Perspective New Spiro[cycloalkane-pyridazinone] Derivatives with Favorable Fsp3 Character
Csilla Sepsey Für and Hedvig Bölcskei * Department of Organic Chemistry and Technology, University of Technology and Economics, Gellért tér 4, H-1111 Budapest, Hungary; [email protected] * Correspondence: [email protected]
Received: 29 July 2020; Accepted: 21 September 2020; Published: 6 October 2020
Abstract: The large originator pharmaceutical companies need more and more new compounds for their molecule banks, because high throughput screening (HTS) is still a widely used method to find new hits in the course of the lead discovery. In the design and synthesis of a new compound library, important points are in focus nowadays: Lipinski’s rule of five (RO5); the high Fsp3 character; the use of bioisosteric heterocycles instead of aromatic rings. With said aim in mind, we have synthesized a small compound library of new spiro[cycloalkane-pyridazinones] with 36 members. The compounds with this new scaffold may be useful in various drug discovery projects.
Keywords: Friedel–Crafts reaction; Grignard reaction; Fsp3 character; pyridazinones; spiro[cycloalkane-pyridazinone]; hydrazine
1. Introduction There are various methods used to find a hit that will later be a lead compound in the development of a new drug, a new chemical entity. Nowadays the most up-to-date methods are, e.g., computer aided drug design and the fragment-based techniques. High-throughput screening (HTS) [1,2] is a widely used method, which needs a large number of compounds. The large companies which are interested in the development of originator pharmaceutical products have their own molecule banks, with possible extensive compound libraries. In the building up of a compound library, the advantageous physicochemical parameters of the compounds, the so called ADME (absorption, distribution, metabolism, excretion) parameters, are very important aspects. Large companies do not allow one to put new compounds with disadvantageous parameters or with known toxicity into their molecule banks. After the publication of Lipinski’s “rule of five” (RO5) [3–5], more and more attention was paid to the physicochemical parameters of the drug candidate molecules. According to Lipinski’s rules, it is advantageous from the points of view of solubility and permeability if the number of H-bond donors is less than 5, the number of H-bond acceptors is less 10, the calculated logP (P = octanol–water partition coefficient, clogP) is under 5, and the molecular mass is lower than 500. LogP provides valuable information about the lipophilic/hydrophobic property of the molecule which strongly influences the absorption of the substance, its interaction with the receptor, its metabolism, and its toxicity. Later, other important properties were studied. Veber et al. [6] suggested that the polar surface area should be smaller than 140 A2 and the number of rotatable bonds should be ten or less in an ideal case. The fulfillment of these two criteria provides the opportunity for good oral bioavailability. Today these parameters are routinely studied to predict the drug candidates’ pharmacokinetics and ADME profiles [3]. Over the past decade there has been an increasing practice of creating structurally more complex molecules which are closer to natural materials and provide an opportunity to produce new types of compounds.
Chemistry 2020, 2, 837–848; doi:10.3390/chemistry2040055 www.mdpi.com/journal/chemistry Chemistry 2020, 2, x 2
more complex molecules which are closer to natural materials and provide an opportunity to produce Chemistry 2020, 2 838 new types of compounds. Lovering et al. [7,8] defined the complexity with the saturation of molecules. Saturation allows the formationLovering etof al. molecules [7,8] defined with the more complexity complex with st theructures saturation and of the molecules. expansion Saturation of the allowsstructural the formationversatility ofof moleculesthe compounds with more without complex significant structures increases and the in molecular expansion weight. of the structural It was also versatility supposed of thethat compounds increasing withoutFsp3 character significant may increases improve inthe molecular physicochemical weight. It properties was also supposed of the molecules that increasing which Fspcontribute3 character to clinical may improve success. theLovering physicochemical and his coworkers properties [7,8] of introduced the molecules the definition which contribute of the Fsp to3 clinicalcharacter, success. which is Lovering an important and his parameter coworkers to characterize [7,8] introduced the drug-likeness. the definition Fraction of the Fsp of sp3 character,3 carbons whichmeans: is Fsp an3 important= number of parameter carbons with to characterize sp3 hybridization the drug-likeness. /total number Fraction of carbon of sp atoms.3 carbons Thousands means: Fspof compounds3 = number which of carbons reached with a phase sp3 hybridization of drug rese/archtotal (research number ofphase, carbon Phase atoms. I–III, Thousands drugs) were of compoundsselected from which GVK reached BIO Biosciences’ a phase of drugdatabase research and (researchanalyzed phase, by their Phase sp3 I–III,character. drugs) From were the selected data fromobtained, GVK it BIO was Biosciences’ concluded that database the average and analyzed Fsp3 character by their was sp3 0.36character. for research From compounds the data obtained, and it itincreased was concluded to 0.47 for that drugs. the average This growth Fsp3 character trend was was observed 0.36 for in research all phases compounds of drug research. and it increased The degree to 0.47of saturation for drugs. also This affects growth the trend physical was prop observederties in of all the phases compounds. of drug research.With increasing The degree sp3 character, of saturation the alsowater aff solubilityects the physical increases properties and the of melting the compounds. point decreases. With increasing This way, sp 3onecharacter, is more the likely water to solubility produce increasescompounds and which the melting have favorable point decreases. ADME This parameters way, one, which is more increases likely to producetheir chances compounds of becoming which haveclinical favorable candidates ADME [7,8]. parameters, which increases their chances of becoming clinical candidates [7,8]. M. Hansson et al.al. studied the relationship between molecular hit rates in HTS and molecularmolecular descriptors. They They established established that that ClogP ClogP and and Fsp Fsp3 had3 had the thelargest largest influences influences on the on hit the rate hit [9]. rate This [9]. Thisinspired inspired researchers researchers to synthesize to synthesize new newcompound compound withwith highhigh Fsp3 Fspcharacter.3 character. For example, For example, after aftera HTS a HTSstudy, study, Hirata Hirata and andcoworkers coworkers [10 developed [10 developed a new a new series series of ROR of RORγ inhibitors,γ inhibitors, which which was was guided guided by byFsp Fsp3 character3 character and and ligand ligand efficiency efficiency (LE). (LE). Both Both of of them them are are important important drug-likeness drug-likeness metrics. metrics. With With a careful design, the authors could improve the metabolic stability and reduce the CYPCYP inhibitioninhibition of their orallyorally eefficaciousfficacious RORRORγγ inhibitorsinhibitors (Scheme(Scheme1 1).).
SchemeScheme 1.1. Development ofof aa newnew seriesseries ofof RORRORγγ inhibitorsinhibitors guidedguided byby LELE andand FspFsp33..
3 M. H. Clausen et al. published another example for the synthesis of compounds with high FspFsp3 3 19 character [[10,11].10,11]. They established a librarylibrary ofof fluorinatedfluorinated FspFsp3-rich-rich fragmentsfragments forfor 19F-NMR based screening in fragment based drug discovery (FBDD), which is one of the most important methods of searching for a lead in drug discovery. The synthesized 115 fluorinatedfluorinated fragments gave valuable hits 19 against four diverse protein targetstargets inin 19FF-NMR NMR screening. screening. Normally, thethe 3D3D descriptorsdescriptors performperform better in lead-compound searches than 2D descriptors, 3 such as Fsp3 or logP. D. C.C. KomboKombo et al.al. [[12]12] showedshowed thethe importanceimportance of thethe 2D2D andand 3D3D molecularmolecular descriptors for clinical clinical success. success. They They studied studied the the MDL MDL Drug Drug Data Data Report Report (MDDR) (MDDR) database; database; the thecompounds compounds were were monitored monitored from from the the preclinical preclinical phase phase to to the the market. market. According According their their experience, experience, these shape-basedshape-based 3D3D molecularmolecular descriptorsdescriptors predicted predicted the the success success or or withdrawal withdrawal from from the the market market of of a 3 compounda compound at at preclinical preclinical or or Phase Phase I stageI stage better better than than logD logD or or Fsp Fsp. 3. J. H.H. Nettles Nettles and and coworkers coworkers [13 ][13] used used 2D and 2D 3D and molecular 3D molecular descriptors descriptors for target fishingfor target connecting fishing theconnecting chemical the and chemical biological and space. biological They comparedspace. They the compared 2D and 3D the molecular 2D and 3D descriptors molecular for descriptors prediction offorthe prediction biological of targets.the biological This method targets. was This based method on the was similarity based on to the reference similarity molecules to reference of the biologicallymolecules of active the biologically compounds active in a compounds chemical database in a chemical with 46,000 database compounds. with 46,000 They compounds. concluded They that 2D molecular descriptors were more successful in target prediction, while the 3D molecular descriptors
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concluded that 2D molecular descriptors were more successful in target prediction, while the 3D seemedmolecular to bedescriptors better in casesseemed of singletons, to be better which in cases showed of lowsingletons, structural which similarity showed to other low moleculesstructural insimilarity the database. to other It ismolecules worth combining in the database. both 2D It andis worth 3D descriptors. combining both 2D and 3D descriptors. Ritchie and coworkers [[14]14] studied the role of thethe number of aromatic ringsrings in thethe compound’scompound’s developability. The The effects effects of aromatic ring number on variousvarious developmentaldevelopmental parameters were analyzed, suchsuch as as water water solubility, solubility, lipophilicity, lipophilicity, serum serum albumin albumin binding, binding, CyP450 CyP450 inhibition, inhibition, and hERG and inhibition.hERG inhibition. They They concluded concluded that thethat presence the presence of fewer of fewer aromatic aromatic rings rings in an in oralan oral drug drug candidate candidate is beneficialis beneficial in in regard regard of of developability. developability. In In addition, addition, the the presence presenceof of moremore thanthan threethree aromaticaromatic ringsrings inin aa moleculemolecule correlatescorrelates withwith poorpoor prospectsprospects inin thethe development,development, therebythereby reducingreducing thethe chanceschances ofof successful drug discovery. FurtherFurther analyzesanalyzes [[15]15] havehave also shown that the replacement of an aromatic ring withwith aa bioisosterbioisoster heteroaromatic heteroaromatic ring ring has has a gooda good eff effectect on on development. development. This This can can explain explain why why the numberthe number of approved of approved drugs drugs with with heteroaromatic heteroaromatic rings rings is rising. is rising. The expansion of of the the chemical chemical space space is isanother another im importantportant point point of view of view when when building building up a upnew a newcompound compound library. library. In spite In spiteof the of fact the that fact spiroc that spirocyclesycles have havebeen beenpublishe publishedd for sixty for sixtyyears, years, this thiscompound compound family family remained remained at the at periphery the periphery of dr ofug drugdiscovery discovery earlier earlier [16]. [Nowadays16]. Nowadays there thereare a arefew adrugs few drugs on the on market the market or under or under development development [17–21]. [17– 21The]. Thenatural natural product product Griseofulvin Griseofulvin has hasantifungal antifungal activity activity [22]. [22 The]. The steroid steroid derivative derivative spironolactone spironolactone is isused used for for the the treatment treatment of of fluidfluid retention, edema, and symptoms of heartheart failurefailure (Figure(Figure1 )[1) [23].23]. Recently the FDA approvedapproved thethe calcitonin gene-relatedgene-related peptide peptide receptor receptor antagonist antagonist ubrogepant ubrogepant for for the the acute acute treatment treatment of migraines of migraines [24]. The[24]. spiroThe spiro moiety moiety usually usually has high has Fsp high3 character Fsp3 character and its and advantage its advantage is that itis makesthat it possiblemakes possible greater three-dimensionalitygreater three-dimensionality than the than aromatic the aromatic rings. Y-J. rings. Zheng Y-J. and Zheng C. M. and Tice C. collected M. Tice interestingcollected interesting examples whereinexamples spirocyclic wherein spirocyclic scaffolds were scaffolds applied were in applied drug discovery in drug [discovery25]. [25].
Figure 1. Drugs with spirocyclic scascaffolds.ffolds.
A further way to improveimprove thethe physicochemicalphysicochemical propertiesproperties of the compounds is to replace the phenyl or pyridyl rings rings with with bioisoster bioisoster rings rings cont containingaining two two nitrogens: nitrogens: py pyridazine,ridazine, pyrimidine, pyrimidine, or orpyrazine. pyrazine. This This increases increases the drug-likeness the drug-likeness of the of molecules, the molecules, and generally and generally the ADME the ADME profile, profile, log P logvalues, P values, solubility, solubility, and absorption and absorption are more are more favorable favorable [26]. [26For]. example, For example, pyridazin-3(2H)-on pyridazin-3(2H)-on is a isvaluable a valuable structural structural moiety moiety which which can be can a begood a good starting starting point point for drug for drugresearch research projects projects [27]. [The27]. Thepyridazine pyridazine ring ring can canbe ea besily easily functionalized functionalized in invarious various position positions,s, making making it it an an attractive attractive synthetic building block for the preparationpreparation of newnew compoundscompounds [[28].28]. Various structuralstructural modificationsmodifications on thethe ring system containing the pyridazinonepyridazinone unit have resulted in compounds with favorable biological activity [[29].29]. Over the past few decades, many paperspapers and patents have been published on bioactive pyridazines andand pyridazinones,pyridazinones, whichwhich havehave beenbeen utilized in almost all therapeutic fieldsfields with various mechanisms of action [30,31]. [30,31]. For For example, example, the the anti antihypertensivehypertensive hydralazine hydralazine (Apresoline) (Apresoline) is used is used to totreat treat high high blood blood pressure pressure and and heart heart failure failure [32]. [32 The]. The calcium calcium sensitizer sensitizer levosimendan levosimendan is effective is effective in
Chemistry 2020, 2, x 4 Chemistry 2020, 2, x 4 congestiveChemistry heart2020 failure, 2 [33]. The antihypertensive bemoradan is an inhibitor of cardiac muscle840 cyclic AMPcongestive phosphodiesterase heart failure [33]. (PDE), The whichantihypertensive explains its bemoradan cardiotonic is effect an inhibitor [34]. The of cardiacmonoamine muscle oxidase cyclic inhibitorAMP phosphodiesterasein minaprine congestive [35,36] heart failure(PDE), has an [33 which ].antidepressant The antihypertensiveexplains itseffect. cardiotonic bemoradan The tricyclic effect is an pipofezine inhibitor [34]. The of cardiac(Azafenmonoamine muscle or Azaphen) oxidase [37]inhibitor acts cyclicas minaprine a serotonin AMP phosphodiesterase [35,36] reuptake has an inhibitor. antidepressant (PDE), which It was explains launchedeffect. itsThe cardiotonic as tricyclic an antidepressant epipofezineffect [34]. The (Azafenin monoamine the 1960s or Azaphen) and it is oxidase inhibitor minaprine [35,36] has an antidepressant effect. The tricyclic pipofezine (Azafen or still[37] onacts the as marketa serotonin today. reuptake Emorfazone inhibitor. [38], It as was a nonsteroidal launched as anti-inflammatoryan antidepressant inagent, the 1960s has analgesic and it is Azaphen) [37] acts as a serotonin reuptake inhibitor. It was launched as an antidepressant in the effects. See Figure 2 for said examples. still on the1960s market and it istoday. still on Emorfazone the market today. [38], Emorfazone as a nonsteroidal [38], as a nonsteroidal anti-inflammatory anti-inflammatory agent, has agent, analgesic effects. Seehas Figure analgesic 2 eforffects. said See examples. Figure2 for said examples.
Figure 2. Antihypertensive, antidepressant, and anti-inflammatory pyridazinone derivatives. Figure 2.Figure Antihypertensive, 2. Antihypertensive, antidepressant, antidepressant, and and anti-inflammatoryanti-inflammatory pyridazinone pyridazinone derivatives. derivatives. Imazodan [39], Amipizone [40], Zardaverine [41], and Indolidan [42] are used in veterinary Imazodan [39], Amipizone [40], Zardaverine [41], and Indolidan [42] are used in veterinary medicine.Imazodanmedicine. Pimobendan [39], Pimobendan Amipizone [43] belongs [43] belongs [40], to aZardaverine to group a group of of selective selective [41], and phosphodiesterase phosphodiesterase Indolidan [42] (PDE3) are(PDE3) inhibitors used inhibitors in used veterinary used tomedicine. treat heartto Pimobendan treat problems heart problems of[43] dogs ofbelongs dogs (Figure (Figure to a 3). group3). of selective phosphodiesterase (PDE3) inhibitors used to treat heart problems of dogs (Figure 3). F F H C CH 3 F O O F H H C CH N O N 3 O N H C O O NNH 3 H NNH O O N O Cl N O H C NNH N H C 3 NNH 3 NNH O O Cl H C NNH Imazodan Amipizone 3 Zardaverine Imazodan Amipizone Zardaverine O H3C O CH3 H3C H3C NHO NHO N N CH3 N O OH3C NH NH H C N N N N 3 H O H O N H3C N H H Indolidan Pimobendan IndolidanFigure 3. Figure 3. PyridazinonePyridazinone derivatives derivatives in in veterinaryPimobendan veterinary medicine. medicine. The pyridazine-containingFigure 3. Pyridazinone fused ring system derivatives may have in veterinary valuable biological medicine. activity. Zopolrestat is Theused pyridazine-containing as an aldose reductase inhibitorfused ring to treat system diabetic may neuropathy have valuable and nephropathy biological [44 ].activity. The melanin Zopolrestat is usedThe asconcentrating pyridazine-containing an aldose hormone reductase 1 (MHCR-1) fusedinhibitor ring antagonist tosystem treat thienopyridazinones maydiabetic have neuropathy valuable [45 ]biological showed and nephropathyin vivoactivity.anorectic Zopolrestat [44]. The properties. The pyrazolo-pyrimidinopyridazinones exhibit potent and elective phosphodiesterase melaninis used asconcentrating an aldose reductase hormone inhibitor1 (MHCR-1) to tr antagonieat diabeticst thienopyridazinones neuropathy and nephropathy [45] showed [44]. in vivoThe 5 (PDE5) inhibitory activity [46]. KK 505 is used as an anti-asthma agent [47] (Figure4). anorecticmelanin concentrating properties. hormoneThe pyrazolo-pyrimidinop 1 (MHCR-1) antagoniyridazinonesst thienopyridazinones exhibit potent [45] showedand electivein vivo phosphodiesteraseanorectic properties. 5 (PDE5) The inhibitorypyrazolo-pyrimidinop activity [46].yridazinones KK 505 is used exhibit as an anti-asthmapotent and agent elective [47] (Figurephosphodiesterase 4). 5 (PDE5) inhibitory activity [46]. KK 505 is used as an anti-asthma agent [47] (Figure 4).
Chemistry 2020, 2 841
Figure 4. Biologically active pyridazinones.
2. Synthesis of Spiro[cycloalkane-pyridazinone] Derivatives Taking into account the expected bioactivity of the pyridazine derivatives and their favorable physicochemical parameters, our attention turned to this family of compounds. Considering the advantages of compounds with high Fsp3 character, we have designed a compound library with a spiro[cycloalkane-pyridazinone] scaffold instead of the usual phenyl-pyridazinone derivatives.
2.1. Synthesis of the Starting Materials The preparation of our starting materials 2-oxaspiro[4.5]decane-1,3-dione and 2-oxaspiro[4.4] nonane-1,3-dione was performed according to methods known in the literature, optimizing them [48,49]. In the first step, starting from cyclohexanone or cyclopentanone, we performed Knoevenagel condensation in the presence of ethyl 2-cyanoacetate (1) followed by the addition of a cyanide group. The nitrile groups were hydrolyzed with concentrated hydrochloric acid. The anhydride formation from the cycloalkyl dicarboxylic acids (4a, 4b) was also examined with two reagents: acetic anhydride and acetyl chloride. The cyclization with acetyl chloride was clearly more favorable as the desired spirocyclic anhydrides formed at lower temperatures and with higher yields (5a, 5b) (Scheme2).
1
Chemistry 2020, 2, x 5
CH N 3 N CH 3 O O NN C OOH N S N F C N 3 N S
CF 3 MC H R- 1 antagonist Zopol restat
O O H C N 3 O N N N N O CH N NN 3 C H 3 KK 505 PDE5 inhibitor
Figure 4. Biologically active pyridazinones.
2. Synthesis of Spiro[cycloalkane-pyridazinone] Derivatives Taking into account the expected bioactivity of the pyridazine derivatives and their favorable physicochemical parameters, our attention turned to this family of compounds. Considering the advantages of compounds with high Fsp3 character, we have designed a compound library with a spiro[cycloalkane-pyridazinone] scaffold instead of the usual phenyl-pyridazinone derivatives.
2.1. Synthesis of the Starting Materials The preparation of our starting materials 2-oxaspiro[4.5]decane-1,3-dione and 2- oxaspiro[4.4]nonane-1,3-dione was performed according to methods known in the literature, optimizing them [48,49]. In the first step, starting from cyclohexanone or cyclopentanone, we performed Knoevenagel condensation in the presence of ethyl 2-cyanoacetate (1) followed by the addition of a cyanide group. The nitrile groups were hydrolyzed with concentrated hydrochloric acid. The anhydride formation from the cycloalkyl dicarboxylic acids (4a, 4b) was also examined with two reagents: acetic anhydride and acetyl chloride. The cyclization with acetyl chloride was clearly Chemistrymore favorable2020, 2 as the desired spirocyclic anhydrides formed at lower temperatures and with higher842 yields (5a, 5b) (Scheme 2).
Scheme 2. Synthesis of starting materials. 2.2. Friedel–Crafts and Grignard Reactions 2.2. Friedel–Crafts and Grignard Reactions Chemistry 2020In, course 2, x of the synthesis of our pyridazinone derivatives, we prepared first the isomeric 6 In course of the synthesis of our pyridazinone derivatives, we prepared first the isomeric γ- γ-oxocarboxylic acids containing 1,1-disubstituted cycloalkanes from the starting compounds oxocarboxylic acids containing 1,1-disubstituted cycloalkanes from the starting compounds (5a, 5b) according(5a, 5b to) and a patentedvariously process substituted in which benzene 2-oxaspiro[4.4]nonane-1,3-dione derivatives by Friedel–Crafts reaction was (Scheme reacted 4). with This ( was5b) 1,2- and variously substituted benzene derivatives by Friedel–Crafts reaction (Scheme 4). This was done dimethoxybenzenedone according toin a the patented presence process of inAlCl which3 [50]. 2-oxaspiro[4.4]nonane-1,3-dione In our work, eight new isomeric was reacted γ-oxocarboxylic with (5b) acids1,2-dimethoxybenzene containing 1,1-disubstituted in the presence cycloalkanes of AlCl3 [were50]. In prepared. our work, Compounds eight new isomeric 6b andγ-oxocarboxylic 6c were obtained only acidsin very containing low yields 1,1-disubstituted because the cycloalkanes electrophilic were aromatic prepared. substitution Compounds favors6b and electron-rich6c were obtained groups. Furthermore,only in very in lowthe yieldsFriedel–Crafts because the reaction electrophilic of compound aromatic substitution5b with anisole, favors in electron-rich addition to groups. the main productFurthermore, 7b, 7c—a inby-product the Friedel–Crafts with an reaction isomeric of structure—was compound 5b with also anisole, identified. in addition to the main productAnother7b ,way7c—a by-productto prepare with isomeric an isomeric γ-oxocarboxylic structure—was alsoacids identified. containing 1,1-disubstituted γ cycloalkanesAnother is via way the to Grignard prepare isomeric reaction-oxocarboxylic [51]. This was acids used containing in cases 1,1-disubstitutedwhere only low cycloalkanesyields could be is via the Grignard reaction [51]. This was used in cases where only low yields could be achieved achieved in Friedel–Crafts reactions, for example, in cases with less active reagents, such as toluene in Friedel–Crafts reactions, for example, in cases with less active reagents, such as toluene and and chlorobenzene. Grignard reactions were performed in tetrahydrofuran with p-tolyl magnesium chlorobenzene. Grignard reactions were performed in tetrahydrofuran with p-tolyl magnesium bromidebromide and and (4-chlorophenyl) (4-chlorophenyl) magnesium magnesium bromide,bromide, under under inert inert conditions. conditions. For compoundsFor compounds6b and 6b6c and 6c thethe yield yield waswas improved. improved. Furthermore, Furthermore, for compounds for compounds7a and 7f 7a, molecules and 7f, withmolecules isomeric with structures isomeric structures(7e and (7e7g )and were 7g also) were isolated also andisolated identified and (Schemeidentified3) (Table(Scheme1). 3) (Table 1).
SchemeScheme 3. 3. Friedel–CraftsFriedel–Crafts and GrignardGrignard reaction. reaction.
Table 1. Fsp3 values of γ-oxocarboxylic acids.
Starting Material R1 R2 Product Fsp3 LogP CLogP
5a OCH3 H 6a 0.50 2.91 3.4955
5a CH3 H 6b 0.50 3.53 3.7746 5a Cl H 6c 0.46 3.60 4.0642
5a OCH3 OCH3 6d 0.53 2.79 3.17319
5b CH3 H 7a 0.47 3.11 3.2156
5b OCH3 H 7b 0.47 2.50 2.9365
1 5b OCH3 H 7c 0.47 2.50 2.9365
5b OCH3 OCH3 7d 0.50 2.37 2.61419
1 5b CH3 H 7e 0.47 3.11 3.2156 5b Cl H 7f 0.43 3.18 3.5052 5b Cl H 7g 1 0.43 3.18 3.5052 1 Isomeric structure.
2.3. Formation of Pyridazinone Ring Pyridazinones were formed from isomeric γ-oxocarboxylic acids containing 1,1-disubstituted cycloalkanes with hydrazine and hydrazine derivatives (methyl- and phenylhydrazine). We used the reaction conditions developed by Van der May et al. [51]. The pyridazinones (8a–d) were prepared
Chemistry 2020, 2 843
Table 1. Fsp3 values of γ-oxocarboxylic acids.
Starting Material R1 R2 Product Fsp3 LogP CLogP
5a OCH3 H 6a 0.50 2.91 3.4955 5a CH3 H 6b 0.50 3.53 3.7746 5a Cl H 6c 0.46 3.60 4.0642 5a OCH3 OCH3 6d 0.53 2.79 3.17319 5b CH3 H 7a 0.47 3.11 3.2156 5b OCH3 H 7b 0.47 2.50 2.9365 1 5b OCH3 H 7c 0.47 2.50 2.9365 5b OCH3 OCH3 7d 0.50 2.37 2.61419 1 5b CH3 H 7e 0.47 3.11 3.2156 5b Cl H 7f 0.43 3.18 3.5052 5b Cl H 7g 1 0.43 3.18 3.5052 1 Isomeric structure.
2.3. Formation of Pyridazinone Ring Pyridazinones were formed from isomeric γ-oxocarboxylic acids containing 1,1-disubstituted Chemistry 2020, 2, x 7 cycloalkanesChemistry 2020, 2 with, x hydrazine and hydrazine derivatives (methyl- and phenylhydrazine). We used the7 reaction conditions developed by Van der May et al. [51]. The pyridazinones (8a–d) were prepared in in good yields. Pyridazinone derivatives (9) and (10) were also isolated in medium yields (Scheme 4). goodin good yields. yields. Pyridazinone Pyridazinone derivatives derivatives (9 ()9) and and ( 10(10)) were were also also isolatedisolated inin mediummedium yields (Scheme 44).). In the case of compound 7b, in addition to the expected structure (11a), a compound with an isomeric In the case of compound 7b, in in addition addition to to the the expected expected structure structure ( 11a), a compound with an isomeric structure (11b) was also isolated and identified by 2D NMR (Scheme 5) (Table 2). structure (11b) was alsoalso isolatedisolated andand identifiedidentified byby 2D2D NMRNMR (Scheme(Scheme5 5)) (Table (Table2). 2).
Scheme 4. Ring closure with hydrazine. Scheme 4. Ring closure with hydrazine.
Scheme 5. Ring closure of the isomeric compound 7c. Scheme 5. Ring closure of the isomeric compound 7c.
Table 2. Fsp3 values of pyridazinones. Table 2. Fsp3 values of pyridazinones. Starting Material R1 R2 Product Fsp3 LogP CLogP Starting Material R1 R2 Product Fsp3 LogP CLogP 6a OCH3 H 8a 0.50 2.91 2.753 6a OCH3 H 8a 0.50 2.91 2.753 6b CH3 H 8b 0.50 3.52 3.333 6b CH3 H 8b 0.50 3.52 3.333 6c Cl H 8c 0.47 3.59 3.547 6c Cl H 8c 0.47 3.59 3.547 6d OCH3 OCH3 8d 0.53 2.78 2.492 6d OCH3 OCH3 8d 0.53 2.78 2.492 7a CH3 H 9 0.46 3.10 2.774 7a CH3 H 9 0.46 3.10 2.774 7f Cl H 10 0.43 3.17 2.988 7f Cl H 10 0.43 3.17 2.988 11a 0.46 2.49 2.194 7b OCH H 11a 0.46 2.49 2.194 3 1 7b OCH3 H 11b 0.46 2.49 2.194 11b 1 0.46 2.49 2.194 7c OCH3 OCH3 12 0.50 2.36 1.933 7c OCH3 OCH3 12 0.50 2.36 1.933 1 Isomeric structure. 1 Isomeric structure. 2.4. N-substituted Pyridazinone Derivatives 2.4. N-substituted Pyridazinone Derivatives N-substituted pyridazinone derivatives were formed with methyl- and phenyl hydrazine and in N-substituted pyridazinone derivatives were formed with methyl- and phenyl hydrazine and in N-alkylation/aralkylation reactions. Reactions with methylhydrazine were performed under the N-alkylation/aralkylation reactions. Reactions with methylhydrazine were performed under the above-mentioned conditions starting from the mixture of 6a and 6h [51] by boiling in ethanol. The above-mentioned conditions starting from the mixture of 6a and 6h [51] by boiling in ethanol. The crude product was purified by preparative thin layer chromatography. The pyridazinones (13a and crude product was purified by preparative thin layer chromatography. The pyridazinones (13a and isomeric 13b) shown in Scheme 6 were isolated and identified. isomeric 13b) shown in Scheme 6 were isolated and identified.
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Table 2. Fsp3 values of pyridazinones.
Starting Material R1 R2 Product Fsp3 LogP CLogP
6a OCH3 H 8a 0.50 2.91 2.753 6b CH3 H 8b 0.50 3.52 3.333 6c Cl H 8c 0.47 3.59 3.547 6d OCH3 OCH3 8d 0.53 2.78 2.492 7a CH3 H 9 0.46 3.10 2.774 7f Cl H 10 0.43 3.17 2.988 11a 0.46 2.49 2.194 7b OCH H 3 11b 1 0.46 2.49 2.194 7c OCH3 OCH3 12 0.50 2.36 1.933 1 Isomeric structure.
2.4. N-Substituted Pyridazinone Derivatives N-substituted pyridazinone derivatives were formed with methyl- and phenyl hydrazine and Chemistry 2020in N,-alkylation 2, x /aralkylation reactions. Reactions with methylhydrazine were performed under the 8 above-mentioned conditions starting from the mixture of 6a and 6h [51] by boiling in ethanol. The crude product was purified by preparative thin layer chromatography. The pyridazinones (13a and isomeric 13bChemistry) shown 2020,in 2, x Scheme 6 were isolated and identified. 8
Scheme 6. Ring closure with methyl hydrazine. Scheme 6. Ring closure with methyl hydrazine. The N-phenyl derivatives were prepared first by boiling compounds 6a–c, 7a,f with The N-phenyl derivatives were prepared first by boiling compounds 6a–c, 7a,f with phenylhydrazineThe N in-phenyl ethanol, derivatives but only were very preparedlow yields first were by achieved.boiling compounds Changing 6a–c, the solvent7a,f with to toluene phenylhydrazine in in ethanol, ethanol, but but only only very very low low yields yields were were achieved. achieved. Changing Changing the solvent the solventto toluene to improved the yields and N-phenyl derivatives (14–18) were isolated (Scheme 7). tolueneimproved improved the yields the and yields N-phenyl and N -phenylderivatives derivatives (14–18) were (14–18 isolated) were isolated(Scheme (Scheme 7). 7).
Scheme 7. Ring closure with phenyl hydrazine. N-methyl derivativesScheme wereScheme also 7. Ring 7. preparedRing closure closure by withN-alkylation phenyl phenyl hydrazine. hydrazine.reactions [52]. By starting from the previously isolated pyridazinone derivatives (8b, 8c, 9, 10) and alkylating them with methyl iodide N-methyl derivatives were also prepared by N-alkylation reactions [52]. By starting from the in tetrahydrofuran in the presence of sodium hydride, the N-methylated compounds (19–22) were N-methylpreviously derivatives isolated pyridazinone were alsoderivatives prepared ( 8b,by 8c,N-alkylation 9, 10) and alkylating reactions them [52]. with By methyl starting iodide from the isolated in medium yields. In the preparation of N-benzylated derivatives we first chose the classical previouslyin tetrahydrofuran isolated pyridazinone in the presence derivatives of sodium (8b, hydride, 8c, 9, the 10N) -methylatedand alkylating compounds them with (19–22 methyl) were iodide potassium carbonate method, but it did not produce the desired product, so we changed to cesium in tetrahydrofurancarbonate, which in the enabled presence us to isolate of sodium our desired hydride, N-benzylated the N pyridazinone-methylated derivatives compounds in medium (19–22 ) were isolated yieldsin medium (23–27) yields.(Scheme In 8) the(Table preparation 3). of N-benzylated derivatives we first chose the classical potassium carbonate method, but it did not produce the desired product, so we changed to cesium carbonate, which enabled us to isolate our desired N-benzylated pyridazinone derivatives in medium yields (23–27) (Scheme 8) (Table 3).
Scheme 8. N-methyl- and N-benzyl derivatives of pyridazinones.
Scheme 8. N-methyl- and N-benzyl derivatives of pyridazinones.
Chemistry 2020, 2, x 8
Scheme 6. Ring closure with methyl hydrazine.
The N-phenyl derivatives were prepared first by boiling compounds 6a–c, 7a,f with phenylhydrazine in ethanol, but only very low yields were achieved. Changing the solvent to toluene improved the yields and N-phenyl derivatives (14–18) were isolated (Scheme 7).
Scheme 7. Ring closure with phenyl hydrazine.
N-methyl derivatives were also prepared by N-alkylation reactions [52]. By starting from the previously isolated pyridazinone derivatives (8b, 8c, 9, 10) and alkylating them with methyl iodide Chemistry 2020, 2 845 in tetrahydrofuran in the presence of sodium hydride, the N-methylated compounds (19–22) were isolated in medium yields. In the preparation of N-benzylated derivatives we first chose the classical isolated in medium yields. In the preparation of N-benzylated derivatives we first chose the classical potassium carbonate method, but it did not produce the desired product, so we changed to cesium potassium carbonate method, but it did not produce the desired product, so we changed to cesium carbonate,carbonate, which whichenabled enabled us to us isolate to isolate our our desired desired NN-benzylated pyridazinone pyridazinone derivatives derivatives in medium in medium yields (23–27yields) ((Scheme23–27) (Scheme 8) (Table8) (Table 3).3 ).
SchemeScheme 8. N 8.-methyl-N-methyl- and and NN-benzyl-benzyl derivativesderivatives of pyridazinones.of pyridazinones. Table 3. Fsp3 values of substituted pyridazinones.
Starting Material R1 R3 Product Fsp3 LogP CLogP 6a 13a 0.53 3.14 2.845 OCH CH 6h 3 3 13b 1 0.53 3.14 2.845
6a OCH3 Ph 14 0.36 4.81 4.744 6b CH3 Ph 15 0.36 5.42 5.324 6c Cl Ph 16 0.33 5.49 5.538 7a CH3 Ph 17 0.33 5.00 4.765 7f Cl Ph 18 0.30 5.07 4.979 8b CH3 CH3 19 0.53 3.76 3.425 8c Cl CH3 20 0.47 3.83 3.639 9 CH3 CH3 21 0.50 3.34 2.866 10 Cl CH3 22 0.44 3.41 3.080 8a OCH3 Bn 23 0.39 4.87 5.077 8b CH3 Bn 24 0.39 5.49 5.657 8c Cl Bn 25 0.36 5.56 5.871 9 CH3 Bn 26 0.36 5.07 5.098 10 Cl Bn 27 0.33 5.14 5.312 1 Isomeric structure.
3. Conclusions In summary, our starting materials 2-oxaspiro[4.5]decane-1,3-dione (5a) and 2-oxaspiro[4.4]nonane-1,3-dione (5b) were prepared and optimized using methods known in the literature [48,49]. From these 1,3-diones, eleven new isomeric γ-oxocarboxylic acids containing 1,1-disubstituted cycloalkanes were prepared by Friedel–Crafts and Grignard reactions. These were reacted with various hydrazine derivatives, and with further N-alkyl/aralkylation reactions we isolated 25 new pyridazinone derivatives. The Fsp3 values of our compounds showed good correlations with logP values; e.g., the logP values of compounds with high Fsp3 character (8a–d, 9, 10, 11a–b, 12) Chemistry 2020, 2 846 were between 2.36 and 3.59, under 5 (see Table2). The situation was similar for compounds 13a,b–27 (Table3). The introduction of a further aromatic ring into compounds 14–18 and 23–27 decreased the Fsp3 character and increased the logP values to over 4.8. A smaller molecule library was created with 36 new compounds with high Fsp3 character, which could be a good starting point for drug research projects [53,54].
Author Contributions: C.S.F. and H.B. wrote the paper. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest.
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