WO2013076590A1 - Benzothiazine compounds as h3 receptor ligands - Google Patents

Benzothiazine compounds as h3 receptor ligands Download PDF

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WO2013076590A1
WO2013076590A1 PCT/IB2012/050219 IB2012050219W WO2013076590A1 WO 2013076590 A1 WO2013076590 A1 WO 2013076590A1 IB 2012050219 W IB2012050219 W IB 2012050219W WO 2013076590 A1 WO2013076590 A1 WO 2013076590A1
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Prior art keywords
dihydro
benzo
thiazin
propoxy
thiazine
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PCT/IB2012/050219
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English (en)
French (fr)
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Vikas S. Shirsath
Shailesh M PATEL
Nehal M. SHETH
Jitendra K. Singh
Pawan D. PATIL
Anil D. PAWAR
Jitendra D. MOTIVARAS
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Oxygen Healthcare Research Pvt. Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention includes compounds described by general formula (I), its stereoisomers, its radio-isotopes, its geometric forms, its N-oxides, its polymorphs, their tautomeric forms, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, its useful bio- active metabolites and any suitable combination of the above.
  • the invention also describes various methods of administering these compounds of general formula (I), i. e. pharmaceutically acceptable dosage forms compositions and the use of such compounds and composition in either theraphy or diagnosis.
  • the compounds of general formula (I) of this invention are H 3 receptor agonists or antagonist.
  • the compounds of the general formula (I) of this invention by the virtue of its chemical characteristic, could either independently or simultaneously modulate the H 3 receptor.
  • compounds of general formula (I) of this invention are useful for treating disease wherein activity of histamine and/or other neurotransmitter is modulated to obtain the desired therapeutic effect.
  • H 3 receptor functions as a heteroreceptor regulating the release of multiple neurotransmitters including acetylcholine (ACh), norepinephrine (NE) and dopamine (DA), suggesting that H 3 antagonists could affect a number of behaviors and be useful in the treatment of cognitive deficits associated with a variety of disease states including Alzheimer's disease (AD), attention deficit hyperactivity disorder (ADHD) and schizophrenia. More recently discovered H 3 receptor antagonists with improved selectivity and pharmacokinetic properties have enhanced the understanding of the effects of H 3 receptor antagonists in the CNS at both biochemical and behavioral levels. BACKGROUND OF INVENTION
  • Histaminergic neurons are localized in the tuberomammillary nucleus of the hypothalamus, project to all major areas of the brain and are involved in many functions, including the regulation of sleep/wakefulness, feeding and memory process.
  • Histamine is a biogenic amine involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Schwartz and his colleagues studied that histamine could inhibit its own release, and they used and H 2 antagonists to characterize the receptor involved [SCHWARTZ, J.-C, 1975]. This led them to suggest, in 1983, the possibility of a H 3 receptor. Their suggestion was confirmed and the receptor definitively characterised in 1987 by their discovery that (R)-a-methylhistamine was a potent agonist and that thioperamide was a very specific competitive antagonist [ARRANG, J.M et al, 1987].
  • the H 3 R is expressed predominantly in the central nervous system (CNS), with highest expression in the cerebral cortex, hippocampal formation, basal ganglia and hypothalamus [Drutel, G. et al., 2001 and Martinezmir, M.I. et al., 1990]. These brain regions have been associated with cognition (cortex and hippocampus), sleep and homeostatic regulation (hypothalamus).
  • H 3 receptors are located in regions involved in nociception (specific thalamic areas, dorsal root ganglia and spinal cord) and therefore, might offer treatment opportunities for different modalities of pain [Cannon, K.E. et al., 2007].
  • the histamine receptor is an attractive G protein-coupled receptor drug target that regulates neurotransmission in the central nervous system and plays a role in above therapeutic indication.
  • Various CNS disorders like cognitive disorders, ADHD, narcolepsy, pain, dementias, schizophrenia, obesity as well as sleep disorders and cataplexy are considered as result of imbalance in the neurotransmitter present in the CNS especially histamine.
  • histamine mediates all its actions in both the CNS and periphery through 4 distinct histamine receptors, the histamine receptor subtypes H ⁇ H 2 , H 3 and H 4 .
  • H 3 R activity has been proposed for a broad range of indications such as Alzheimer's disease (AD), attention deficit hyperactivity disorder (ADHD), sleep disorders [Passani, M. B. et al., 2004], pain and obesity. Detailed coverage of all these indications is given in Wijtmans et al [Wijtmas, M.B et al., 2007].
  • H 3 receptor antagonists may be useful in treating various neuropsychiatric conditions, where cognitive deficits are an integral part of the disease, specifically ADHD, schizophrenia and Alzheimer's disease.
  • Imidazole H 3 receptor antagonists are well known in the art. Over the past 20 years, numerous imidazole-based H 3 ligands have been described. Still in line with the archetypal 4- substituted imidazole scaffold, several agonists and antagonists are used extensively in the receptor characterization [B Celanire, S et al., 2005 and Leurs, R et al., 2005]. Imidazole containing compounds are inherently associated with risk of inhibition of cytochrome P450 isoenzymes, resulting in unacceptable drug drug interaction as well as complex H3R pharmacology [J. Pharm. Sci, 2, 47-52, Clini. Pharmacokinetic, 35, 361 -390].
  • non-imidazole H 3 receptor antagonists have been disclosed in recent patents WO 201001 1657A1 , WO 2009152071 A1 ,WO 2009147149 A1 , WO 2009143153 A1 , CN 101560179 A, WO 2009121812 A1 , WO 2009105206 A1 , WO 2009095394 A1 , WO 2009092764 A1 US 2009069300 A1.
  • International patent Application WO 201001 1657 and US Pat. No. US20080082949, WO 201001 1657 A1 , US20100009969, US20090312309 and US20090163464 suggest that H 3 antagonist has pivotal role to play in the CNS disorder.
  • 1 ,4-Benzothiazine (1 ,4-BT) derivatives have been reported to exhibit a wide range of pharmacological properties including antifungal[Baruffini, A et al., 1967], immunostimulating, anti- aldoso-reductase[Kador, P.F Et.
  • MX-68(2) inhibited the activity of DHFR In vitro to the same degree as MTX-polyglutamate.
  • This compound treatment treatment produced a similar antiproliferative effect to that of MTX [Urakawa, K. et al., 2002].
  • VUF-K-8788(3) was shown to be a potent and selective histamine H receptor antagonist without anti-cholinergic or anti-serotonin activity. After systemic administration in guinea pigs, VUF-K- 8788 barely antagonized the CNS receptors at the dose in which it showed anti-histaminergic effect suggesting that it could be useful in the treatment of allergic disorders such as atopic dermatitis and eczema.
  • N-Acetic acid derivatives of 2-substituted 1 , 4-BT (4) were synthesized for evaluation as new aldose reductase inhibitors (ARI)[Tawada, H et al., 1990].
  • ARI new aldose reductase inhibitors
  • racemic 8-(fertbutylamino-2-hydroxypropoxy)-3,4-dihydro-3-oxo- 2/-/-1 ,4-benzothiazine (6) showed remarkable ⁇ -blocking activity.
  • Pharmacological results indicate that the incorporation of o-chlorobenzenesulfonamidic moiety into the molcule by an amidoethylamino group allowed the desired diuretic activity and also maintained that of ⁇ -blockers in some cases.
  • compound (7) was found to exhibit differently modulated ⁇ -adrenoceptor blocking and diuretic activities.
  • derivative (8) was synthesized according to a symbiotic approach [Quadri, L. et al., 1998].
  • T-477(12) is a benzothiazinic analogue of diltiazem, synthesized at the Discovery Research Laboratory of Tanabe Seiyaku Co. and has shown significant differences in pharmacological activity with respect to the parent compound [Maeda, K. et al., 1991 ].
  • DHBT-1 (13) might be an endotoxin formed specifically in pigmented dopaminergic neurons that contribute to irreversible damage to mithocondrial complex I and substantia nigra cell death in Parkinson's disease [Li, H et al., 1997].
  • the present inventors have surprisely found the claimed benzothizine compounds having affinities towards H 3 receptors.
  • H 3 receptor modulators may be useful for therapeutic indications including but not confined for treatment of diseases associated with a deficit in memory, cognition, and learning such as Alzheimer's and attention deficit disorder, pain, schizophrenia, obesity as well as sleep related disorder.
  • the present invention relates to compounds described by general formula (I), its stereoisomers, its radio-isotopes, its geometric forms, its N-oxides, its polymorphs, their tautomeric forms, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, its useful bio- active metabolites and any suitable combination of the above.
  • the compounds of general formula (I) are as follows,
  • R 7 and R 8 independently represents hydrogen, halogen, cyano, (C C 5 )alkyl, halo(C C 5 )alkyl, halo(C C 5 )alkene, thio(C r C 5 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkylene, (C r C 5 )alkoxy, cyclo(C 3 - C 7 )alkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl with and without branching, various bases including but not limited to substituted piperidine, pyrolidine, morpholine, piperizine, azitidine, aniline and its derivative or R 5 and R 6 may form a 5, 6 or 7 membered "Cyclic structure"; R 10 and R ⁇ represents hydrogen, (C C 5 )alkyl, halo(C C 5 )alkyl and(C C 5 )alkylthio
  • the invention relates to pharmaceutical compositions containing a therapeutically effective amount of atleast one compound of fonnula (I), or individual stereoisomers, racemic or non-racemic mixture of stereoisomers, or pharmaceutically acceptable salts or solvates thereof, in admixture with atleast one suitable carrier.
  • the invention relates to the use of a therapeutically effective amount of compound of formula (I), in manufacture of a medicament, for the treatment or prevention of disorders involving selective affinity for the H 3 receptor.
  • the invention further relates to the process for preparing compounds of formula (I).
  • the compounds provided may also be used to further study and elucidate the H 3 receptor.
  • Phenyl(6-(3-(piperidin-1 -yl)propoxy)-2H-benzo[b][1 ,4]thiazin-4(3H)-yl)methanone (O2H25/08) 4-(2-chloro-5-(trifluoromethyl)phenylsulfonyl)-6-(3-(piperidin-1 -yl)propoxy)-3,4-dihydro-2H- benzo[b][1 ,4]thiazine (02H26)
  • N-(4-benzoyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)-4-morpholinobutanamide (02H39) N-(4-benzoyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)-3-(dimethylamino)propanamide(O2H40) N-(4-benzoyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)-3-(4-methylpiperazin-1 - yl)propanamide(02H41 )
  • a stereoisomer, or a polymorph or any suitable combination of above such as a nitrogen oxide thereof , a prodrug of the compound or the nitrogen oxide, a pharmaceutically acceptable salt of the compound, the nitrogen or sulfur oxide, or the prodrug; or a solvate or hydrate of the compound, the nitrogen oxide, the prodrug or the pharmaceutically acceptable salt.
  • the present invention also relates to the process for preparing the compound of general formula (I) its stereoisomers, its radioisotopes, its geometric forms, its N-Oxide, its polymorphs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, its useful bioactive metabolites and any suitable combination of above.
  • Fig 1 Results of hH 3 receptor Functional assay (Luciferase reporter gene assay)
  • the Histamine H 3 receptor is receptors to be identified by molcular cloning. It has stimulated significant interest in new compounds which are capable of interacting with or affecting said receptor. Surprisingly, it has now been found that 1 ,4 Benzothiazine derivatives of formula (I) demonstrate histamine H 3 receptor affinity,
  • R 2 , R 3 R 6 R 7 and R 8 independently represents hydrogen, halogen, cyano, (C C 5 )alkyl, halo(C r C 5 )alkyl, halo(C C 5 )alkene, thio(C r C 5 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkylene, (C r C 5 )alkoxy, cyclo(C 3 - C 7 )alkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl with and without branching, various bases including but not limited to substituted piperidine, pyrolidine, morph
  • (C r C 5 )alkoxy as used herein and unless the context indicates otherwise means straight and branched chain alkyl radicals containing from one to three carbon atoms and includes methoxy, ethoxy, propyloxy and iso-propyloxy, which may be further substituted.
  • halo(C C 5 )alkyl as used herein and unless the context indicates otherwise means straight and branched chain alkyl radicals containing from one to three carbon atoms and includes fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, fluoroetliyl, difluoroethyl and the like.
  • halo(C C 5 )alkoxy as used herein and unless the context indicates otherwise means straight and branched chain alkyl radicals containing from one to three carbon atoms and includes fluoromethoxy, difluoromethoxy, trifiuoromethoxy, trifluoroethoxy, fluoroethoxy, difluoroethoxy and the like.
  • cyclo(C 3 -C 7 )alkyl as used herein and unless the context indicates otherwise means straight and branched chain alkyl radicals containing from three to six carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the cycloalkyl group may be substituted.
  • cyclo(C 3 -C 7 )alkoxy as used herein and unless the context indicates otherwise means straight and branched chain alkyl radicals containing from three to six carbon atoms and includes cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, the cycloalkoxy group may be substituted and the like.
  • Suitable "cyclic structures” formed by 3, 4, 5, 6 or 7 ring atoms as defined in the description, which may optionally contain one or more heteroatoms selected from oxygen, nitrogen or sulfur and optionally contain one or more double bonds and optionally contain combination of double bond and hetero atoms as described earlier.
  • Examples for the "cyclic structures” include benzene, pyridyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrimidinyl, pyrazinyl and the like, which may be optionally substituted.
  • Suitable substituents on the "cyclic structure" as defined above include oxo, hydroxy, halogen atom such as chlorine, bromine and iodine; nitro, cyano, amino, (C r C 5 )alkyl, (C C 5 )alkoxy, thioalkyl, alkylthio, phenyl or benzyl groups.
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms (e. g. diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • the different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • the invention also extends to any tautomeric forms and mixtures thereof.
  • stereoisomers is a general term for all isomers of the individual molcules that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric (cis-trans) isomers and isomers of compounds with more than one chiral centre that are not mirror images of one another (diastereomers).
  • the stereoisomers as a rule are generally obtained as racemates that can be separated into the optically active isomers in a manner known per se.
  • the present invention relates to the D-form, the L-form and D,L- mixtures and in the case of a number of asymmetric carbon atoms, the diastereomeric forms and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • Those compounds of general formula (I) which have an asymmetric carbon and as a rule are obtained as racemates can be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • the present in vension also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises of following schemes ;
  • Cysteamine hydrochloride (19.63 g, 0.172 mol) was dissolved in 3,4-difluoronitrobenzene (25 g, 0.157 mol), cooled to 0°C.
  • a solution of potassium hydroxide (83.05 g, 1.57 mol) in 620 mL water and 250 mL isopropyl alcohol was added slowly under stirring within 25-35 min at 0°C. Then it was stirred for
  • 6-Nitro-3,4-dihydro-2H-benzo[b][1 ,4]thiazine (22 g, 1.0 eq.) was dissolved in THF (220 mL) and stirred for 10 to 15 min at 5°C. Then DIPEA (17.40 g, 0.1346 mol) and benzoyl chloride (16.56 g, 0.118 mol) were added drop wise alternatively. This reaction mixture was stirred for 16-18 hrs at 20-25°C. after completion of reaction, it was quenched by water and extracted with ethyl acetate (3x 100 mL).
  • Example 8 Synthesis of Substituted-amino (propoxy)-3,4-dihydro-2H-benzo[b][1 ,4]thiazine (Intermediate 8).
  • N-(4-benzoyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)-5-chloropentanamide (5.00 g, 0.0128 mol) was dissolved in anhydrous tetrahydrofuran (50 mL) under nitrogen atmosphere. Piperidine (3.28 g, 0.039 mol) was added dropwise. Diisopropylethylamine (2.5 g, 0.019 mol) was added at 0-5°C and stir it for 20-30 min. Then the reaction Mass was heated at 60-70°C for 3-4 hrs. Reaction was monitored by TLC.
  • reaction Mass was quenched with DM water and extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulphate and distilled off the ethyl acetate under reduced pressure to get crude compound. Crude was purified by flash chromatography in dichloromethane and methanol to get pure compound 3.66 g, 65 % yield.
  • reaction Mass was quenched by DM water and extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous Na 2 S0 4 and distilled ethyl acetate under reduced pressure to get crude compound which was further purified by flash chromatography in dichloromethane and methanol to get pure compound 8.65 g, 78 % yield.
  • N-(4-benzoyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)-4-chlorobutanamide (6.50 g, 0.0173 mol) was dissolved in anhydrous tetrahydrofuran (65 mL) under nitrogen atmosphere. Piperidine (3.69 g , 0.0433 mol) was added dropwise. Then diisopropylethylamine (3.36 g, 0.26 mol) was added at 0-5°C and stirred for 20-30 min. Then the reaction Mass was heated at 60-70°C for 3-4 hrs. Reaction was monitored by TLC.
  • reaction Mass was quenched by DM water and extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous Na 2 S0 4 and distilled ethyl acetate under reduced pressure to get crude compound which was further purified by column chromatography in dichloromethane and methanol to get pure compound 4.41 g, Yield 60 %.
  • Example 14 Synthesis of N-(4-benzoyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-chloroprop anamide (Intermediate 14).
  • 6-amino-2H-benzo[b][1 ,4]thiazin-4(3H)-yl)(Phenyl)methanone 8.0 g, 0.0296 mol
  • anhydrous tetrahydrofuran 80 mL
  • Diisopropylethylamine (4.97 g, 0.0384 mol) was added at 0-5°C and stirred for 20-30 min.
  • reaction Mass was quenched by DM water and extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous Na 2 S0 4 and distilled ethyl acetate under reduced pressure to get crude compound which was purified by flash chromatography in dichloromethane and methanol to get pure compound 8.01 g, 75 % yield.
  • N-(4-benzoyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)-3-chloropropanamide (8.00 g, 0.022 mol) was dissolved in anhydrous tetrahydrofuran (80mL)under nitrogen atmosphere. Piperidine (5.66 g , 0.067 mol) was added dropwise. Diisopropylethylamine (4.3 g, 0.033 mol) was added at 0- 5°C and stirred it for 20-30 min. Then the reaction Mass was heated at 60-70°C for 3-4 hrs. Reaction was monitored by TLC.
  • reaction Mass was quenched by DM water and extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous Na 2 S0 4 and distilled ethyl acetate under reduced pressure to get crude compound which was further purified by flash chromatography in dichloromethane and methanol to get pure compound 4.713 g, Yield: 52 %.
  • Example 16 Synthesis of phenyl (6-(3-(piperidin-1-yl) propylamino)-2H-benzo[b][1,4]thiazin- 4(3H)-yl)methanone (Intermediate 16).
  • N-(4-benzoyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)-3-(piperidin-1 -yl)propanamide (2.0 g, 0.0048 mol) was dissolved in anhydrous THF (10 mL) and cooled the reaction Mass at 0-5°C under nitrogen atmosphere.
  • Borane dimethyl sulfide (BH 3 DMS) (0.40 g, 0.0052 mol) was added drop wised and stirred the reaction Mass for 14-16 h at room temperature. Reaction was monitored by TLC. After completion of reaction, reaction Mass was quenched with dil HCI solution and extracted with ethyl acetate.
  • Example 17 Synthesis of N-(3-(piperidin-1-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6- amine (Intermediate 17).
  • Example 18 Synthesis of 4-(phenylsulfonyl)-N-(3-(piperidin-1-yl)propyl)-3,4-dihydro-2H- benzo[b][1 ,4]thiazin-6-amine (Intermediate 18).
  • 6-nitro-4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazine (3.66 g, 10.8 mmol) was dissolved in methanol (40 mL) under nitrogen atmosphere. Then iron powder (3.64 g, 0.065 mol) was added portion wise and stirred the reaction Mass for 10 to 15 minutes at same temperature. Hydrochloric acid (2mL) was added dropwise in the above reaction mixture under stirring. Then it was slowly heated to 65- 70°C for 2-3 hrs. The progress of the reaction was monitored by TLC. After completion of the reaction, it was filtered by celite and filtrate was concentrated under vacuum.
  • Example 22 N-(4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)-3-(4-tosylpiperazin -1 -yl)propanamide (Intermediate 22).
  • reaction Mass was poured in water, extracted with ethyl acetate (3x60mL), washed with brine, dried over anhydrous Na 2 S0 4 and distilled under reduced pressure to obtain crude compound, which was further purified by column chromatography in dichloromethane and methanol to get 0.44 g pure compound. Yield 25.82 % ; yellow solid; Rf 0.65 (methanol); tR-LCMS: 6.76 min (94.52%).
  • Example 23 4-(phenylsulfonyl)-N-(3-(4-tosylpiperazin-1 -yl)propyl)-3,4-dihydro-2H- benzo[b][1 ,4]thiazin-6-amine (Intermediate 23).
  • N-(4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)-3-(4-tosylpiperazin-1 - yl)propanamide (0.150 g, 0.00024 mol) was dissolved in anhydrous THF ( 5 mL) and cooled the reaction Mass at 0-5°C.
  • 6-nitro-3,4-dihydro-2H-benzo[b][1 ,4]thiazine (1 .00 g, 0.0050 mol) was dissolved in pyridine (4 mL) and 4- methyl benzene benzene sulfonyl chloride (1.46 g, 0.0076 mol) was added to it and stirred for 12-14 hrs at room temperature. Progress of reaction was monitored on TLC. After completion of reaction, pyridine was distilled under reduced pressure. Solid residue obtained was poured in 10 mL water and extracted with ethyl acetate.
  • reaction mixture was quenched with water, extracted with ethyl acetate, washed with brine, dried over anhydrous Na 2 S0 4 and distilled under reduced pressure to obtain crude compound, which was further purified by column chromatography in dichloromethane and methanol to get 1.28 g, 50% yield.
  • reaction Mass was poured in water, extracted with ethyl acetate, washed with brine, dried over anhydrous Na 2 S0 4 and distilled under reduced pressure to obtain crude compound, which purified by flash chromatography in dichloromethane and methanol to get 0.67 g, Yield 35 %. yellow solid; Rf 0.68 (methanol); tR-LCMS: 5.51 min (96.93%).
  • Example 28 Synthesis of 4-tosyl-N-(3-(4-tosylpiperazin-1 -yl)propyl)-3,4-dihydro-2H- benzo[b][1 ,4]thiazin-6-amine (Intermediate 28).
  • N-(4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)-3-(4-tosylpiperazin-1 - yl)propanamide (0.67 g, 0.0010 mol) was dissolved in anhydrous THF (8 mL) and cooled the reaction Mass at 0-5°C .
  • BH 3 DMS (0.1 g, 0.0013 mol) was added drop wised under nitrogen atmosphere. Reaction Mass was stirred for 14-16 hrs at room temperature. Reaction was monitored by TLC.
  • Example 31 Synthesis of 3-chloro-N-(4-(naphthalen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4] thiazin-6-yl)propanamide (Intermediate 31).
  • Example 32 Synthesis of N-(4-(naphthalen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6- yl)-3-(4-tosylpiperazin-1-yl)propanamide (Intermediate 32).
  • Example 33 Synthesis of 4-(naphthalen-2-ylsulfonyl)-N-(3-(4-tosylpiperazin-1-yl)propyl)-3,4- dihydro-2H-benzo[b][1 ,4]thiazin-6-amine (Intermediate 33).
  • N-(4-(naphthalen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)-3-(4- tosylpiperazin-1 -yl)propanamide (1.17 g, 0.0018 mol) was dissolved in anhydrous THF (15 mL) and cooled the reaction Mass at 0-5°C.
  • BH 3 DMS (0.150 g, 0.0019 mol) was added drop wised under nitrogen atmosphere. The reaction mixture was stirred for 14-16 hrs at room temperature. Reaction was monitored by TLC.
  • reaction Mass was quenched with dil HCI solution and extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous Na 2 S0 4 and distilled under reduced pressure to get crude compound which was further purified by flash chromatography in dichloromethane and methanol to get pure compound 0.251 g, 22% yield.
  • reaction Mass was quenched by water and extracted with MDC. Organic layer was washed with brine, dried over anhydrous Na 2 S0 4 and distilled under reduced pressure to get crude compound.
  • This crude was purified by column chromatography in dichloromethane in methanol to obtain pure compound 4.6 g (oil). Yield 30.36% ;Yellow oily ; Rf 0.65 (methanol); tR 3.98 min ;LCMS (92 %).
  • Example 35 4-(2-(dimethylamino) ethylthio)-3-fluoroaniline (Intermediate 35).
  • reaction Mass was cooled at room temperature and quenched with water, extracted with ethyl acetate, Organic layer was washed with brine, dried over anhydrous Na 2 S0 4 and distilled under reduced pressure to get crude compound.
  • the crude was purified by column purification in ethyl acetate in hexane to obtain pure compound 0.047 g. Yield 27% ; white solid; Rf 0.65 (methanol); tR-LCMS: 4.20 min (98.91 %).
  • Example 37 Synthesis of phenyl (6-(3-(piperidin-1 -yl) propoxy)-2H-benzo[b][1 ,4] thiazin-4(3H)- yl)methanone (Intermediate 37).
  • Example 37a Synthesis of 1 -(3-chloropropyl) piperidine (Intermediate 37 a).
  • Example 39 Synthesis of 4-(phenylsulfonyl)-6-(3-(piperidin-1 -yl)propoxy)-3,4-dihydro-2H- benzo[b][1 ,4]thiazine (Intermediate 39).
  • Example 40 H3 receptor binding assay using [3H]-N-a-Methyl Histamine
  • the histamine receptor binding assay was conducted using standard laboratory procedure as described below.
  • the human recombinant H 3 receptor protein expressed in HEK 293T cells was procured from the Perkin Elmer. Membrane proteins were stored in -80°C deep freezer until used. Frozen membranes were thawed and resuspended in ice-cold assay buffer consisting of 50mM Tris HCI (pH-7.4) and 5mM MgCI 2 . 30 micrograms ( g) of membrane protein was added in each well of 96 well assay plate along with test compound and [ 3 H]-N-a-Methyl Histamine (3 nanomolar (nM) final assay concentration). Histamine was used as an assay positive control at varying concentration.
  • Example 41 hH 3 receptor Functional assay (Luciferase reporter gene assay)
  • the CRE (cAMP-responsive elements containing promoter) directed Luciferase reporter gene assay was performed for the selection of agonist and antagonist.
  • the hH 3 R DNA and pTLNC-21 CRE plasmid were co-transected in HEK293T cells using polyethyleneimine (PEI).
  • PEI polyethyleneimine
  • the doubly transfected (hH 3 R DNA & CRE) cell lines were plated at 50K cells/well in a Poly-L-Lysine coated 96 well plate.
  • the test compound was added to the cells followed by 1 ⁇ Histamine to the cells and further incubated for 4 hours.
  • the 1 ⁇ forskoline was also added to the cells.
  • the cells were harvested and Luciferase activity was measured.
  • Luciferase assay reagent (20mM Tricin pH 7.8, 1.07mM MgC0 3 , 2.67 mM MgS0 4 , 0.1 mM EDTA, 33.3 mM DTT, 530mM ATP, 270 ⁇ Coenzyme A, 470 ⁇ luciferin) was prepared and added 100 ⁇ _ in each well containing supernatant. The plate was allowed to luminometer (Victor 3 1420, Perkin Elmer) for the luminescence count.
  • the hERG binding assay was conducted using standard laboratory procedure as described below.
  • the recombinant hERG K + channel membranes expressed in HEK 293 cells was procured from the Perkin Elmer. Membrane proteins were stored in -80°C deep freezer until used. Frozen membranes were thawed and resuspended in ice-cold assay buffer consisting of 50mM Tris HCI (pH-7.4) and 5mM MgCI 2 . 10 micrograms ⁇ g) of membrane protein was added in each well of 96 well assay plate along with test compound and [ 3 H]-Astemizole (3 nanomolar (nM) final assay concentration). Astemizole was used as an assay positive control at varying concentration.
  • Aqueous Solubility assay was performed for some of the lead molcules as per the standard operation protocol described below.
  • the standard shake flask method was used to check the solubility of the compounds at different buffer and pH conditions.
  • the compounds stocks were prepared at 1000 ⁇ concentration in DMSO. These stocks were further diluted in semi log mode to perform the linearity in DMSO. These samples were subjected to UV-spectrophotometer and based on optical density data, a standard curve was prepared.
  • the 2 mg. of the each compound was weighed and incubated in 1 mL. of Milli-Q water and PBS (pH-7.4) for 16 hours at 25 °C. These solutions were filtered by 0.45 ⁇ syringe filter and compounds were quantified at respective wavelength.
  • the Aq. Solubility was calculated in ⁇ by the standard equation which was obtained by linear curve. The following table shows the observed Aq. Solubility for certain compounds of the present invention.
  • the brain artificial membrane penetration assay was performed in a 96 well sandwich plate format.
  • the porcine brain lipid membrane (20 mg/mL. of dodecane) was constituted by adding the 4 ⁇ _. of PBL membrane preparation on the PVDF filter in each well of 96 well plates.
  • the donor wells had an initial test compound concentration of 250 ⁇ in PBS buffer (pH 7.4); the acceptor wells contained 5% PBS buffer.
  • the assembly was incubated for 16 hours at 25 °C. The concentration in the acceptor well was determined by UV spectrophotometer (Spectramax 190, Molcular devices). Equilibrium solutions were prepared by mixing 150 ⁇ of donor solutions to 150 ⁇ of PBS Buffer (pH 7.4).
  • the following table shows the observed brain penetration capability for certain compounds of the present invention.
  • Example 45 Human recombinant CYP 450 Inhibition Assay (Isoforms 1 A2; 2C9; 2C19; 2D6; 3A4)
  • Cyp-450 inhibition assays were performed in 96 well plates according to the protocols described by BD Gentest CYP inhibition kits. The percentage inhibition assay for the test compounds was performed at 10 ⁇ concentration. Assay was run in duplicate for each concentration. Incubation was performed for individual CYP and the reaction mixture for a period of time appropriate for the particular CYP. Finally, fluorescent metabolite was measured using fluorescence plate reader.
  • Example 47 Spontaneous Alternation Performance On day 7, all animals were tested for spontaneous alternation performance in the Ymaze, an index of spatial working memory.
  • the Y-maze is made of grey polyvinylchloride.
  • Each arm is 40 cm long, 13 cm high, 3 cm wide at the bottom, 10 cm wide at the top, and converging at an equal angle.
  • Each mouse was placed at the end of one arm and allowed to move freely through the maze during an 8 min session.
  • the series of arm entries including possible returns into the same arm, were checked visually.
  • An alternation was defined as entries into all three arms on consecutiveoccasions. The number of maximum alternations was therefore the total number of arm entries minus two and the percentage of alternation was calculated as (actual alternations / maximum alternations) x 100.
  • Parameters included the percentage of alternation (memory index) and total number of arm entries (exploration index). Animals that showed an extreme behaviour (Alternation percentage ⁇ 25% or > 85% or number of arm entries ⁇ 10) were discarded. Usually, it accounts for 0-5% of the animals.
  • volume The compounds were administered under a volume calculated according to the individual body weight of each mouse (5 mL/Kg).
  • test compounds or the vehicle solution were administered IP once a day. This treatment last until day 7 post ⁇ injection and until 2 h before the behavioual procedure.
  • Denomination Scrambled amyloid- ⁇ protein (25-35), human, mouse, rat
  • Group 1 Sc.A (3 mM) + vehicle solution for test compounds, i.p.
  • Group 3 ⁇ 25-35 (3 mM) + test compound 1 at 3 mg/kg, i.p.
  • Group 4 ⁇ 25-35 (3 mM) + test compound 1 at 10 mg/kg, i.p.
  • Group 6 ⁇ 25-35 (3 mM) + test compound 2 at 10 mg/kg, i.p. 25-35 induced a significant spontaneous alternation deficit as compared to Sc. ⁇ 25 .35 injected mice.
  • Compound O2H10 alleviated deficits induced by ⁇ 25 .35 injection in mice. There was no statistical difference among groups in terms of total number of arms entered except a slight decrease for the higher dose of O2H10 compared to Sc. ⁇ group. 25-35 induced a significant alternation behavior performance deficit as compared to Sc. ⁇ injected mice.
  • Compound O2H90 was ineffective to alleviate deficits induced by ⁇ 25 .35 i.c.v. injection, at tested doses of 3 and 10 mg/kg. There is no statistical difference on locomotion among groups.
  • the apparatus is a two-compartment (15 ⁇ 20 « 15 cm high) box with one illuminated with white polyvinylchloride walls and the other darkened with black polyvinylchloride walls and a grid floor.
  • a guillotine door separates each compartment.
  • a 60 W lamp positioned 40 cm above the apparatus lights up the white compartment during the experiment.
  • Scrambled footshocks (0.3 mA for 3 s) could be delivered to the grid floor using a shock generator scrambler (Lafayette Instruments, Lafayette, USA).
  • the guillotine door was initially closed during the training session. Each mouse was placed into the white compartment. After 5 s, the door was raised.
  • the step-through latency that is, the latency spent to enter the darkened compartment, and the number of vocalizations was recorded.
  • the retention test was carried out 24 h after training. Each mouse will be placed again into the white compartment. After 5s, the door was raised. The step-through latency and the escape latencies were recorded up to 300s.
  • ⁇ 25-35 induced a significant passive avoidance deficint as compared to Sc. ⁇ -injected mice.
  • O2H10 siginificantly and fully alleviated deficits at the dose of 3 and 10 mg/Kg. ⁇ 25 .35 induced as significant passive avoidance deficit as compared to Sc. ⁇ - injected mice.
  • O2H90 is in effective to alleviate deficits induced by ⁇ 25 .35 i.c.v. injection, at tested doses of 3 and 10 mg/Kg.

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Publication number Priority date Publication date Assignee Title
CN110627744A (zh) * 2019-09-10 2019-12-31 株洲千金药业股份有限公司 一种盐酸地芬尼多中间体的制备方法

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Publication number Priority date Publication date Assignee Title
CN110627744A (zh) * 2019-09-10 2019-12-31 株洲千金药业股份有限公司 一种盐酸地芬尼多中间体的制备方法

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