- Development of a Practical Process for the Synthesis of PDE4 Inhibitors
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A practical, safe, and efficient process for the synthesis of PDE4 (phosphodiesterase type 4) inhibitors represented by 1 and 2 was developed and demonstrated on a multi-kilogram scale. Key aspects of the process include the regioselective synthesis of dihydrothieno[3,2-d]pyrimidine-2,4-diol 9 and the asymmetric sulfur oxidation of intermediate 11.
- Frutos, Rogelio P.,Tampone, Thomas G.,Mulder, Jason A.,Rodriguez, Sonia,Yee, Nathan K.,Yang, Bing-Shiou,Senanayake, Chris H.
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p. 982 - 988
(2016/06/09)
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- NOVEL PIPERIDINO-DIHYDROTHIENOPYRIMIDINE SULFOXIDES AND THEIR USE FOR TREATING COPD AND ASTHMA
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Piperidino-dihydrothienopyrimidine sulfoxides of formula I wherein: Ring A is a 6-membered aromatic ring optionally comprising one or two nitrogen atoms andR is Cl and is located in the para-, meta-, or ortho-position of Ring A,S* is a sulphur atom that represents a chiral center, and all pharmaceutically acceptable salts, enantiomers and racemates, hydrates and solvates thereof and the use of these compounds for the treatment of inflammatory or allergic diseases of the respiratory tract such as COPD or asthma.
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Paragraph 0073-0074
(2015/02/25)
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- SPECIFIC PDE4B-INHIBITORS FOR THE TREATMENT OF DIABETES MELLITUS
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A method of treating diabetes mellitus or a microvascular or macrovascular complication of diabetes mellitus in a patient in need thereof, the method comprising administering to the patient a compound of formula 1 wherein R1, R2, R3, and R4 are as defined in claim 1.
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Paragraph 0240-0241
(2014/08/19)
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- SPECIFIC PDE4B-INHIBITORS FOR THE TREATMENT OF DIABETES MELLITUS
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The invention relates to compounds of formula 1 for their use for the treatment of diabetes mellitus or for the treatment of a microvascular or macrovascular complication of diabetes mellitus wherein R1, R2, R3 and R4 are defined as summarized in claim 1. Further the invention relates to the use of compounds of the above formula 1 for the manufacture of a medicament for the treatment of diabetes mellitus or for the treatment of a microvascular or macrovascular complication of diabetes mellitus.
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Page/Page column 41; 42
(2014/09/03)
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- MORPHOLINO SUBSTITUTED BICYCLIC PYRIMIDINE UREA OR CARBAMATE DERIVATIVES AS MTOR INHIBITORS
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The invention relates to compounds of formula (I) wherein m, o, Ra, Rb, R1 and T1 have the meaning as cited in the description and the claims. Said compounds are useful as inhibitors of mTOR for the treatment or prophylaxis of mTOR related diseases and disorders. The invention also relates to pharmaceutical compositions including said compounds, the preparation of such compounds as well as the use as medicaments
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Page/Page column 42; 55
(2013/04/24)
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- NOVEL PIPERIDINO-DIHYDROTHIENOPYRIMIDINE SULFOXIDES AND THEIR USE FOR TREATING COPD AND ASTHMA
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The invention relates to novel piperidino-dihydrothienopyrimidine sulfoxides of formula I, wherein Ring A is a 6-membered aromatic ring which may optionally comprise one or two nitrogen atoms and wherein R is CI and wherein R may be located either in the para-, meta- or ortho-position of Ring A, wherein S* is a sulphur atom that represents a chiral center, and all pharmaceutically acceptable salts, enantiomers and racemates, hydrates and solvates thereof and the use of these compounds for the treatment of inflammatory or allergic diseases of the respiratory tract such as COPD or asthma.
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Page/Page column 22-23
(2013/03/26)
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- PREPARATION OF DIHYDROTHIENO [3, 2-D] PYRIMIDINES AND INTERMEDIATES USED THEREIN
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The invention relates to improved methods of preparing dihydrothienopyrimidines of formula 1, and intermediates thereof,(I) wherein X is SO or SO2, preferably SO, and wherein RA, R1, R2, R3, R4and R5 have the meanings given in the description. The methods according to this invention are more suitable for large-scale synthesis of said compounds than prior methods because the new synthetic process avoids distillation and chromatographic purification between steps and results in a higher overall yield of the desired product.
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Page/Page column 65-66
(2009/05/28)
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- N-Hydroxyamides Omege-Substituted with Tricyclic Groups as Histone Deacetylase Inhibitors, Their Preparation and Use in Pharmaceutical Formulations
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New N-hydroxyamides of n-alkyl carboxylic acids omega substituted with suitable tricyclic systems characterised by a central 7-membered ring, having activity as inhibitors of histone deacetylase (HDAC).
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Page/Page column 9
(2008/12/08)
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- N-HYDROXYAMIDES OMEGA-SUBSTITUTED WITH TRICYCLIC GROUPS AS HISTONE DEACETYLASE INHIBITORS, THEIR PREPARATION AND USE IN PHARMACEUTICAL FORMULATIONS
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New N-hydroxyamides of n-alkyl carboxylic acids omega substituted with suitable tricyclic systems characterised by a central 7-membered ring, having activity as inhibitors of histone deacetylase (HDAC).
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Page/Page column 24-25
(2010/11/23)
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- 2-Phenyl-5,6-dihydro-2H-thieno[3,2-c]pyrazol-3-ol derivatives as new inhibitors of bacterial cell wall biosynthesis
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Twenty-five 2-phenyl-5,6-dihydro-2H-thieno[3,2-c]pyrazol-3-ol derivatives were synthesized for evaluation as new inhibitors of bacterial cell wall biosynthesis. Many of them demonstrated good inhibitory activity against Staphylococcus aureus MurB, MurC and MurD enzymes in vitro and antimicrobial activity against gram-positive bacteria including MRSA, VRE and PRSP. However, when they were tested in the presence of 4% bovine serum albumin, the MIC values increased to greater than 128 μg/mL against PRSP. None of the compounds demonstrated activity against gram-negative bacteria at MIC 32 μg/mL.
- Li, Zhong,Francisco, Gerardo D.,Hu, William,Labthavikul, Pornpen,Petersen, Peter J.,Severin, Anatoly,Singh, Guy,Yang, Youjun,Rasmussen, Beth A.,Lin, Yang-I,Skotnicki, Jerauld S.,Mansour, Tarek S.
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p. 2591 - 2594
(2007/10/03)
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- Regioselective titanium tetrachloride mediated five membered hetero-cyclisations
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Highly regioselective titanium IV mediated, Dieckmann type cyclisation in the synthesis of 5-membered nitrogen and sulfur heterocycles is described.
- Deshmukh,Gangakhedkar,Sampath Kumar
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p. 1657 - 1661
(2007/10/03)
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- Free Radical Ring-Expansion Leading to Novel Six- and Seven-Membered Heterocycles
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Free radical promoted ring-expansion of nitrogen-, oxygen- and sulfur-containing heterocyclic β-keto esters is described.Treatment of the derived phenylselenomethyl derivatives with tri-n-butyltin hydride leads to smooth one-carbon ring expansion.
- Dowd, Paul,Choi, Soo-Chang
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p. 4847 - 4860
(2007/10/02)
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- Process for preparing 2- and 4-alkoxycarbonyl thiolan-3-ones
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The invention concerns a process for preparing 2- and 4-alkoxycarbonylthiolan-3-ones useful as intermediates, which process involves cyclising a 3-akloxycarbonylmethylthiopropanoic acid ester using lithium alkoxide. Novel lithium salts are also included.
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- Thio-sugars. Part 10. The Nucleoside from 5-Fluoroacil and 2-Amino-2,3-dideoxy-4-thio-DL-glycero-tetrofuranose and Related Compounds
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Another molecular combination of a chloroethylnitrosourea and a pyrimidine antimetabolite (5-fluorouracil) linked through a sugar or sugar-like moiety has been synthesised for biological testing.In this case 2-amino-2,3-dideoxy-4-thio-DL-glycero-tetrofuranose was derived from thiolan-3-one, nitrogen being introduced as azide in preference to the route involving oxime and phthalimide.Some derivatives of 3-amino-3-deoxy-4-thio-DL-erythrofuranose were prepared from trans-4-aminothiolan-3-ol, inverted by way of a fused oxazoline, but although a (5-iodouracil) nucleoside ester was obtained it proved difficult to remove the protecting groups.
- Jones, John O.,McElhinney, R. Stanley
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p. 1501 - 1517
(2007/10/02)
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- An improved procedure for the preparation of 3-carbomethoxy-4-oxotetrahydrothiopyran, 2- and 4-carbomethoxy-3-oxotetrahydrothiophene
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An improved procedure for the preparation of the title compounds 1-3 has been developed.Direct condensation of methyl 3-mercaptopropionate with methyl acrylate using sodium hydride as a base gave compound 1 in good yield.The reaction of methyl thioglycolate and methyl acrylate at 0 degC gave compound 2 as the major product whereas at lower temperature (-40 degC) isomer 3 was found as the major product.The condensation reactions of methyl thioglycolate with methyl metacrylate and crotonate were also carried out.
- Liu, Hsing-Jang,Ngooi, Teng Ko
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p. 437 - 439
(2007/10/02)
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- A DIRECTION CONTROLLED DIECKMANN TYPE CYCLIZATION OF HALF-THIOL DIESTERS
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A direction controlled Dieckmann type cyclization was performed on treatment of the half-thiol diesters(1) with base to give exclusively the β-keto esters(2).
- Yamada, Yasuji,Ishii, Toshihide,Kimura, Masayuki,Hosaka, Kunio
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p. 1353 - 1354
(2007/10/02)
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- Anesthesia methods using benzopyrans and esters thereof as pre-anesthesia medication
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Improved anesthesia methods comprising pretreating a patient to be anesthetized with a benzopyran of formula I STR1 wherein, in the C ring, X is NR1, S, CH2 or STR2 R1 is hydrogen, loweralkyl, loweralkenyl, loweralkynyl, loweralkanoyl, cycloalkyloweralkyl, cycloalkylloweralkanoyl, cycloalkyl, haloloweralkyl, haloloweralkenyl, phenylloweralkyl, phenyloweralkenyl or phenyloweralkylnyl; m is an integer from 0 to 3, n is an integer from 0 to 3 and n + m = 2 or 3; or the C ring is quinuclidine ring STR3 R2 is loweralkyl; R3 is hydrogen or STR4 wherein Y is a straight or branched chain alkylene group having from one to eight carbon atoms, a is an integer from 1 to 4, b is an integer from 1 to 4, Z is CH2, O, S or NR6, R6 being hydrogen or loweralkyl, with the limitation that when Z is O, S or NR5, the sum of a and b is 3 or 4, and R5 is hydrogen or loweralkyl; R4 is C1 -C20 straight or branched chain alkyl, cycloalkyl, or STR5 wherein Y is a straight or branched chain alkylene group having from one to ten carbon atoms, and each R7, R8 and R9 are the same or different members of the group consisting of hydrogen, halo, trifluoromethyl or loweralkyl; and the pharmaceutically acceptable salts thereof, with the limitation that when X is STR6 m = 2 and n = 2, R3 cannot be hydrogen.
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- Esters of thienobenzopyrans and thiopyranobenzopyrans
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Novel thienobenzopyran and thiopyranobenzopyran esters represented by the formula SPC1 Wherein n is 0 to 3 and m is 0 to 3 and m + n = 2 or 3, R1 is lower alkyl, R2 is alkyl or cycloalkyl-lower alkyl, R4 is hydrogen or lower alkyl, R5 is hydrogen or lower alkyl, and R3 is EQU1 wherein Y is a straight or branched chain C1 to C8 alkylene, R6 is hydrogen or a lower alkyl, a is an integer from 1 to 4, b is an integer from 1 to 4, X is CH2, O, S or NR7 wherein R7 is hydrogen or lower alkyl, with the limitation that when X is O, S or NR7, a and b each must be 2; and the acid addition salts thereof.
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- Method of treating hypertension with, and compositions useful therein containing, a 4H-thieno[2,3-c][1]benzopyran or a 3H,5H-thiopyrano[2,3-c][1]
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A method of reducing blood pressure in a hypertensive mammalian patient by administering 1,2-dihydro-4,4-dimethyl-9-hydroxy-7-(3-methyl-2-octyl)-4H-thieno[2,3-c][1]benzopyran or 1,2-dihydro-5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-3H,5H-thiopyrano-8 2,3-c][1]benzopyran. Pharmaceutical compositions containing 1,2-dihydro-4,4-dimethyl-9-hydroxy-7-(3-methyl-2-octyl)-4H-thieno[2,3-c][1]benzopyran or 1,2-dihydro-5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-3H,5H-thiopyrano[2,3-c][1]benzopyran dispersed in a pharmaceutical carrier.
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