Brevetti
Ital. Appl. (1992), IT 91MI0347 A1 19920812
Preparation of 1-β-ribofuranosylpyrazole derivatives and their pharmacological application
Baraldi, Pier Giovanni; Bazzanini, Rita; Guarneri, Mario; La Colla, Paolo; Manfredini, Stefano; Marongiu, Maria Elena; Pani, Alessandra; Simoni, Daniele
The invention relates to 1-β-ribofuranosylpyrazole derivs. I (R1 = H, Me, t-Bu; R2 = Br, iodo, NO2; R3 = H, Me), including their prepn. and use for the treatment of neoplasia characterized by the proliferation of lymphocyte T and diseases caused by ...
The invention relates to 1-β-ribofuranosylpyrazole derivs. I (R1 = H, Me, t-Bu; R2 = Br, iodo, NO2; R3 = H, Me), including their prepn. and use for the treatment of neoplasia characterized by the proliferation of lymphocyte T and diseases caused by the coxsackie B1 virus. Thus, I (R1 = R3 = H, R2 = Br) was prepd. by treating tribenzoyl-β-ribofuranosyl acetate with 4-bromopyrazole-3-carboxamide in acetonitrile in the presence of hexamethyldisilazane, ammonium sulfate, Me3SiCl, and CF3SO3H. Cytostatic and antiviral activities are tabulated for compds. I.
MOSTRA DI PIU'
Brevetti
Ital. Appl. (1994), IT 92MI1913 A1 19940205
Preparatioon of heterocyclic analogs of pyrrolo[1,4]benzodiazepine with antitumor activity and pharmaceutical compositions containing them
Baraldi, Pier Giovanni; Leoni, Alberto
The invention is related to the prepn. of (un)substituted pyrrolobenzodiazepines in which the benzenoid ring is replaced with a 5-6 membered arom. heterocyclic ring selected from pyridine, pyrazine, pyrimidine, pyridazine, imidazole, thiophene and is...
The invention is related to the prepn. of (un)substituted pyrrolobenzodiazepines in which the benzenoid ring is replaced with a 5-6 membered arom. heterocyclic ring selected from pyridine, pyrazine, pyrimidine, pyridazine, imidazole, thiophene and isothiophene, e.g., (11aS)-7,9-dimethoxy-5H-pyrrolo[2,1-c]pyrimido[5,4-e][1,4]diazepin-5-one (I), as antitumor agents and their pharmaceutical compns. Thus, esterification of 5-nitroorotic acid potassium salt with MeOH, chlorination of Me 5-nitrouracil-6-carboxylate with POCl3, reaction of Me 2,4-dichloro-5-nitropyrimidine-6-carboxylate with NaOMe and sapon. of Me 2,4-dimethoxy-5-nitropyrimidine-6-carboxylate gave 2,4-dimethoxy-5-nitropyrimidine-6-carboxylic acid. Treatment of the resulting acid with (COCl)2, reaction of the acid chloride with (2S)-pyrrolidine-2-carboxyaldehyde di-Et thioacetal (II) in tHF in the presence of TEA, redn. of the nitro amide N-(2,4-dimethoxy-5-nitropyrimidin-6-yl)-(2S)-pyrrolidine-2-carboxaldehyde diethylthioacetal (III) with SnCl2.bul.2H2O in MeOH at reflux, deprotection/cyclization of the amino thioacetal N-(2,4-dimethoxy-5-aminopyrimidin-6-yl)-(2S)-pyrrolidine-2-carboxyaldehyde Diethylthioacetal with HgCl2/CaCO3 in MeCN/H2O (4:1), reaction of the carbinol amine (11RS,11aS)-7,9-dimethoxy-11-hydroxy-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c ]pyrimido[5,4-e][1,4]diazepin-5-one (IV) with MeOH at room temp. for 24 h, preparative HPLC sepn. of V into diastereomers and vacuum treatment (0.1 Torr) of (11S,11aS)-V at room temp. for 6 h gave I. The compds. of the invention displayed a strong cytotoxic activity in vitro against rat and human cancer cells of solid and liq. cancers, a low acute toxicity and good therapeutic index.
MOSTRA DI PIU'
Brevetti
PCT Int. Appl. (1995), WO 9501356 A1 19950112
Preparation of 1,2,4-triazolo[1,5-c]pyrimidines as adenosine A2 receptor antagonists
Baraldi, Pier Giovanni; Zappaterra, Laura; Ongini, Ennio
Title compds. [I; A = atoms to complete a pyrazole, imidazole, or triazole ring; R = H, (cyclo)alkyl, alkenyl, aryl(alkyl), etc.; R1 = NH2] were prepd. Thus, 1-(2-phenylethyl)-4-cyano-5-aminopyrazole (prepn. given) was condensed with HC(OEt)3 and th...
Title compds. [I; A = atoms to complete a pyrazole, imidazole, or triazole ring; R = H, (cyclo)alkyl, alkenyl, aryl(alkyl), etc.; R1 = NH2] were prepd. Thus, 1-(2-phenylethyl)-4-cyano-5-aminopyrazole (prepn. given) was condensed with HC(OEt)3 and the product cyclocondensed with 2-furoic acid hydrazide to give title compd. II (R1 = H) which was ring opened and the product cyclocondensed with NCNH2 to give II (R1 = NH2). The latter had Ki of 123 and 2.4nM for binding at adenosine A1 and A2 receptors in vitro, resp.
MOSTRA DI PIU'
Brevetti
Brit. UK Pat. Appl. (1996), GB 2300857 A 19961120.
Preparation of pyrrolo[3,2-c]indazoles and analogs as antitumor agents
Cozzi, Paolo; Baraldi, Pier Giovanni; Beria, Italo; Capolongo, Laura; Spalluto, Giampiero
Title compds. [e.g., I; R1 = H, alkyl, alkanoyl, alkylcarbamoyl, etc.; R2 = halo; R3,R4 = H or alkyl; R5 = H, COR7, (aryl)hydrocarbyl, etc.; R7 = (aryl)hydrocarbyl, alkoxy, etc.; Z = N or CR; R = H or alkyl] were prepd. as antitumor agents (no data)....
Title compds. [e.g., I; R1 = H, alkyl, alkanoyl, alkylcarbamoyl, etc.; R2 = halo; R3,R4 = H or alkyl; R5 = H, COR7, (aryl)hydrocarbyl, etc.; R7 = (aryl)hydrocarbyl, alkoxy, etc.; Z = N or CR; R = H or alkyl] were prepd. as antitumor agents (no data). Thus, 4-formyl-3-methylpyrazole (prepn. given) was converted in 15 steps to title compd. II.
MOSTRA DI PIU'
Brevetti
PCT Int. Appl. (1996), WO 9640704 A1 19961219.
Preparation of pyrazole nucleosides as antitumors and antivirals
La Colla, Paolo; Manfredini, Stefano; Simoni, Daniele; Baraldi, Pier Giovanni; Pani, Alessandra
Pyrazole-nucleosides I wherein R is COOH, COOR', and R' is a C1-C5 alkyl radical; R1 is iodo, Br, Cl, F, CF3, CN, SCN, CHO, CH=CH2, CH=CH Br, C≡C-Si(cH3)3, CH=CH COOCH2CH3, C≡CH, CH2=CH NO2; X = (CH2)n, n is 0 or 1; R2 is H, CH2OH, CH2 OcOPh, CH2...
Pyrazole-nucleosides I wherein R is COOH, COOR', and R' is a C1-C5 alkyl radical; R1 is iodo, Br, Cl, F, CF3, CN, SCN, CHO, CH=CH2, CH=CH Br, C≡C-Si(cH3)3, CH=CH COOCH2CH3, C≡CH, CH2=CH NO2; X = (CH2)n, n is 0 or 1; R2 is H, CH2OH, CH2 OcOPh, CH2O Si(CH3)2C(cH3)3, CH2OPO3 Na2, CH2OPO[OcH2O-COC(CH3)3]2, CH2OPO[O CH2 CH2 SCOC(CH3)3]2; R3 and R4 equal or different from each other are H, OH, CH2 OCOPh, CH2O Si(CH3)2C(CH3)3, or they form together an isopropylidene group, provided that when R2 = R3 = R4 = H n is always 1. These compds. are endowed with antitumor and are able to enhance antiviral activity of known antiviral agents. The procedures for prepn. of compd. of formula I and of pharmaceutical formulations contg. them are also reported. Thus, Me 4-iodo-1-β-D-ribofuranosylpyrazole-3-carboxylate was prepd. and showed antiproliferative activity with IC50 between 0.2 and 8.6 μM and cytotoxicity in human cells with cytotoxic concn. CC50 between 1.5 and 500 μM.
MOSTRA DI PIU'
Brevetti
PCT Int. Appl. (1996), WO 9638728 A1 19961205
A method for measuring the adenosine A2a receptor binding activity of compounds of pharmacological interest by the use of the tritiated ligand [3H]-SCH 58261
Zocchi, Cristina; Baraldi, Pier Giovanni; Cacciari, Barbara; Dionisotti, Silvio; Ongini, Ennio
The invention relates to a method for evaluating the adenosine A2a receptor binding affinity of compds. of pharmacol. interest. Moreover, the invention relates to reagents and a kit particularly suitable for the above mentioned purpose. Tritiation ...
The invention relates to a method for evaluating the adenosine A2a receptor binding affinity of compds. of pharmacol. interest. Moreover, the invention relates to reagents and a kit particularly suitable for the above mentioned purpose. Tritiation of SCH 58261 is described, as are results of binding competition expts.
MOSTRA DI PIU'
Brevetti
PCT Int. Appl. (1997), WO 9705138 A1 19970213.
Preparation of 1,2,4-triazolo[1,5-c]pyrimidine heterocyclic analogs having antagonistic activity on adenosine A2a receptor
Baraldi, Pier Giovanni; Cacciari, Barbara; Viziano, Monica; Dionisotti, Silvio; Ongini, Ennio
The title compds. [I; A = fused pyrazole, imidazole or triazole ring, R = II (wherein R1, R2 = H, OH, halo, etc.); moreover the OH group, together with one of R1 or R2, or R1 and R2, can form the methylenedioxy group OCH2O; n = 0-4], useful as therap...
The title compds. [I; A = fused pyrazole, imidazole or triazole ring, R = II (wherein R1, R2 = H, OH, halo, etc.); moreover the OH group, together with one of R1 or R2, or R1 and R2, can form the methylenedioxy group OCH2O; n = 0-4], useful as therapeutical agents, were prepd. Thus, treatment of 5-amino-7-[β-(4-benzyloxy)phenylethyl]-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine with HCOONH4 and 10% Pd/C in THF afforded 41% the title compd. III. A no. of compds. I showed a marked A2a affinity with Ki of 1-10 nM.
MOSTRA DI PIU'
Brevetti
PCT Int. Appl. (1998), WO 9821202 A1 19980522.
Preparation of benzoheterocyclic distamycin derivatives and their use as antitumor and antiviral agents
Cozzi, Paolo; Baraldi, Pier Giovanni; Beria, Italo; Caldarelli, Marina; Capolongo, Laura; Spalluto, Giampiero; Romagnoli, Romeo
Benzoheterocyclic distamycin derivs. I [n = 2, 3, 4; A = O, S, NR with R = H, C1-C4 alkyl; B = CH, N; R1 = H, C1-C4 alkyl; T = aminobenzamido deriv., X2C(:CH2)CONH with X2 = halo], useful as antineoplastic and antiviral agents (no data), were prepd. ...
Benzoheterocyclic distamycin derivs. I [n = 2, 3, 4; A = O, S, NR with R = H, C1-C4 alkyl; B = CH, N; R1 = H, C1-C4 alkyl; T = aminobenzamido deriv., X2C(:CH2)CONH with X2 = halo], useful as antineoplastic and antiviral agents (no data), were prepd. E.g., reaction of N-deformyldistamycin A dihydrochloride with 5-N,N-bis(2-chloroethyl)aminoindole-2-carboxylic acid in presence of diisopropylethylamine and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide gave 3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[5-N,N-bis(2-chloroethyl)aminoindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride.
MOSTRA DI PIU'
Brevetti
PCT Int. Appl. (1999), WO 9921617 A2 19990506.
Preparation of thienylmethanones as allosteric adenosine receptor modulators
Baraldi, Pier Giovanni
Title compds. [I, II, III; R1 is hydrogen, alkyl, haloacetyl; R2, R3, R4 are independently hydrogen, halogen, alkyl, aryl, heteroaryl, heterocyclic, alkenyl, nitro, cyano; m is 0-3; Z is NH, NCXNH-aryl, NCXOalkyl, etc.; X is O, S, N-alkyl; R5 and R6 ...
Title compds. [I, II, III; R1 is hydrogen, alkyl, haloacetyl; R2, R3, R4 are independently hydrogen, halogen, alkyl, aryl, heteroaryl, heterocyclic, alkenyl, nitro, cyano; m is 0-3; Z is NH, NCXNH-aryl, NCXOalkyl, etc.; X is O, S, N-alkyl; R5 and R6 are independently hydrogen, alkyl, or taken together form a lower alkenyl ring; R7 is hydrogen, alkyl, etc.; Y is nitrogen CH, CCN, etc.] prepn. as well as pharmaceutical formulations thereof and their use in medicine as allosteric adenosine receptor modulators for uses including protection against hypoxia and ischemia induced injury and treatment of adenosine-sensitive cardiac arrhythmias are discussed. Thus, compd. I (Z = NCH2CH2Ph; R1 = H; R2 = H; R3 = Cl; R4 = H; m = 1) were prepd.
MOSTRA DI PIU'
Brevetti
PCT Int. Appl. (1999), WO 9906053 A1 19990211,
Preparation of N6-substituted-adenosine-5'-uronamides as adenosine receptor modulators
Baraldi, Pier G.
A series of adenosine-5'-uronamides I (R = H, alkyl, substituted alkyl, alkaryl, aryl; R1 = acyl, amide; R2 = H, alkyl, substituted alkyl, alkaryl, acyl, amide; R3, R4 = independently OH, H, halo, ether, alkaryl, thio, thioester, amine, amide) bearin...
A series of adenosine-5'-uronamides I (R = H, alkyl, substituted alkyl, alkaryl, aryl; R1 = acyl, amide; R2 = H, alkyl, substituted alkyl, alkaryl, acyl, amide; R3, R4 = independently OH, H, halo, ether, alkaryl, thio, thioester, amine, amide) bearing N6-arylurea, alkarylurea, heteroarylurea, arylcarbonyl, alkarylcarbonyl or heteroarylcarbonyl groups which have affinity and, in some cases, selectivity for the adenosine A1 or A3 receptors are disclosed. These compds. can be used in a pharmaceutical compn. to treat disorders caused by excessive activation of the A1 or A3 receptors, or can be used in a diagnostic application to det. the relative binding of other compds. to the A1 or A3 receptors. Thus, N6-(4-biphenyl-carbonylamino)-adenosine-5'-N-ethyluronamide was prepd. and tested for its binding activity with A1 or A3 receptors (Ki = 5.92-979 nM).
MOSTRA DI PIU'
Brevetti
PCT Int. Appl. (1999), WO 9950265 A1 19991007
Preparation of distamycin acryloyl derivatives as antitumor agents
Cozzi, Paolo; Baraldi, Pier Giovanni; Beria, Italo; Caldarelli, Marina; Capolongo, Laura; Romagnoli, Romeo
Distamycin acryloyl derivs. I [n = 2-4; m = 1 or 2; X, Y = N or CH, selected independently for each heterocyclic ring; R1, R2 = H, halo, alkyl; R3 = H, halo; B = C(NH2):NCN, C(NR4R5):NR6, C(NH2):NNH2, CONR7R8, NHC(NH2):NR9, NR10R11, C(NH2):NOR12, CN;...
Distamycin acryloyl derivs. I [n = 2-4; m = 1 or 2; X, Y = N or CH, selected independently for each heterocyclic ring; R1, R2 = H, halo, alkyl; R3 = H, halo; B = C(NH2):NCN, C(NR4R5):NR6, C(NH2):NNH2, CONR7R8, NHC(NH2):NR9, NR10R11, C(NH2):NOR12, CN; R4-8 and R10-12 are H or alkyl and R9 is H or OH] or their pharmaceutically acceptable salts were prepd. as antitumor agents. Thus, treatment of cyanamide with NaH in DMF, followed by addn. of distamycin A and hydrolysis of the formyl group with aq. HCl afforded an amino deriv., which was treated with 1-methyl-3-(α-bromoacrylamido)pyrrole-5-carbonyl chloride (prepn. given) to give I [n = 4, m = 1, X = Y = CH, R1 = R2 = H, R3 = Br, B = C(NH2):NCN].
MOSTRA DI PIU'
Brevetti
PCT Int. Appl. (1999), WO 9964413 A1 19991216,
Preparation of cinnamoyl distamycin analogs as antitumor agents
Cozzi, Paolo; Baraldi, Pier Giovanni; Beria, Italo; Caldarelli, Marina; Geroni, Maria Cristina; Pennella, Giulia; Romagnoli, Romeo
Cinnamoyl distamycin derivs. I [n = 2, 3, 4; R = alkyl, haloalkyl; R1, R2 = H, alkyl, fluoroalkyl, alkoxy; X = halo; Y, Z = N, CH (selected independently for each heterocyclic ring); B = 4,5-dihydro-2-imidazolyl, 1,4,5,6-tetrahydro-2-pyrimidinyl, -C(...
Cinnamoyl distamycin derivs. I [n = 2, 3, 4; R = alkyl, haloalkyl; R1, R2 = H, alkyl, fluoroalkyl, alkoxy; X = halo; Y, Z = N, CH (selected independently for each heterocyclic ring); B = 4,5-dihydro-2-imidazolyl, 1,4,5,6-tetrahydro-2-pyrimidinyl, -C(NH2):NCN, -C(NR4R5):NR3, -C(NH2):NOH, -NHC(NH2):NH, -CN, or -CONR6R7 (R3-R7 are H or alkyl)] or their pharmaceutically acceptable salts were prepd. as antitumor agents. Thus, 3-[1-methyl-3-[1-methyl-3-[1-methyl-4-[4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrazole-5-carboxamido]pyrazole-5-carboxamido]propionamidine was prepd. by acylation of 3-[1-methyl-3-[1-methyl-3-[1-methyl-4-aminopyrrole-2-carboxamido]pyrazole-5-carboxamido]pyrazole-5-carboxamido]propionamidine dihydrochloride with 4-N,N'-bis(2-chloroethyl)aminocinnamic acid.
MOSTRA DI PIU'
Brevetti
PCT Int. Appl. (1999), WO 9950266 A1 19991007,
Preparation of benzoheterocyclic distamycin derivatives as antitumor agents
Cozzi, Paolo; Baraldi, Pier Giovanni; Beria, Italo; Caldarelli, Marina; Capolongo, Laura; Romagnoli, Romeo
Benzoheterocyclic distamycin derivs. I [n = 2, 3, 4; A = O, S, NR, where R = H, alkyl; B = CH, N; R1 = H, alkyl; G = 2-imidazolyl or 4,5-dihydro-2-imidazolyl, 1,4,5,6-tetrahydro-2-pyrimidinyl, C(NH2):NCN, C(NR5R6):NR7, C(NH2):NNH2, CONR8R9, NHC(NH2):...
Benzoheterocyclic distamycin derivs. I [n = 2, 3, 4; A = O, S, NR, where R = H, alkyl; B = CH, N; R1 = H, alkyl; G = 2-imidazolyl or 4,5-dihydro-2-imidazolyl, 1,4,5,6-tetrahydro-2-pyrimidinyl, C(NH2):NCN, C(NR5R6):NR7, C(NH2):NNH2, CONR8R9, NHC(NH2):NH, NR10R11, C(NH2):NOR12, CN, where R5-12 are H or alkyl; T = aminobenzamido deriv., 2-haloacrylamido] or their pharmaceutically acceptable salts were prepd. as antitumor agents. Thus, reaction of N-deformyldistamycin A N,N'-dimethyl dihydrochloride with 5-α-bromoacrylamidobenzofuran-2-carboxylic acid (prepn. given) in presence of diisopropylethylamine and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide gave 3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[5-(α-bromoacrylamido)benzofuran-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N'-dimethylamidine hydrochloride.
MOSTRA DI PIU'
Brevetti
Brit. UK Pat. Appl. (2000), GB 2344818 A 20000621.
Preparation of thienoindoles as antitumor agents.
Beria, Italo; Cozzi, Paolo; Baraldi, Pier Giovanni; Spalluto, Giampiero; Geroni, Maria Cristina
Title compds. [I, II; R1 = H, alkyl, COR6; R6 = alkyl, (substituted) phenylalkyl; R2 = halo; R3, R4 = H, alkyl; R5 = H, (unsatd.) (substituted) aliph. hydrocarbon chain, COR7, etc.; R7 = alkoxy, (unsatd.) (substituted) aliph. hydrocarbon chain; R12R1...
Title compds. [I, II; R1 = H, alkyl, COR6; R6 = alkyl, (substituted) phenylalkyl; R2 = halo; R3, R4 = H, alkyl; R5 = H, (unsatd.) (substituted) aliph. hydrocarbon chain, COR7, etc.; R7 = alkoxy, (unsatd.) (substituted) aliph. hydrocarbon chain; R12R13 = R11C:CHS; R11 = H, alkyl], were prepd. as neoplasm inhibitors (no data). Thus, 3-methyl-4-chloromethyl-8-hydroxy-4,5-dihydrothieno[3,2-e]indole hydrochloride (prepn. given) in THF/DMF was treated with NaH followed by stirring at 0°-room temp. to give 70% 7-methyl-1,2,8,8a-tetrahydrocyclopropa[c]thieno[3,2-e]indol-4-one hydrochloride.
MOSTRA DI PIU'
Brevetti
PCT Int. Appl. (2000), WO 2000015231 A1 20000323.
1,2,4-Triazolo[1,5-c]pyrimidine adenosine A3 receptor modulators, preparation thereof, and therapeutic and diagnostic use255
Baraldi, Pier Giovanni; Borea, Pier Andrea
The title compds. (Markush included), which have selective A3 adenosine receptor agonist activity, are provided. These compds. can be used in a pharmaceutical compn. to treat disorders caused by excessive activation of the A3 receptor, or can be use...
The title compds. (Markush included), which have selective A3 adenosine receptor agonist activity, are provided. These compds. can be used in a pharmaceutical compn. to treat disorders caused by excessive activation of the A3 receptor, or can be used in a diagnostic application to det. the relative binding of other compds. to the A3 receptor. The compds. can be labeled, for example with fluorescent or radiolabels, and the labels used in vivo or in vitro to det. the presence of tumor cells which possess a high concn. of adenosine A3 receptors.
MOSTRA DI PIU'
Brevetti
U.S. (2001), US 6323214 B1 20011127.
Preparation of thienylmethanones as allosteric adenosine receptor modulators
Baraldi, Pier Giovanni
The title compds. [I-III; R1 = H, alkyl, haloacetyl; R2-R4 = H, halo, alkyl, etc.; m = 0-3; Z = NH, NCXNHaryl, NCXOalkyl, etc.; X = O, S, Nalkyl; R5, R6 = H, alkyl, or taken together form a lower alkenyl ring; R7 = H, alkyl, etc.; Y = N, CH, CCN, etc...
The title compds. [I-III; R1 = H, alkyl, haloacetyl; R2-R4 = H, halo, alkyl, etc.; m = 0-3; Z = NH, NCXNHaryl, NCXOalkyl, etc.; X = O, S, Nalkyl; R5, R6 = H, alkyl, or taken together form a lower alkenyl ring; R7 = H, alkyl, etc.; Y = N, CH, CCN, etc.], useful in medicine as allosteric adenosine receptor modulators for uses including protection against hypoxia and ischemia induced injury and treatment of adenosine-sensitive cardiac arrhythmias, were prepd. and formulated. E.g., a 3-step synthesis of I [R1-R4 = H; Z = NR; R = benzyloxycarbonyl; t = 1] was described. Data for biol. activity of compds. I-III were given.
MOSTRA DI PIU'
Brevetti
U.S. Pat. Appl. Publ. (2001), US 20010047008 A1 20011129.
Preparation of acyl-amino-(fused)thiophenes as allosteric adenosine receptor modulators
Baraldi, Pier Giovanni
A method for cardioprotection, neuroprotection, pain management, etc. using compds. of formulas I and II [R1 = (un)substituted pyrrole, furan, thiophene, Ph, etc.; R2 = H, C(O); R3-4 = H, alk(en/yn)yl, aryl, halo, OH, etc.; A, B = O, S, aza; m, n = 0...
A method for cardioprotection, neuroprotection, pain management, etc. using compds. of formulas I and II [R1 = (un)substituted pyrrole, furan, thiophene, Ph, etc.; R2 = H, C(O); R3-4 = H, alk(en/yn)yl, aryl, halo, OH, etc.; A, B = O, S, aza; m, n = 0 - 3]. Included are over 60 synthetic examples, an adenosine A1 receptor binding assay and 4 representative formulations. For instance, reaction of benzoylacetonitrile (prepn. given), tetrahydro-4H-thiopyran-4-one and S8 (morpholine, 70°C/1h, room temp./20 h) gave (2-Amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-yl)phenylmethanone (III) in 68% yield after recrystn., m.p. 92 - 95°C. Allosteric activation by example compds. was detd. using CHO cells expressing adenosine A1 receptors by detn. of cAMP prodn. III at 0.1 mM resulted in 6% change in cAMP prodn. and at 10 mM a 35% change vs. control.
MOSTRA DI PIU'
Brevetti
PCT Int. Appl. (2001), WO 2001040181 A1 20010607.
Preparation of acryloyl peptidic derivatives as antitumor agents
Cozzi, Paolo; Beria, Italo; Caldarelli, Marina; Geroni, Maria Cristina Rosa; Baraldi, Pier Giovanni; Romagnoli, Romeo
Acryloyl peptidic derivs. I [n = 3 or 4; m = 0-2; X, Y = N, CH; R1, R2 = H, halo, C1-C4 alkyl; R3 = H, halo; B = NHC(NH2):NCN, NHC(NH2):NNH2, NHC(NR4R5):NR6 (R4, R5 = H, C1-C4 alkyl; R6 = H, OH, C1-C4 alkyl), NHC(O)NR7R8 (R7, R8 = H, C1-4 alkyl), 2-i...
Acryloyl peptidic derivs. I [n = 3 or 4; m = 0-2; X, Y = N, CH; R1, R2 = H, halo, C1-C4 alkyl; R3 = H, halo; B = NHC(NH2):NCN, NHC(NH2):NNH2, NHC(NR4R5):NR6 (R4, R5 = H, C1-C4 alkyl; R6 = H, OH, C1-C4 alkyl), NHC(O)NR7R8 (R7, R8 = H, C1-4 alkyl), 2-imidazolin-2-ylamino, imidazol-2-ylamino, or 1,4,5,6-tetrahydropyrimidin-2-yl (with provisos)] or their pharmaceutically acceptable salts were prepd. as antitumor agents. Thus, 4-[(2-bromoacryloyl)amino]-N-[5-[[[5-[[[5-[[[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethyl]amino]carbonyl]-1-methyl-1H-pyrrol-3-yl]amino]carbonyl]-1-methyl-1H-pyrrol-3-yl]amino]carbonyl]-1-methyl-1H-pyrrol-3-yl]-1-methyl-1H-pyrrole-2-carboxamide hydrochloride was prepd. by a multistep procedure starting with reaction of N-(4,5-dihydro-1H-imidazol-2-yl)-1,2-ethanediamine dihydrochloride with 1-methyl-4-nitro-1H-pyrrole-2-carbonyl chloride, followed nitro group redn., and reaction with 4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrrole-2-carbonyl chloride.
MOSTRA DI PIU'
Brevetti
U.S. (2002), US 6358964 B1 20020319,
Preparation of triazoloquinazoline derivatives as adenosine A3 receptor modulators
Baraldi, Pier G.
Title compds. I [R = C(X)R1, C(X)N(R1)2, C(X)OR1, C(X)SR1, SOnR1, SOnOR1, SOnSR1, SOnN(R1)2; R1 = H, alk(en/yn)yl, (hetero)aryl, heterocyclic, etc.; R2 = H, halo, alkyl, aralkyl, (hetero)aryl; R3 = (un)substituted furan, pyrrole, thiophene, benzofura...
Title compds. I [R = C(X)R1, C(X)N(R1)2, C(X)OR1, C(X)SR1, SOnR1, SOnOR1, SOnSR1, SOnN(R1)2; R1 = H, alk(en/yn)yl, (hetero)aryl, heterocyclic, etc.; R2 = H, halo, alkyl, aralkyl, (hetero)aryl; R3 = (un)substituted furan, pyrrole, thiophene, benzofuran, benzylpyrrole, benzothiophene, X = O, S, NR1; n = 1-2; with the proviso that R2 is not halo when R = C(X)R1.] were prepd. For instance, starting material CGS 15943 (prior art) was reacted with 4-methoxyphenylisocyanate to afford II. II bound to human A3 (hA3) receptors with a binding affinity of 0.14 nM, and showed binding selectivities of hA1/hA3=43, hA2a/hA3=50 and hA2b/hA3=158. I are useful for, e.g., treatment of hypertension, inflammation, allergic reaction, mast cell degranulation, etc. Furthermore, compds. of the invention can be used in a diagnostic application to det. the presence of tumor cells which possess a high concn. of adensosine A3 receptors.
MOSTRA DI PIU'
Brevetti
U.S. (2002), US 6407236 B1 20020618.
Preparation of pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines and analogs as adenosine A3 receptor modulators for therapeutic and diagnostic use
Baraldi, Pier Giovanni; Borea, Pier Andrea
Title compds. I [wherein A = imidazole, pyrazole, or triazole; R = CXR1, CXN(R1)2, CXOR1, CXSR1, SOnR1, SOnSR1, or SOnN(R1)2; R1 = H, (hetero)aryl, heterocyclyl, alkanoyl, or (un)substituted alkyl, alkenyl, or alkynyl; or N(R1)2 = azetidinyl or 5-6 m...
Title compds. I [wherein A = imidazole, pyrazole, or triazole; R = CXR1, CXN(R1)2, CXOR1, CXSR1, SOnR1, SOnSR1, or SOnN(R1)2; R1 = H, (hetero)aryl, heterocyclyl, alkanoyl, or (un)substituted alkyl, alkenyl, or alkynyl; or N(R1)2 = azetidinyl or 5-6 membered heterocyclyl; R2 = H or (un)substituted alkyl, alkenyl, aralkyl, or (hetero)aryl; R3 = (un)substituted (benzo)furanyl, (benzo)pyrrolyl, or (benzo)thiophenyl; X = O, S, or NR1; n = 0-2; or pharmaceutically acceptable salts thereof] were prepd. as selective A3 adenosine receptor agonists. Thus, 3-amino-1H-pyrazole-4-carbonitrile was methylated, treated with tri-Et orthoformate to give the imidate, and cyclized with 2-furoic acid hydrazide to give 8-methyl-2-(2-furyl)pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine (45%). Amination (53%) and addn. of 3-chlorophenyl isocyanate (98%) afforded II, which exhibited binding affinity at the A1, A2, and A3 receptors with Ki values of 5,045 nM, >10,1000 nM, and 0.22 nM, resp. I are useful for the treatment disorders caused by excessive activation of the A3 receptor, such as hypertension, inflammation, mast cell degranulation, cardiac hypoxia, allergic disease, and for protection against cerebral ischemia (no data). In addn., I are useful in diagnostic applications to det. the relative binding of other compds. to the A3 receptor. For instance, the compds. can be labeled, for example with fluorescent or radiolabels, and the labels used in vivo or in vitro to det. the presence of tumor cells which possess a high concn. of adenosine A3 receptors.
MOSTRA DI PIU'
