Iptakalim Hydrochloride 盐酸埃他卡林
NDA Filed china
A K(ir) 6.1/SUR2B activator potentially for the treatment of pulmonary arterial hypertension.
179.7, C9H21N.HCl
CAS No. 642407-44-1(Iptakalim)
642407-63-4(Iptakalim Hydrochloride)
N-(1-methylethyl)-2,3-dimethyl-2-butylamine
Hypertension
is a multifactorial disorder, and effective blood pressure control is
not achieved in most individuals. According to the most recent report of
the American Heart Association, for 2010, the estimated direct and
indirect financial burden for managing hypertension is estimated to be
$76.6 billion. Overall, almost 75% of adults with cardiovascular
diseases/comorbidities have hypertension, which is associated with a
shorter overall life expectancy. Alarmingly, rates of prehypertension
and hypertension are increasing among children and adolescents due, in
part, to the obesity epidemic we currently face. There is also the
problem of an aging population and the growing rates of diabetes and
obesity in adults, all factors that are associated with high blood
pressure.Thus, the need is great for novel drugs that target the various
contributing causes of hypertension and the processes leading to end
organ damage.
Iptakalim (IPT), chemically 2,
3–dimethyl-N-(1-methylethyl)-2-butanamine hydrochloride, is novel
adenosine triphosphate–sensitive potassium (KATP) channel opener. KATP
channels are composed of discrete pore-forming inward rectifier
subunits (Kir6.1s) and regulatory sulphonylurea subunits (SUR).IPT shows
high selectivity for cardiac KATP (SUR2A/Kir6.2) and vascular KATP
(SUR2B/Kir6.1 or SUR6B/Kir6.2). Because of this high selectivity, IPT
does not exhibit the adverse side effects associated with the older
nonspecific K+ channel openers, which limit their use to the
treatment of severe or refractory hypertension. IPT produces arteriolar
and small artery vasodilatation, with no significant effect on
capacitance vessels or large arteries. Vasodilatation is induced by
causing cellular hyperpolarization via the opening of K+ channels, which in turn decreases the opening probability of L-type Ca2+
channels. Of particular note, IPT is very effective in lowering the
blood pressure of hypertensive humans but not of those with normal blood
pressure.
The
present compd relates generally to a novel method for decreasing a
human's cravings for cigarettes and reducing instances of relapse during
detoxification once smoking abstinence has been achieved, and more
specifically, to a method for decreasing nicotine use by treating a
human with a novel type of nicotinic acetylcholine receptor antagonist,
iptakalim hydrochloride (IPT).
Cigarette
smoking is a prevalent, modifiable risk factor for increased morbidity
and mortality in the United States, and perhaps in the world. Smokers
incur medical risks attributable to direct inhalation. Bystanders,
termed passive smokers, also incur medical risks from second-hand smoke.
Society, as a whole, also bears the economic costs associated with
death and disease attributable to smoking. Although the majority of
smokers have tried repeatedly to quit smoking, eighty percent of smokers
return to tobacco in less than two years after quitting. Therefore,
tobacco dependence is a health hazard for millions of Americans.
Nicotine
is the biologically active substance that is thought to promote the use
of tobacco products by approximately one-quarter of the world
populations. Tobacco-related disease is personally and economically
costly to the any nation. Unfortunately, once use of tobacco has begun,
it is hard for a smoker to quit because of nicotinic dependence and
addiction.
The
initiation and maintenance of tobacco dependence in a human is due to
certain bio-behavioral and neuromolecular mechanisms. Nicotinic
acetylcholine receptors (nAChRs) in humans are the initial binding sites
for nicotine. The binding of nicotine to nAChRs is thought to modulate
the brain's “reward” function by triggering dopamine release in the
human brain. The nAChRs exist as a diverse family of molecules composed
of different combinations of subunits derived from at least sixteen
genes. nAChRs are prototypical members of the ligand-gated ion channel
superfamily of neurotransmitter receptors. nAChRs represent both
classical and contemporary models for the establishment of concepts
pertaining to mechanisms of drug action, synaptic transmission, and
structure and function of transmembrane signaling molecules.
Basic
cellular mechanisms of nicotinic dependence also involve the functional
state changes during repeated nicotinic agonists exposure and receptor
changes in the number of receptors during chronic nicotinic exposure.
nAChRs can exist in many different functional states, such as resting,
activated, desensitized or inactivated The activation and/or
desensitization of nAChRs plays an important role in initiating
nicotinic tolerance and dependence. Recovery from receptor activation
and/or desensitization contributes to nicotinic withdrawal symptoms.
The
most abundant form of nAChRs in the brain contains α4 and β2 subunits.
α4β2-nAChRs bind nicotine with high affinity and respond to levels of
nicotine found in the plasma of smokers. α4β2-nAChR also have been
implicated in nicotine self-administration, reward, and dependence.
Therefore, selective drug action at nAChRs, especially at those
containing α4 subunits, is thought to be an ideal way for nicotine
cessation and reducing nicotine withdrawal syndrome. Unfortunately, thus
far, no optimal compound can meet this purpose. The brain-blood-barrier
permeable nAChR antagonist, mecamylamine is popularly used systemically
but exhibits much less nAChR subtype selectivity.
Although
a variety of psychopharmacological effects contribute to drug
reinforcement, actions on the mesolimbic dopaminergic pathway is the
predominant hypothesis for mechanisms of nicotinic reward. The
mesolimbic dopaminergic pathway originates in the ventral tegmental area
(VTA) of the midbrain and projects to forebrain structures including
the prefrontal cortex and to limbic areas such as the olfactory
tubercle, the amygdala, the septal region, and the nucleus accumbens.
Many studies have indicated that dopamine release in the nucleus
accumbens of the human brain is “rewarding” or signals an encounter with
a “reward” from the environment. Other substances, such as alcohol,
cocaine, and opiates, operate in the same manner, resulting in a cycle
of substance or alcohol abuse.
Therefore,
a considerable need exists for a novel compound that can selectively
block α4 subtypes of nAChRs to prevent smoking-induced “reward”, to
limit increasing nicotine-induced dopamine release, and/or to diminish
nicotinic withdrawal symptoms.
Patent
Production
of N-(1-methylethyl)-2,3-dimethyl-2-butylamine (Compound 1): Method 1.
The solution of 7.6 g (0.0745 mole) 2,3-dimethyl-2-butanol in 3.24 mL
glacial acetic acid was cooled and maintained at −5 to −8 degree of
centigrade (° C.), then was added 7.3 g (0.49 mole) of powdered
potassium cyanide in several times under stirring. 32.4 mL concentrated
sulfuric acid was added dropwise while keeping the temperatue below 20°
C., after which, the reaction mixture was stirred for 3.5 hours below
20° C. and another 6 hours at room temperature, then stood overnight.
After poured into ice colded water, the mixture was adjusted to pH10
with 20% aqueous sodium hydroxide solution, and extracted with ether
(×4). The extract was dried over anhydrous sodium sulfate. After
filtration on the next day, the dessicator was removed, and the filtrate
was evaporated off the ether, then distilled in vacuum to give 8.8 g
(yield 91.6%) N-[2-(2,3-dimethylbutyl)]-fomide; bp 105-108° C./5 mmHg.
To
the mixture of 7.7 g (0.0597 mole) N-[2-(2,3-dimethylbutyl)]-formide,
6.2 mL ethanol and 51.6 mL wate, 17.4 mL concentrated hydrochloric acid
was added. The reaction mixture was refluxed for 4 hours in the oil
bath, then distilled off ethanol in vacuum. The residue was adjusted to
above pH12 with 40% aqueous sodium hydroxide solution, and extracted
with ether. The extract was dried over anhydrous potassiun carbonate.
After recovering the ether, The residue was distilled at atmosphere to
give 3.75 g (yield 62.2%) 2,3-dimethyl-2-butylamine, bp 97-104° C.
The
mixture of 10.6 g (0.15 mole) 2,3-dimethyl-2-butylamine, 6.45 g (0.0524
mole) 2-bromopropane, 3.0 mL glycol and 22.0 mL toluene was added into
an autoclave, and heated with stirring for 17 hours at temperature of
170° C., after which, the organic layer was separated and extracted with
6N hydrochloric acid (15 mL×4). The extract was combined and washed
once with toluene, then adjusted to pH 12-13 with 4% aqueous sodium
hydroxide in the ice bath. The mixture was extracted with ether and then
dried over anhydrous potassium carbonate. After recovering the ether,
The filtrate was distilled to yield the fraction of bp 135-145° C.
(yield 68.8%). The hydrochloride's Mp is 228-230° C. (1-PrOH-Et2O). Elemental analysis for C9H22ClN(%): Calculated C, 60.14; H, 12.34; N, 7.79, Cl 19.73; Found C, 60.14; H, 12.48; N, 7.31, Cl 19.67.
1H-NMR(D2O, ppm) 0.98(d, J=6.75H, 6H), 1.33(s, 6H), 1.37(d, J=6.46, 6H), 2.10(m, 1H), 3.70(m, 1H). MS(m/z) 143 (M+), 100(B).
Method
2. To the mixture of 288 mL glacial acetic acid, 412 g (6.86 mole) urea
and 288 g (3.43 mole) 2,3-dimethyl-2-butene, the solution of 412 mL
concentrated sulfuric acid and 412 mL of glacial acetic acid was added
dropwise under stirring, while maintaining the reaction temperature at
the range of 45° C. to 50° C., then stirred for 5 hours at the
temperature of 50-55° C. The mixture stood overnight. Next day, the
mixture was reacted for another 7 hours at the temperature of 50-55° C.,
then poured into the solution of 1200 g (30 mole) sodium hydroxide in
8L glacial water. The resulting solid was filtered, washed with water
(200 mL×5) and dried to give 404 g (yield 81.8%)
N-(2,3-dimethyl-2-butyl)urea as white solid, mp 175-176° C. Elemental
analysis for C7H16N2O(%): Calculated C 58.30, H 11.18, N 19.42; Found C, 58.70; H, 11.54; N, 19.25, 1H-NMR(CDCl3, ppm) 0.88-0.91(d, 6H, 2×CH3), 1.26(s, 6H, 2×CH3), 2.20-2.26(m, 1H, CH), 4,45(br, 2H), 4.65(br, 1H). MS(m/z) 145.0, 144.0(M+), 143.0, 129.1, 101.0, 86.1, 69.1, 58.0(B).
To
the mixture of 196 g (1.36 mole) N-(2,3-dimethyl-2-butyl)urea and 392
mL glycol or tri-(ethanol)amine, a solution of 118 g (2.95 mole) sodium
hydroxide in 118 mL water was added. The reaction mixture was heated for
8 hours in an oil bath at temperature of 120° C., then distilled at
atmosphere to collect the fraction of bp 95-102° C. To the fraction, 75 g
anhydrous potassium carbonate and. 40 g sodium hydroxide were added.
The resulting mixture was distilled to give 88.5 g (yield 64.3%)
2,3-dimethyl-2-butylamine as colorless liquid, bp 99-101° C.
1H-NMR(CDCl3, ppm) 0.88-0.91(d, 6H, 2×CH3), 1.04 (s, 6H, 2×CH3), 1.53(m, 1H, CH).
To
a 50.0 ml autoclave, 10.6 g (0.15 mole) 2,3-dimethyl-2-butylamine, 6.45
g (0.0524 mol) 2-bromopropane, 3.0 ml glycol and 22.0 ml toluene were
added, and heated with stirring for 17 hours at 170° C., after which the
organic layer was seperated and extracted with 6N hydrochloric acid (15
ml×4). The extract was combined and washed once with toluene, then
adjusted to pH 12-13 with 4% aqueous sodium hydroxide in the ice bath.
The mixture was extracted with ether and then dried over anhydrous
potassium carbonate the ether was recovered, and distilled to give the
fraction of bp 135-145° C. (yield 68.8%). mp of the hydrochloride is
228-230° C., (i-PrOH: Et2O). Elemental analysis for C9H22ClN(%): Calculated C, 60.14; H, 12.34; N, 7.79, Cl 19.73; Found C 60.14, H 12.48, N 7.31, Cl 19.67. 1H-NMR(D2O, ppm) 0.98(d, J=6.75H, 6H), 1.33(s, 6H), 1.37(d, J=6.46, 6H), 2.10(m, 1H), 3.70(m, 1H). MS(m/z) 143 (M+), 100(B).
Method
3. a solution of 0.10 mole enamine (prepared from the condensation of
methyl iso-propyl ketone and iso-propylamine) in 20 mL hexane was filled
with N2 and added dropwise to a solution containing 0.10
mole lithium methide with stirring in ice bath. After the reaction is
complete, the mixture was poured into 500 g glacial water, and stirred.
The aqueous layer was extracted with ether (×2). The resulting organic
layer was concentrated. 3N hydrochloric acid was added to acified the
organic layer to pH<1. The mixture was kept for ten minutes and
adjusted to pH>11 with 10% aqueous sodium hydroxide, then extracted
with ether (×3). The extract was dried over anhydrous potassium
carbonate and filtered. The filtrate was distilled at atmosphere to give
a fraction of bp 140-145° C. with a yield of 80%.
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