25 °C, diluted with MeOH ( 10 mL) and basified using Na2C0 3 to pH 10. The mixture
was filtered and the organic layer was concentrated. The residue was suspended in
water (5 mL), stirred for 30 minutes filtered and dried to obtain the compound, (+)-
trans-2-(2-chloro-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1 -methyl-pyrrolidin-3-yl)-
chromen-4-one.
Yield: 0.25 g (70 %); IR (KBr): 3422, 3 135, 1664, 1623, 1559 cm 1 ;
1H NMR (CDCI3, 300MHz): d 7.56 (d, 1H), 7.36 (m, 3H), 6.36 (s, 1H), 6.20 (s, 1H),
4.02 (m, 1H), 3.70 (m, 2H), 3.15 (m, 2H), 2.88 (m, 1H), 2.58 (s, 3H), 2.35 (m, 1H),
1.88 (m, 1H); MS (ES+): m/z 402 (M+1);
Analysis: C21 H20CINO5; C, 62.24 (62.71); H, 5.07 (4.97); N, 3.60 (3.48); CI, 9.01
(8.83).
The compound (0.2 g, 0.48 mmol) as obtained above was suspended in IPA (5 mL)
and 3.5 % HCI (25 mL) was added. The suspension was heated to get a clear
solution. The solution was cooled and solid filtered to obtain the compound, (+)-
trans-2-(2-Chlorophenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-
chromen-4-one hydrochloride.
Yield: 0.21 g (97 %); mp: 188 - 192 € ; [a]D25 = +21 .3° (c = 0. 2, methanol);
1H NMR (CD3OD, 300MHz): d 7.80 (d, 1H), 7.60 (m, 3H), 6.53 (s, 1H), 6.37 (s, 1H),
4.23 (m, 1H), 3.89 (m, 2H), 3.63 (m, 1H), 3.59 (dd, 1H), 3.38 (m, 1H), 2.90 (s, 3H),
2.45 (m, 1H), 2.35 (m, 1H); MS (ES+): m/z 402 (M + 1)( free base).
This compound was subjected to chiral HPLC. Chiral HPLC was done using column
Chiralcel OD-H (250 x 4.6 mm) and solvent system haxane:ethanol (92:08) with TFA
(0.4%). The results are recorded at 264nm with solvent flow rate of 1mL/minute The
chiral HPLC showed 100% e.e of the compound, (+)-trans-2-(2-chloro-phenyl)-5,7-
dihydroxy-8-(2-hydroxy-methyl-1 -methyl-pyrrolidin-3-yl)-chromen-4-one
hydrochloride.
B) Preparation of (+)-trans-2-(2-chloro-4-trifluoromethyl-phenyl)-5,7-dihydroxy-
8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one hydrochloride
(Compound B)
A mixture of the compound, (+)-trans-2-(2-Chloro-4-trifluoromethylphenyl)-8-(2-
hydroxymethyl-1 -methyl pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one (0.25 g, 0.5
mmol), pyridine hydrochloride (0.25 g, 2.16 mmol) and a catalytic amount of
quinoline was heated at 180 ° for a period of 2.5 h. The reaction mixture was
diluted with methanol (25 mL) and basified with solid Na2C0 3 to pH 10. The reaction
mixture was filtered, and washed with methanol. The organic layer was concentrated
and the residue purified by column chromatography using 0.1 % ammonia and 4.5 %
MeOH in chloroform as eluent to yield the compound, (+)-trans-2-(2-chloro-4-
trifluoromethylphenyl)-5,7-dihydroxy-8-(2-hydroxy-methyl-1-methylpyrrolidin-3-yl)-
chromen-4-one, as a yellow solid.
Yield: 0.15 g (63.7 %); 1H NMR (CDCI3, 300MHz): d 7.99 (m, 2H), 7.83 (d, 1H), 6.65
(s, 1H), 6.41 (s, 1H), 4.24 (m, 1H), 3.90 (m, 2H), 3.70 (m, 1H), 3.60 (m, 1H), 3.41 (m,
1H), 2.99 (s, 3H), 2.54 (m, 1H), 2.28 (m, 1H); MS (ES+): m/z 470 (M+1).
The compound (0.1 g, 0.2 mmol) as obtained above was suspended in methanol (2
ml.) and treated with ethereal HCI and the organic solvent evaporated to yield the
compound, (+)-trans-2-(2-chloro-4-trifluoromethyl-phenyl)-5,7-dihydroxy-8-(2-
hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one hydrochloride.
Yield: 0.1g (92.8 %); 1H NMR (CDCI3, 300MHz): d 8.02 (d, 2H), 7.83 (d, 1H), 6.64 (s,
1H), 6.41 (s, 1H), 4.23 (m, 1H), 3.73 (m, 2H), 3.68 (m, 1H), 3.51 (m, 1H), 3.39 (m,
1H), 2.99 (s, 3H), 2.54 (m, 1H), 2.31 (m, 1H).
PHARMACOLOGY
Example 1: To assess the effect of compound A in the prevention and/or treatment
of radiation induced oral mucositis in Hamsters
The experiment was carried out at Biomodel's facility in Watertown,
Massachusetts, USA. IACUC (Institutional Animal Care and Use Committee)
approval for this study ( 10-0614-06) was obtained from Biomodel's IACUC.
Materials and Methods:
Animals:
Male LVG Syrian Golden Hamsters, 5 to 6 weeks old, weighing 87.7 to 97.1 g
(Charles River Laboratories, US) at the commencement of the study, were used. An
ear punch was used to number the animals individually. Approximately 8-1 0 animals
were housed per cage. The animals were acclimatized for at least 3 days before
experimentation. During this period, they were observed daily to ensure that the
animals are in good condition. The animals that presented poor condition were
rejected.
Animal room housing the aforesaid animals was provided with filtered air at a
temperature of 65 to 75 °F and 30 to 70% humidity. Animal room received a
minimum of 12 to 15 air changes per hour and was maintained on an automatic timer
for a light/dark cycle of 12 hours each with no twilight. Animals were fed with Purina
Labdiet® 5053 sterile rodent chow and soft food. Sterile water was provided ad
libitum.
Conditions for storage of the compounds and Dose preparation
Compound A: 5 mg/mL and 10 mg/mL; vehicle: dextrose (5%) prepared in water.
All the compounds including the standard were stored at 2 °C to 8 °C.
Animal Randomization and Allocation:
Animals were randomly and prospectively divided into 5 groups:
i) Group 1: Animals (n=8) were administered with 5% w/v dextrose monohydrate
intraperitoneally from Day 0 to Day 4 or from Day 0 to Day 9.
ii) Group 2: Animals (n=10) were administered with 10 mg/kg of compound A
intraperitoneally from Day 0 to Day 4.
iii) Group 3: Animals (n=10) were administered with 20 mg/kg of compound A
intraperitoneally from Day 0 to Day 4.
iv) Group 4: Animals (n=1 0) administered with 10 mg/kg of compound A
intraperitoneally from Day 0 to Day 9.
v) Group 5: Animals (n=1 0) administered with 20 mg/kg of compound A
intraperitoneally from day Day 0 to Day 9.
Treatment:
Mucositis induction: The animals were anesthetized and the left buccal pouch was
everted, fixed and isolated using a lead shield. The left buccal pouch mucosa of the
animal was exposed to radiation at a rate of 2.0 Gy/minute. A single dose of
radiation (40 Gy/dose) was administered to all animals on Day 0. Radiation was
generated with 160 kilovolt potential source at a focal distance of 2 1 cm, hardened
with a 0.35 mm Al filtration system. Animals of Group 2 to 5 were treated with
compound A as per the schedule detailed above one hour prior to the radiation. The
volume administered to all the above Groups was 0.2 mL/100g.
Mucositis:
For evaluation of mucositis, the animals were anesthetized with an inhalation
anesthetic and the left buccal pouch everted. Mucositis was scored visually using the
following criteria for evaluation:
Score Description
0 Pouch completely healthy. No erythema or vasodilation.
1 Light to severe erythema and vasodilation. No erosion of mucosa.
2 Severe erythema and vasodilation. Erosion of superficial aspects of mucosa
leaving denuded areas. Decreased stippling of mucosa.
3 Formation of off-white ulcers in one or more places. Ulcers may have a yellow/
gray color due to pseudomembrane. Cumulative size of ulcers should equal
less than or equal to 1/4th of the pouch. Severe erythema and vasodilation.
4 Cumulative size of ulcers should equal about 1/2 of the pouch. Loss of
pliability. Severe erythema and vasodilation.
5 Virtually all of pouch is ulcerated. Loss of pliability (pouch can only partially be
extracted from mouth).
Weight change and survival were also measured throughout the study.
Observations and Results:
Survival:
Three deaths occurred during the study. Two deaths were attributed to the use of
anesthesia during radiation. One animal was sacrificed on Day 19, upon
development of fistula that formed on the abdomen following ulceration of the
injection site.
Weight Change:
The one-way ANOVA test revealed that there was no significant difference in percent
body weight change among groups.
Mucositis:
Mean daily mucositis scores for each group were evaluated. The maximum mean
mucositis score observed in the vehicle control group was 3.0, which occurred on
Day 16. The treatment Groups 2 and 3 had maximum mean mucositis scores of 3.0
and 3.0 on Day 18 and Day 16, respectively. The treatment Groups 4 and 5 had
maximum mean mucositis scores on Day 16 with average scores of 3.0 and 3.1
respectively.
Duration of Ulcerative Mucositis:
The significance of differences observed between the different treatment groups was
evaluated by comparing the days with mucositis scores > 3 and < 3 between groups
using a chi-squared analysis.
Result: For the entire duration of the study, the percentage of animal days
with a score of > 3 in the vehicle control group was 63.0%. The percentage of days
with a score of > 3 was significantly reduced to 43.5% in Group 4. The percentage of
animal days with a score of > 3 for the other 3 treatment groups was not significantly
different compared to the vehicle control group.
Mucositis Severity:
An analysis of the severity of mucositis was performed using Mann-Whitney rank
sum analysis to compare the visual mucositis scores for each treatment group to the
vehicle control on each day of the analysis.
Result: The treatment Group 4 showed significant reductions in mucositis on
Day 24 (p=0.002) and Day 26 (p=0.024) and also it showed strong trend of lower
scores on Day 18 (p=0.073) and Day 28 (p=0.064) compared to the vehicle control
i.e Group 1.
Percentage of Animals with Ulcerative Mucositis by Day
The percentage of animals in each group with ulcerative mucositis at each day of the
study was evaluated.
Result: The treatment Group 4 showed notably low percentage of ulceration
by Day with Mucositis Score > 3. On Days 24 to 28 of the study the percentage of
animals with ulcerative mucositis was reduced significantly by 72.7%, 83.8 and
77.8% respectively, compared to the Group 1.
Conclusions:
1. Treatment with Compound A at 10 mg/kg from Days 0 to 9 significantly
reduced the percent of days and the number of days with ulcerative mucositis (score
>3) compared to the vehicle control Group.
2. Treatment with Compound A at 10 mg/kg from Days 0 to 9 resulted in a
significant improvement in mucositis scores on Day 24 and 26 of the study compared
to the vehicle control Group.
Example 2 : To assess the effect of compound A in the prevention and/or
treatment of radiation induced oral mucositis
Clinical Study
5
The clinical study was carried out by the method described below:
Patient selection:
A total of 23 patients with squamous cell carcinoma of oral cavity, oropharynx and
hypopharynx were enrolled in the clinical study of compound A. Of the 23 patients,
i o 19 patients underwent a complete treatment schedule and hence 19 patients were
evaluated for efficacy.
Treatment Schedule:
The compound A and external beam radiotherapy (EBRT) were administered for six
15 weeks i.e., 2 cycles of compound A and 60 fractions of radiation. One, three weeks
(21 days) cycle of combination regimen comprised of dosing compound A for days 1
to 5 and EBRT on days 1 to 5, 8 to 12 and 15 to 19. The combination treatment
schedule is depicted in the following table:
The tick mark symbol ) indicates that compound A or radiation, as applicable is
administered to the subject.
The cross symbol (x) indicates that compound A or radiation, as applicable, is not
administered to the subject.
25
Treatment Procedure:
A] Dose of compound A: In the Phase I part of the clinical trial, 11 patients were
enrolled and 100 mg/m /day of compound A was determined to be the maximum
tolerated dose (MTD) as two dose limiting toxicities occurred at the higher dose of
140 mg/m /day. Additional 1 subjects were enrolled at the MTD dose level to
confirm the safety and tolerability of that dose.
B] Procedure: Compound A ( 100 mg/m /day) in 5% dextrose (200 ml.) was
administered to 19 patients as intravenous infusion over 30 minutes on days 1 to 5 of
a 2 1 day cycle. After about 1.5 hours of infusion of compound A, the patients
received EBRT (2 Grays per day for 5 days) to the affected body parts (primary
tumor site and involved cervical lymph nodes) through linear accelerator. Patients
continued to receive EBRT (2 Grays per day) on days 8-1 2 and 15-19. On days 6, 7,
13 and 14 patients were not infused with compound A, neither were exposed to
radiotherapy.
The procedure was repeated for cycle 2.
At investigator's discretion, some patients were given additional radiation of
up to 10 additional Grays (2 Grays per day for 5 days) commencing immediately
after the completion of the prescribed radiation dose of 60 Grays. Total radiation
dose for spinal cord was less than 48 Grays.
The radiation breaks were compensated by delivering the missed doses over
weekends or an additional dose on the next day with a minimum gap of 6 hours
between two radiation doses or immediately after the end of cycle 2.
Evaluation of toxicity criteria for oral mucositis in radiation therapy:
The Common Terminology Criteria for Adverse Events (version 3) (version 3,
Publish Date: August 09, 2006) laid down by the National Cancer Institute for oral
mucositis in radiation therapy was followed. The criteria for evaluation were as
follows:
Grade Adverse Event
(mild) Erythema of the mucosa
(moderate) Patchy ulcerations or pseudomemb
3 (severe) Confluent ulcerations or pseudomembranes;
bleeding with minor trauma
4 (severe) Tissue necrosis; significant spontaneous bleeding;
life threatening consequences
5 Death
Observations and Results: After completion of the trial, it was found that only five
events of mucositis were reported in the 19 evaluable patients:
a) one severe mucositis (Grade 3),
b) two moderate stomatitis (Grade 2),
c) one moderate mucositis (Grade 2),
d) one mild mucositis (Grade 1).
The results show that the compound A has radioprotective effects and compares
favourably with historical rates of serious RIM (Grade 3 and above) as reported by
Trotti et al., in Radiotherapy and Oncology, 2003, 66, 253-262.
Example 3 : To assess the effect of compound A in the prevention and/or
treatment of chemo-radiotherapy induced oral mucositis
Protocol 1
Patient selection:
A total of 60 patients with locally advanced squamous cell carcinoma of head
and neck (SCCHN), will be enrolled in the clinical study of compound A.
Treatment Schedule:
Compound A and external beam radiotherapy (EBRT) will be administered to
the patients for seven weeks. Cisplatin will be administered intravenously on Day 1
or Day 2 of every week. Compound A will be administered over 30 minutes on Days
1 to 5 of weeks 1, 4 and 7. The patients will be irradiated within 2 hours after the end
of the infusion of Compound A.
The patients treated with cisplatin and Compound A are scheduled to receive
at least 66 Gy of cumulative radiation.
A typical combination treatment schedule for seven weeks comprising of
dosing of cisplatin as chemotherapeutic agent, compound A and EBRT is depicted in
the following table:
Table 1:
The cross symbol (x) indicates that compound A will not be administered to
the subject.
5
Treatment Procedure:
A] Dose of compound A: 100 mg/m /day of compound A is determined to be the
maximum tolerated dose (MTD).
B] Procedure: Cisplatin will be administered at a dose of 30 to 40 mg/m2 (the
i o selection of the dose is left open to investigator and institutional standards) on the
first or second day of week 1 of the treatment and then will be administered on the
weekly basis the same day of the week in the subsequent weeks (week 2 to 7).
Compound A ( 100 mg/m /day) in 5% dextrose will be administered as intravenous
infusion over 30 minutes on days 1 to 5 of weeks 1, 4 and 7. Within 2 hours of
15 infusion of compound A, the patients will be exposed to EBRT to the involved body
parts (primary tumor site and grossly involved cervical lymph nodes and sub-clinical
lymph nodes) by using standard conventional fractionation of 2 Grays per day for 5
days per week for a total radiation dose of at least 66 Gy over 7 weeks.
The radiation breaks will be compensated by delivering the missed doses
20 over weekends or an additional dose on the next day with a minimum gap of 6 hours
between two radiation doses or immediately after the end of the week 7 treatment.
Evaluation of Toxicity criteria for oral mucositis in radiation therapy:
The WHO Toxicity Criteria was followed (WHO Handbook for Reporting
25 Results of Cancer Treatment).
The criteria for evaluation were as follows:
Grade Scale
5 0 None
1 Soreness and Erythema; no ulcers
2 Ulcers; able to eat a solid diet
3 Ulcers; requires a liquid diet
4 Ulcers; not able to tolerate a solid or liquid diet; requires IV or
i o tube feeding.
The following parameters will be evaluated:
1. The incidence of severe radiation induced mucositis (WHO Grade > 3) occurring
upto a cumulative radiation dose of 66 Gy.
2. The time for onset of severe radiation induced mucositis (WHO Grade > 3) from
the start of study treatment i.e. the number of days between start of study
treatment and the first time that WHO Grade 3 or 4 mucositis is observed.
3. The duration of severe radiation induced mucositis (WHO Grade > 3) i.e. the
number of days from the onset of severe radiation induced mucositis to the day
when severe radiation induced mucositis is resolved (WHO Grade < 3).
4. Locoregional control.
5. Progression-free survival.
6. Overall survival.
7. Safety and tolerability of the combination regimen of compound A with radiation
and cisplatin.
Protocol 2 :
The protocol for the clinical study is described below:
Patient selection:
An appropriate number of patients with locally advanced squamous cell
carcinoma of head and neck (SCCHN), will be enrolled in the clinical study of
compound A.
Treatment Schedule:
The study will be carried out in two different treatment arms, wherein the patients
will be scheduled to receive:
Treatment arm 1: Cisplatin, compound A and radiation therapy or
Treatment arm 2: Cisplatin and radiation therapy.
Compound A (for treatment arm 1) and external beam radiotherapy (EBRT)
will be administered to the patients for seven weeks. Cisplatin will be administered
intravenously on Day 1 or Day 2 of every week. Compound A (for treatment arm 1)
will be administered over 30 minutes on Days 1 to 5 of weeks 1, 4 and 7. The
patients will be irradiated within 2 hours after the end of the infusion of Compound A.
A typical combination treatment schedule for seven weeks comprising of dosing
of cisplatin as chemotherapeutic agent, compound A and EBRT is depicted in the
following tables:
Table 2: Treatment Arm 1
Treatment Procedure:
A] Dose of compound A: 100 mg/m /day of compound A is determined to be the
maximum tolerated dose (MTD).
B] Procedure: Cisplatin will be administered at a dose of 30 to 40 mg/m2 (the
selection of the dose is left open to investigator and institutional standards) on the
first or second day of week 1 of the treatment and then given on the weekly basis the
same day of the week in subsequent weeks (week 2 to 7). Compound A ( 100
mg/m /day), in 5% dextrose will be administered as intravenous infusion over 30
minutes on days 1 to 5 of weeks 1, 4 and 7, to the patients of treatment arm 1.
Patients enrolled in treatment arm 2 will not receive compound A. Within 2 hours of
infusion of compound A (treatment arm 1) or within 2 hours of administration of
cisplatin (treatment arm 2), the patients will be exposed to EBRT to the involved
body parts (primary tumor site and grossly involved cervical lymph nodes and sub
clinical lymph nodes) by using standard conventional fractionation of 2 Grays per day
for 5 days per week for a total radiation dose of at least 66 Gy over 7 weeks.
The radiation breaks will be compensated by delivering the missed doses
over weekends or an additional dose on the next day with a minimum gap of 6 hours
between two radiation doses or immediately after the end of the week 7 treatment.
Evaluation of Toxicity criteria for oral mucositis in radiation therapy:
The WHO Toxicity Criteria was followed (WHO Handbook for Reporting
Results of Cancer Treatment).
The criteria for evaluation were as follows:
Grade Scale
0 None
Soreness and Erythema; no ulcers
2 Ulcers; able to eat a solid diet
3 Ulcers; requires a liquid diet
4 Ulcers; not able to tolerate a solid or liquid diet; requi
or tube feeding.
The following parameters will be evaluated:
1. The incidence of severe radiation induced mucositis (WHO Grade > 3)
occurring upto a cumulative radiation dose of 54 Gy.
2. The incidence of severe radiation induced mucositis (WHO Grade > 3)
occurring upto a cumulative radiation dose of 66 Gy.
3. The time for onset of severe radiation induced mucositis (WHO Grade > 3) from
the start of study treatment i.e. the number of days between start of study
treatment and the first time the WHO Grade 3 or 4 mucositis was observed.
4. The duration of severe radiation induced mucositis (WHO Grade > 3) i.e. the
number of days from the onset of severe radiation induced mucositis to the day
when severe radiation induced mucositis is resolved (WHO Grade < 3).
5. Locoregional control
6. Progression-free survival
7. Overall survival
8. Safety and tolerability of the two treatment arms.
The examples described above do not limit the scope of the invention. The
present invention encompasses the modifications and variations apparent to the
person skilled in the art.
It should also be noted that the term "or" is generally employed in its sense
including "and/or" unless the content clearly dictates otherwise.
All publications and patent applications in this specification are indicative of
the level of ordinary skill in the art to which this invention pertains.
A compound of Formula (I)
Formula (I)
5 wherein Ar is a phenyl group, which is unsubstituted or substituted by 1, 2, or 3
identical or different substituents selected from: halogen, nitro, cyano, Ci-C4-alkyl,
trifluoromethyl, hydroxyl and C C4-alkoxy; or a pharmaceutically acceptable salt, a
solvate, a stereoisomer or a diastereoisomer thereof, for use in the prevention,
treatment or reduction in severity of oral mucositis in a subject undergoing cancer
i o therapy.
2. The compound for the use according to claim 1, wherein Ar is a phenyl group
substituted by 1, 2 or 3 identical or different substituents selected from chlorine,
bromine, fluorine, iodine, Ci-C4-alkyl or trifluoromethyl.
15 3. The compound for the use according to claim 1, wherein the compound of
Formula (I) is a (+)-trans isomer represented by Formula (IA),
Formula (IA)
wherein Ar is a phenyl group, which is unsubstituted or substituted by 1, 2, or 3
20 identical or different substituents selected from halogen, nitro, cyano, Ci-C4-alkyl,
trifluoromethyl, hydroxyl or C C4-alkoxy; or a pharmaceutically acceptable salt or a
solvate thereof.
4. The compound for the use according to any one of the preceding claims 1 to
3, wherein the compound is administered to the subject, prior to cancer therapy,
concurrently with the cancer therapy, after the cancer therapy or in between two
cancer therapies.
5. The compound for the use according to claim 4, wherein the compound is
administered to the subject prior to the cancer therapy.
6. The compound for the use according to claim 4, wherein the compound is
administered to the subject concurrently with the cancer therapy.
7. The compound for the use according to claim 4, wherein the compound is
administered to the subject after the cancer therapy.
8. The compound for the use according to claim 4, wherein the compound is
administered to the subject after administration of chemotherapy and before
administration of radiation therapy.
9. The compound for the use according to any one of the preceding claims 1 to
8, wherein the subject undergoing cancer therapy is a patient suffering from acute
myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, Hodgkin's
disease, multiple myeloma, non-Hodgkin's disease or head and neck cancer.
10. The compound of Formula (I) for the use according to claim 9, wherein the
subject undergoing cancer therapy is a patient suffering from head and neck cancer.
11. The compound for the use according to any one of the preceding claims 1 to
10, wherein the compound is (+)-frans-2-(2-Chloro-phenyl)-5,7-dihydroxy-8-(2-
hydroxy-methyl-1 -methyl-pyrrolidin-3-yl)-chromen-4-one hydrochloride (compound
A).
12. The compound for the use according to claim 11, wherein the compound A is
administered in a dose from 9 mg/m /day to 259 mg/m /day.
13. The compound for the use according to one of the preceding claims 1 to 10 ,
wherein the compound is (+)-trans-3-[2[(2-Chloro-4-trifluoromethyl-phenyl)-5,7-
dihydroxy-8-(2-hydroxy-methyl-1 -methyl-pyrrolidin-3-yl)-chromen-4-one
hydrochloride (compound B).
14. The compound for the use according to any one of the preceding claims 1 to
13, wherein the cancer therapy is selected from radiation therapy, chemotherapy,
hematopoietic stem cell transplantation, bone marrow transplantation or a
combination thereof.
15. The compound for the use according to claim 14, wherein the cancer therapy
is radiation therapy, chemotherapy or a combination thereof.
16. The compound for the use according to claim 15, wherein the cumulative
dose of the radiation administered to a subject in need thereof is selected from 30
Grays to 82 Grays.
17. The compound for the use according to claim 15, wherein chemotherapy
involves use of cisplatin.
18. The compound for the use according to claim 17, wherein the dose of cisplatin
administered to a subject in need thereof, is from 30 mg/m2 to 40 mg/m2.
19. A pharmaceutical composition for use in the prevention, treatment or
reduction in severity of oral mucositis in a subject undergoing cancer therapy,
comprising a therapeutically effective amount of compound of Formula (I),
Formula (I)
or a pharmaceutically acceptable salt, a solvate, a stereoisomer
diastereoisomer thereof and a pharmaceutically acceptable carrier.