Tricyclic and tetracyclic systems acting upon the vascular and central nervous systems

A pharmaceutical composition comprises a tricyclic or tetracyclic composition acting upon the vascular and central nervous systems, comprising one of a general formula:

• in its racemic modification and as each separately levorotatory and dextrorotatory enantiomer, wherein for compounds of the general formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, and XII, R represents H, alkyl group (preferably straight or branched chain alkyl groups having up to 8 carbon atoms such as methyl, ethyl, propyl, butyl pentyl, hexyl, heptyl, and octyl and all chain isomers thereof;
• as well as cyclic alkyl and alkyl-substituted compounds, preferably substituted with halogens;
• vinyl and vinyl-substituted compounds;
• and cycloalkyl chains, preferably the cyclohexyl group;
• R represents an aryl group (benzyl, naphtyl, and substituted naphtyl or antracyl). The aryl and aryl-substituted group, represent, preferably, unsubstituted phenyl or phenyl substituted by one and up to five substituents independently selected from —NO2, —NH2, —OH, F, Cl, Br, I, —CN—OCH3, —N(CH3)2), —CH3, —OCOCH3, —COOCH3, —OCF3, —SH, —NH(C═O)—CH3, —CHO, —C═NH, —C═NH—NH2, —C═NH—OH;
• R represents heteroaryl, and heteroaryl substituted, wherein heteroaryl and heteroaryl substituted refer preferably to furfuryl, furfuryl substituted, pyrrolidyl, pyrrolidyl substituted, thiophenyl, thiophenyl substituted, pyridyl, (2-pyridyl, 3-pyridyl, and 4-pyridyl), pyridyl substituted, quinoline (2-quinoline, 3-quinoline, and 4-quinoline), pyrazolyl;
• R represents an heteroaryl, preferably pyrrol, thiophen, and phenyl-substituted furan, wherein the phenyl group can be substituted in turn by one or more substituents selected from —CN, —C(C═O)—CH3, F, Cl, Br, NH2, NO2;
• and
• for compounds of general formula I, II, and III, R1 represents H, straight or branched chain alkyl group, and alicyclics, preferably having 1 to 16 carbon atoms;
• for compounds of general formula I, II, and III, R1 also represents OR′, wherein R′ independently represents H or its Sodium (Na) and Potassium (K) salts;
• straight or branched chain alkyl groups having 1 to 24 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl, heptyl, octyl, nonyl, decyl, undecyl, duodecyl, and all straight or branched chain position isomers thereof:
• —(CH2)n-O—(CH2)n-CH3;
• —(CH2)n-O—(CH2)n-O—(CH2)n-CH3) wherein n is equal to 1 and less than 8, —(CH2)n-CN, wherein n is a number between 1 and 8;
• R′ also represents lipid chains derived from mono or polyunsaturated fatty acids having up to 24 carbon atoms;
• R1 also represents —NHR″, wherein R″ independently represents H, straight or branched alkyl groups of carbonate chains having from 1 to 24 carbon atoms;
• —(CH2)n-O—(CH2)n-CH3;
• —(CH2)n-O—(CH2)n-O—(CH2)n-CH3) wherein n is a number between 1 and 8, —(CH2)n-CN, wherein n=1-8;
• R″ also represents lipid chains derived from mono and polyunsaturated fatty acids having up to 24 carbon atoms;
• R1 also represents —NHR′″, wherein R′″ independently represents —(CH2)n-NH2, wherein n is a number between 1 and 10, like for example (and preferably) —NH—(CH2)6—NH2, —NH—(CH2)8—NH2;
• R1 also represents chains of the —NH—(CH2)n-NH(C═O)—R3 type, wherein n is a number between 1 and 10 and R3 represents straight or branched alkyl groups;
• unsaturated alkylate remnants of the —(CH2)n-C═C—(CH2)n-CH3 type, preferably long chains having up to 18 carbon atoms. For example (and preferably) —NH—(CH2)6—NH(C═O)—C11H23, —NH—(CH2)6—NH(C═O)—C7H14—CH═CH—C8H17;
• and
• for compounds of the general formula I, II, and III, R1 also represents amino acid remnants of the —NH—CH(R4)—COOH type, wherein R4 is amino acid remnants, preferably from valine, phenylalanine, alanine, histidine, lysine, tryptophan, cysteine, leucine, tyrosine, isoleucine, proline, and methionine;
• R1 also represents small peptide chains having 2 and up to 12 amino acids, obtained by combining some of them, independently selected;
• R1 also represents —NH—OH;
• —NH—NH2;
• —NH—NH—(C═O)—NH2;
• —NH—NH—(C═S)—NH2;
• R1 also represents —NHR5, wherein R5 is a thiazole or thiazole-substituted ring, 4-phenylthiazole or 4-phenylthiazole substituted;
• R5 also represents a phenyl or a phenyl-substituted substituent;
• For compounds of general formula I, II, and III, R2 represents an alkyl or cycloalkyl group;
• alkyl groups can be straight or branched chained having 1 to 16 carbon atoms;
• —(CH2)n-NH2 groups, and —(CH2)n-OH groups, wherein n is 1 to 8;
• and
• for compounds of general formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, and XII, cycle A is a 6-membered aromatic ring fused to the diazepine ring and represents a benzene or benzene-substituted ring, conforming a benzodiazepine, fused to comprise isomers and tautomers;
• and wherein
• benzene fused diazepine, represented as Ring A, is in turn substituted by one and up to four substituents independently selected from OH, COOH, CH3, NO2, NH2, CHO (formyl group), halogens and combinations thereof;
• the benzene group fused diazepine, represented by A, can also be replaced with carboxylic acid derivatives —C(C═O)—R6, wherein R6 represents O-alkyl, —O-aryl, NH2, —NH-alkyl, —NH-aryl;
• and further
• the benzene group fused diazepine, represented by A, can also be replaced by a —NH—C(C═O,S)—N(R7)2 group, wherein R7 is an H, or a small straight or branched chain alkyl group having 1 to 6 carbon atoms;
• and
• the benzene group fused diazepine, represented by A, can also be replaced by a —NH—(C═O,S)—OR7 group, wherein R7 is an H or small straight or branched chain alkyl group having 1 to 8 carbon atoms;
• and
• for compounds of general formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, and XII, cycle A is also a 6-membered heterocyclic ring fused to the diazepine ring and represents a pyridine and pyridine-substituted ring, preferably with halogens, and wherein the pyridine ring can be fused to the isomers and tautomers thereof;
• and
• for compounds of general formula I, II, Ill, IV, V, VI, VII, VIII, IX, X, XI, and XII, cycle A is also a 6-membered heterocyclic ring fused to the diazepine ring and represents a pyrimidine substituted or unsubstituted ring, wherein one or both nitrogen atoms of the pyrimidine can be substituted by H, CH3, OH, SH y NH2 and combinations thereof, independently selected;
• the carbon atoms of the pyrimidine can be independently substituted by one or more substituents selected from H or CH3 as well as OH, SH, NH2, —C═O, —C═S, —C═NH, and isomers and tautomeric forms derived thereof;
• and
• for compounds of general formula I, II, Ill, IV, V, VI, VII, VIII, IX, X, XI, and XII, wherein cycle A is a pyrimidine-substituted ring, such pyrimidine ring can also be substituted in the carbon positions of the cycle by a R8 substituent, wherein R3 represents a straight or branched chain alkyl group having 1 to 6 carbon atoms, and preferably by an unsubstituted phenyl group or a phenyl group substituted by one and up to 5 substituents, independently selected from —NO2, —NH2, —OH, F, Cl, Br, I, —CN—OCH3, —N(CH3)2), —CH3, —OCOCH3, —COOCH3, —OCF3, —SH, —NH(C═O)—CH3, —CHO, —C═NH, —C═NH—NH2, —C═NH—OH, in such a manner that it implies a structure and all its possible position isomers and all tautomeric forms derived thereof.