cas 139756-22-2, 5-(5-Chlorosulfonyl-2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

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Discovery of in Vivo Chemical Probes for Treating Alzheimer's Disease: Dual Phosphodiesterase 5 (PDE5) and Class i Histone Deacetylase Selective Inhibitors
In order to determine the contributions of histone deacetylase (HDAC) isoforms to the beneficial effects of dual phosphodiesterase 5 (PDE5) and pan-HDAC inhibitors on in vivo models of Alzheimer's disease (AD), we have designed, synthesized, and tested novel chemical probes with the desired target compound profile of PDE5 and class I HDAC selective inhibitors. Compared to previous hydroxamate-based series, these molecules exhibit longer residence times on HDACs. In this scenario, shorter or longer preincubation times may have a significant impact on the IC50 values of these compounds and therefore on their corresponding selectivity profiles on the different HDAC isoforms. On the other hand, different chemical series have been explored and, as expected, some pairwise comparisons show a clear impact of the scaffold on biological responses (e.g., 35a vs 40a). The lead identification process led to compound 29a, which shows an adequate ADME-Tox profile and in vivo target engagement (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation) in the central nervous system (CNS), suggesting that this compound represents an optimized chemical probe; thus, 29a has been assayed in a mouse model of AD (Tg2576).
Rabal, Obdulia,Sánchez-Arias, Juan A.,Cuadrado-Tejedor, Mar,De Miguel, Irene,Pérez-González, Marta,García-Barroso, Carolina,Ugarte, Ana,Estella-Hermoso De Mendoza, Ander,Sáez, Elena,Espelosin, Maria,Ursua, Susana,Haizhong, Tan,Wei, Wu,Musheng, Xu,Garcia-Osta, Ana,Oyarzabal, Julen
p. 1765 - 1782
(2019)
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α-Keto Acids as Triggers and Partners for the Synthesis of Quinazolinones, Quinoxalinones, Benzooxazinones, and Benzothiazoles in Water
A general and efficient method for the synthesis of quinazolinones, quinoxalinones, benzooxazinones, and benzothiazoles from the reactions of α-keto acids with 2-aminobenzamides, benzene-1,2-diamines, 2-aminophenols, and 2-aminobenzenethiols, respectively, is described. The reactions were conducted under catalyst-free conditions, using water as the sole solvent with no additive required, and successfully applied to the synthesis of sildenafil. More importantly, these reactions can be conducted on a mass scale, and the products can be easily purified through filtration and washing with ethanol (or crystallized).
Huang, Jian,Chen, Wei,Liang, Jiazhi,Yang, Qin,Fan, Yan,Chen, Mu-Wang,Peng, Yiyuan
p. 14866 - 14882
(2021/10/25)

Improved synthesis process of sildenafil
The invention discloses an improved synthesis process of sildenafil, belonging to the technical field of preparation of drug intermediates. In the process, high-concentration chlorosulfonic acid is prevented from being used as a reaction solvent and reagent, and 3-5 equivalent chlorosulfonic acid is used as a reaction reagent. Compared with the prior art, the process has the characteristics of economical performance, environmental protection, safety and the like, for example, equipment cannot be corroded, the post-treatment of reaction becomes simpler, the solvent is single and can be reused, product purity is high, and the like.
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(2021/06/21)

Improved, gram-scale synthesis of sildenafil in water using arylacetic acid as the acyl source in the pyrazolo[4,3-d]pyrimidin-7-one ring formation
An improved, gram-scale synthesis of the blockbuster drug sildenafil, used for the treatment of male erectile dysfunction, has been developed. Unlike the previous literature, the current method demonstrates the use of arylacetic acid as an acyl source, a cheap oxidant K2S2O8, and water as the reaction medium in the key step of pyrrazolo[4,3-d]pyrimidin-7-one ring formation. As well as being a green and benign approach, the current method reduces the cost by half compared to our previous strategy. In addition, the general relevance of the method has been demonstrated in the synthesis of a variety of quinazolinone and benzothiazole derivatives with excellent functional group tolerance.
Laha, Joydev K.,Gulati, Upma,Saima,Gupta, Anjali,Indurthi, Harish Kumar
p. 2643 - 2648
(2021/02/16)

NOVEL DUAL MODE OF ACTION SOLUBLE GUANYLATE CYCLASE ACTIVATORS AND PHOSPHODIESTERASE INHIBITORS AND USES THEREOF
The present invention relates to compounds of formula (I) or formula (II) or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein said compound of formula (I) and said compound of formula II each comprises at least one ONO2 or ONO moiety; R1 is C1-C3alkyl; R2 is H, C1-C6alkyl, C3-C6cycloalkyl, C1-C2alkoxy, C2-C4alkenyl; R3 is C1-C4alkyl optionally substituted with C1-C2alkoxy, C3-C4cycloalkyl, C2-C4alkenyl; R4 and R5 are each independently H or C1-C6alkyl optionally substituted with F, OH, ONO, ONO2, COOH, C1-C3alkoxy, C3-C6cycloalkyl; or together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein preferably said heterocyclic ring is selected from aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine, homo-piperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, wherein said heterocyclic ring is optionally substituted with independently one or more R6; R6 is C1-C6alkyl optionally substituted with independently one or more halogen, OH, ONO, ONO2, C1-C3alkoxy, C1-C3haloalkoxy, COOR7, NR8R9, C=NR10; R7 is H, or C1-C4alkyl optionally substituted with F, OH, ONO, ONO2, NR8R9; R8 and R9 are independently H, or C1-C4alkyl optionally substituted with ONO, ONO2; R10 is C1-C4alkyl optionally substituted with F, ONO, ONO2; C3-C6cycloalkyl; pharmaceutical compositions thereof, and their use in methods of treating or preventing a disease alleviated by inhibition of PDE5 in a human or in a non-human mammal.
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(2020/06/19)

Method for preparing sildenafil citrate
The invention discloses a method for preparing sildenafil citrate. The preparation method comprises the following steps: (a) adding a compound II into chlorosulfonic acid for a reaction to generate anintermediate III; (b) reacting the intermediate III with N-methyl piperazine to generate a crude sildenafil product; (c) recrystallizing the crude sildenafil product to obtain a pure sildenafil product; and (d) carrying out a salifying reaction on the pure sildenafil product to obtain sildenafil citrate. The method is beneficial for industrial production.
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(2020/05/30)

Design, synthesis and biological evaluation of pyrazolopyrimidinone based potent and selective PDE5 inhibitors for treatment of erectile dysfunction
Our previous discovery of series of pyrazolopyrimidinone based PDE5 inhibitors led to find potent leads but with low aqueous solubility and poor bioavailability, and low selectivity. Now, a new series of same pyrazolopyrimidinone scaffold is designed, synthesized and evaluated for its PDE5 inhibitory potential. In this study, some of the molecules are found more potent and selective PDE5 inhibitors in vitro than sildenafil. The studies revealed that compound 5 is 20 fold selective to PDE5 against PDE6. As PDE6 enzyme is involved in the phototransduction pathway in the retina and creates distortion problem, the selectivity for PDE5 specifically against PDE6 enzyme is preferred for any development candidate and in present study, compound 5 has been found to be devoid of this liability of selectivity issue. Moreover, compound 5 has shown excellent in vivo efficacy in conscious rabbit model, it's almost comparable to sildenafil. The preclinical pharmacology including pharmacokinetic and physicochemical parameter studies were also performed for compound 5, it was found to have good PK properties and other physicochemical parameters. The development of these selective PDE5 inhibitors can further lead to draw strategies for the novel preclinical and/or clinical candidates based on pyrazolopyrimidinone scaffold.
Reddy, G. Lakshma,Dar, Mohd. Ishaq,Hudwekar, Abhinandan D.,Mahajan, Priya,Nargotra, Amit,Baba, Adil Manzoor,Nandi, Utpal,Wazir, Priya,Singh, Gurdarshan,Vishwakarma, Ram A.,Syed, Sajad Hussain,Sawant, Sanghapal D.
(2019/06/11)

Efficient Synthesis of Trifluoromethyl Amines through a Formal Umpolung Strategy from the Bench-Stable Precursor (Me4N)SCF3
Reported herein is the one-pot synthesis of trifluoromethylated amines at room temperature using the bench-stable (Me4N)SCF3reagent and AgF. The method is rapid, operationally simple and highly selective. It proceeds via a formal umpolung reaction of the SCF3with the amine, giving quantitative formation of thiocarbamoyl fluoride intermediates within minutes that can readily be transformed to N-CF3. The mildness and high functional group tolerance render the method highly attractive for the late-stage introduction of trifluoromethyl groups on amines, as demonstrated herein for a range of pharmaceutically relevant drug molecules.
Scattolin, Thomas,Deckers, Kristina,Schoenebeck, Franziska
supporting information
p. 221 - 224
(2016/12/30)

Formation of amides, their intramolecular reactions for the synthesis of N-heterocycles, and preparation of a marketed drug, sildenafil: A comprehensive coverage
A unified approach to the tandem preparation of diverse nitrogen heterocycles via decarboxylative acylation of ortho-substituted amines with α-oxocarboxylic acids and subsequent intramolecular cyclizations has been developed. The key features of this work include: the first example of transition-metal-free decarboxylative amidation of α-oxocarboxylic acids with ortho-substituted amines, realization of intramolecular cyclization of amides employing nucleophiles that have previously been unexplored, mechanistic investigation of an unprecedented K2S2O8 promoted amide formation and its subsequent intramolecular cyclizations, and application to the synthesis of a best-selling marketed drug.
Laha, Joydev K.,Patel, Ketul V.,Satyanarayana Tummalapalli,Dayal, Neetu
p. 10245 - 10248
(2016/08/23)

NOVEL COMPOUNDS FOR USE IN COGNITION IMPROVEMENT
Novel compounds for use in cognition improvement It relates to certain compounds having a polycyclic structure and a -(C=O)NRaRb moiety, wherein the polycyclic structure comprises at least three ring systems, wherein one ring system is a polycyclic ring system comprising from 2 to 4 rings; at least one ring is an aromatic ring; and wherein the structure comprises at least 3 nitrogen atoms and 1 oxygen atom. It also relates to pharmaceutical compositions containing them, and to their use in medicine, in particular in the treatment and/or prevention of neurological disorders coursing with a cognition deficit or impairment, or neurodegenerative diseases.
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(2016/04/19)

Design, Synthesis, and Biological Evaluation of First-in-Class Dual Acting Histone Deacetylases (HDACs) and Phosphodiesterase 5 (PDE5) Inhibitors for the Treatment of Alzheimer's Disease
Simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylases (HDAC) has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). To further extend this concept, we designed and synthesized the first chemical series of dual acting PDE5 and HDAC inhibitors, and we validated this systems therapeutics approach. Following the implementation of structure- and knowledge-based approaches, initial hits were designed and were shown to validate our hypothesis of dual in vitro inhibition. Then, an optimization strategy was pursued to obtain a proper tool compound for in vivo testing in AD models. Initial hits were translated into molecules with adequate cellular functional responses (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation in the nanomolar range), an acceptable therapeutic window (>1 log unit), and the ability to cross the blood-brain barrier, leading to the identification of 7 as a candidate for in vivo proof-of-concept testing (Cuadrado-Tejedor, M.; Garcia-Barroso, C.; Sánchez-Arias, J. A.; Rabal, O.; Mederos, S.; Ugarte, A.; Franco, R.; Segura, V.; Perea, G.; Oyarzabal, J.; Garcia-Osta, A. Neuropsychopharmacology 2016, in press, doi: 10.1038/npp.2016.163).
Rabal, Obdulia,Sánchez-Arias, Juan A.,Cuadrado-Tejedor, Mar,De Miguel, Irene,Pérez-González, Marta,García-Barroso, Carolina,Ugarte, Ana,Estella-Hermoso De Mendoza, Ander,Sáez, Elena,Espelosin, Maria,Ursua, Susana,Haizhong, Tan,Wei, Wu,Musheng, Xu,Garcia-Osta, Ana,Oyarzabal, Julen
p. 8967 - 9004
(2016/10/22)

PYRAZOLOPYRIMIDINONES FOR THE TREATMENT OF IMPOTENCE AND PROCESS FOR THE PREPARATION THEREOF
The present invention relates to Pyrazolopyrimidinone compounds as PDE5 inhibitors with better IC50 value, good in vivo efficacy and PK profile and a process for the preparation thereof. The present invention covers the pyrazolo pyrimidinone based compounds that have been designed, synthesized and screened for PDE5 inhibitory activity and its PDE5 inhibitory potential is provided in this invention. These designer compounds have shown nanomolar potency when screened for PDE5 inhibitory activity and also shown better in vivo efficacy. These compounds can be used in the treatment of male erectile dysfunction or in the treatment of impotence.
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(2015/09/23)

NOVEL COMPOUNDS AS DUAL INHIBITORS OF PHOSPHODIESTERASES AND HISTONE DEACETYLASES
It relates to certain compounds having a polycyclic structure and a hydroxamic acid moiety, wherein the polycyclic structure comprises at least three ring systems, wherein one ring system is a polycyclic ring system comprising from 2 to 4 rings; at least one ring is an aromatic ring; and wherein the structure comprises at least 3 nitrogen atoms and 1 oxygen atom. It also relates to a process for their preparation, as well as to pharmaceutical compositions containing them, and to their use in medicine, in particular in the treatment and/or prevention of neurological disorders coursing with a cognition deficit or impairment, or neurodegenerative diseases. wherein B1 is a radical selected from the group consisting of formula (A"), formula (B"), formula (C"), and formula (D"):
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(2014/09/16)

Pyrazolopyrimidinone Compound and Imidazo Triazone Compound for Treating Erectile Dysfunction
Disclosed are selective phosphodiesterase inhibitor compounds shown in formula (I) or (II) for treating Erectile Dysfunction, the pharmaceutically acceptable salts and configurational isomers thereof. In the formula, the substituents R1, R2, R3, R4 and R5are defined as in the specification. Also disclosed are a medical composition comprising compounds of formula (I) or (II), and the use of these compounds for preparing a drug treating or preventing male Erectile Dysfunction.
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Paragraph 0044; 0045

(2014/02/16)

PYRAZOLOPYRIMIDINONE COMPOUND AND IMIDAZO-TRIAZONE COMPOUND FOR TREATING ERECTILE DYSFUNCTION
Disclosed are selective phosphodiesterase inhibitor compounds shown in formula (I) or (II) for treating Erectile Dysfunction, the pharmaceutically acceptable salts and configurational isomers thereof. In the formula, the substituents R1, R2, R3, R4 and R5 are defined as in the specification. Also disclosed are a medical composition comprising compounds of formula (I) or (II), and the use of these compounds for preparing a drug treating or preventing male Erectile Dysfunction.
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Paragraph 0022; 0023

(2014/01/07)

COMPOUND FOR INHIBITING TYPE 5 PHOSPHODIESTERASE AND PREPARATION METHOD THEREOF
The present invention discloses a compound of formula (I) and citrate thereof as type 5 phosphodiesterase inhibitor, a preparation method thereof, and a pharmaceutical composition including the compound of formula (I) and citrate thereof. The experimental results of the present invention prove that the compound of formula (I) and citrate thereof can inhibit activity of type 5 phosphodiesterase, and can be used for treating erectile dysfunction, inhibiting platelet aggregation and treating thrombosis, decreasing pulmonary hypertension and treating cardiovascular diseases, treating asthma and treating diabetes gastroparesis.
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Paragraph 0030; 0031

(2013/05/21)

COMPOUND FOR INHIBITING TYPE 5 PHOSPHODIESTERASE AND PREPARATION METHOD THEREOF
The present invention discloses a compound of formula (I) and citrate thereof as type 5 phosphodiesterase inhibitor, a preparation method thereof, and a pharmaceutical composition including the compound of formula (I) and citrate thereof. The experimental results of the present invention prove that the compound of formula (I) and citrate thereof can inhibit activity of type 5 phosphodiesterase, and can be used for treating erectile dysfunction, inhibiting platelet aggregation and treating thrombosis, decreasing pulmonary hypertension and treating cardiovascular diseases, treating asthma and treating diabetes gastroparesis.
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Paragraph 0019; 0030; 0031

(2013/05/22)

Synthesis, spectral studies and biological activity of novel 1H-1,4-diazepine derivatives
Sulphonation of 5-(2-ethoxyphenyl)-l-methyl-3-propyl-l,6-dihydro-7H- pyrazolo[4,3-d] pyrimidin-7-one 1 with chlorosulphonic acid affords 5-[(5-chlorosulphonyl-2-ethoxy) phenyl]-l-methyl-3-propyl-l,6-dihydro-7H- pyrazolo[4,3-d] pyrimidin-7-one 2. Further, compound 2 is condensed with different β-diketones/β-ketoesters 3a-e, to obtain new βdiketones/β-ketoesters 4a-e. The synthesized new β-diketones/ β-ketoesters and ethylenediamine (EDA) gives biologically active lH-l,4-diazepines 5a-e. All the newly synthesized compounds are characterized by elemental analysis and spectral studies. The compounds 5a-e have been screened for antimicrobial, antifungal and anthelmintic activity.
Kumar, Rajesh,Joshi, Yogesh C.
experimental part
p. 84 - 88
(2010/04/26)

Synthesis and pharmacological evaluations of sildenafil analogues for treatment of erectile dysfunction
The 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1-methyl-3- propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, sildenafil, is a cGMP-specific phosphodiesterase-5 (PDE5) inhibitor used for penile erectile dysfunction. In the search for more potent and selective PDE5 inhibitors, new sildenafil analogues (6a-v), characterized by the presence on the sulfonyl group in the 5′ position of novel N-4-substituted piperazines or ethylenediamine moiety, were prepared by traditional and microwave-assisted synthesis and tested in rabbit isolated aorta and corpus cavernosum. Similarly to sildenafil, several analogues showed IC50 values in the nanomolar range. In the in vitro studies, all the tested compounds caused concentration-dependent relaxations in both rabbit isolated aorta and corpus cavernosum. All sildenafil analogues potentiated the nitric oxide-dependent vasodilation in endothelium-intact rabbit aorta. Compound 6f exhibited great pEC50 value in corpus cavernosum, and compounds 6r and 6u in isolated aorta were found as potent as sildenafil for inhibiting PDE5. Because several analogues were significantly more lipophilic than sildenafil, these compounds may offer a new lead for development of new sildenafil analogues.
Flores Toque, Haroldo A.,Priviero, Fernanda B. M.,Teixeira, Cleber E.,Perissutti, Elisa,Fiorino, Ferdinando,Severino, Beatrice,Frecentese, Francesco,Lorenzetti, Raquel,Baracat, Juliana S.,Santagada, Vincenzo,Caliendo, Giuseppe,Antunes, Edson,De Nucci, Gilberto
p. 2807 - 2815
(2008/12/22)

A highly efficient synthesis of 3H-1,5-benzodiazepine derivatives using lanthanum(III) nitrate hexahydrate as a catalyst
Sulphonation of 5-(2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one (1) with chlorosulphonic acid affords 5-[(5-chlorosulphonyl-2-ethoxy)pyrimidin]-1-methyl-3-propyl-1, 6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (2). Compound (2) condensed with different β-diketones/β-ketoesters (3a-e) to obtain new β-diketones/β-ketoesters (4a-e). These β-diketones/β- ketoesters were condensed with o-phenylenediamine (o-PDA) in presence of lanthanum(III) nitrate hexahydrate to afford biologically active 3H-1,5-benzodiazepines (5a-e) in excellent yield. The compounds (5a-e) have been screened for antimicrobial, antifungal and anthelmintic activities.
Kumar, Rajesh,Joshi
experimental part
p. 1045 - 1049
(2010/03/03)

Method of treating a patient having precancerous lesions with phenyl purinone derivatives
Derivatives of Phenyl Purinone are useful for the treatment of patients having precancerous lesions. These compounds are also useful to inhibit growth of neoplastic cells.
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(2008/06/13)

PYRAZOLOPYRIMIDINONE ANTIANGINAL AGENTS
Compounds of the formula:wherein R1 is H, C1-C3 alkyl, C3-C5 cycloalkyl or C1-C3 perfluoroalkyl; R2 is H, C1-C6 alkyl optionally substituted by OH, C1-C3 alkoxy or C3-C6 cycloalkyl, or C1-C3 perfluoroalkyl; R3 is C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C7 cycloalkyl, C1-C6 perfluoroalkyl or (C3 -C6 cycloalkyl)C1-C6 alkyl; R4 taken together with the nitrogen atom to which it is attached completes a pyrrolidinyl, piperidino, morpholino, or 4-N-(R6)-piperazinyl group; R5 is H, C1-C4 alkyl, C1-C3 alkoxy, NR7 R8, or CONR7 R8 ; R6 is H, C1-C6 alkyl, (C1-C3 alkoxy) C2-C6 alkyl, hydroxy C2-C6 alkyl, (R7 R8 N)C2 -C6 alkyl, (R7 R8 NCO)C1-C6 alkyl, CONR7 R8, CSNR7 R8 or C(NH)NR7 R8 ; R7 and R8 are each independently H, C1-C4 alkyl, (C1-C3 alkoxy)C2-C4 alkyl or hydroxy C2-C4 alkyl; and pharmaceutically acceptable salts thereof, are selective cGMP PDE inhibitors useful in the treatment of cardiovascular disorders such as angina, hypertension, heart failure and atherosclerosis
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(2008/06/13)