FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
TREATMENT FOR GLOMERULAR DISEASES
APPLICANT(S):
a) NAME ZYDUS LIFESCIENCES LIMITED
b) NATIONALITY INDIAN
c) ADDRESS ZYDUS CORPORATE PARK, SCHEME NO. 63,
SURVEY NO. 536, KHORAJ (GANDHINAGAR),
NR. VAISHNODEVI CIRCLE, AHMEDABAD,
GANDHINAGAR, GUJARAT, INDIA, 382481
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in
which it has to be performed.
2
Field of the invention
Present invention relates to the development of therapeutic compound for the treatment
of glomerular diseases. Specifically, present invention relates to use of compound of
formula (Ia) or its pharmaceutically acceptable salt or combination thereof or
pharmaceutical composition thereof for the treatment of glomerular diseases.
Background of the invention
Glomeruli is the functional part of nephron, that is involved in the filtration and clearing
the waste material from the body. The diseases affecting the glomeruli is known as
glomerulopathy. It may be of inflammatory or non-inflammatory origin. The
impairment of the function of glomeruli deteriorates the function of kidney. The
glomerulopathy is also associated with hematuria or proteinuria, dysfunction of the
endothelium, glomerular filtration barrier or podocyte. Subsequently, leads to
proteinuria, hypoalbuminemia, edema, and hyperlipidemia known as
nephrotic/nephritic syndrome. The glomerulopathy can also be of genetic origin such
as IgAN, IgMAN, C3G, aHUS, iMN, Alport syndrome, autosomal dominant polycystic
kidney disease and LN. Other diseases associated or enhances the inflammatory
nephropathy is lupus nephritis if caused by systemic lupus erythematosus.
Glomerulopathy develops or accelerated in presence of obesity, diabetes, and another
comorbidity. Scarring of glomeruli or the blood vessels in glomeruli also affect the
function of kidney, and is known as glomerulosclerosis. Focal segmental
glomerulosclerosis (FSGS) or nodular glomerulosclerosis, are the forms of
glomerulosclerosis. FSGC leads to end-stage renal disease, and is irreversible lead to
nephrotic syndrome. Glomerulopathy or glomerulosclerosis can develop without any
known cause or can also be secondary to the drugs, toxins or underlying disease. It is
reported that chronic hypoxia leads to anemia, and is one of the complication and cause
of the development of renal diseases such as glomerulopathy and glomerulosclerosis
(1–3). Glomerulonephritis is also called glomerular disease. It is a type of kidney
disease caused by damage to your glomeruli due to over activation of your immune
3
system. This damage means the glomeruli cannot do their job to remove waste and
fluid like they should.
Oxygen is an important factor which regulates acute and chronic inflammation.
Oxygen levels in the tissues are sensed by hypoxia-inducible factors (HIFs: HIF-1 and
HIF-2), regulated by prolyl hydroxylase enzymes (4). Activation of HIF prevents
nephropathy and ischemia-reperfusion injury (5,6). Inhibition of PHD can stabilize HIF
thus increasing the availability of HIF at the site of inflammation. Hypoxia inducible
factor (HIF) regulates erythropoietin (EPO) secretion and inhibition of PHD thus
increases EPO by stabilizing HIF. Thus, PHD inhibitor reduces anemia, and this
increases oxygen to the kidney and progression of glomerulopathy or
glomerulosclerosis may be delayed. HIF regulates inflammatory stimuli and mediators
of inflammation (7,8). HIF has been reported to regulate nuclear factor-κB (NF-κB)
and extracellular signal-regulated kinase (ERK) mediated inflammatory pathways (9).
Desidustat is a PHD inhibitor currently approved for the treatment of chronic kidney
disease-associated anemia in India. It is reported that Desidustat treatment stabilizes
HIF and thus induces erythropoiesis in animal model of anemia (10). Desidustat also
improves hemoglobin in clinical trials (11). Desidustat treatment reduced IL-6 and IL-
1ß levels in ischemia condition (12). These inflammatory markers were increased in
renal dysfunction either nephropathy or nephritis (13). It also decreases SOD and MDA
thus decreases oxidative stress (12). The standard therapy used glomerulopathy or
glomerulonephritis are the steroid to suppress inflammation or anti-infective agents.
Other agents such as RAAS inhibitors, mineralocorticoid antagonists, SGLT2
inhibitors, complement system inhibitors, anti-diabetic agents, anti-hyperlipidemic,
diuretic or other agents used in the management of symptoms of glomerular disease or
renal dysfunction or ESRD. Other investigations therapy may be useful in reducing
progression or reversal of these diseases such as anti-inflammatory agents, NRF2
regulators, endothelin antagonist, immunomodulators, ACE inhibitors, discoidin
domain receptor 1 inhibitors, osteopontin blocking agents, vasopressin receptor
antagonists, gene editing therapy, or stem cell therapy. Thus, compound of formula (Ia)
4
may be used to in the management of glomerulopathy or glomerulonephritis, and
related diseases, and associated complications, either alone or in combination of agents
mentioned above.
Some of the prolyl hydroxylase inhibitors have been disclosed in EP 661269, WO
2007070359, WO 2008076425, WO 2011007856, WO 2012106472, WO 2013043621,
WO 2004108681 and WO 2008002576 covers the prolyl hydroxylase inhibitors.
Pharmaceutical composition for treatment of oxidative stress disorders and treatment
of hemoglobin disorders have been disclosed in WIPO publications WO 2014200773,
WO 2017027810 and WO 2019028150 respectively.
WO 2014102818 discloses compounds of the following general formula
The compound of formula (Ia) as given below
and its pharmaceutically acceptable salts are found effective in the treatment of
glomerular diseases.
5
Objectives of the invention
In an embodiment, the present invention provides a method of treating glomerular
diseases using compound of formula (Ia) or its pharmaceutically acceptable salts.
In another embodiment, the present invention provides a method of treating glomerular
disease using combination of compound of formula (Ia) or its pharmaceutically
acceptable salts with suitable second therapeutic agent selected from suitable Factor B
inhibitors or suitable Angiotensin II receptor antagonist or suitable Factor D inhibitors
or suitable C3 inhibitors or suitable C5 inhibitors or suitable C6 inhibitors or suitable
Lectin pathway inhibitors or suitable Properdin inhibitors or suitable C9 antibody and
multitarget complement inhibitor.
In another embodiment, the present invention provides a method of treating glomerular
disease using combination of compound of formula (Ia) or its pharmaceutically
acceptable salts with suitable Factor B inhibitors.
In another embodiment, the present invention provides a method of treating glomerular
disease using combination of compound of formula (Ia) or its pharmaceutically
acceptable salts with suitable Angiotensin II receptor antagonist.
In another embodiment, the present invention provides a suitable pharmaceutical
composition comprising compound of formula (Ia) or its pharmaceutically acceptable
salts for the treatment of glomerular diseases.
In another embodiment, the present invention provides a combination of compound of
formula (Ia) or its pharmaceutically acceptable salts with suitable second therapeutic
agent selected from suitable Factor B inhibitors or suitable Angiotensin II receptor
antagonist or suitable Factor D inhibitors or suitable C3 inhibitors or suitable C5
inhibitors or suitable C6 inhibitors or suitable Lectin pathway inhibitors or suitable
Properdin inhibitors or suitable C9 antibody and multitarget complement inhibitor.
In another embodiment, the present invention provides a combination of compound of
formula (Ia) or its pharmaceutically acceptable salts with suitable Factor B inhibitors.
6
In another embodiment, the present invention provides a combination of compound of
formula (Ia) or its pharmaceutically acceptable salts with suitable Angiotensin II
receptor antagonist.
In another embodiment, the present invention provides a suitable pharmaceutical
composition comprising compound of formula (Ia) or its pharmaceutically acceptable
salts and suitable Factor B inhibitors for the treatment of glomerular diseases.
In another embodiment, the present invention provides a suitable pharmaceutical
composition comprising compound of formula (Ia) or its pharmaceutically acceptable
salts and suitable Angiotensin II receptor antagonist for the treatment of glomerular
diseases.
In another embodiment, present invention provides use of compound of formula (I) or
its pharmaceutically acceptable salts for the treatment of glomerular diseases.
In another embodiment, present invention provides use of combination of compound
of formula (I) or its pharmaceutically acceptable salts with suitable Factor B inhibitors
for the treatment of glomerular diseases.
In another embodiment, present invention provides use of combination of compound
of formula (I) or its pharmaceutically acceptable salts with suitable Angiotensin II
receptor antagonist for the treatment of glomerular diseases.
In an embodiment, compound of formula (Ia) or its pharmaceutically acceptable salts
alone or suitable combination thereof for use may be further characterized according
to a reduction in the amount of urine protein.
In another embodiment, the present invention provides the administration of compound
of formula (Ia) or its pharmaceutically acceptable salts alone or in combination with
suitable second therapeutic agents for the treatment of glomerular diseases.
In another embodiment, the present invention compound of formula (Ia) or its
pharmaceutically acceptable salts or suitable combination thereof for the treatment of
glomerular disease in patient with diabetes.
7
Brief description of drawings
Figure 1A. Effect of compound of formula (Ia) and its combination with Iptacopan on
serum creatinine (A) in LPS treated mice;
Figure 1B. Effect of compound of formula (Ia) and its combination with Iptacopan on
serum urea (B) in LPS treated mice;
Figure 1C. Effect of compound of formula (Ia) and its combination with Iptacopan on
urine total protein (C) in doxorubicin treated mice;
Figure 1D. Effect of compound of formula (Ia) and its combination with Fimasartan on
urine total protein (D) in BSA overload induced mice.
Figure 2A. Effect of compound of formula (Ia) on Urine albumin (A) in 5/6
nephrectomized rat;
Figure 2B. Effect of compound of formula (Ia) on Serum creatinine (B) in 5/6
nephrectomized rat;
Figure 2C. Effect of compound of formula (Ia) on Serum urea (C) in 5/6
nephrectomized rat;
Figure 2D. Effect of compound of formula (Ia) on Urine albumin (D) in db/db mice;
Figure 2E. Effect of compound of formula (Ia) on Serum creatinine (E) in db/db mice;
Figure 2F. Effect of compound of formula (Ia) on Serum urea (F) in db/db mice.
Summary of the invention
Present invention relates to compound of formula (Ia) or its pharmaceutically
acceptable salts or combination thereof for the treatment of glomerular diseases.
Invention also relates to pharmaceutical composition comprising compound of formula
(Ia) or pharmaceutically acceptable excipients useful for the treatment of glomerular
diseases.
8
Description of the Invention
Definition:
The terms ‘treatment’ or ‘treat’ refer to slowing, stopping, or delaying the progression
of the disease or clinical symptoms in a patient, as evidenced by a decrease or
elimination of a clinical or diagnostic symptom of the disease, disorder or condition.
The term ‘subject’ refer to a mammals. The term ‘effective amount’ in the context of
the administration of the amount of the drug substance sufficient to have the desired
effect. The term ‘pharmaceutically acceptable’ use embraces both human and
veterinary use. A compound of formula (Ia) is Desidustat.
Method of treating glomerular disease by compound of formula (Ia)
In an embodiment the present invention provides a method of treating glomerular
disease in a subject, comprising administering an effective amount of compound of
formula (Ia) or its pharmaceutically acceptable salts; wherein formula (Ia) is
represented by:
The glomerular disease includes Nephrotic Syndrome, Focal Segmental
Glomerulosclerosis (FSGS), Minimal Change Disease (MCD), Membranous
Nephropathy (MN), IgA Nephropathy (IgAN), C3 Glomerulopathy (MPGN3),
Diabetic nephropathy, Lupus nephritis and other condition associated with Glomerular
Diseases.
Pharmaceutically acceptable salts of the compound of formula (Ia) is selected from
metal salt, amine base salt and amino acid salt.
9
Wherein metal salt is selected from calcium, sodium, potassium, lithium, barium,
strontium, magnesium, cesium, copper, cobalt , iron, manganese, lead, aluminum,
cadmium , silver, zinc, ammonium and the like; wherein amine base salt is selected
from methylamine, dimethylamine, ethylamine, diethyl amine, n-propyl amine,
isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t-butyl
amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-trimethyl
ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl
cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine,
benzene-methanamine, ethanolamine, diethanolamine, tris-
(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-
methylbenzylamine, N-ethyl benzylamine, 4-methoxybenzylamine, pyrrolidine,
piperidine, piperazine, morpholine, 2-aminopyrimidine, 2-thiopheneethanamine, (2S)-
3,3-dimethyl-2-butanamine, cyclopentanamine, cycloheptanamine, meglumine,
benethamine, dibenzylamine, diphenylamine, α-naphthylamine, O-phenylenediamine,
1,3-Diaminopropane, (S)-α-naphthylethylamine, (S)-3-methoxyphenylethylamine, (S)-
4-methoxyphenylethylamine, (S)-4-chlorophenylethylamine, (S)-4-
methylphenylethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine,
imidazole, ethylenediamine, epolamine, morpholine 4-(2-hydroxyethyl), N-N-
diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L-
adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine,
metformin, hexane-1,6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine,
and N-ethylmorpholine; wherein amino acid salt is selected from alanine, lysine,
arginine, histidine, threonine, proline, glutamine and glycine.
In certain embodiments, compounds of formula (Ia) or its pharmaceutically acceptable
salts, for administration to a subject at a dose in the range of 1 mg to 500 mg. In certain
embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salts for
administration to a subject to provide the compound of formula (Ia) or a
pharmaceutically acceptable salts at a dose of 1 mg to 150 mg. In certain embodiments,
the compound of formula (Ia) or a pharmaceutically acceptable salts for administration
10
to a subject to provide the compound of formula (Ia) or a pharmaceutically acceptable
salts at a dose of 25 mg, 50 mg and 100 mg to the subject.
In a further embodiment, the compound of formula (Ia) or its pharmaceutically
acceptable salts is administered to a subject in an amount of about 1 mg to about 500
mg, about 50 mg to about 450 mg, about 100 mg to about 400 mg, about 150 mg to
about 350 mg, about 200 mg to about 300 mg, about 1 mg to about 50 mg, about 1 mg
to about 25 mg to the subject.
In certain embodiments, compounds of formula (Ia) or its pharmaceutically acceptable
salts can be further characterized according to the dose of compound administered to a
subject, where subject is animal or human.
In a further embodiment, the present invention provides effective amount of compound
of formula (Ia) or its pharmaceutically acceptable salt is administered to subject by
oral, parenteral, intravenous or intramuscular route of administration.
Method of treating glomerular disease in combination of compound of formula
(Ia) or its pharmaceutically acceptable salts with other suitable inhibitors
In an embodiment, the present invention provides a method of treating glomerular
disease in a subject, comprising administering a combination of compound of formula
(Ia) or its pharmaceutically acceptable salts with suitable second therapeutic agent
selected from suitable Factor B inhibitors or suitable Angiotensin II receptor antagonist
or suitable Factor D inhibitors or suitable C3 inhibitors or suitable C5 inhibitors or
suitable C6 inhibitors or suitable Lectin pathway inhibitors or suitable Properdin
inhibitors or suitable C9 antibody and multitarget complement inhibitor.
Factor B inhibitors is Iptacopan; Angiotensin II receptor antagonist is Fimasartan,
Azilsartan, Candesartan, Eprosartan, Losartan, Olmesartan, Telmisartan, Valsartan;
Factor D inhibitors is selected from Danicopan, ALXN2050, BCX9930; C3 inhibitors
is selected from pegcitacoplan and AMY 201; C5 inhibitors is selected from
eculizumab, vilobelimab, RA 101348, DF2593A, Tesidolumab, SOBI-002,
Ravulizumab, Cemdsiran, ARC1905 and Avacopan; C6 inhibitors is CP 010; Lectin
11
pathway inhibitors is Narsoplimab; Properdin inhibitors is NM9401; C9 antibody and
multitarget complement inhibitor is MFHR1.
Method of treating glomerular disease in combination of compound of formula
(Ia) or its pharmaceutically acceptable salts with suitable Factor B inhibitors
In an embodiment, the present invention provides a method of treating glomerular
disease in a subject, comprising administering a combination of compound of formula
(Ia) or its pharmaceutically acceptable salts with suitable Factor B inhibitors.
The glomerular disease includes Nephrotic Syndrome, Focal Segmental
Glomerulosclerosis (FSGS), Minimal Change Disease (MCD), Membranous
Nephropathy (MN), IgA Nephropathy (IgAN), C3 Glomerulopathy (MPGN3),
Diabetic nephropathy, Lupus nephritis and other condition associated with Glomerular
Diseases.
Pharmaceutically acceptable salts of the compound of formula (Ia) is selected from
metal salt, amine base salt and amino acid salt.
Wherein metal salt is selected from calcium, sodium, potassium, lithium, barium,
strontium, magnesium, cesium, copper, cobalt , iron, manganese, lead, aluminum,
cadmium , silver, zinc, ammonium and the like; wherein amine base salt is selected
from methylamine, dimethylamine, ethylamine, diethyl amine, n-propyl amine,
isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t-butyl
amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-trimethyl
ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl
cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine,
benzene-methanamine, ethanolamine, diethanolamine, tris-
(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-
methylbenzylamine, N-ethyl benzylamine, 4-methoxybenzylamine, pyrrolidine,
piperidine, piperazine, morpholine, 2-aminopyrimidine, 2-thiopheneethanamine, (2S)-
3,3-dimethyl-2-butanamine, cyclopentanamine, cycloheptanamine, meglumine,
benethamine, dibenzylamine, diphenylamine, α-naphthylamine, O-phenylenediamine,
12
1,3-Diaminopropane, (S)-α-naphthylethylamine, (S)-3-methoxyphenylethylamine, (S)-
4-methoxyphenylethylamine, (S)-4-chlorophenylethylamine, (S)-4-
methylphenylethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine,
imidazole, ethylenediamine, epolamine, morpholine 4-(2-hydroxyethyl), N-N-
diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L-
adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine,
metformin, hexane-1,6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine,
and N-ethylmorpholine; wherein amino acid salt is selected from alanine, lysine,
arginine, histidine, threonine, proline, glutamine and glycine.
Factor B inhibitor use in combination with compound of formula (Ia) or its
pharmaceutically acceptable salts is Iptacopan.
In certain embodiments, compounds of formula (Ia) or its pharmaceutically acceptable
salts, for administration to a subject at a dose in the range of 1 mg to 500 mg. In certain
embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salts for
administration to a subject to provide the compound of formula (Ia) or a
pharmaceutically acceptable salts at a dose of 1 mg to 150 mg. In certain embodiments,
the compound of formula (Ia) or a pharmaceutically acceptable salts for administration
to a subject to provide the compound of formula (Ia) or a pharmaceutically acceptable
salts at a dose of 25 mg, 50 mg and 100 mg to the subject.
In a further embodiment, the compound of formula (Ia) or its pharmaceutically
acceptable salts is administered to a subject in an amount of about 1 mg to about 500
mg, about 50 mg to about 450 mg, about 100 mg to about 400 mg, about 150 mg to
about 350 mg, about 200 mg to about 300 mg, about 1 mg to about 50 mg, about 1 mg
to about 25 mg to the subject.
In a further embodiment, Iptacopan is administered to a subject in an amount of about
1 mg to about 500 mg, about 50 mg to about 450 mg, about 100 mg to about 400 mg,
about 150 mg to about 350 mg, about 200 mg to about 300 mg. In a certain
embodiment, Iptacopan is administered in an amount of 200 mg.
13
In certain embodiments, compounds of formula (Ia) or its pharmaceutically acceptable
salts can be further characterized according to the dose of compound administered to a
subject, where subject is animal or human.
In a further embodiment, the present invention provides effective amount of compound
of formula (Ia) or its pharmaceutically acceptable salt is administered to subject by
oral, parenteral, intravenous or intramuscular route of administration.
Method of treating glomerular disease in combination of compound of formula
(Ia) or its pharmaceutically acceptable salts with suitable Angiotensin II receptor
antagonist
In an embodiment, the present invention provides a method of treating glomerular
disease in a subject, comprising administering a combination of compound of formula
(Ia) or its pharmaceutically acceptable salts with suitable Angiotensin II receptor
antagonist.
The glomerular disease includes Nephrotic Syndrome, Focal Segmental
Glomerulosclerosis (FSGS), Minimal Change Disease (MCD), Membranous
Nephropathy (MN), IgA Nephropathy (IgAN), C3 Glomerulopathy (MPGN3),
Diabetic nephropathy, Lupus nephritis and other condition associated with Glomerular
Diseases.
Pharmaceutically acceptable salts of the compound of formula (Ia) is selected from
metal salt, amine base salt and amino acid salt.
Wherein metal salt is selected from calcium, sodium, potassium, lithium, barium,
strontium, magnesium, cesium, copper, cobalt , iron, manganese, lead, aluminum,
cadmium , silver, zinc, ammonium and the like; wherein amine base salt is selected
from methylamine, dimethylamine, ethylamine, diethyl amine, n-propyl amine,
isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t-butyl
amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-trimethyl
ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl
cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine,
14
benzene-methanamine, ethanolamine, diethanolamine, tris-
(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-
methylbenzylamine, N-ethyl benzylamine, 4-methoxybenzylamine, pyrrolidine,
piperidine, piperazine, morpholine, 2-aminopyrimidine, 2-thiopheneethanamine, (2S)-
3,3-dimethyl-2-butanamine, cyclopentanamine, cycloheptanamine, meglumine,
benethamine, dibenzylamine, diphenylamine, α-naphthylamine, O-phenylenediamine,
1,3-Diaminopropane, (S)-α-naphthylethylamine, (S)-3-methoxyphenylethylamine, (S)-
4-methoxyphenylethylamine, (S)-4-chlorophenylethylamine, (S)-4-
methylphenylethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine,
imidazole, ethylenediamine, epolamine, morpholine 4-(2-hydroxyethyl), N-N-
diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L-
adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine,
metformin, hexane-1,6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine,
and N-ethylmorpholine; wherein amino acid salt is selected from alanine, lysine,
arginine, histidine, threonine, proline, glutamine and glycine.
Angiotensin II receptor antagonist use in combination with compound of formula (Ia)
or its pharmaceutically acceptable salts is Fimasartan, Azilsartan, Candesartan,
Eprosartan, Losartan, Olmesartan, Telmisartan and Valsartan.
In certain embodiments, compounds of formula (Ia) or its pharmaceutically acceptable
salts, for administration to a subject at a dose in the range of 1 mg to 500 mg. In certain
embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salts for
administration to a subject to provide the compound of formula (Ia) or a
pharmaceutically acceptable salts at a dose of 1 mg to 150 mg. In certain embodiments,
the compound of formula (Ia) or a pharmaceutically acceptable salts for administration
to a subject to provide the compound of formula (Ia) or a pharmaceutically acceptable
salts at a dose of 25 mg, 50 mg and 100 mg to the subject.
In a further embodiment, the compound of formula (Ia) or its pharmaceutically
acceptable salts is administered to a subject in an amount of about 1 mg to about 500
mg, about 50 mg to about 450 mg, about 100 mg to about 400 mg, about 150 mg to
15
about 350 mg, about 200 mg to about 300 mg, about 1 mg to about 50 mg, about 1 mg
to about 25 mg to the subject.
In a further embodiment, Fimasartan is administered to a subject in an amount of about
1 mg to about 500 mg, about 50 mg to about 450 mg, about 100 mg to about 400 mg,
about 150 mg to about 350 mg, about 200 mg to about 300 mg. In a further
embodiment, Azilsartan is administered to a subject in an amount of about 1 mg to
about 500 mg. In a further embodiment, Candesartan is administered to a subject in an
amount of about 1 mg to about 200 mg. In a further embodiment, Eprosartan is
administered to a subject in an amount of about 1 mg to about 1000 mg. In a further
embodiment, Losartan is administered to a subject in an amount of about 1 mg to about
500 mg. In a further embodiment, Olmesartan is administered to a subject in an amount
of about 1 mg to about 200 mg. In a further embodiment, Telmisartan is administered
to a subject in an amount of about 1 mg to about 500 mg. In a further embodiment,
Valsartan is administered to a subject in an amount of about 1 mg to about 500 mg.
In a certain embodiment, Fimasartan is administered to a subject in an amount of about
60 mg and 120 mg. In a further embodiment, Azilsartan is administered to a subject in
an amount of about 40 mg and 80 mg. In a further embodiment, Candesartan is
administered to a subject in an amount of about 4 mg, 8 mg, 16 mg and 32 mg. In a
further embodiment, Eprosartan is administered to a subject in an amount of about 400
mg and 600 mg. In a further embodiment, Losartan is administered to a subject in an
amount of about 25 mg, 50 mg and 100 mg. In a further embodiment, Olmesartan is
administered to a subject in an amount of about 5 mg, 20 mg and 40 mg. In a further
embodiment, Telmisartan is administered to a subject in an amount of about 20 mg, 40
mg and 80 mg. In a further embodiment, Valsartan is administered to a subject in an
amount of about 40 mg, 80 mg, 160 mg and 320 mg.
In certain embodiments, compounds of formula (Ia) or its pharmaceutically acceptable
salts can be further characterized according to the dose of compound administered to a
subject, where subject is animal or human.
16
In a further embodiment, the present invention provides effective amount of compound
of formula (Ia) or its pharmaceutically acceptable salt is administered to subject by
oral, parenteral, intravenous or intramuscular route of administration.
Pharmaceutical composition of compound of formula (Ia) or its pharmaceutically
acceptable salts for use in treating glomerular diseases
In an embodiment, present invention provides a pharmaceutical composition
comprising compound of formula (Ia) or its pharmaceutically acceptable salts
optionally with one or more pharmaceutically acceptable excipients for use in treating
glomerular diseases.
The glomerular disease includes Nephrotic Syndrome, Focal Segmental
Glomerulosclerosis (FSGS), Minimal Change Disease (MCD), Membranous
Nephropathy (MN), IgA Nephropathy (IgAN), C3 Glomerulopathy (MPGN3),
Diabetic nephropathy, Lupus nephritis and other condition associated with Glomerular
Diseases.
Pharmaceutically acceptable salts of the compound of formula (Ia) is selected from
metal salt, amine base salt and amino acid salt.
Wherein metal salt is selected from calcium, sodium, potassium, lithium, barium,
strontium, magnesium, cesium, copper, cobalt , iron, manganese, lead, aluminum,
cadmium , silver, zinc, ammonium and the like; wherein amine base salt is selected
from methylamine, dimethylamine, ethylamine, diethyl amine, n-propyl amine,
isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t-butyl
amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-trimethyl
ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl
cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine,
benzene-methanamine, ethanolamine, diethanolamine, tris-
(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-
methylbenzylamine, N-ethyl benzylamine, 4-methoxybenzylamine, pyrrolidine,
piperidine, piperazine, morpholine, 2-aminopyrimidine, 2-thiopheneethanamine, (2S)-
17
3,3-dimethyl-2-butanamine, cyclopentanamine, cycloheptanamine, meglumine,
benethamine, dibenzylamine, diphenylamine, α-naphthylamine, O-phenylenediamine,
1,3-Diaminopropane, (S)-α-naphthylethylamine, (S)-3-methoxyphenylethylamine, (S)-
4-methoxyphenylethylamine, (S)-4-chlorophenylethylamine, (S)-4-
methylphenylethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine,
imidazole, ethylenediamine, epolamine, morpholine 4-(2-hydroxyethyl), N-N-
diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L-
adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine,
metformin, hexane-1,6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine,
and N-ethylmorpholine; wherein amino acid salt is selected from alanine, lysine,
arginine, histidine, threonine, proline, glutamine and glycine.
The pharmaceutically acceptable excipients are selected at least one from diluent,
binders, disintegrating agents, lubricating agents, glidant agent, sweetener, pH
modifier, suspending agent or viscosity modifying agent, flavouring agent and
optionally coating redimix.
Diluents include, but are not limited to lactose monohydrate, lactose, microcrystalline
cellulose, polymethacrylates selected from Eudragit, potassium chloride,
sulfobutylether b-cyclodextrin, sodium chloride, spray dried lactose, and preferably
sulfobutyl ether b-cyclodextrin combinations thereof and other such materials known
to those of ordinary skill in the art.
Binders include, but are not limited to hypromellose 3 Cps, carbomers selected from
carbopol, gellan, gum Arabic, hydrogenated vegetable oil, polymethacrylates selected
from Eudragit, xanthan, lactose and Zein combinations thereof and other such materials
known to those of ordinary skill in the art.
Disintegrating agents include, but are not limited to, croscarmellose Sodium,
bicarbonate salt, chitin, gellan gum, polacrillin potassium and docusate Sodium
combinations thereof and other such materials known to those of ordinary skill in the
art.
18
Glidant agents include, but are not limited to, colloidal silica, calcium silicate,
magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other
such materials known to those of ordinary skill in the art.
Lubricant agents include, but are not limited to, calcium stearate, magnesium stearate,
mineral oil, stearic acid, zinc stearate, glycerin behenate, hydrogenated vegetable oil,
sodium stearyl fumarate and myristic Acid suitable combinations thereof and other
such materials known to those of ordinary skill in the art.
Suitable pH modifying agents which maintain the pH of the formulation according to
the present invention include, but are not limited to Citric acid and other similar
excipients and their suitable combinations and other materials known to those of
ordinary skill in the art.
Suspending agents or viscosity agent according to the present invention include, but
are not limited to microcrystalline cellulose and carboxymethylcellulose sodium
(Avicel CL 611) and other similar excipients and their suitable combinations and other
materials known to those of ordinary skill in the art.
Sweetener is selected from Sucrose and all such materials known to those of ordinary
skill in the art.
Flavouring agent is selected from cherry flavour, orange flavour, mango flavour and
all such fruit flavour known to those of ordinary skill in the art.
Coating redimix is selected from Opadry Pink all such materials known to those of
ordinary skill in the art.
In certain embodiments, Pharmaceutical composition of compounds of formula (Ia) or
its pharmaceutically acceptable salts are as below;
19
The stable pharmaceutical composition according to the present invention may be in
the form of tablet or capsule or a powder or a suspension in a liquid or an aerosol
formulation or solutions, preferably in the form of tablet or capsule or suspension.
In certain embodiments, compounds of formula (Ia) or its pharmaceutically acceptable
salts, for administration to a subject at a dose in the range of 1 mg to 500 mg. In certain
embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salts for
administration to a subject to provide the compound of formula (Ia) or a
pharmaceutically acceptable salts at a dose of 1 mg to 150 mg. In certain embodiments,
the compound of formula (Ia) or a pharmaceutically acceptable salts for administration
to a subject to provide the compound of formula (Ia) or a pharmaceutically acceptable
salts at a dose of 25 mg, 50 mg and 100 mg to the subject.
In a further embodiment, the compound of formula (Ia) or its pharmaceutically
acceptable salts is administered to a subject in an amount of about 1 mg to about 500
mg, about 50 mg to about 450 mg, about 100 mg to about 400 mg, about 150 mg to
about 350 mg, about 200 mg to about 300 mg, about 1 mg to about 50 mg, about 1 mg
to about 25 mg to the subject.
Strength – 5
mg/ml
Strength – 20
mg/ml
Ingredients mg/5ml mg/5ml
compounds of formula (Ia) 25.00 100.00
Sucrose 3085.66 3010.66
Citric Acid, Anhydrous USP 10.00 10.00
Microcrystalline Cellulose
and Carboxymethylcellulose Sodium (Avicel CL 611)
164.85 164.85
Xanthan Gum NF (Xantural 75) 6.49 6.49
Cherry Flavour 8.00 8.00
20
In certain embodiments, compounds of formula (Ia) or its pharmaceutically acceptable
salts can be further characterized according to the dose of compound administered to a
subject, where subject is animal or human.
In a further embodiment, the present invention provides effective amount of compound
of formula (Ia) or its pharmaceutically acceptable salt is administered to subject by
oral, parenteral, intravenous or intramuscular route of administration.
Combination of compound of formula (Ia) or its pharmaceutically acceptable salts
with other suitable inhibitors
In an embodiment, present invention provides a combination of compound of formula
(Ia) or its pharmaceutically acceptable salts with suitable second therapeutic agent
selected from suitable Factor B inhibitors or suitable Angiotensin II receptor antagonist
or suitable Factor D inhibitors or suitable C3 inhibitors or suitable C5 inhibitors or
suitable C6 inhibitors or suitable Lectin pathway inhibitors or suitable Properdin
inhibitors or suitable C9 antibody and multitarget complement inhibitor.
Factor B inhibitors is Iptacopan; Angiotensin II receptor antagonist is Fimasartan,
Azilsartan, Candesartan, Eprosartan, Losartan, Olmesartan, Telmisartan, Valsartan;
Factor D inhibitors is selected from Danicopan, ALXN2050, BCX9930; C3 inhibitors
is selected from pegcitacoplan and AMY 201; C5 inhibitors is selected from
eculizumab, vilobelimab, RA 101348, DF2593A, Tesidolumab, SOBI-002,
Ravulizumab, Cemdsiran, ARC1905 and Avacopan; C6 inhibitors is CP 010; Lectin
pathway inhibitors is Narsoplimab; Properdin inhibitors is NM9401; C9 antibody and
multitarget complement inhibitor is MFHR1.
Combination of compound of formula (Ia) or its pharmaceutically acceptable salts
with suitable Factor B inhibitors
In an embodiment, present invention provides a combination of compound of formula
(Ia) or its pharmaceutically acceptable salts with suitable Factor B inhibitors.
21
Factor B inhibitor use in combination with compound of formula (Ia) or its
pharmaceutically acceptable salts is Iptacopan.
Combination of compound of formula (Ia) or its pharmaceutically acceptable salts
with suitable Angiotensin II receptor antagonist
In an embodiment, present invention provides a combination of compound of formula
(Ia) or its pharmaceutically acceptable salts with suitable Angiotensin II receptor
antagonist.
Angiotensin II receptor antagonist use in combination with compound of formula (Ia)
or its pharmaceutically acceptable salts is Fimasartan, Azilsartan, Candesartan,
Eprosartan, Losartan, Olmesartan, Telmisartan and Valsartan.
Pharmaceutical composition of compound of formula (Ia) or its pharmaceutically
acceptable salts and suitable Factor B inhibitors for use in treating glomerular
diseases.
In an embodiment, present invention provides a pharmaceutical composition
comprising compound of formula (Ia) or its pharmaceutically acceptable salts and
suitable Factor B inhibitors optionally with one or more pharmaceutically acceptable
excipients for use in treating glomerular diseases.
The glomerular disease includes Nephrotic Syndrome, Focal Segmental
Glomerulosclerosis (FSGS), Minimal Change Disease (MCD), Membranous
Nephropathy (MN), IgA Nephropathy (IgAN), C3 Glomerulopathy (MPGN3),
Diabetic nephropathy, Lupus nephritis and other condition associated with Glomerular
Diseases.
Pharmaceutically acceptable salts of the compound of formula (Ia) is selected from
metal salt, amine base salt and amino acid salt.
Wherein metal salt is selected from calcium, sodium, potassium, lithium, barium,
strontium, magnesium, cesium, copper, cobalt , iron, manganese, lead, aluminum,
cadmium , silver, zinc, ammonium and the like; wherein amine base salt is selected
22
from methylamine, dimethylamine, ethylamine, diethyl amine, n-propyl amine,
isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t-butyl
amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-trimethyl
ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl
cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine,
benzene-methanamine, ethanolamine, diethanolamine, tris-
(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-
methylbenzylamine, N-ethyl benzylamine, 4-methoxybenzylamine, pyrrolidine,
piperidine, piperazine, morpholine, 2-aminopyrimidine, 2-thiopheneethanamine, (2S)-
3,3-dimethyl-2-butanamine, cyclopentanamine, cycloheptanamine, meglumine,
benethamine, dibenzylamine, diphenylamine, α-naphthylamine, O-phenylenediamine,
1,3-Diaminopropane, (S)-α-naphthylethylamine, (S)-3-methoxyphenylethylamine, (S)-
4-methoxyphenylethylamine, (S)-4-chlorophenylethylamine, (S)-4-
methylphenylethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine,
imidazole, ethylenediamine, epolamine, morpholine 4-(2-hydroxyethyl), N-N-
diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L-
adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine,
metformin, hexane-1,6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine,
and N-ethylmorpholine; wherein amino acid salt is selected from alanine, lysine,
arginine, histidine, threonine, proline, glutamine and glycine.
The Factor B inhibitor is Iptacopan.
The pharmaceutically acceptable excipients are selected at least one from diluent,
binders, disintegrating agents, lubricating agents, glidant agent, sweetener, pH
modifier, suspending agent or viscosity modifying agent, flavouring agent and
optionally coating redimix.
Diluents include, but are not limited to lactose monohydrate, lactose, microcrystalline
cellulose, polymethacrylates selected from Eudragit, potassium chloride,
sulfobutylether b-cyclodextrin, sodium chloride, spray dried lactose, and preferably
23
sulfobutyl ether b-cyclodextrin combinations thereof and other such materials known
to those of ordinary skill in the art.
Binders include, but are not limited to hypromellose 3 Cps, carbomers selected from
carbopol, gellan, gum Arabic, hydrogenated vegetable oil, polymethacrylates selected
from Eudragit, xanthan, lactose and Zein combinations thereof and other such materials
known to those of ordinary skill in the art.
Disintegrating agents include, but are not limited to, croscarmellose Sodium,
bicarbonate salt, chitin, gellan gum, polacrillin potassium and docusate Sodium
combinations thereof and other such materials known to those of ordinary skill in the
art.
Glidant agents include, but are not limited to, colloidal silica, calcium silicate,
magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other
such materials known to those of ordinary skill in the art.
Lubricant agents include, but are not limited to, calcium stearate, magnesium stearate,
mineral oil, stearic acid, zinc stearate, glycerin behenate, hydrogenated vegetable oil,
sodium stearyl fumarate and myristic Acid suitable combinations thereof and other
such materials known to those of ordinary skill in the art.
Coating redimix is selected from Opadry Pink all such materials known to those of
ordinary skill in the art.
In certain embodiments, compounds of formula (Ia) or its pharmaceutically acceptable
salts, for administration to a subject at a dose in the range of 1 mg to 500 mg. In certain
embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salts for
administration to a subject to provide the compound of formula (Ia) or a
pharmaceutically acceptable salts at a dose of 1 mg to 150 mg. In certain embodiments,
the compound of formula (Ia) or a pharmaceutically acceptable salts for administration
to a subject to provide the compound of formula (Ia) or a pharmaceutically acceptable
salts at a dose of 25 mg, 50 mg and 100 mg to the subject.
In a further embodiment, the compound of formula (Ia) or its pharmaceutically
acceptable salts is administered to a subject in an amount of about 1 mg to about 500
24
mg, about 50 mg to about 450 mg, about 100 mg to about 400 mg, about 150 mg to
about 350 mg, about 200 mg to about 300 mg, about 1 mg to about 50 mg, about 1 mg
to about 25 mg to the subject.
In a further embodiment, Iptacopan is administered to a subject in an amount of about
1 mg to about 500 mg, about 50 mg to about 450 mg, about 100 mg to about 400 mg,
about 150 mg to about 350 mg, about 200 mg to about 300 mg. In a certain
embodiment, Iptacopan is administered in an amount of 200 mg.
In certain embodiments, compounds of formula (Ia) or its pharmaceutically acceptable
salts can be further characterized according to the dose of compound administered to a
subject, where subject is animal or human.
In a further embodiment, the present invention provides effective amount of compound
of formula (Ia) or its pharmaceutically acceptable salt is administered to subject by
oral, parenteral, intravenous or intramuscular route of administration.
Pharmaceutical composition of compound of formula (Ia) or its pharmaceutically
acceptable salts and suitable Angiotensin II receptor antagonist for use in treating
glomerular diseases.
In an embodiment, present invention provides a pharmaceutical composition
comprising compound of formula (Ia) or its pharmaceutically acceptable salts and
suitable Angiotensin II receptor antagonist optionally with one or more
pharmaceutically acceptable excipients for use in treating glomerular diseases.
The glomerular disease includes Nephrotic Syndrome, Focal Segmental
Glomerulosclerosis (FSGS), Minimal Change Disease (MCD), Membranous
Nephropathy (MN), IgA Nephropathy (IgAN), C3 Glomerulopathy (MPGN3),
Diabetic nephropathy, Lupus nephritis and other condition associated with Glomerular
Diseases.
Pharmaceutically acceptable salts of the compound of formula (Ia) is selected from
metal salt, amine base salt and amino acid salt.
25
Wherein metal salt is selected from calcium, sodium, potassium, lithium, barium,
strontium, magnesium, cesium, copper, cobalt , iron, manganese, lead, aluminum,
cadmium , silver, zinc, ammonium and the like; wherein amine base salt is selected
from methylamine, dimethylamine, ethylamine, diethyl amine, n-propyl amine,
isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t-butyl
amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-trimethyl
ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl
cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine,
benzene-methanamine, ethanolamine, diethanolamine, tris-
(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-
methylbenzylamine, N-ethyl benzylamine, 4-methoxybenzylamine, pyrrolidine,
piperidine, piperazine, morpholine, 2-aminopyrimidine, 2-thiopheneethanamine, (2S)-
3,3-dimethyl-2-butanamine, cyclopentanamine, cycloheptanamine, meglumine,
benethamine, dibenzylamine, diphenylamine, α-naphthylamine, O-phenylenediamine,
1,3-Diaminopropane, (S)-α-naphthylethylamine, (S)-3-methoxyphenylethylamine, (S)-
4-methoxyphenylethylamine, (S)-4-chlorophenylethylamine, (S)-4-
methylphenylethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine,
imidazole, ethylenediamine, epolamine, morpholine 4-(2-hydroxyethyl), N-N-
diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L-
adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine,
metformin, hexane-1,6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine,
and N-ethylmorpholine; wherein amino acid salt is selected from alanine, lysine,
arginine, histidine, threonine, proline, glutamine and glycine.
The Angiotensin II receptor antagonist is Fimasartan, Azilsartan, Candesartan,
Eprosartan, Losartan, Olmesartan, Telmisartan and Valsartan.
The pharmaceutically acceptable excipients are selected at least one from diluent,
binders, disintegrating agents, lubricating agents, glidant agent, sweetener, pH
modifier, suspending agent or viscosity modifying agent, flavouring agent and
optionally coating redimix.
26
Diluents include, but are not limited to lactose monohydrate, lactose, microcrystalline
cellulose, polymethacrylates selected from Eudragit, potassium chloride,
sulfobutylether b-cyclodextrin, sodium chloride, spray dried lactose, and preferably
sulfobutyl ether b-cyclodextrin combinations thereof and other such materials known
to those of ordinary skill in the art.
Binders include, but are not limited to hypromellose 3 Cps, carbomers selected from
carbopol, gellan, gum Arabic, hydrogenated vegetable oil, polymethacrylates selected
from Eudragit, xanthan, lactose and Zein combinations thereof and other such materials
known to those of ordinary skill in the art.
Disintegrating agents include, but are not limited to, croscarmellose Sodium,
bicarbonate salt, chitin, gellan gum, polacrillin potassium and docusate Sodium
combinations thereof and other such materials known to those of ordinary skill in the
art.
Glidant agents include, but are not limited to, colloidal silica, calcium silicate,
magnesium silicate, silicon hydrogel, corn starch, talc, combinations thereof and other
such materials known to those of ordinary skill in the art.
Lubricant agents include, but are not limited to, calcium stearate, magnesium stearate,
mineral oil, stearic acid, zinc stearate, glycerin behenate, hydrogenated vegetable oil,
sodium stearyl fumarate and myristic Acid suitable combinations thereof and other
such materials known to those of ordinary skill in the art.
Coating redimix is selected from Opadry Pink all such materials known to those of
ordinary skill in the art.
In certain embodiments, compounds of formula (Ia) or its pharmaceutically acceptable
salts, for administration to a subject at a dose in the range of 1 mg to 500 mg. In certain
embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salts for
administration to a subject to provide the compound of formula (Ia) or a
pharmaceutically acceptable salts at a dose of 1 mg to 150 mg. In certain embodiments,
the compound of formula (Ia) or a pharmaceutically acceptable salts for administration
27
to a subject to provide the compound of formula (Ia) or a pharmaceutically acceptable
salts at a dose of 25 mg, 50 mg and 100 mg to the subject.
In a further embodiment, the compound of formula (Ia) or its pharmaceutically
acceptable salts is administered to a subject in an amount of about 1 mg to about 500
mg, about 50 mg to about 450 mg, about 100 mg to about 400 mg, about 150 mg to
about 350 mg, about 200 mg to about 300 mg, about 1 mg to about 50 mg, about 1 mg
to about 25 mg to the subject.
In a further embodiment, Fimasartan is administered to a subject in an amount of about
1 mg to about 500 mg, about 50 mg to about 450 mg, about 100 mg to about 400 mg,
about 150 mg to about 350 mg, about 200 mg to about 300 mg. In a further
embodiment, Azilsartan is administered to a subject in an amount of about 1 mg to
about 500 mg. In a further embodiment, Candesartan is administered to a subject in an
amount of about 1 mg to about 200 mg. In a further embodiment, Eprosartan is
administered to a subject in an amount of about 1 mg to about 1000 mg. In a further
embodiment, Losartan is administered to a subject in an amount of about 1 mg to about
500 mg. In a further embodiment, Olmesartan is administered to a subject in an amount
of about 1 mg to about 200 mg. In a further embodiment, Telmisartan is administered
to a subject in an amount of about 1 mg to about 500 mg. In a further embodiment,
Valsartan is administered to a subject in an amount of about 1 mg to about 500 mg.
In a certain embodiment, Fimasartan is administered to a subject in an amount of about
60 mg and 120 mg. In a further embodiment, Azilsartan is administered to a subject in
an amount of about 40 mg and 80 mg. In a further embodiment, Candesartan is
administered to a subject in an amount of about 4 mg, 8 mg, 16 mg and 32 mg. In a
further embodiment, Eprosartan is administered to a subject in an amount of about 400
mg and 600 mg. In a further embodiment, Losartan is administered to a subject in an
amount of about 25 mg, 50 mg and 100 mg. In a further embodiment, Olmesartan is
administered to a subject in an amount of about 5 mg, 20 mg and 40 mg. In a further
embodiment, Telmisartan is administered to a subject in an amount of about 20 mg, 40
28
mg and 80 mg. In a further embodiment, Valsartan is administered to a subject in an
amount of about 40 mg, 80 mg, 160 mg and 320 mg.
In certain embodiments, compounds of formula (Ia) or its pharmaceutically acceptable
salts can be further characterized according to the dose of compound administered to a
subject, where subject is animal or human.
In a further embodiment, the present invention provides effective amount of compound
of formula (Ia) or its pharmaceutically acceptable salt is administered to subject by
oral, parenteral, intravenous or intramuscular route of administration.
Use of compound of formula (Ia) or its pharmaceutically acceptable salts for the
treatment of glomerular diseases
In an embodiment, present invention provides use of compound of formula (I) or its
pharmaceutically acceptable salts for the treatment of glomerular diseases.
The glomerular disease includes Nephrotic Syndrome, Focal Segmental
Glomerulosclerosis (FSGS), Minimal Change Disease (MCD), Membranous
Nephropathy (MN), IgA Nephropathy (IgAN), C3 Glomerulopathy (MPGN3),
Diabetic nephropathy, Lupus nephritis and other condition associated with Glomerular
Diseases.
Pharmaceutically acceptable salts of the compound of formula (Ia) is selected from
metal salt, amine base salt and amino acid salt.
Wherein metal salt is selected from calcium, sodium, potassium, lithium, barium,
strontium, magnesium, cesium, copper, cobalt , iron, manganese, lead, aluminum,
cadmium , silver, zinc, ammonium and the like; wherein amine base salt is selected
from methylamine, dimethylamine, ethylamine, diethyl amine, n-propyl amine,
isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t-butyl
amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-trimethyl
ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl
cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine,
benzene-methanamine, ethanolamine, diethanolamine, tris-
29
(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-
methylbenzylamine, N-ethyl benzylamine, 4-methoxybenzylamine, pyrrolidine,
piperidine, piperazine, morpholine, 2-aminopyrimidine, 2-thiopheneethanamine, (2S)-
3,3-dimethyl-2-butanamine, cyclopentanamine, cycloheptanamine, meglumine,
benethamine, dibenzylamine, diphenylamine, α-naphthylamine, O-phenylenediamine,
1,3-Diaminopropane, (S)-α-naphthylethylamine, (S)-3-methoxyphenylethylamine, (S)-
4-methoxyphenylethylamine, (S)-4-chlorophenylethylamine, (S)-4-
methylphenylethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine,
imidazole, ethylenediamine, epolamine, morpholine 4-(2-hydroxyethyl), N-N-
diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L-
adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine,
metformin, hexane-1,6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine,
and N-ethylmorpholine; wherein amino acid salt is selected from alanine, lysine,
arginine, histidine, threonine, proline, glutamine and glycine.
In certain embodiments, compounds of formula (Ia) or its pharmaceutically acceptable
salts, for administration to a subject at a dose in the range of 1 mg to 500 mg. In certain
embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salts for
administration to a subject to provide the compound of formula (Ia) or a
pharmaceutically acceptable salts at a dose of 1 mg to 150 mg. In certain embodiments,
the compound of formula (Ia) or a pharmaceutically acceptable salts for administration
to a subject to provide the compound of formula (Ia) or a pharmaceutically acceptable
salts at a dose of 25 mg, 50 mg and 100 mg to the subject.
In a further embodiment, the compound of formula (Ia) or its pharmaceutically
acceptable salts is administered to a subject in an amount of about 1 mg to about 500
mg, about 50 mg to about 450 mg, about 100 mg to about 400 mg, about 150 mg to
about 350 mg, about 200 mg to about 300 mg, about 1 mg to about 50 mg, about 1 mg
to about 25 mg to the subject.
30
In certain embodiments, compounds of formula (Ia) or its pharmaceutically acceptable
salts can be further characterized according to the dose of compound administered to a
subject, where subject is animal or human.
In a further embodiment, the present invention provides effective amount of compound
of formula (Ia) or its pharmaceutically acceptable salt is administered to subject by
oral, parenteral, intravenous or intramuscular route of administration.
Use of compound of formula (Ia) or its pharmaceutically acceptable salts in
combination with suitable Factor B for the treatment of glomerular diseases.
In an embodiment, present invention provides use of combination of compound of
formula (I) or its pharmaceutically acceptable salts with suitable Factor B inhibitors for
the treatment of glomerular diseases.
The glomerular disease includes Nephrotic Syndrome, Focal Segmental
Glomerulosclerosis (FSGS), Minimal Change Disease (MCD), Membranous
Nephropathy (MN), IgA Nephropathy (IgAN), C3 Glomerulopathy (MPGN3),
Diabetic nephropathy, Lupus nephritis and other condition associated with Glomerular
Diseases.
Pharmaceutically acceptable salts of the compound of formula (Ia) is selected from
metal salt, amine base salt and amino acid salt.
Wherein metal salt is selected from calcium, sodium, potassium, lithium, barium,
strontium, magnesium, cesium, copper, cobalt , iron, manganese, lead, aluminum,
cadmium , silver, zinc, ammonium and the like; wherein amine base salt is selected
from methylamine, dimethylamine, ethylamine, diethyl amine, n-propyl amine,
isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t-butyl
amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-trimethyl
ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl
cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine,
benzene-methanamine, ethanolamine, diethanolamine, tris-
(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-
31
methylbenzylamine, N-ethyl benzylamine, 4-methoxybenzylamine, pyrrolidine,
piperidine, piperazine, morpholine, 2-aminopyrimidine, 2-thiopheneethanamine, (2S)-
3,3-dimethyl-2-butanamine, cyclopentanamine, cycloheptanamine, meglumine,
benethamine, dibenzylamine, diphenylamine, α-naphthylamine, O-phenylenediamine,
1,3-Diaminopropane, (S)-α-naphthylethylamine, (S)-3-methoxyphenylethylamine, (S)-
4-methoxyphenylethylamine, (S)-4-chlorophenylethylamine, (S)-4-
methylphenylethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine,
imidazole, ethylenediamine, epolamine, morpholine 4-(2-hydroxyethyl), N-N-
diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L-
adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine,
metformin, hexane-1,6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine,
and N-ethylmorpholine; wherein amino acid salt is selected from alanine, lysine,
arginine, histidine, threonine, proline, glutamine and glycine.
Factor B inhibitor use in combination with compound of formula (Ia) or its
pharmaceutically acceptable salts is Iptacopan for the treatment of glomerular diseases.
In certain embodiments, compounds of formula (Ia) or its pharmaceutically acceptable
salts, for administration to a subject at a dose in the range of 1 mg to 500 mg. In certain
embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salts for
administration to a subject to provide the compound of formula (Ia) or a
pharmaceutically acceptable salts at a dose of 1 mg to 150 mg. In certain embodiments,
the compound of formula (Ia) or a pharmaceutically acceptable salts for administration
to a subject to provide the compound of formula (Ia) or a pharmaceutically acceptable
salts at a dose of 25 mg, 50 mg and 100 mg to the subject.
In a further embodiment, the compound of formula (Ia) or its pharmaceutically
acceptable salts is administered to a subject in an amount of about 1 mg to about 500
mg, about 50 mg to about 450 mg, about 100 mg to about 400 mg, about 150 mg to
about 350 mg, about 200 mg to about 300 mg, about 1 mg to about 50 mg, about 1 mg
to about 25 mg to the subject.
32
In a further embodiment, Iptacopan is administered to a subject in an amount of about
1 mg to about 500 mg, about 50 mg to about 450 mg, about 100 mg to about 400 mg,
about 150 mg to about 350 mg, about 200 mg to about 300 mg. In a certain
embodiment, Iptacopan is administered in an amount of 200 mg.
In certain embodiments, compounds of formula (Ia) or its pharmaceutically acceptable
salts can be further characterized according to the dose of compound administered to a
subject, where subject is animal or human.
In a further embodiment, the present invention provides effective amount of compound
of formula (Ia) or its pharmaceutically acceptable salt is administered to subject by
oral, parenteral, intravenous or intramuscular route of administration.
Use of compound of formula (Ia) or its pharmaceutically acceptable salts in
combination with suitable Angiotensin II receptor antagonist for the treatment of
glomerular diseases.
In an embodiment, present invention provides use of combination of compound of
formula (I) or its pharmaceutically acceptable salts with suitable Angiotensin II
receptor antagonist for the treatment of glomerular diseases.
The glomerular disease includes Nephrotic Syndrome, Focal Segmental
Glomerulosclerosis (FSGS), Minimal Change Disease (MCD), Membranous
Nephropathy (MN), IgA Nephropathy (IgAN), C3 Glomerulopathy (MPGN3),
Diabetic nephropathy, Lupus nephritis and other condition associated with Glomerular
Diseases.
Pharmaceutically acceptable salts of the compound of formula (Ia) is selected from
metal salt, amine base salt and amino acid salt.
Wherein metal salt is selected from calcium, sodium, potassium, lithium, barium,
strontium, magnesium, cesium, copper, cobalt , iron, manganese, lead, aluminum,
cadmium , silver, zinc, ammonium and the like; wherein amine base salt is selected
from methylamine, dimethylamine, ethylamine, diethyl amine, n-propyl amine,
isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t-butyl
33
amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-trimethyl
ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl
cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine,
benzene-methanamine, ethanolamine, diethanolamine, tris-
(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-
methylbenzylamine, N-ethyl benzylamine, 4-methoxybenzylamine, pyrrolidine,
piperidine, piperazine, morpholine, 2-aminopyrimidine, 2-thiopheneethanamine, (2S)-
3,3-dimethyl-2-butanamine, cyclopentanamine, cycloheptanamine, meglumine,
benethamine, dibenzylamine, diphenylamine, α-naphthylamine, O-phenylenediamine,
1,3-Diaminopropane, (S)-α-naphthylethylamine, (S)-3-methoxyphenylethylamine, (S)-
4-methoxyphenylethylamine, (S)-4-chlorophenylethylamine, (S)-4-
methylphenylethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine,
imidazole, ethylenediamine, epolamine, morpholine 4-(2-hydroxyethyl), N-N-
diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L-
adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine,
metformin, hexane-1,6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine,
and N-ethylmorpholine; wherein amino acid salt is selected from alanine, lysine,
arginine, histidine, threonine, proline, glutamine and glycine.
Angiotensin II receptor antagonist use in combination with compound of formula (Ia)
or its pharmaceutically acceptable salts is Fimasartan, Azilsartan, Candesartan,
Eprosartan, Losartan, Olmesartan, Telmisartan and Valsartan for the treatment of
glomerular diseases.
In certain embodiments, compounds of formula (Ia) or its pharmaceutically acceptable
salts, for administration to a subject at a dose in the range of 1 mg to 500 mg. In certain
embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salts for
administration to a subject to provide the compound of formula (Ia) or a
pharmaceutically acceptable salts at a dose of 1 mg to 150 mg. In certain embodiments,
the compound of formula (Ia) or a pharmaceutically acceptable salts for administration
34
to a subject to provide the compound of formula (Ia) or a pharmaceutically acceptable
salts at a dose of 25 mg, 50 mg and 100 mg to the subject.
In a further embodiment, the compound of formula (Ia) or its pharmaceutically
acceptable salts is administered to a subject in an amount of about 1 mg to about 500
mg, about 50 mg to about 450 mg, about 100 mg to about 400 mg, about 150 mg to
about 350 mg, about 200 mg to about 300 mg, about 1 mg to about 50 mg, about 1 mg
to about 25 mg to the subject.
In a further embodiment, Fimasartan is administered to a subject in an amount of about
1 mg to about 500 mg, about 50 mg to about 450 mg, about 100 mg to about 400 mg,
about 150 mg to about 350 mg, about 200 mg to about 300 mg. In a further
embodiment, Azilsartan is administered to a subject in an amount of about 1 mg to
about 500 mg. In a further embodiment, Candesartan is administered to a subject in an
amount of about 1 mg to about 200 mg. In a further embodiment, Eprosartan is
administered to a subject in an amount of about 1 mg to about 1000 mg. In a further
embodiment, Losartan is administered to a subject in an amount of about 1 mg to about
500 mg. In a further embodiment, Olmesartan is administered to a subject in an amount
of about 1 mg to about 200 mg. In a further embodiment, Telmisartan is administered
to a subject in an amount of about 1 mg to about 500 mg. In a further embodiment,
Valsartan is administered to a subject in an amount of about 1 mg to about 500 mg.
In a certain embodiment, Fimasartan is administered to a subject in an amount of about
60 mg and 120 mg. In a further embodiment, Azilsartan is administered to a subject in
an amount of about 40 mg and 80 mg. In a further embodiment, Candesartan is
administered to a subject in an amount of about 4 mg, 8 mg, 16 mg and 32 mg. In a
further embodiment, Eprosartan is administered to a subject in an amount of about 400
mg and 600 mg. In a further embodiment, Losartan is administered to a subject in an
amount of about 25 mg, 50 mg and 100 mg. In a further embodiment, Olmesartan is
administered to a subject in an amount of about 5 mg, 20 mg and 40 mg. In a further
embodiment, Telmisartan is administered to a subject in an amount of about 20 mg, 40
35
mg and 80 mg. In a further embodiment, Valsartan is administered to a subject in an
amount of about 40 mg, 80 mg, 160 mg and 320 mg.
In certain embodiments, compounds of formula (Ia) or its pharmaceutically acceptable
salts can be further characterized according to the dose of compound administered to a
subject, where subject is animal or human.
In a further embodiment, the present invention provides effective amount of compound
of formula (Ia) or its pharmaceutically acceptable salt is administered to subject by
oral, parenteral, intravenous or intramuscular route of administration.
Reduction in the amount Urine protein
In an embodiment, compound of formula (Ia) or its pharmaceutically acceptable salts
alone or in combination with suitable other inhibitors when administered in subject
according to a reduction in the amount of urine protein.
For example, in certain embodiments, there is a reduction in the amount of urine
protein.
In certain embodiments, there is at least a 5% reduction in the amount of urine protein.
In certain embodiments, there is at least a 10% reduction in the amount of urine protein.
In certain embodiments, there is at least a 15% reduction in the amount of urine protein.
In certain embodiments, there is at least a 20% reduction in the amount of urine protein.
In certain embodiments, there is at least a 25% reduction in the amount of urine protein.
In certain embodiments, there is at least a 30% reduction in the amount of urine protein.
In certain embodiments, there is at least a 35% reduction in the amount of urine protein.
In certain embodiments, there is at least a 40% reduction in the amount of urine protein.
In certain embodiments, there is at least a 50% reduction in the amount of urine protein.
In certain embodiments, there is at least a 60% reduction in the amount of urine protein.
In certain embodiments, there is at least a 70% reduction in the amount of urine protein.
In certain embodiments, there is at least an 80% reduction in the amount of urine
protein. In certain embodiments, there is at least a 90% reduction in the amount of urine
protein.
36
Dosing Schedule
The method may be further characterized according to a dosing schedule by which the
compound of formula (Ia) or its pharmaceutically acceptable salts alone or in
combination, pharmaceutical composition of compound of formula (Ia) or its
pharmaceutically acceptable salts alone or in combination is administered.
In certain embodiments, compound is administered to the subject once a daily, twice a
daily and thrice a daily. In another embodiments, compound is administered to the
subject for at least 1 week. In another embodiments, compound is administered to the
subject for at least 2 week. In another embodiments, compound is administered to the
subject for at least 3 week. In another embodiments, compound is administered to the
subject for at least 4 week. In another embodiments, compound is administered to the
subject for at least 6 week. In another embodiments, compound is administered to the
subject for at least 8 week. In another embodiments, compound is administered to the
subject for at least 10 week. In another embodiments, compound is administered to the
subject for at least 12 week. In another embodiments, compound is administered to the
subject for at least 14 week. In another embodiments, compound is administered to the
subject for at least 16 week.
In an embodiment, the present invention provides a method of treating glomerular
disease in a patient with diabetes, comprising administering an effective amount of
compound of formula (Ia) or its pharmaceutically acceptable salts or combination of
compound of formula (Ia) or its pharmaceutically acceptable salts with suitable Factor
B inhibitors or Angiotensin II receptor antagonist.
The scope of pharmaceutically acceptable salts, dosage form, suitable Factor B
inhibitors, suitable Angiotensin II receptor antagonist, glomerular disease as define
anywhere in the specification.
In another embodiment the present invention provides compound of formula (Ia) or its
pharmaceutically acceptable salt in combination of other prolyl hydroxylase inhibitors
such as Roxadustat, Vadadustat, Molidustat, Daprodustat and the like.
Compound of formula (Ia) is prepared as per method disclosed in WO 2014102818.
37
Iptacopan is prepared as per method disclosed in WO2015009616.
Fimasartan is prepared as per method disclose in WO199955681.
Examples
The effect of compounds of formula (Ia) and its combination thereof in animal models
for glomerular disease is shown herein below.
Animal models of glomerular disease
Example 1: Effect of compound of formula (Ia) and combination thereof on LPS-
induced nephritis in C57 mice
Single dose of lipopolysachharide (LPS)-induced acute nephritis was generated in C57
mice and the effect of compound of formula (Ia) and combination as shown below.
Male C57 mice were treated with vehicle/compound of formula (Ia) (15 mg/kg) and
combination of compound of formula (Ia) (15 mg/kg) and Iptacopan (20 mg/kg, twice
a day) by oral route. These mice were bled after 24 h of LPS treatment and serum was
obtained. The creatinine and urea levels were measured in the serum.
Sr. No. Compound Serum creatinine Serum urea
1 Formula (Ia) 34.1 ± 5.2 % 44.9 ± 5.2 %
2 Combination of Formula (Ia)
and Iptacopan
55.6 ± 4.8 % 65.6 ± 3.2 %
Acute treatment with compound of formula (Ia) reduced serum creatinine by 34.1 ± 5.2
against LPS treated mice while combination of compound of formula (Ia) and
Iptacopan reduced serum creatinine by 55.6 ± 4.8 % (Figure 1A). Serum urea was
decreased by compound of formula (Ia) by 44.9 ± 5.2 while combination of Iptacopan
and compound of formula (Ia) reduced it by 65.6 ± 3.2 % when compared with LPS
treated mice (Figure 1B).
38
Example 2: Effect of compound of formula (Ia) on 5/6 nephrectomy induced renal
dysfunction in Male SD rats
Male SD rats will be operated for 5/6 nephrectomy to induce the focal segmental
glomerulosclerosis. After a week of recovery, animals were treated with compound of
formula (Ia). The randomized rats were treated with compound of formula (Ia) (15
mg/kg) for four weeks. At the end of treatment serum creatinine, serum urea and urine
microalbumin was measured.
Sr.
No.
Compound Microalbumin Serum creatinine Serum urea
1 Formula (Ia) 35.9 ± 12.0 % 14.9 ± 3.2 % 15.9 ± 8.8 %
Compound of formula (Ia) treatment reduced urinary excretion of microalbumin by
35.9 ± 12.0 when compared against diabetic mice (Figure 2A). It also reduced serum
creatinine and urea by 14.9 ± 3.2 and 15.9 ± 8.8 %, respectively (Figure 2B-C).
Example 3: Effect of compound of formula (Ia) or combination thereof on
Doxorubicin-induced glomerulosclerosis in Male Balb/c mice
Male Balb/c mice were treated with doxorubicin (10 mg/kg, IV). After 5 weeks of
treatment, mice were randomized based on protein excretion urine into four groups:
Doxorubicin, compound of formula (Ia) (15 mg/kg) and combination of compound of
formula (Ia) (15 mg/kg) and Fimasartan (15 mg/kg) by oral route. The treatment
continued for two weeks. These mice kept in metabolic cage and 24 h urine protein
excretion was measured.
39
Sr. No. Compound Urine total protein
1 Formula (Ia) 47.8 ± 5.8 %
2 Combination of Formula (Ia) and
Fimasartan
64.4 ± 10.1 %
After two weeks of treatment compound of formula (Ia) reduced excretion of total
protein in urine by 47.8 ± 5.8 against doxorubicin treated animals. Combination of
Fimasartan and compound of formula (Ia) reduced proteinuria by 64.4 ± 10.1 % against
doxorubicin treatment Figure 1C.
Example 4: Effect of compound of formula (Ia) or combination thereof on
Cationic bovine serum albumin (cBSA) induced nephritis in Male C57 mice
Male C57 mice were treated with bovine serum albumin (BSA) at 2, 4, 6, 8 and 10
mg/kg on day 1, 2, 3, 4, and 5 days by intraperitoneal route, respectively. The BSA at
10 mg/kg was treated for next 5 days. On the same day, mice were treated with either
vehicle/ compound of formula (Ia) (15 mg/kg) and combination of compound of
formula (Ia) (15 mg/kg) and Iptacopan (20 mg/kg, BID) by oral route and continued
for 10 days. On 11th day mice kept in metabolic cage and 24 h urine protein excretion
was measured.
Sr. No. Compound Urine total protein
1 Formula (Ia) 40.1 ± 7.6 %
2 Combination of Formula (Ia) and
Iptacopan
65.7 ± 7.8 %
40
Compound of formula (Ia) treatment reduced excretion of total protein by 40.1 ± 7.6
% against BSA treated mice. Combination of Iptacopan and compound of formula (Ia)
treatment reduced proteinuria by 65.7 ± 7.8 % (Figure 1D).
Example 5: Diabetes induced renal dysfunction and effect of Formula I(a).
For inducing diabetes-induced renal dysfunction, one kidney was removed from male
db/db mice and they were treated with compound of formula (Ia) and combination for
8 weeks. At the end of treatment, renal dysfunction was estimated. Histological change
in renal disease was also accessed with biochemical changes in serum and urine.
Male db/db mice were randomized and were treated with compound of formula (Ia)
(15 mg/kg) for eight weeks. At the end of treatment serum creatinine, serum urea and
urine microalbumin was measured.
Sr.
No.
Compound Urine
microalbumin
Serum creatinine Serum urea
1 Formula (Ia) 50.2 ± 3.2 % 28.4 ± 4.4 % 25.8 ± 4.8 %
Compound of formula (Ia) treatment reduced urinary excretion of microalbumin by
50.2 ± 3.2 when compared against diabetic mice (Figure 2D). It also reduced serum
creatinine and urea by 28.4 ± 4.4 and 25.8 ± 4.8 %, respectively (Figure 2E-F).
Compound of formula (Ia) alone or in combination with Iptacopan or Fimasartan
showed synergistic effect as described and elucidated in above table.
References
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2. Fu Q, Colgan SP, Shelley CS. Hypoxia: The Force that Drives Chronic Kidney Disease.
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/pmc/articles/PMC4851450/
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Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy. Am J Pathol [Internet].
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Inhibitors: A Breakthrough in the Therapy of Anemia Associated with Chronic
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Hypoxia Inducible Factor Hydroxylases Protects Against Renal Ischemia-Reperfusion
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43
We claim:
1. A pharmaceutical composition comprising a compound of formula (Ia) or its
pharmaceutically acceptable salts optionally with one or more pharmaceutically
acceptable excipients for use in treating glomerular diseases.
2. The composition for use as claimed in claim 1, wherein the glomerular disease is
selected from Nephrotic Syndrome, Focal Segmental Glomerulosclerosis (FSGS),
Minimal Change Disease (MCD), Membranous Nephropathy (MN), IgA Nephropathy
(IgAN), C3 Glomerulopathy (MPGN), Diabetic nephropathy and Lupus nephritis.
3. The composition for use as claimed in claim 1, wherein the pharmaceutically
acceptable salts of the compound of formula (Ia) is selected from metal salt, amine base
salt and amino acids salt.
4. The composition for use as claimed in claim 3, wherein metal salt is selected from
calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper,
cobalt , iron, manganese, lead, aluminum, cadmium , silver, zinc, ammonium and the
like; wherein amine base salt is selected from methylamine, dimethylamine,
ethylamine, diethyl amine, n-propyl amine, isopropyl amine, diisopropyl amine, N-
methyl isopropyl amine, n-butyl amine, t-butyl amine, 2-butamine, 1,2-ethane diamine,
N-methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline),
tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4-
aminobutyl) guanidine, dicyclohexylamine, benzene-methanamine, ethanolamine,
diethanolamine, tris-(hydroxymethyl)methylamine, hydroxylamine, methanaminium,
benzylamine, N-methylbenzylamine, N-ethyl benzylamine, 4-methoxybenzylamine,
pyrrolidine, piperidine, piperazine, morpholine, 2-aminopyrimidine, 2-
thiopheneethanamine, (2S)-3,3-dimethyl-2-butanamine, cyclopentanamine,
cycloheptanamine, meglumine, benethamine, dibenzylamine, diphenylamine, α-
naphthylamine, O-phenylenediamine, 1,3-Diaminopropane, (S)-α-
naphthylethylamine, (S)-3-methoxyphenylethylamine, (S)-4-
methoxyphenylethylamine, (S)-4-chlorophenylethylamine, (S)-4-
methylphenylethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine,
44
imidazole, ethylenediamine, epolamine, morpholine 4-(2-hydroxyethyl), N-N-
diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L-
adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine,
metformin, hexane-1,6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine,
and N-ethylmorpholine; wherein amino acid salt is selected from alanine, lysine,
arginine, histidine, threonine, proline, glutamine and glycine.
5. The composition for use as claimed in claim 1, wherein the pharmaceutically
acceptable excipients are selected from diluent, binders, disintegrating agents,
lubricating agents, glidant agent, sweetener, pH modifier, suspending agent or viscosity
modifying agent, flavouring agent and optionally coating redimix.
6. The composition for use as claimed in claim 5, wherein diluents are selected from
monohydrate, lactose, microcrystalline cellulose, polymethacrylates, potassium
chloride, sulfobutylether b-cyclodextrin, sodium chloride, spray dried lactose, and
sulfobutyl ether b-cyclodextrin.
7. The composition for use as claimed in claim 5, wherein binders are selected from
hypromellose 3 Cps, carbomers, gellan, gum Arabic, hydrogenated vegetable oil,
polymethacrylates, xanthan, lactose and Zein.
8. The composition for use as claimed in claim 5, wherein disintegrating agents are
selected from croscarmellose sodium, bicarbonate salt, chitin, gellan gum, polacrillin
potassium and docusate sodium.
9. The composition for use as claimed in claim 5, wherein are selected from colloidal
silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch and talc.
10. The composition for use as claimed in claim 5, wherein lubricants are selected from
calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, glycerin
behenate, hydrogenated vegetable oil, sodium stearyl fumarate and myristic acid.
11. The composition for use as claimed in claim 5, wherein coating redimix is Opadry Pink.
45
12. The composition for use as claimed in claim 1, wherein the compound of formula (Ia)
or its pharmaceutically acceptable salt is administered to a subject in amount of 1 mg
to 500 mg, 50 mg to 450 mg, 100 mg to 400 mg, 150 mg to 350 mg, 200 mg to 300
mg, 1 mg to 50 mg, 1 mg to 25 mg to the subject.
13. The composition for use as claimed in claim 1, wherein the compound of formula (Ia)
or its pharmaceutically acceptable salt is administered to a subject at a dose of 1 mg to
150 mg.
14. The composition for use as claimed in claim 1, wherein the compound of formula (Ia)
or its pharmaceutically acceptable salt is administered to a subject at a dose of 25 mg,
50 mg and 100 mg.
15. The composition for use as claimed in claim 1, wherein the compound of formula (Ia)
or its pharmaceutically acceptable salt is administered to a subject, where subject is
animal or human.
16. The composition for use as claimed in claim 1, wherein the compound of formula (Ia)
or its pharmaceutically acceptable salt is administered to a subject by oral, parenteral,
intravenous or intramuscular route of administration.
17. A combination of compound of formula (Ia) or its pharmaceutically acceptable salts
with suitable second therapeutic agent, wherein suitable second therapeutic agent
selected from suitable Factor B inhibitors or suitable Angiotensin II receptor antagonist
or suitable Factor D inhibitors or suitable C3 inhibitors or suitable C5 inhibitors or
suitable C6 inhibitors or suitable Lectin pathway inhibitors or suitable Properdin
inhibitors or suitable C9 antibody and multitarget complement inhibitor.
18. The combination as claimed in claim 17, wherein suitable second therapeutic agent is
suitable Factor B inhibitors or suitable Angiotensin II receptor antagonist.
19. The combination as claimed in claim 18, wherein suitable Factor B inhibitors is
Iptacopan and suitable Angiotensin II receptor antagonist is Fimasartan, Azilsartan,
Candesartan, Eprosartan, Losartan, Olmesartan, Telmisartan and Valsartan.
20. A pharmaceutical composition comprising a compound of formula (Ia) or its
pharmaceutically acceptable salts and suitable Factor B inhibitors or suitable
46
Angiotensin II receptor antagonist optionally with one or more pharmaceutically
acceptable excipients for use in treating glomerular diseases.
21. The composition for use as claimed in claim 20, wherein the glomerular disease is
selected from Nephrotic Syndrome, Focal Segmental Glomerulosclerosis (FSGS),
Minimal Change Disease (MCD), Membranous Nephropathy (MN), IgA Nephropathy
(IgAN), C3 Glomerulopathy (MPGN), Diabetic nephropathy and Lupus nephritis.
22. The composition for use as claimed in claim 20, wherein the pharmaceutically
acceptable salts of the compound of formula (Ia) is selected from metal salt, amine base
salt and amino acids salt.
23. The composition for use as claimed in claim 22, wherein metal salt is selected from
calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper,
cobalt , iron, manganese, lead, aluminum, cadmium , silver, zinc, ammonium and the
like; wherein amine base salt is selected from methylamine, dimethylamine,
ethylamine, diethyl amine, n-propyl amine, isopropyl amine, diisopropyl amine, N-
methyl isopropyl amine, n-butyl amine, t-butyl amine, 2-butamine, 1,2-ethane diamine,
N-methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline),
tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4-
aminobutyl) guanidine, dicyclohexylamine, benzene-methanamine, ethanolamine,
diethanolamine, tris-(hydroxymethyl)methylamine, hydroxylamine, methanaminium,
benzylamine, N-methylbenzylamine, N-ethyl benzylamine, 4-methoxybenzylamine,
pyrrolidine, piperidine, piperazine, morpholine, 2-aminopyrimidine, 2-
thiopheneethanamine, (2S)-3,3-dimethyl-2-butanamine, cyclopentanamine,
cycloheptanamine, meglumine, benethamine, dibenzylamine, diphenylamine, α-
naphthylamine, O-phenylenediamine, 1,3-Diaminopropane, (S)-α-
naphthylethylamine, (S)-3-methoxyphenylethylamine, (S)-4-
methoxyphenylethylamine, (S)-4-chlorophenylethylamine, (S)-4-
methylphenylethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine,
imidazole, ethylenediamine, epolamine, morpholine 4-(2-hydroxyethyl), N-N-
diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L-
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adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine,
metformin, hexane-1,6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine,
and N-ethylmorpholine; wherein amino acid salt is selected from alanine, lysine,
arginine, histidine, threonine, proline, glutamine and glycine.
24. The composition for use as claimed in claim 20, wherein suitable Factor B inhibitor is
Iptacopan and suitable Angiotensin II receptor antagonist is Fimasartan, Azilsartan,
Candesartan, Eprosartan, Losartan, Olmesartan, Telmisartan and Valsartan.
25. The composition for use as claimed in claim 20, wherein the pharmaceutically
acceptable excipients are selected from diluent, binders, disintegrating agents,
lubricating agents, glidant agent, sweetener, pH modifier, suspending agent or viscosity
modifying agent, flavouring agent and optionally coating redimix
26. The composition for use as claimed in claim 25, wherein diluents are selected from
monohydrate, lactose, microcrystalline cellulose, polymethacrylates, potassium
chloride, sulfobutylether b-cyclodextrin, sodium chloride, spray dried lactose, and
sulfobutyl ether b-cyclodextrin.
27. The composition for use as claimed in claim 25, wherein binders are selected from
hypromellose 3 Cps, carbomers, gellan, gum Arabic, hydrogenated vegetable oil,
polymethacrylates, xanthan, lactose and Zein.
28. The composition for use as claimed in claim 25, wherein disintegrating agents are
selected from croscarmellose sodium, bicarbonate salt, chitin, gellan gum, polacrillin
potassium and docusate sodium.
29. The composition for use as claimed in claim 25, wherein glidants are selected from
colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch and
talc.
30. The composition for use as claimed in claim 25, wherein lubricants are selected from
calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, glycerin
behenate, hydrogenated vegetable oil, sodium stearyl fumarate and myristic acid.
31. The composition for use as claimed in claim 25, wherein coating redimix is Opadry
Pink.
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32. The composition for use as claimed in claim 20, wherein the compound of formula (Ia)
or its pharmaceutically acceptable salt is administered to a subject in amount of 1 mg
to 500 mg, 50 mg to 450 mg, 100 mg to 400 mg, 150 mg to 350 mg, 200 mg to 300
mg, 1 mg to 50 mg, 1 mg to 25 mg to the subject.
33. The composition for use as claimed in claim 20, wherein the compound of formula (Ia)
or its pharmaceutically acceptable salt is administered to a subject at a dose of 1 mg to
150 mg.
34. The composition for use as claimed in claim 20, wherein the compound of formula (Ia)
or its pharmaceutically acceptable salt is administered to a subject at a dose of 25 mg,
50 mg and 100 mg.
35. The composition for use as claimed in claim 24, wherein Iptacopan is administered to
a subject in amount of 1 mg to 500 mg, 50 mg to 450 mg, 100 mg to 400 mg, 150 mg
to 350 mg, 200 mg to 300 mg.
36. The composition for use as claimed in claim 24, wherein Iptacopan is administered to
a subject in amount of 200 mg.
37. The composition for use as claimed in claim 24, wherein Fimasartan is administered to
a subject in amount of 1 mg to 500 mg, 50 mg to 450 mg, 100 mg to 400 mg, 150 mg
to 350 mg, 200 mg to 300 mg, Azilsartan is administered to a subject in an amount of
1 mg to about 500 mg, Candesartan is administered to a subject in an amount of 1 mg
to 200 mg, Eprosartan is administered to a subject in an amount of 1 mg to 1000 mg,
Losartan is administered to a subject in an amount of 1 mg to 500 mg, Olmesartan is
administered to a subject in an amount of 1 mg to 200 mg, Telmisartan is administered
to a subject in an amount of 1 mg to 500 mg, Valsartan is administered to a subject in
an amount of about 1 mg to 500 mg.
38. The composition for use as claimed in claim 24, wherein Fimasartan is administered to
a subject in amount of 60 mg to 120 mg, Azilsartan is administered to a subject in an
amount of 40 mg and 80 mg, Candesartan is administered to a subject in an amount of
4 mg, 8 mg, 16 mg and 32 mg, Eprosartan is administered to a subject in an amount of
400 mg and 600 mg, Losartan is administered to a subject in an amount of 25 mg, 50
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mg and 100 mg, Olmesartan is administered to a subject in an amount of 5 mg, 20 mg
and 40 mg, Telmisartan is administered to a subject in an amount of 20 mg, 40 mg and
80 mg, Valsartan is administered to a subject in an amount of 40 mg, 80 mg, 160 mg
and 320 mg.
39. The composition for use as claimed in claim 20, wherein the compound of formula (Ia)
or its pharmaceutically acceptable salt is administered to a subject, where subject is
animal or human.
40. The composition for use as claimed in claim 20, wherein the compound of formula (Ia)
or its pharmaceutically acceptable salt is administered to a subject by oral, parenteral,
intravenous or intramuscular route of administration.