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Iptakalim Hydrochloride 盐酸埃他卡林



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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)


Catholic Healthcare West (D/B/A/ St. Joseph’s Hospital And Medical Center)



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.

Example 1

  • 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 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%.



//////Iptakalim Hydrochloride,  盐酸埃他卡林 , K(ir) 6.1/SUR2B activator,  pulmonary arterial hypertension, nda



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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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