MXPA06006193A - Nitrooxyderivatives of carvedilol and other beta blockers as antihypertensive drugs - Google Patents
Nitrooxyderivatives of carvedilol and other beta blockers as antihypertensive drugsInfo
- Publication number
- MXPA06006193A MXPA06006193A MXPA/A/2006/006193A MXPA06006193A MXPA06006193A MX PA06006193 A MXPA06006193 A MX PA06006193A MX PA06006193 A MXPA06006193 A MX PA06006193A MX PA06006193 A MXPA06006193 A MX PA06006193A
- Authority
- MX
- Mexico
- Prior art keywords
- integer
- enantiomers
- diastereoisomers
- pharmaceutically acceptable
- group
- Prior art date
Links
- 239000002876 beta blocker Substances 0.000 title claims description 30
- NPAKNKYSJIDKMW-UHFFFAOYSA-N Carvedilol Chemical class COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=NC3=CC=C[CH]C3=C12 NPAKNKYSJIDKMW-UHFFFAOYSA-N 0.000 title description 11
- 239000002220 antihypertensive agent Substances 0.000 title description 2
- 229910004679 ONO2 Inorganic materials 0.000 claims abstract description 44
- 150000001875 compounds Chemical class 0.000 claims description 198
- -1 NHCOCH3 Chemical group 0.000 claims description 112
- 239000011780 sodium chloride Substances 0.000 claims description 110
- 150000003839 salts Chemical class 0.000 claims description 107
- 229910052760 oxygen Inorganic materials 0.000 claims description 78
- 229910052717 sulfur Inorganic materials 0.000 claims description 75
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 52
- 239000001301 oxygen Substances 0.000 claims description 52
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 49
- 239000011593 sulfur Chemical group 0.000 claims description 49
- 125000000217 alkyl group Chemical group 0.000 claims description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- 125000002947 alkylene group Chemical group 0.000 claims description 25
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 claims description 12
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000005842 heteroatoms Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
- 125000006832 (C1-C10) alkylene group Chemical group 0.000 claims description 7
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 7
- NXYIECYJINSHGC-UHFFFAOYSA-N 4-(nitrooxymethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(CO[N+]([O-])=O)C=C1 NXYIECYJINSHGC-UHFFFAOYSA-N 0.000 claims description 6
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 208000008787 Cardiovascular Disease Diseases 0.000 claims description 5
- 206010020772 Hypertension Diseases 0.000 claims description 5
- 125000004429 atoms Chemical group 0.000 claims description 4
- 229940079593 drugs Drugs 0.000 claims description 4
- 230000004406 elevated intraocular pressure Effects 0.000 claims description 4
- 208000010412 Glaucoma Diseases 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 201000011528 vascular disease Diseases 0.000 claims description 3
- 229910052727 yttrium Inorganic materials 0.000 claims description 3
- WSYBEYKVEHVSOI-UHFFFAOYSA-N [N+](=O)([O-])OCCC(=O)NCC(C)O Chemical compound [N+](=O)([O-])OCCC(=O)NCC(C)O WSYBEYKVEHVSOI-UHFFFAOYSA-N 0.000 claims description 2
- OEADFOJRQZPRPI-UHFFFAOYSA-N [N+](=O)([O-])OCCCCCC(=O)NCC(C)O Chemical compound [N+](=O)([O-])OCCCCCC(=O)NCC(C)O OEADFOJRQZPRPI-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 230000000069 prophylaxis Effects 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- GYUHXQQRIBDGGP-UHFFFAOYSA-N 1-(9H-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)ethylamino]propan-2-ol;6-nitrooxyhexanoic acid;hydrochloride Chemical group Cl.OC(=O)CCCCCO[N+]([O-])=O.COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=C1C1=CC=CC=C1N2 GYUHXQQRIBDGGP-UHFFFAOYSA-N 0.000 claims 1
- CBSFPBTYVIYRQZ-UHFFFAOYSA-N 6-nitrooxyhexanoic acid Chemical compound OC(=O)CCCCCO[N+]([O-])=O CBSFPBTYVIYRQZ-UHFFFAOYSA-N 0.000 claims 1
- 239000005711 Benzoic acid Substances 0.000 claims 1
- 235000010233 benzoic acid Nutrition 0.000 claims 1
- 239000000674 adrenergic antagonist Substances 0.000 abstract 2
- 238000006243 chemical reaction Methods 0.000 description 47
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(I) nitrate Inorganic materials [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 32
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- 150000003254 radicals Chemical class 0.000 description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 229910001961 silver nitrate Inorganic materials 0.000 description 12
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- 229960004195 carvedilol Drugs 0.000 description 9
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- 239000000243 solution Substances 0.000 description 9
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N Cyclic guanosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 6
- 125000006242 amine protecting group Chemical group 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
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- 229910052740 iodine Inorganic materials 0.000 description 6
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 5
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Abstract
The present invention relates to&bgr;-adrenergic blockers nitrooxyderivatives of general formula (I):A-(Y-ONO2)s, wherein s is an integer equal to 1 or 2;A is selected from the following&bgr;-adrenergic blockers residues of formula (II), wherein R1 is selected from the group consisting of
Description
DERIVATIVES OF CARVEDILOL NITROX1 AND OTHER BETA-BLOCKERS AS ANTIHYPERTENSIVE DRUGS
DESCRIPTIVE MEMORY
The present invention relates to derivatives of β-adrenergic blockers. Very particularly, the present invention relates to nitroxy derivatives of β-adrenergic blockers, pharmaceutical compositions containing them and their use for the treatment of hypertension, cardiovascular diseases, glaucoma, migraine headache, vascular diseases and elevated intraocular pressure. Β-adrenergic blockers (β-blockers) are widely used in the treatment of hypertension and cardiovascular diseases including angina pectoris, arrhythmias, acute myocardial infarction, hypertrophic cardiomyopathy, congestive heart failure. They work by blocking the effects of catecholamines at receptor sites in the heart, but they differ somewhat in their ability to block receptors in blood vessels and lungs. The selective β-blockers have their main actions in the heart, some others are weak stimulators of the β-receptor while they still block the main actions of catecholamines, some block both the ßi receptors and the β2 receptors in the heart and those in the blood vessels and have no stimulatory activity and some block other catecholamine receptors that can lead to additional vascular effects on the blood vessels. Several side effects are associated with this class of drugs such as muscle fatigue, sleep disturbances, decreased heart rate, hypotension, cold extremities, bronchospasm in asthmatic patients, hypoglycemia, increased plasma lipids. Moreover, abrupt abstinence after long-term treatment with β-blockers has to be avoided, because an increased sensitivity to the β-adrenergic system develops. The patent of E.U.A. No. 6,242,432 discloses derivatives of the formula A- (X NO2) or having an antithrombotic activity, wherein A is the residue of a β-adrenergic blocker, X. is a bivalent connecting bridge and t0 is 1 or 2. The invention is limited to particular residues of β-adrenergic blockers. The patent of E.U.A. No. 5,502,237 and the patent of E.U.A. Do not
,639,904 disclose derivatives of the formula R, -Ar-0-CH 2 -CH (OH) -CH 2 -NH-CH (CH 3) 2 used for the treatment of cardiovascular conditions, wherein Ri is a chain having at least one group nitroxy as a substituent. The patent of E.U.A. No. 4,801, 596 discloses aminopropanol derivatives of the formula
. { 0-NO) nBXN.R1) - ^ - V "0-CH2-CH {OH) -CH2-NH-R3 which can be used for prophylaxis and / or treatment of cardiac and circulatory diseases, wherein R3 is an alkali or a nitroxyalkyl radical containing 3 to 8 carbon atoms An object of the present invention is to provide new nitroxy derivatives of β-adrenergic blockers having a significantly improved overall pharmacological profile compared to native β-blockers which are capable not only eliminate or at least reduce the side effects associated with their parent compounds, but also have improved pharmacological activity and tolerance It has surprisingly been found that the nitroxy derivatives of β-adrenergic blockers of the present invention have a better pharmacological activity and protective properties of organs, increased effects as anti-inflammatory, and on renal functions, are also effective in other pathologies including Going atherosclerosis, diabetes, peripheral vascular diseases (PVD) and elevated intraocular pressure. In particular, it has been recognized that the nitroxy derivatives of β-adrenergic biociders of the present invention, unlike the aforementioned compounds of the prior art, exhibit improved activity on the cardiovascular system and increased tolerance and can be used to treat or prevent hypertension, cardiovascular diseases, glaucoma, migraine headache, vascular diseases and elevated intraocular pressure.
Objects of the present invention are nitroxy derivatives of β-adrenergic blockers of the general formula (I): A- (Y-ONO2) s and enantiomers and diastereomers and pharmaceutically acceptable salts thereof, wherein s is an integer equal to 1 or 2; A is selected from the following ß-adrenergic blocker residues of the formula (ii):
(ll) where Ri is selected from the group consisting of:
(lia) (llb) (lie)
(ll) (He) (llf) (iig) (llh)
(«0 (HL)
R2 is selected from the group consisting of: -CH (CH3) 2,
-C (CH3) 3 or
(Illa) (Hlb) when the radical Ri has been chosen from the formulas (lia), (ilc), (lid), (llg), (llh), (lli), (llm), R2 is-CH (CH3 )2; when the radical Ri has been chosen from the formulas (lie), (llf) or (Un), R2 is -C (CH3) 3; when Ri is the radical (lib), R2 is (Illa); when Ri is the radical (IIL), R2 is (lllb); Z is H or is a group capable of joining Y selected from the group consisting of: -C (O) -, -C (0) O- or
wherein R 'and R "are the same or different, and are H or straight or branched chain C 1 -C 4 alkyl, Zi is H or a -C (O) - capable of binding to Y; with the proviso that when s of formula (I) is 1, Z or Zi is H, preferably when s of formula (l) is 2, Z and Zi are -C (O) -; Y is a bivalent radical having the following meanings a) - C 1 -C 20 straight or branched chain alkylene, preferably C 1 -C 10 alkylene, most preferably C 3 -C 6 alkylene, being optionally substituted with one or more of the substituents selected from the group consisting of: halogen, hydroxy, -ON02 or T, wherein T is -OC (O) (C 1 -C 0 alkyl) -ONO 2, -O (C 1 -C 0 alkyl) -ON 0 2; b) -cycloalkylene with 5 to 7 carbon atoms in cycloalkylene ring, the ring being optionally substituted with Ti side chains, where Ti is straight or branched chain alkyl with 1 to 10 carbon atoms, Ti is preferably CH 3; c)
wherein: n is an integer from 0 to 20, preferably n is an integer from 0 to 10, most preferably n is 0 or 1, n1 is an integer from 1 to 20, preferably from 1 to 10, most preferably n1 is 1; n2, n3, n4 and n5 are integers equal or different from each other, equal to 0 or 1; R3 and R4 are independently selected from H or CH3; Y-i is -CH2- or - (CH2) na-CH = CH- where na is an integer from 0 to
, preferably na is equal to 0; X. is -WC (O) - or -C (O) W-, wherein W is oxygen, sulfur or NH, preferably W is oxygen; d)
(V) wherein: n1 is an integer from 1 to 20, preferably from 1 to 10; Xi is -WC (O) - or -C (O) W-, where W is oxygen, sulfur or NH, preferably W is sulfur or NH, n6 is an integer from 1 to 20, preferably from 1 to 5, very preferably n6 is 1, n7 is an integer from 0 to 20, preferably from 0 to 5, most preferably n7 is 1, R5, R5, R6 and R6 are independently selected from the group consisting of: H, CH3, OH, NH2, NHCOCH3, COOH, CH2SH and C (CH3) 2SH; when the bond between the CA and CB carbons is a double bond, R5 and R6 or R6 'and R5' are absent; with the proviso that when Y is selected from the bivalent radicals mentioned under c) -d), the group -ONO2 is linked to the group - (CH2) ni-; and)
(i)
(VII) where X2 is O or S, n10a, n10 and n12 are integers independently selected from 0 to 20, n10a is preferably selected from 0 to 10, most preferably n10a is 0 or 1, n10 and n12 are preferably selected from 1 to 10, most preferably n10 and n12 are 1 or 2 n11 is an integer from 0 to 6, preferably from 0 to 4, most preferably n 1 is 0 or 1, R11 is H, CH3 or nitroxy group, preferably R11 is H or a nitroxy group and R11a is CH3 or nitroxy group; 0
(HIV)
where nd is an integer from 0 to 10; n9 is an integer from 1 to 10; R9, R10, R8, R7 are the same or different, and are H or straight or branched chain C4 alkyl, preferably R9, R10, R8, R7 are H; wherein the group -ONO2 is linked to - [C I] ng where n9 is as defined above; Y2 is a saturated, unsaturated or aromatic 5 or 6 membered heterocyclic ring, which contains one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from the group consisting of
(Y11) (Y12) (Y13)
One embodiment provides compounds of the formula (I) wherein: s is 2, A is selected from the following β-adrenergic blocker residues of the formula (II):
wherein R, is selected from the group consisting of:
(Ha) (llb) (He)
(lid) (He) (»(Hg) (llh) (Hi) (liL)
(llm) (One)
R2 is selected from the group consisting of: -CH (CH3) 2, -C (CH3) 3 or
(Illa) (II Ib) when the radical R ^ has been chosen from the formulas (Ha), (Me), (lid), (llg), (llh), (lli), (llm), R2 is -CH (CH3) 2; when the radical R has been chosen from the formulas (lie), (llf) or (Un), R2 is -C (CH3) 3; when R. is the radical (llb), R2 is (Illa); when Ri is the radical (IIL), R2 is (lllb); Z is a group capable of joining Y selected from the group consisting of: -C (O) -, -C (O) O- or
wherein R 'and R "are the same or different, and are H or straight or branched chain C4 alkyl, Zi is H or a -C (O) - capable of binding to Y, preferably Z and Zi are - C (O) -; Y is a bivalent radical having the following meaning: a) - straight or branched chain C-C20 alkylene, preferably CrC10 alkylene, most preferably C3-C6 alkylene, being optionally substituted with one or more of the substituents selected from the group consisting of: halogen, hydroxy, -ON02 or T atoms, wherein T is -OC (O) (CC? 0 alkyl) -ONO2, -O (C.C.C. alkyl. 0) -ONO2; b) - cycloalkylene with 5 to 7 carbon atoms in the cycloalkylene ring, the ring being optionally substituted with Ti side chains, where Ti is straight or branched chain alkyl with 1 to 10 carbon atoms , Ti is preferably CH3; c)
(IV) wherein: n is an integer from 0 to 20, preferably n is an integer from 0 to 10, most preferably n is 0 or 1, n1 is an integer from 1 to 20, preferably from 1 to 10, most preferably n1 is 1; n2, n3, n4 and n5 are integers equal or different from each other, equal to 0 or 1; R3 and R4 are independently selected from H or CH3; Y1 is -CH2- or - (CH2) na-CH = CH- wherein na is an integer from 0 to 20, preferably na is equal to 0; Xi is -WC (O) - or -C (O) W-, wherein W is oxygen, sulfur or NH, preferably W is oxygen; d)
(V) wherein: n1 is an integer from 1 to 20, preferably from 1 to 10; Xi is -WC (O) - or -C (O) W-, wherein W is oxygen, sulfur or NH, preferably W is sulfur or NH; n6 is an integer from 1 to 20, preferably from 1 to 5, most preferably n6 is 1, n7 is an integer from 0 to 20, preferably from 0 to 5, most preferably n7 is 1, R5 and R5, R6 and R6 are independently selected from the group consisting of: H, CH3, OH, NH2, NHCOCH3, COOH, CH2SH and C (CH3) 2SH; when the bond between the carbons CA and CB is a double bond,
R5 and R6 or R6 'and R5' are absent; with the proviso that when Y is selected from the divalent radicals mentioned under c) -d), the group -ON02 is linked to the group - (CH2) n- ?; and)
(VI) (il) wherein X2 is O or S, n10a, n10 and n12 are integers independently selected from 0 to 20, n10a is preferably selected from 0 to 10, most preferably n10a is 0 or 1; n10 and n12 are preferably selected from 1 to 10, most preferably n10 and n12 are 1 or 2;
n11 is an integer from 0 to 6, preferably from 0 to 4, most preferably n11 is 0 or 1; R11 is H, CH3 or nitroxy group, preferably R11 is H or nitroxy; R11a is CH3 or nitroxy group; F)
(VIII)
where n8 is an integer from 0 to 10; n9 is an integer from 1 to 10; R9, R10, R8, R7 are the same or different, and are H or straight or branched chain CrC alkyl, preferably R9, R10, R8, R7 are H; where the group -ONO2 is linked to
| ng where n9 is as defined above; Y2 is a saturated, unsaturated or aromatic heterocyclic ring of
or 6 members, which contains one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from the group consisting of (Y1) (Y2) (Y3) (Y4) (Yd)
Another embodiment provides compounds of the formula (I) wherein: s is 1, A is selected from the following β-adrenergic blocker residues of the formula (II):
(H) where Ri is selected from the group consisting of: (llb) (lio)
(Ha) ie) (Hf) (lld) (l
(HL) (ll) (llm) (Un) R2 is selected from the group consisting of: -CH (CH3) 2, -C (CH3) 3
(Illa) (lllb) when the radical Ri has been chosen from the formulas (lia), (lie), (lid), (llg), (llh), (lli), (llm), R2 is -CH (CH3 )2; when the radical Ri has been chosen from the formulas (lie), (llf) or (Un), R2 is -C (CH3) 3; when Ri is the radical (llb), R2 is (Illa); when Ri is the radical (IIL), R2 is (lllb); Z is H and Zi a -C (O) - capable of binding to Y; Y is a bivalent radical having the following meaning: a) straight or branched chain C-C 20 alkylene, preferably C 1 -C 10 alkylene, most preferably C 3 -C 6 alkylene, being optionally substituted with one or more of the selected substituents of the group consisting of: halogen atoms, hydroxy, -ON02 or T, wherein T is -OC (0) (C 1 0 alkyl) -ONO 2, -0 (C 10 alkyl) -ON 0 2; b) - cycloalkylene with 5 to 7 carbon atoms in the cycloalkylene ring, the ring being optionally substituted with Ti side chains, where Ti is straight or branched chain alkyl with 1 to 10 carbon atoms, Ti is preferably CH 3; c)
(IV) wherein: n is an integer from 0 to 20, preferably n is an integer from 0 to 10, most preferably n is 0 or 1, and n1 is an integer from 1 to 20, preferably from 1 to 10, very preferably n1 is 1; n2, n3, n4 and n5 are integers equal or different from each other, equal to 0 or 1; R3 and R4 are independently selected from H or CH3; Y1 is -CH2- or - (CH2) na-CH = CH- wherein na is an integer from 0 to 20, preferably na is equal to 0; Xi is -WC (O) - or -C (O) W-, wherein W is oxygen, sulfur or NH, preferably W is oxygen; d)
(V) wherein: n1 is an integer from 1 to 20, preferably from 1 to 10;
XT is -WC (O) - or -C (0) W-, wherein W is oxygen, sulfur or NH, preferably W is sulfur or NH; n6 is an integer from 1 to 20, preferably from 1 to 5, most preferably n6 is 1, n7 is an integer from 0 to 20, preferably from 0 to 5, most preferably n7 is 1, R5 and R5 R6 and R6 are selected independently of the group consisting of: H, CH3, OH, NH2, NHCOCH3, COOH, CH2SH and C (CH3) 2SH; when the bond between the carbons CA and CB is a double bond, R5 and R3 or R6 'and R5 are absent; with the proviso that when Y is selected from the divalent radicals mentioned under c) -d), the group -ONO2 is linked to a group - (CH2) n? -; and)
(VI) (VII) where X2 is O or S, n10a, n10 and n12 are independently selected from 0 to 20, n10a is preferably selected from 0 to 10, most preferably n10a is 0 or 1; n10 and n12 are preferably selected from 1 to 10, most preferably n10 and n12 are 1 or 2; n11 is an integer from 0 to 6, preferably from 0 to 4, most preferably n11 is 0 or 1; R11 is H, CH3 or nitroxy group, preferably R11 is H or nitroxy; R11a is CH3 or nitroxy group; F)
(viii)
where n8 is an integer from 0 to 10; n9 is an integer from 1 to 10; R9, R10, R8, R7 are the same or different, and are H or straight or branched chain C4 alkyl, preferably R9, R10, R8, R7 are H; where the group -ON02 is linked to
- [C] | p9 where n9 is as defined above;
Y2 is a saturated, unsaturated or aromatic 5 or 6 membered heterocyclic ring, which contains one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from the group consisting of
CY1) (Y2) (Y3) (Y4) - (Yd) - (Yd) (Y7) (Y8) (Y9) (Y10) (Y11) (Y12) (Y13) Another embodiment provides compounds of the formula (I) wherein: s is 1, A is selected from the following ß-adrenergic biochemistry residues of the formula (II): (II) wherein Ri is selected from the group consisting of:
(Ha) (lie)
(Hd) (lie) (llf)
(iig) (llh) (IIL) (ll) Oln)
R2 is selected from the group consisting of: -CH (CH3) 2, -C (CH3) 3
when the radical Ri has been chosen from the formulas (lia), (He), (lid), (llg), (llh), (lli), (llm), R2 is -CH (CH3) 2; when the radical Ri has been chosen from the formulas (lie), (llf) or (Un), R2 is -C (CH3) 3; when Ri is the radical (IIL), R2 is (lllb); Z is H; Z is a group capable of joining Y selected from the group consisting of: -C (O) -, -C (O) O- or
wherein R 'and R "are the same or different, and are H or straight or branched chain C-1-C4 alkyl, and is a bivalent radical having the following meaning: c)
(IV) where: n is an integer from 0 to 20, preferably n is an integer from 0 to
, most preferably n is 0 or 1, n1 is an integer from 1 to 20, preferably from 1 to 10, most preferably n1 is 1; n2, n3, n4 and n5 are integers equal or different from each other, equal to O or l; R3 and R4 are independently selected from H or CH3; Y1 is -CH2- or - (CH2) na-CH = CH- wherein na is an integer from 0 to 20, preferably na is equal to 0;
Xi is -WC (O) - or -C (0) W-, wherein W is oxygen, sulfur or NH, preferably W is oxygen; and)
(SAW) '
(VII) where X2 is O or S, n10a is 0 or 1, n11 is O or 1, n10 and n12 are 1 or 2; R11 is H, CH3 or nitroxy group; R11a is CH3 or nitroxy group; F)
(HIV) where nd is an integer from 0 to 10;
n9 is an integer from 1 to 10; R9, R10, R8, R7 are the same or different, and are H or straight or branched chain C4 alkyl, preferably R9, R10, R8, R7 are H;
where the group -ONO2 is linked to
I _?] P9
where n9 is as defined above; Y2 is a saturated, unsaturated or aromatic 5 or 6 membered heterocyclic ring, which contains one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from the group consisting of
(Y1) (Y2) (Y3) (Y4) (Y5)
(Y11) (Y13)
another embodiment provides compounds of the formula (I) wherein s is an integer equal to 1 or 2 A is the β-adrenergic blocker residue of the formula (II):
(ll) where
(llb) R2 is (Illa)
(Illa)
Z is H or is a group capable of joining Y selected from the group consisting of: -C (O) -, -C (O) 0- or? ? wherein R 'and R "are the same or different, and are H or straight or branched chain C4 alkyl, Zi is H or a -C (O) - capable of binding to Y, with the proviso that when s of the formula (I) is 1, Z or Zi is
H; preferably when s of the formula (I) is 2, Z and Zi are
-CO)-; Y is a bivalent radical having the following meaning: a) - straight or branched chain C-C20 alkylene, preferably C1-C10 alkylene, most preferably C3-C6 alkylene, being optionally substituted with one or more of the selected substituents of the group consisting of: halogen atoms, hydroxy, -ON02 or T, wherein T is -OC (0) (C? -C10 alkyl) -ONO2, -0 (C10 alkyl) -ONO2; b) - cycloalkylene with 5 to 7 carbon atoms in the cycloalkylene ring, the ring being optionally substituted with Ti side chains, where Ti is straight or branched chain alkyl with 1 to 10 carbon atoms, Ti is preferably CH 3; c)
(IV) wherein: n is an integer from 0 to 20, preferably n is an integer from 0 to 10, most preferably n is 0 or 1, n1 is an integer from 1 to 20, preferably from 1 to 10, most preferably n1 is 1, n2, n3, n4 and n5 are integers equal or different from one another, equal to 0 or 1, R3 and R4 are independently selected from H or CH3; Y1 is -CH2- or - (CH2) na-CH = CH- wherein na is an integer from 0 to 20, preferably na is equal to 0; Xi is -WC (O) - or -C (O) W-, wherein W is oxygen, sulfur or NH, preferably W is oxygen; d)
(V) wherein: n1 is an integer from 1 to 20, preferably from 1 to 10; Xi is -WC (O) - or -C (O) W-, wherein W is oxygen, sulfur or NH, preferably W is sulfur or NH; n6 is an integer from 1 to 20, preferably from 1 to 5, most preferably n6 is 1, n7 is an integer from 0 to 20, preferably from 0 to 5, most preferably n7 is 1, R5 and R5 R6 and R6 'are independently selected from the group consisting of: H, CH3, OH, NH2, NHCOCH3, COOH, CH2SH and C (CH3) 2SH; when the link between the carbons CA and CB is a double bond
R5 and R3 or R6 'and R5 are absent; with the proviso that when Y is selected from the divalent radicals mentioned under c) -d), the -ONO2 group is linked to a group - (CH2) nr; and)
(SAW)
(Vile)
wherein X2 is O or S, n10a, n10 and n12 are integers independently selected from 0 to 20, n10a is preferably selected from 0 to 10, most preferably n10a is 0 or 1; n10 and n12 are preferably selected from 1 to 10, most preferably n10 and n12 are 1 or 2; n11 is an integer from 0 to 6, preferably from 0 to 4, most preferably n11 is O or 1; R1 is H, CH3 or nitroxy group, preferably R11 is H or nitroxy; R11a is CH3 or nitroxy group; F)
(vni) where nd is an integer from 0 to 10; n9 is an integer from 1 to 10; R9, R10, R8, R7 are the same or different, and are H or straight or branched chain C? -C4 alkyl, preferably R9, R10, R8, R7 are H; where the group -ON02 is linked to
• [C | l n9 where n9 is as defined above; Y2 is a saturated, unsaturated or aromatic 5 or 6 membered heterocyclic ring, which contains one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from the group consisting of (Y11) (Y12) (Y13)
Preferred compounds are those of the formula (I) wherein: s is 2, A is a β-adrenergic blocker residue of the formula (II) as defined above Z and Zi are - (CO) - Y is a radical bivalent having the following meanings: a) straight chain alkylene C1-C10, preferably C3-Ce alkylene;
c)
(IV) where the group -ONO2 joins (CH2) n ?; n, n2, n3, n4, n5 are equal to 0, n1 is 1 and the group - (CH2) nr is attached to the phenyl ring through [C] 2 or [C] 3 or [C] 4; on, n2, n5 are 1, n3 and n4 are equal to 0, and n1 is an integer from 1 to 10, Y1 is - (CH2) na-CH = CH- where na is 0, X is -WC (O ) - where W is oxygen and the WC (O) group is attached to the phenyl ring through [C] 4, R4 is CH3 and the group (OR4) is attached to the phenyl ring through [C] 3; d)
(V) where n1 is an integer from 1 to 10, n6 and n7 are 1, Xi is -WC (O) - where W is sulfur, R5, R5 'and R6' and H, R6 is NHCOCH3 and the group -ON02 joins the group - (CH2) ni-; and)
(VI) where X2 is O or S, and n11 is O, n10a is an integer from 0 to 10, n12 is an integer from 1 to 10, R11 is H or a nitroxy group and the group -ONO2 joins ( CH2) ni2; Another group of preferred compounds comprises compounds of the formula (I) wherein s is 1, A is a β-adrenergic blocker residue of the formula (II) as defined above, Z is H, Z is - (CO) - Y is a bivalent radical having the following meanings: a) straight-chain alkylene of C-C10, preferably C3-C6-alkylene; c) (IV) wherein the group -ONO2 joins (CH2) p ?; n, n2, n3, n4, n5 are equal to 0, n1 is 1 and the group - (CH2) n is attached to the phenyl ring through [C] 2 or [C] 3 or [C] 4; on, n2, n5 are 1, n3 and n4 are equal to 0, and n1 is an integer from 1 to 10, Y1 is - (CH2) na-CH = CH- where na is 0, Xi is -WC (O ) - where W is oxygen and the WC (O) group is attached to the phenyl ring through [C], R4 is CH3 and the group (OR4) is attached to the phenyl ring through [C] 3; d)
(V) where n1 is an integer from 1 to 10, Xi is -WC (O) - where W is sulfur, n6 is 1 n7 is 1, R5, R5 'and R6' and H, R6 is NHCOCH3 and the group -ON02 joins the group - (CH2) nr;
and)
(VI) where X2 is O or S, and n11 is O, n10a is an integer from 0 to 10, n12 is an integer from 1 to 10, R11 is H or a nitroxy group and the group -ONO2 joins ( CH2) ni2. Another group of preferred compounds comprises compounds of formula (I) wherein s is 1, A is a β-adrenergic blocker residue of formula (II) as defined above, Z is H, Y is a bivalent radical having the following meanings: c)
(IV) wherein the group -ONO2 joins (CH2) ni; n, n2, n3, n4, n5 are equal to 0, n1 is 1 and the group - (CH2) nr is attached to the phenyl ring through [C] 2 or [C] 3 or [C] 4; or in the formula (IV) n, n2, n5 are 1, n3 and n4 are equal to 0, n1 is an integer from 1 to 10, Y1 is - (CH2) na-CH = CH- where na is 0, Xi is -WC (O) - where W is oxygen and the WC (O) group is attached to the phenyl ring through [C] 4, R4 is CH3 and the group (OR4) is attached to the phenyl ring through [C] 3. Other groups of preferred compounds comprise compounds of the formula (I) wherein: s is 1, A is the β-adrenergic blocker residue of the formula (II) wherein R is (IIb) R2 is
(Illa)
Zi is H and Z is - (CO) - or -C (O) 0- and Y is a bivalent radical having the following meanings: a) C 1 -C 10 straight chain alkylene, preferably C 3 -C 6 alkylene; c)
(IV) where the group -ONO2 joins (CH2) n ?; n, n2, n3, n4, n5 are equal to 0, n1 is 1 and the group - (CH2) nr is attached to the phenyl ring through [CJ2 or [C] 3 or [C] 4; or in the formula (IV) n, n2, n5 are 1, n3 and n4 are equal to 0, n1 is an integer from 1 to 10, Y1 is - (CH2) na-CH = CH- where na is 0, Xi is -WC (O) - where W is oxygen and the WC (O) group is attached to the phenyl ring through [C] 4, R4 is CH3 and the group (OR4) is attached to the phenyl ring through [C] 3; d)
(V) where n1 is an integer from 1 to 10, nd and n7 are 1, Xi is -WC (O) - where W is sulfur, R5, R5"and R6 'and H, R6 are NHCOCH3 and the group -ONO2 joins the group - (CH2) n? -; e)
(SAW)
where X2 is O or S, and n11 is 0, n10a is an integer from 0 to 10, n12 is an integer from 1 to 10, R11 is H or a nitroxy group and the group -ON02 is attached to (CH2) ni2 - The most preferred compounds of the formula (I) according to the present invention are the following:
(31) (33), (47)
(59) (60)
(72) (70) (71) (73) (74) (75)
(83) (84)
(82)
(85) (86) (87) (100) (101) (108) (109) (110)
(111) (112) (113) Examples of "straight or branched chain C 2 O alkylene" include, but are not limited to, methylene, ethylene, propylene, isopropylene, n-butylene, pentylene, n-hexylene and the like. As indicated above, the invention also includes the pharmaceutically acceptable salts of the compounds of the formula (I) and stereoisomers thereof. Examples of pharmaceutically acceptable salts are those with inorganic bases, such as sodium, potassium, calcium and aluminum hydroxides, or with organic bases, such as lysine, arginine, triethylamine, dibenzylamine, piperidine and other acceptable organic amines. The compounds according to the present invention, when they contain in the molecule a salifiable nitrogen atom, can be transformed to the corresponding salts by reaction in an organic solvent such as acetonitrile, tetrahydrofuran with the corresponding organic or inorganic acids. Examples of pharmaceutically acceptable organic acids are: oxalic, tartaric, maleic, succinic, citric acids. Examples of pharmaceutically acceptable inorganic acids: nitric, hydrochloric, sulfuric, phosphoric acids. Salts with nitric acid are preferred. The compounds of the invention having one or more asymmetric carbon atoms can exist as optically pure enantiomers, optically pure diastereomers, mixtures of enantiomers, mixtures of diastereomers, racemic mixtures of enantiomers, racemates or mixtures of racemates. All possible isomers, stereoisomers and their mixtures of the compounds of the formula (1) are also included within the object of the invention. The compounds and compositions of the present invention can be administered by any available and effective delivery system including but not limited to oral, buccal, parenteral, inhalation, topical, injection, transdermal or rectal (e.g., by using suppositories) in unit dose formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Parenterals include subcutaneous, intravenous, intramuscular, intraestemal injection, or infusion technique. Solid dosage forms for oral administration may include, for example, capsules, tablets, pills, powders, granules and gel. In such solid dosage forms, the active compounds can be mixed with at least one inert diluent such as sucrose, lactose or starch. Said dosage form may also comprise, as normal practice, an additional substance other than the inert diluent, e.g., lubricating agent such as magnesium stearate. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using dispersing agents, wetting agents and / or suspending agents.
The composition of this invention may further include conventional excipients, i.e., pharmaceutically acceptable organic or inorganic substances that do not react in a deleterious manner with the active compounds. The dose of nitroxy derivatives of β-adrenergic blockers can be determined by standard clinical technique and are in the same or smaller ranges as described for commercially available compounds as reported in: Physician's Desk Reference, Medical Economics Company, Inc., Oradell, NJ, 58a. ed., 2004; The pharmacological basis of therapeutics, Goodman and Gilman, J. G. Hardman, L. e. Limbird, 20a. ed.
Experimental section
Synthesis process The compounds of the invention can be synthesized as shown in schemes 1 to 6. The compounds of the general formula (I) A- (Y-ON02), defined in scheme 1-3 as compounds of the formula D, where s is 1, Y is as defined above and A is a residue of a β-adrenergic blocker of the formula (II), wherein Z is -C (O) - and Zi is H, the enantiomers, diastereoisomer and a pharmaceutically acceptable salt thereof, can be prepared as outlined in schemes 1-3.
SCHEME 1
(A) (F) (G)
(L) (?) (H)
(D) The compounds of the formula (i) wherein Ri, R2, Z and Y are as defined above, Pi is an amine protecting group such as tert-butyloxycarbonyl ester (t-Boc) and X3 is a halogen preferably Cl, Br and I, are converted to compounds of the formula (L) wherein Ri, R2, Pi, Z and Y are as defined above, by reaction with AgN03 in a suitable organic solvent such as acetonitrile, tetrahydrofuran, A molar excess of silver nitrate is preferably used and the reaction is carried out, in the dark, at a temperature from room temperature to the boiling temperature of the solvent. The compounds of the formula (L) are converted to the compounds of the formula (D) by deprotecting the amine group (strong acid, such as HCi in dioxane or trifluoroacetic acid, used to remove a t-butyl carbamate). Other preferred methods for removing the amine protecting groups are those described in TW Greene "Protective groups in organic synthesis", Harvard University Press, 1980. The compounds of the formula (H) wherein Ri, R2, Z, Pi and Y are as defined above, they are converted to the esters of the formula (i) wherein Ri, R2, Y, Z, X3 and P, are as defined above, by reaction with an appropriate acid (Q1) of the formula X3- Y-COOH where Y and X3 are as defined above. The reaction is generally carried out in an inert organic solvent such as N, N'-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature of 0 ° C to 50 ° C in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDAC HCl) with a catalyst, such as 4-N, N-dimethylaminopyridine (D AP). The compounds of the formula (H) wherein Ri, R2 and P1 are as defined above, can be obtained by deprotection of the hydroxyl group of the compounds of the formula (G) wherein Ri, R2 are as defined above and P is a hydroxylic protecting group such as silyl ethers, such as trimethylsilyl or tert-butyl-dimethylsilyl and those described in TW Greene "Protective groups in organic synthesis", Harvard University Press, 1980. The fluoride ion is the preferred method to remove a protective group of silyl ether.
The compounds of the formula (G) wherein Ri, R2, P and Pi are as defined above, can be obtained by reacting the compounds of the formula (F) wherein Ri, R2 and P are as defined above with a suitable amine protecting group (Pi) as described above. The alcohol group of the compounds of the formula (A) wherein
Ri, R2 are as defined above, it is protected to give the compounds of the formula (F) wherein Ri, R2 are as defined above. The preferred protecting group for the alcohol moiety are silyl ethers, such as trimethylsilyl or tert-butyldimethylsilyl.
The compounds (A) wherein Ri, R2 are as defined above are commercially available, the acids of the formula X3-Y-COOH wherein X3 is as defined above, are commercially available.
SCHEME 2
(A) (B) (D)
The compounds of the formula (B) wherein Ri, R2, Z, Y are as defined above and X3 is a halogen atom, such as Cl, Br and I, are converted to compounds of the formula (D) wherein R1, R2, Z and Y are as defined above, by reaction with AgNÜ3 in a suitable organic solvent such as acetonitrile, tetrahydrofuran, a molar excess of silver nitrate is preferably used and the reaction is carried out, in the dark, at a temperature from room temperature and the boiling temperature of the solvent. The compounds of the formula (B) wherein Ri, R2, Z, Y and X3 are as defined above can be obtained by reaction of the compounds of the formula (A) with an appropriate acyl chloride (Q) of the formula X3-YC (O) CI, wherein X3 is chosen from chlorine, bromine and Y is as defined above. The esterification is carried out in an inert organic solvent such as N, N'-dimethylformamide, tetrahydrofuran, benzene, toluene, chloroform in the presence of a base such as triethylamine, pyridine at a temperature from room temperature and 50 ° C. The reaction was completed for a time interval of 30 minutes to 24 hours. Alternatively, the compounds of the formula (B) can be obtained by reacting compounds of the formula (A) with an acid (Q1) of the formula X3-YC (0) OH in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (EDAC) and a catalyst, such as N, N-dimethylaminopyridine. The reaction is carried out in an inert organic solvent such as N, N'-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature of 0 ° C and 50 ° C. The reaction is completed with a time interval of 30 minutes to 36 hours. Compounds of the formula (Q1), wherein X3 is a halogen atom are commercially available or can be obtained from the corresponding commercially available hydroxy acid by well-known reactions, for example by reaction with thionyl chloride or oxalyl, halides of P1" or Pv in inert solvents such as toluene, chloroform, DMF, etc. The compounds (A) wherein Ri, R2 are as defined above are commercially available.
SCHEME 3
(A) (D) Alternatively, the compounds of the formula (D) can be obtained as described below. The compounds of the formula are converted to the compounds (D) by reaction of the hydroxy group with nitroxiderivative, which contains an activated acylation group, of the formula
CI (0) C-Y-ONO2. The nitroxy compounds can be obtained from the corresponding alcohols of the formula CI (0) CY-OH by reaction with nitric acid and acetic anhydride in a temperature range from -50 ° C to 0 ° C or from the derivatives of corresponding halogen of the formula CI (0) CY-Hal by reaction with silver nitrate in the presence of an inert solvent such as acetonitrile, tetrahydrofuran. A molar excess of silver nitrate is preferably used and the reaction is carried out, in the dark, at temperature from the boiling temperature and room temperature. The reaction is completed with a time interval of 30 minutes to 3 days. The compounds of the general formula (I) A- (Y-ONO2) s, defined in scheme 4 as compounds of the formula (D1), wherein s is, Y is as defined above and A is a residue of a ß-adrenergic blocker of the formula (II), wherein Z is -C (O) 0- and Z-? is H, the enantiomers, diastereoisomer and a pharmaceutically acceptable salt thereof, can be prepared as outlined in scheme 4.
SCHEME 4
(A) (B1) (D1) The compounds of the formula (B) wherein R-t, R2, Z, Y are as defined above and X3 is a halogen atom, such as Cl, Br and I, are converted to compounds of the formula (D) wherein Ri, R2 and Y are as defined above, by reaction with AgNO3 in a suitable organic solvent such as acetonitrile, tetrahydrofuran, a molar excess of silver nitrate it is preferably used and the reaction is carried out, in the dark, at a temperature from room temperature and the boiling temperature of the solvent. ) The compounds of the formula (A) wherein Ri and R2 are as defined above are converted to the compounds (B1) by reaction with an appropriate compound (Q2) having the formula X3-Y-OC (0) CI in where X3 is Cl, Br or I, and Y is as defined above. The reaction was generally carried out in the presence of a base in a polar or non-polar aprotic solvent such as THF or CH2Cl2 at a temperature ranging from 0 ° -65 ° C or in a double phase system H20 / Et2O at a temperature which varies between 20o-40 ° C. The compounds of the formula (Q2) are commercially available or can be obtained from the corresponding alcohols by reaction with triphosgene in the presence of an organic base. The compounds of the general formula (1) A- (Y-ONO2) s, defined in scheme 5 as compounds of the formula (D), wherein s is 1, Y is as defined above and A is a residue of a β-adrenergic blocker of the formula (II), wherein Z is
wherein R 'and R "are H or straight or branched chain d-C4 alkyl and Zi is H, the enantiomers, diastereomer and a pharmaceutically acceptable salt thereof, can be prepared as outlined in scheme 5:
SCHEME 5
(D) w
The compounds of the formula (i) wherein Ri, R2, Z and Y are as defined above, Pi is an amine protecting group such as tert-butyloxycarbonyl ester (t-Boc) and X3 is a halogen atom preferably Cl , Br and I, are converted to compounds of the formula (L) wherein R ^ R2, Pi, Z and Y are as defined above, by reaction with AgN03 in a suitable organic solvent such as acetonitrile, tetrahydrofuran, a molar excess of silver nitrate is preferably used and the reaction is carried out, in the dark, at a temperature from room temperature to the boiling temperature of the solvent. The compounds of the formula (L) are converted to the compounds of the formula (D) by deprotecting the amine group (strong acid, such as HCl in dioxane or trifiuoroacetic acid, used to remove a t-butyl carbamate). Other preferred methods for removing the amine protecting groups are those described in T. W. Greene "Protective groups in organic synthesis", Harvard University Press, 1980.
The compounds of the formula (i) wherein Ri, R2, Y, X3, Z and Pi are as defined above, can be obtained by reacting the compounds of the formula (M) wherein Ri, R2, Pi, R ' , R "and X3 are as defined above, with an acid (Q1) of the formula X3-Y-COOH wherein X3 is a halogen atom and Y is as defined above.The reaction is carried out in a solvent inert organic such as N, N'-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature ranging from 0 ° C to 50 ° C in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or hydrochloride of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDAC HCl) with a catalyst, such as 4-N, N-dimethylaminopyridine (DMAP) The reaction is completed within a time ranging from 30 minutes to 24 hours. The compounds of the formula (M) wherein Ri, R2, Pi, R ', R "and X3 are as defined above, can be obtained by reacting the compounds of the formula (H) with a compound (S) of the formula X3-C (R ') (R ") - OC (O) X3 wherein X3 is a halogen atom. The reaction is carried out in the presence of an organic or inorganic base in a polar solvent such as DMF, THF, acetonitrile at a temperature in the range of -5 ° C to 60 ° C or in a double phase system in accordance with methods well known in the literature. The amine group of the compounds (A) is protected to give the compounds of the formula (H) wherein P 1 is a suitable amine protecting group such as tert-butyloxycarbonyl ester (t-Boc). The compounds (S) are commercially available. The compounds of the general formula (I) A- (Y-ON0) s, defined in scheme 6 as compounds of the formula (E), wherein s is 2, Y is as defined above and A is a residue of a β-adrenergic blocker of the formula (II), wherein Zi and Z are -C (O) -, the enantiomers, diastereoisomer and a pharmaceutically acceptable salt thereof, can be synthesized as shown in scheme 6.
SCHEME 6
The compounds of the formula (C) wherein Ri, R2, Z, Zi and Y are as defined above and X3 is a halogen atom, such as Cl, Br and I, are converted to compounds of the formula (E) wherein R1, R2, Z and Y are as defined above, by reaction with AgNO3 in a suitable organic solvent such as acetonitrile, tetrahydrofuran, a molar excess of silver nitrate is preferably used and the reaction is carried out, in the darkness, at temperature from room temperature and the boiling temperature of the solvent. The compounds of the formula (C) wherein R1 (R2, Z, Z- ?, Y and X3 are as defined above can be obtained by reaction of the compounds of the formula (A) with an appropriate acyl halide (Q ) of the formula X3-YC (O) CI, where X is chosen between chlorine, bromine and Y is as defined above. The reaction is carried out in an inert organic solvent such as N.N'-dimethylformamide, tetrahydrofuran, benzene, toluene, chloroform in the presence of a base such as triethylamine, pyridine at a temperature of room temperature and 50 ° C. The reaction is completed with a time interval of 30 minutes to 24 hours. Alternatively, the compounds of the formula (C) can be obtained by reaction of the compounds of the formula (A) with an acid (Q1) of the formula X3-Y-COOH in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (EDAC) and a catalytic amount of N, N-dimethylaminopyridine. The reaction is carried out in an inert organic solvent such as N, N'-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature ranging from 0 ° C to 50 ° C. The reaction is completed with a time interval of 30 minutes to 36 hours. Compounds of the formula (Q1), wherein X3 is a halogen atom are commercially available or can be obtained from the corresponding commercially available hydroxy acid by well-known reactions, for example, by reaction with thionyl chloride or oxalyl, halides of P1" or Pv in inert solvents such as toluene, chloroform, DMF, etc. The compounds (A) wherein Ri, R 2 are as defined above are commercially available The compounds of the formula (E) can also be obtained as described below The compounds of the formula A are converted to the compounds (E) by reaction with a nitroxiderivative of the formula CI (0) CY-ONO2 which contains an activated acylation group The nitroxy compounds can be obtained from the alcohols of the formula Cl (O) CY-OH by reaction with nitric acid and acetic anhydride in a temperature ranging from -50 ° C to 0 ° C or the corresponding halogen derivatives s of the formula Cl (0) C-Y-Hal by reaction with silver nitrate in the presence of an inert solvent such as acetonitrile, tetrahydrofuran. A molar excess of silver nitrate is preferably used and the reaction is carried out, in the dark, at temperature from the boiling temperature and room temperature. The reaction is completed with a time interval of 30 minutes to 3 days.
EXAMPLES
The following non-limiting examples further describe and enable one skilled in the art to make and use the present invention.
EXAMPLE 1 1- (9H-carbazol-4-yloxy) -3-fr2- (2-methoxyphenoxy) etipanamno-2-propanedic acid 4- (nitroxymethyl) benzoic acid of the formula (8)
(8)
1 a. 1- (9H-carbazol-4-yloxy) -3-y2- (2-methoxyphenoxy) -ethylamino-2- propanoate of 4- (chloromethyl) benzoic acid To a solution of carvedilol (2 g, 5 mmole) in chloroform (50 mi) were added 4-chloromethyl benzoic acid (0.9 g, 5.5 mmoles), EDAC (1.15 g, 6 mmoles) and N, N-dimethylaminopyridine (catalytic amount). The reaction was stirred at room temperature for 24 hours. The solution was treated with water and the organic layer was dried over sodium sulfate. The solvent was evaporated and the residue was purified by flash chromatography eluting with n-hexane / ethyl acetate 6/4 (Rf = 0.2). The title product 0.27 g was obtained as a white powder.
1 B. 1 - (9H-carbazol-4-yloxQ-3-rr2- (2-methoxyphenoxy) ethyl lamino 1-2-propanoate of 4- (nitroxymethyl) benzoic acid A solution of the product of example 1a (0.27 g, 0.48 mmoles) and Silver nitrate (0.16 g, 0.96 mmol) in acetonitrile (30 mL) was stirred at 60 ° C in the dark for 36 hours, the precipitate (silver salts) was filtered and the solvent was evaporated under vacuum. it was treated with chloroform and water, the organic layer was dried over sodium sulfate, the solvent was evaporated and the residue was purified by flash chromatography eluting with ethyl acetate / n-hexane 6/4, and the title product 0.03 g was obtained. as a white powder: 1 H-NMR (DMSO) d (ppm): 11.31 (1H, s), 8.15 (2H, m), 7.8-7.5 (2H, m), 7.43 (1H, d), 7.30 (2H, m), 7.15-6.85 (7H, m), 6.77 (1Hd), 6.03 (1H, m), 5.65 (2H, s), 4.55 (2H, m), 4.33 (2H, m), 4.0-3.7 ( 5H, m); 3.51 (2H, m).
EXAMPLE 2 1- (9H-carbazol-4-yloxy) -3-ff2- (2-methoxyphenoxy) -etipr (4-nitroxymethyl) benzoyH-aminol-2-propanoate of 4- (nitroxymethyl) benzoic acid of the formula (11)
(11) 2a. 1- (9H-carbazol-4-yloxy-V3-y2- (2-methoxyphenoxy) -ethy (4-chloromethyl) -benzoylamino-2-propanoic acid 4- (chloromethyl) benzoic acid To a solution of carvedilol (2 g, 5 mmol) in chloroform (50 ml), 4-chloromethyl benzoic acid (0.9 g, 5.5 mmol), EDAC (1.15 g, 6 mmol) and N, N-dimethylaminopyridine (catalytic amount) were added.The reaction was stirred for 24 hours at room temperature The solution was treated with water and the organic layer was dried over sodium sulfate and filtered, the solvent was evaporated and the residue was purified by flash chromatography eluting with n-hexane / ethyl acetate 1/1 (Rf = 0.42). The title product (0.06 g) was obtained as a white powder.
2b. 1- (9H-carbazol-4-yloxy) -3-rr2- (2-methoxyphenoxy) ethyl (4-nitroxymethyl-benzoipaminol-2-propanoate of 4- (nitroxymethyl) benzoic acid) A solution of the product of example 2a (0.06 g) 0.08 mmol) and silver nitrate (0.06 g, 0.32 mmol) in acetonitrile (20 ml) was stirred at 60 ° C. in the dark for 36 hours, the precipitate (silver salts) was removed by filtration. The mixture was concentrated and the residue was treated with chloroform and water, the extracts of the combined organic layer were dried over sodium sulfate and filtered, the solvent was evaporated and the residue was purified by flash chromatography eluting with n-hexane / ethyl acetate. 6/4 The title product 0.015 g was obtained as a powder: 1 H-NMR (DMSO) d (ppm): 1.24 (1H, s); 8.1 (3H, m); 7.7-7.2 (8H, m); 7.2-6.7 (8H, m), 6.05 (1H, m), 5.6-5.8 (4H, d), 4.55 (1H, m), 4.30 (2H, m), 4.15 (3H, m), 3.71 ( 5H, s).
EXAMPLE 3 1- (9H-carbazol-4-yloxQ-3-rr2- (2-methoxyphenoxyetipr (4-nitroxymethyl) benzoxynamino-2-propanol of the formula (15)
(15) 3 1- (9H-carbazol-4-yloxy) -3-rr2- (2-methoxyphenoxy) etn (4-chloromethyl) benzoylamino-1-propanol To a solution of carvedilol (2 g, 5 mmol) ) in chloroform (50 ml) were added 4-chloromethylbenzoic acid (0.9 g, 5.5 mmol), EDAC (1.15 g, 6 mmol) and N, N-dimethylaminopyridine (catalytic amount). The reaction was stirred for 24 hours at room temperature. The solution was treated with water and the organic layer was dried over sodium sulfate and filtered. The solvent was evaporated and the residue was purified by flash chromatography eluting with n-hexane / ethyl acetate 6/4 (Rf = 0.42). The title product 1.05 g was obtained as a white powder.
3b. 1- (9H-carbazol-4-yloxy) -3-y2- (2-methoxyphenoxy) -ethyl-4-nitroxymethyl) benzoylamino-1-propanol A solution of the product of example 3a (1.0 g, 1.78 mmol) and silver nitrate (0.6 g, 3.6 mmol) in acetonitrile (100 ml) was stirred at 65 ° C, in the dark, for 32 hours. The precipitate (silver salts) was removed by filtration. The filtrate was concentrated and the residue was treated with methylene chloride and water. The extracts of the combined organic layer were dried over sodium sulfate. The solvent was evaporated and the residue was purified by flash chromatography eluting with n-hexane / ethyl acetate 1/1. The title product 0.4 g was obtained as a yellow powder. 1 H-NMR (DMSO) d (ppm): 11.24 (1 H, s); 8.40-6.50 (15H, m); 5.61 (2H, m); 5.51 (1 H, m); 5.36 (1 H, m); 4.40-3.90 (4H, m); 3.74-3.71 (7H, m).
EXAMPLE 4 1- (9H-carbazol-4-yloxy) -3- and [2- (2-methoxyphenoxy) etipf (3-nitroxypropanoyl) aminol-2-propanol of the formula (112)
The compound was synthesized under the analogous procedure described in Example 3 starting from carvedilol and 3-bromopropanoic acid. H NMR (DMSO) d (ppm): 11.24 (1 H, s); 8.25 (1 H, dd); 7.46 (1 H, dd); 7.29 (2H, m); 7.08 (2H, m); 6.90 (4H, m); 6.70 (1 H, dd); 5.50 (1 H, d); 4.80 (2H, m); 4.35 (1 H, m); 4.20-3.6 (9H, m); 3.6-2.8 (4H, m).
EXAMPLE 5 1- (9H-carbazol-4-yloxy) -3-rf2- (2-methoxyphenoxy) etiF) f (6-nitroxyhexanoyl) aminol-2-propanol of the formula (113)
The compound was synthesized under the analogous procedure described in Example 3 starting from carvedilol and 6-bromohexanoic acid. 1 H-NMR (DMSO) d (ppm): 11.24 (1 H, s); 8.25 (1 H, dd); 7.46 (1 H, dd); 7.29 (2H, m); 7.08 (2H, m); 6.90 (4H, m); 6.70 (1 H, dd); 5.40 (1H, d); 4.50-3.50 (13H, m); 2.6-2.3 (2H, m); 1.70-0.50 (6H, m).
EXAMPLE 6 1- (9H-carbazol-4-yloxy) -3-rr2- (2-methoxyphenoxy) etin-r (6-nitroxyhexanoin aminol-2-propanol of 6- (nitrox-hexanoic acid of the formula (111)
The compound was synthesized under the analogous procedure described in Example 2 starting from carvedilol and 6-bromohexanoic acid.
1 H-NMR (DMSO) d (ppm): 11.24 (1 H, s); 8.15 (1 H, dd); 7.46 (1 H, dd); 7.29 (2H, m); 7.08 (2H, m); 6.90 (4H, m); 6.70 (1 H, dd); 5.65 (1 H, m); 4.6-4.20 (6H, m); 4.2-3.5 (9H, m); 2.50 (2H, m); 2.29 (2H, m); 1.70-0.60 (2H, m).
EXAMPLE 7 6- (Nitroxy) hexanoic acid 1- (9H-carbazol-4-yloxy) -3-f [2- (2-methoxyphenoxy)) etipamino'l-2-propanol hydrochloride of the formula (110)
The compound was synthesized under the analogous procedure described in Example 1 starting from carvedilol and 6-bromohexanoic acid. 1 H-NMR (DMSO) d (ppm): 11.30 (1 H, s); 8.15 (1 H, dd); 7.44 (1 H, dd); 7.32 (2H, m); 7.10-6.90 (6H, m); 6.70 (1 H, dd); 5.65 (1 H, m); 4.50-4.20 (7H, m); 3.90-3.40 (7H, m); 2.40 (2H, m); 1.60-1.10 (6H, m).
EXAMPLE 8 Measurements of cGMP in rat PC12 cell line
CGMP contributes to the function and interaction of several types of vascular cells and its dysfunction is implicated in major cardiovascular diseases such as hypertension, diabetic complications, atherosclerosis, and tissue infarction. Therefore, the degree of cGMP formation induced by the compounds of the inventions was evaluated in the rat pheochromocytoma (PC12) cell line.
Test compounds 1) Carvedilol (parent drug) 2) 1 - (9H-carbazol-4-yloxy) -3 - [[2- (2-methoxyphenoxy) ethyl] [(4-nitroxymethyl) benzoyl] aminoj-2-propanol (composed of example 3); 3) 1- (9H-carbazol-4-yloxy) -3 - [[2- (2-methoxyphenoxy) ethyl] amino] -2-propanoate of 4- (nitroxymethyl) benzoic acid (compound of Example 1); 4) 1- (9H-carbazol-4-yloxy) -3 - [[2- (2-methoxyphenoxy) ethyl] [(3-nitroxypropanoyl) amino] -2-propanol (compound of example 4); 5) 1- (9H-carbazol-4-yloxy) -3 - [[2- (2-methoxyphenoxy) ethyl] [(6-nitroxyhexanoyl) amino] -2-propanol (compound of example 5).
Method Cells were maintained at 37 ° C in DMEM medium enriched with 10% horse serum and 5% fetal bovine serum under 5% C02 atmosphere. At the time of the experiments, the cells were washed once with Hank's balanced salt solution (HBSS) supplemented with 0.05% ascorbic acid and preincubated in the same pH regulator for 10 minutes in a floating water bath. After the preincubation step, the cells were exposed for an additional 45 minutes either to control conditions or increase in the concentrations of the test compounds from 0.1 to 25 μM, in the presence of the phosphodiesterase inhibitor, IBMX (100 μM) and the activator of soluble guanylyl cyclase NO, YC-1 (20 μM). The reaction was terminated by the removal of the incubated pH regulator and the consecutive addition of 100 μl of absolute ethanol. The organic extracts were then evaporated to dryness and the residues were dissolved in aqueous pH buffer for quantitative determination of intracellular cGMP levels using the cGMP enzyme immunoassay kit. The results obtained reported in table 1 are expressed as CE5o (μM) and Emax efficiency (% of vehicle). As shown in the table, nitroxy derivatives of carvedilol induce a consistent increase in intracellular cGMP formation in PC12 cell line. On the contrary, this effect was not induced by the parent compound.
TABLE 1 Effects of the nitroxy derivatives of carvedilol and carvedilol on the accumulation of cGMP in PC12 cells
Claims (1)
- NOVELTY OF THE INVENTION CLAIMS 1. A compound of the general formula A- (Y-ON02) s (I) and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof, wherein s is an integer equal to 1 or 2; A is selected from the following β-adrenergic blocker residues of the formula (ii): (II) where Ri is selected from the group consisting of: (lia) (llb) (»c) (iig) (llh) (lli) (IIL) R2 is selected from the group consisting of: -CH (CH3) 2, -C (CH3) 3 or (Illa) (lllb) when the radical Ri has been chosen from the formulas (lia), (lie), (lid), (llg), (llh), (lli), (llm), R2 is-CH (CH3 )2; when the radical Ri has been chosen from the formulas (lie), (llf) or (Un), R2 is -C (CH3) 3; when R-i is the radical (llb), R2 is (Illa); when Ri is the radical (IIL), R is (lllb); Z is H or is a group capable of joining Y selected from the group consisting of: -C (O) -, -C (0) O- or wherein R 'and R "are the same or different, and are H or straight or branched chain C 1 -C 4 alkyl, Zi is H or a -C (O) - capable of binding to Y; with the proviso that when s of formula (I) is 1, Z or Z. is H; Y is a bivalent radical having the following meanings: a) - straight or branched chain C-C2 alkylene, optionally substituted with one or more of substituents selected from the group consisting of: halogen, hydroxy, -ONO2 or T atoms, wherein T is -OC (O) (C -C0 alkyl) -ONO2, -O (CrC? ) -ONO2; b) - cycloalkylene with 5 to 7 carbon atoms in cycloalkylene ring, the ring being optionally substituted with Ti side chains, wherein Ti is straight or branched chain alkyl with 1 to 10 carbon atoms, ) where: n is an integer from 0 to 20, n1 is an integer from 1 to 20; n2, n3, n4 and n5 are integers equal or different from each other, equal to 0 or 1; R3 and R4 are independently selected from H or CH3; Y1 is -CH2- or - (CH2) na-CH = CH-wherein na is an integer from 0 to 20; X, is -WC (O) - or -C (0) W-, wherein W is oxygen, sulfur or NH; d) (V) where: n1 is an integer from 1 to 20; X-, is -WC (O) - or -C (O) W-, wherein W is oxygen, sulfur or NH; n6 is an integer from 1 to 20, n7 is an integer from 0 to 20, R5, R5, R6 and R6 are independently selected from the group consisting of: H, CH3, OH, NH2, NHCOCH3, COOH, CH2SH and C ( CH3) 2SH; when the bond between the CA and CB carbons is a double bond, R5 and R6 or R6 'and R5' are absent; when Y is selected from the divalent radicals mentioned under c) -d), the -ONO2 group is linked to the group - (CH2) nr; and) (SAW) (VII) where X2 is O or S, n10a, n10 and n12 are integers independently selected from 0 to 20, n11 is an integer from 0 to 6; R11 is H, CH3 or nitroxy group; R11a is CH3 or nitroxy group; f) (vm) where nd is an integer from 0 to 10; n9 is an integer from 1 to 10; R9, R10, R8, R7 are the same or different, and are H or straight or branched chain C4 alkyl; where the group -ONO2 is linked to | ng where n9 is as defined above; Y2 is a saturated, unsaturated or aromatic 5 or 6 membered heterocyclic ring, which contains one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from the group consisting of (Y6) (Y7) < Y8) (Y9) (Y10) (Y11) (Y12) (Y13) 2. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 1, further characterized in that s is 2 and Z and Zi they are -C (O) -. 3. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 2, further characterized in that Y is alkylene of C- or C20 straight or branched chain being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, -ON02 or T, wherein T is -OC (0) (C 10 alkyl) -ONO 2. 4. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 3, further characterized in that Y is a straight or branched chain C1-C10 alkylene. 5. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 2, further characterized in that Y is (IV) wherein: n is an integer from 0 to 20, n1 is an integer from 1 to twenty; n2, n3, n4 and n5 are integers equal or different from each other, equal to 0 or 1; R3 and R4 are independently selected from H or CH3; Y1 is -CH2- or - (CH2) na-CH = CH-wherein na is an integer from 0 to 20; X-, is -WC (O) - or -C (0) W-, where W is oxygen, sulfur or NH. 6. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 5, further characterized in that n2, n3, n4, n5 are equal to 0, n1 is -1, n is an integer from 0 to 10, Y1 is CH2. 7. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 5, further characterized in that n, n2, n5 are 1, n3 and n4 are equal to 0, and n1 is an integer of 1 to 10, Y is - (CH2) na-CH = CH- where na is 0, X. is -WC (O) -where W is oxygen and Xi is linked to the phenyl ring through [C], R is CH3 and the group (OR4) is linked to the phenyl ring through [C] 3. 8. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 2, further characterized in that Y is (VI) (Vile) wherein X2 is O or S, n10a, n10 and n12 are integers independently selected from 0 to 20; n11 is an integer from 0 to 6; R11 is H, CH3 or nitroxy group; R11a is CH3 or nitroxy group. 9. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 8, further characterized in that Y is (VI) wherein X2 is O or S, n10a is an integer from 0 to 10, n11 is 0, n12 is an integer from 1 to 10, R11 is H or a nitroxy group; wherein the group -ONO2 joins (CH2) n12; 10. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 2, further characterized in that Y is (V) wherein: n1 is an integer from 1 to 20; X ^ is -WC (O) - or -C (0) W-, wherein W is oxygen, sulfur or NH; n6 is an integer from 1 to 20; n7 is an integer from 0 to 20; R5, R5 ', R6 and R6 are independently selected from the group consisting of: H, CH3, OH, NH2, NHCOCH3, COOH, CH2SH and C (CH3) SH; when the bond between the CA and CB carbons is a double bond, R5 and R6 or R6 'and R5' are absent; 11. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 10, further characterized in that n1 is an integer from 1 to 10, n6 and n7 are 1; Xi is -WC (O) - where W is sulfur; R5, R5 'and R6' are H, R6 is NHCOCH3; with the proviso that the group -ONO2 joins the group - (CH2) n .-. 12. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 1, further characterized in that s is equal to 1, A is selected from the following residues of β-adrenergic blockers of the formula (II) : di) where R. is selected from the group consisting of: (Ha) (He) (iig) (llh) (lli) (IUI) (llm) (Un) R2 is selected from the group consisting of: -CH (CH3) 2, -C (CH3) 3 or (lllb) when the radical Ri has been chosen from the formulas (lia), (He), (lid), (llg), (llh), (lli), (llm), R2 is -CH (CH3) 2; when the radical R-i has been chosen from the formulas (lie), (llf) or (Un), R2 is -C (CH3) 3; when R is the radical (IIb), R2 is (IIIb); Z is a group capable of joining Y selected from the group consisting of: -C (O) -, -C (0) 0- or YXr O where R 'and R "are the same or different, and are H or straight or branched chain C 1 -C 4 alkyl, Z 1 is H and Y is a bivalent radical having the following meanings: c) (! V) where: n is an integer from 0 to 20, n1 is an integer from 1 to 20; n2, n3, n4 and n5 are integers equal or different from each other, equal to 0 or 1; R3 and R4 are independently selected from H or CH3; Y1 is -CH2- or - (CH2) na-CH = CH- where na is an integer from 0 to 20; Xi is -WC (O) - or -C (O) W-, wherein W is oxygen, sulfur or NH; and) (VI) '(VII) wherein X2 is O or S, n10a is 0 or 1, n11 is 0 or 1, n10 and n12 are 1 or 2; R11 is H, CH3 or nitroxy group; R11a is CH3 or nitroxy group; F) (Víll) where: nd is an integer from 0 to 10; n9 is an integer from 1 to 10; R9, R0, R8, R7 are the same or different, and are H or straight or branched chain CrC alkyl; where the group -ONO2 is linked to I - [C] I p9 where n9 is as defined above; Y2 is a saturated, unsaturated or aromatic 5 or 6 membered heterocyclic ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from the group consisting of (Y1) (Y2) (Y3) (Y4) (Y5) (Y11) (Y12) (Y13) 13. - The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 12, further characterized in that Z is -C (O) -. 14. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claims 12 and 13, further characterized in that Y is (IV) where n is an integer from 0 to 20, and n1 is an integer from 1 to 20; n2, n3, n4 and n5 are integers equal or different from each other, equal to 0 or 1; R3 and R4 are independently selected from H or CH3; Y1 is -CH2- or - (CH2) na-CH = CH-wherein na is an integer from 0 to 20; X ^ is -WC (O) - or -C (O) W-, where W is oxygen, sulfur or NH. 15. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 14, further characterized in that n2, n3, n4, n5 are equal to 0, n1 is 1, n is an integer from 0 to 10 , Y1 is CH2. 16. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 14, further characterized in that n, n2, n5 are 1, n3 and n4 are equal to 0, n1 is an integer from 1 to 10 , Y1 is - (CH2) na-CH = CH- where na is 0, ^ is -WC (O) -where W is oxygen and X1 is linked to the phenyl ring through [C], R4 is CH3 and the group (OR4) is linked to the phenyl ring through [C] 3. 17. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claims 12 and 13, further characterized in that Y is (VI) where X2 is O or S, n10a and n11 are 0, n12 is 1, R11 is H; wherein the -ON02 group is linked to the group - (CH2) ni2--18. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 12, further characterized in that Z is -C (0) 0-, 19.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claims 12 and 18, further characterized in that Y is (IV) where n is an integer from 0 to 20, and n1 is an integer from 1 to 20; n2, n3, n4 and n5 are integers equal or different from each other, equal to 0 or 1; R3 and R4 are independently selected from H or CH3; Y1 is -CH2- or - (CH2) na-CH = CH-wherein na is an integer from 0 to 20; Xi is -WC (O) - or -C (0) W-, where W is oxygen, sulfur or NH. 20. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 19, further characterized in that n2, n3, n4, n5 are equal to 0, n1 is 1, n is an integer from 0 to 10 , Y1 is CH2. 21. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claims 12 and 18, further characterized in that Y is (VI) wherein X2 is O or S, n10a and n11 are 0, n12 is 1 , R11 is H; wherein the group -ON02 is linked to the group - (CH2) n-? 2-. 22. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 12, further characterized in that Z is 23. - The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claims 12 and 22, further characterized in that Y is (IV) where n is an integer from 0 to 20, n1 is an integer from 1 to 20; n2, n3, n4 and n5 are equal to 0; Y1 is -CH2-. 24. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 23, further characterized in that n is 0 and n1 is 1. 25.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claims 12 and 22, further characterized in that Y is (VI) where X2 is O or S, n10a and n11 are 0, n12 is 1, R is-H; wherein the group -ONO2 is linked to the group - (CH2) n? 2 - 26.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 1, further characterized in that s is 1, Z is H and Zi are -C (O) -. 27. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 26, further characterized in that Y is a straight or branched chain C-C2 alkylene being optionally substituted with one or more of the substituents selected from the group consisting of a group consisting of halogen, hydroxy, -ON02 or T atoms, wherein T is -OC (0) (CC? oalkyl) -ON02, -0 (CC? oalkyl) -ON02. 2d.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 27, further characterized in that Y is a straight or branched chain C 1 -C 10 alkylene. 29. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 26, further characterized in that Y is (! V) where n is an integer from 0 to 20, n1 is an integer from 1 to 20; n2, n3, n4 and n5 are integers equal or different from each other, equal to 0 or 1; R3 and R4 are independently selected from H or CH3; Y1 is -CH2-o- (CH2) na-CH = CH-wherein na is an integer from 0 to 20; Xi is -WC (O) - or-C (O) W-, where W is oxygen, sulfur or NH. 30. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 29, further characterized in that n2, n3, n4, n5 are equal to 0, n1 is 1, n is an integer from 0 to 10, Y1 is CH2. 31. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 29, further characterized in that n, n2, n5 are 1, n3 and n4 are equal to 0, n1 is an integer from 1 to 10 , Y1 is - (CH2) na-CH = CH- where na is 0, X. is -WC (O) -where W is oxygen and Xi is linked to the phenyl ring through [C] 4, R4 is CH3 and the group (OR4) is linked to the phenyl ring through [C] 3. 32. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 26, further characterized in that Y is (VI) ' (Vile) wherein X2 is O or S, n10a, n10 and n12 are integers independently selected from 0 to 20; n11 is an integer from 0 to 6; R11 is H, CH3 or a nitroxy group; R11a is CH3 or a nitroxy group. 33. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 32, further characterized in that Y is (VI) wherein X2 is O or S, n10a is 0 or 1, n11 is 0 or 1, n10 and n12 are 1 or 2, R11 is H or nitroxy; wherein the group -ONO2 is linked to the group - (CH2) ni2--34.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 26, further characterized in that Y is (V) wherein : n1 is an integer from 1 to 20; X ^ is -WC (O) - or a -C (0) W-, where W is oxygen, sulfur or NH; n6 is an integer from 1 to 20, n7 is an integer from 0 to 20, R5 and R5 'R6 and R6' are independently selected from the group consisting of: H, CH3, OH, NH2, NHCOCH3, COOH, CH2SH and C (CH3) 2SH; when the bond between the carbon atoms CA and CB is a double bond, R5 and R6 or R6 'and R5 are absent. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 34, further characterized in that n1 is an integer from 1 to 10, n6 and n7 are 1; X. is -WC (O) - where W is sulfur; R5, R5 'and R6' are H, R6 is NHCOCH3; with the proviso that the group -ONO2 is linked to - (CH2) n .-. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 1, further characterized in that s is an integer equal to 1 or 2; A is the β-adrenergic blocker residues of the formula (II): (Or where R-i is (llb) R2 is (Illa) Z is H or is a group capable of binding to Y selected from the group consisting of: -C (O) -, -C (O) O- or wherein R 'and R "are the same or different, and are H or straight or branched chain CrC alkyl, Zi is H or a group -C (O) - capable of binding to Y, with the proviso that when s of the formula (I) is 1, Z or Zi is H; Y is a bivalent radical having the following meaning: a) - straight or branched chain C-C20 alkylene being optionally substituted with one or more of the substituents selected from the group consisting of: halogen, hydroxy, -ONO2 or T atoms, wherein T is -OC (O) (CC? oalkyl) -ON02, -C (CC? oalkyl) -ON02; b) - cycloalkylene with 5 to 7 carbon atoms in the cycloalkylene ring, the ring being optionally substituted with side chains T1, wherein T1 is straight or branched chain alkyl with 1 to 10 carbon atoms; (IV) where: n is an integer from 0 to 20, n1 is an integer from 1 to 20; n2, n3, n4 and n5 are integers equal or different from one another, equal to 0 or 1, R3 and R4 are independently selected from H or CH3, Y1 is -CH2-o- (CH2) na-CH = CH-in where na is an integer from 0 to 20; Xi is -WC (O) - or -C (0) W-, wherein W is oxygen, sulfur or NH; d) (V) wherein: n1 is an integer from 1 to 20, Xi is -WC (O) - or -C (0) W-, where W is oxygen, sulfur or NH; n6 is an integer from 1 to 20, n7 is an integer from 0 to 20, R5, R5 ', R6 and R6' are independently selected from the group consisting of: H, CH3l OH, NH2, NHCOCH3lCOOH, CH2SH and C ( CH3) 2SH; when the bond between the carbons CA and CB is a double bond R5 and R6 or R6 'and R5 are absent; when Y is selected from the divalent radicals mentioned under c) -d), the group -ONO2 is linked to the group - (CH2) n.-; and) (SAW) (Vile) wherein X2 isO or S, n10a, n10 and n12 are integers independently selected from 0 to 20, n11 is an integer from 0 to 6; R11 is H, CH3 or nitroxy group; R11a is CH3 or nitroxy group; F) (viii) where: nd is an integer from 0 to 10; n9 is an integer from 1 to 10; R9, R10, R8, R7 are the same or different, and are H or straight or branched chain C1-C4 alkyl; where the group -ONO2 is linked to I I.9 where n9 is as defined above; Y2 is a saturated, unsaturated or aromatic 5 or 6 membered heterocyclic ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from the group consisting of: (Y11) (Y12) (Y13) 37. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 36, further characterized in that s is 2 and Z and Z-i are-C (O) -. 38.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 37, further characterized in that Y is a straight or branched chain C- or C2o alkylene being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, -ON02 or T, wherein T is -OC (0) (CrC10 alkyl) -ON? 2, -0 (CrC? o alkyl) -ON02. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 38, further characterized in that Y is a straight or branched chain C3-C6 alkylene. 40.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 37, further characterized in that Y is (IV) where n is an integer from 0 to 20, n1 is an integer from 1 to 20; n2, n3, n4 and n5 are integers equal or different from each other, equal to 0 or 1; R3 and R4 are independently selected from H or CH3; Y1 is -CH2- or - (CH2) na-CH = CH-wherein na is an integer from 0 to 20; X1 is -WC (O) - or -C (O) W-, where W is oxygen, sulfur or NH. 41. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 40, further characterized in that n2, n3, n4, n5 are equal to 0, n1 is 1, n is an integer from 0 to 10 , Y1 is CH2. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 40, further characterized in that n, n2, n5 are 1, n3 and n4 are equal to 0, and n1 is an integer of 1 to 10, Y1 is - (CH2) na-CH = CH-where na is 0, X1 is - WC (O) - where W is oxygen and Xi is linked to the phenyl ring through [C], R4 is CH3 and the group (OR) is linked to the phenyl ring through [Cj3. 43.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 37, further characterized in that Y is (SAW) (Vile) wherein X2 is O or S, n10a, n10 and n12 are integers independently selected from 0 to 20; n11 is an integer from 0 to 6; R11 is H, CH or a nitroxy group; R11a is CH3 or a nitroxy group. 44.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 43, further characterized in that Y is (VI) wherein X2 is O or S, n10a is an integer from 0 to 10, n11 is 0, n12 is an integer from 1 to 10, R11 is H or a nitroxy group; wherein the group -ONO2 is linked to group- (CH2) ni2-45.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 37, further characterized in that Y is (V) where: n1 is an integer from 1 to 20; Xi is -WC (O) - or a -C (O) W-, where W is oxygen, sulfur or NH, n6 is an integer from 1 to 20, n7 is an integer from 0 to 20, R5, R5 ', R6 and R6 are independently selected from the group consisting of: H, CH3, OH, NH2, NHCOCH3, COOH, CH2SH and C (CH3) 2SH; when the bond between the carbons CA and CB is a double bond, R5 and R6 or R6 'and R5' are absent. 46.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof in accordance with the claim 45, further characterized in that n1 is an integer from 1 to 10, n6 and n7 are 1; X1 is -WC (O) - where W is sulfur; R5, R5 'and R6' are H, R6 is NHCOCH3; with the proviso that the group -ON02 is linked to - (CH2) n .-. 47.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof in accordance with the claim 36, further characterized in that s is 1, Z is H and Z are -C (O) -. 48.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof in accordance with the claim 47, further characterized in that Y is a straight or branched chain C 1 -C 20 alkylene being optionally substituted with one or more of the substituents selected from the group consisting of halogen atoms, hydroxy, -ONO 2 or T, wherein T is - OC (O) (CrC10 alkyl) -ONO2. - (CrC10 alkyl) -ONO2. 49.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof in accordance with the claim 48, further characterized in that Y is straight or branched chain C 1 -C 10 alkylene. 50.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 47, further characterized in that Y is (IV) where n is an integer from 0 to 20, n1 is an integer from 1 to 20; n2, n3, n4 and n5 are integer or equal to each other, equal to 0 or 1; R3 and R4 are independently selected from H or CH3; Y1 is -CH2-o- (CH2) na-CH = CH-wherein na is an integer from 0 to 20; X1 is -WC (O) - or -C (0) W-, where W is oxygen, sulfur or NH. 51. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 50, further characterized in that n2, n3, n4, n5 are equal to 0, n1 is 1, n is an integer from 0 to 10 , Y1 is CH2. 52. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 50, further characterized in that n, n2, n5 are 1, n3 and n4 are equal to 0, n1 is an integer from 1 to 10 , Y1 is - (CH2) na-CH = CH- where na is 0, X ^ is -WC (O) - where W is oxygen and X. is linked to the phenyl ring through [C], R4 is CH3 and the group (OR4) is linked to the phenyl ring through [C] 3. 53. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 47, further characterized in that Y is (VI) '(VII) where X2 is O or S, n10a, n10 and n12 are integers independently selected from 0 to 20; n11 is an integer from 0 to 6; R11 is H, CH3 or a nitroxy group; R11a is CH3 or a nitroxy group. 54.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 53, further characterized in that Y is (VI) where X2 is O or S, n10a and n11 are 0 or 1, n12 is 1, R1 is H; wherein the group -ON02 is linked to the group - (CH2) n .2--55.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 47, further characterized in that Y is (V) where: n1 is an integer from 1 to 20; X-i is -WC (O) - or a -C (0) W-, where W is oxygen, sulfur or NH; n6 is an integer from 1 to 20, n7 is an integer from 0 to 20, R5 and R5 R6 and R6 are independently selected from the group consisting of: H, CH3, OH, NH2, NHCOCH3, COOH, CH2SH and C (CH3 ) 2SH; when the bond between the carbons CA and CB is a double bond, R5 and R6 or R6 'and R5' are absent. 56. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 55, further characterized in that n1 is an integer from 1 to 10, n6 and n7 are 1; X1 is -WC (O) - where W is sulfur; R5, R5 'and R6' are H, R6 is NHCOCH3; with - the condition that the -ON02 group is linked to - (CH2) nr- 57.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof in accordance with the claim 36, further characterized in that s is 1, Zi is H and Z-C (O) -. 58.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof in accordance with the claim 57, further characterized in that Y is straight or branched chain C 1 -C 2 alkylene being optionally substituted with one or more of the substituents selected from the group consisting of halogen atoms, hydroxy, -ONO 2 or T, wherein T is - OC (O) (C 1 -C 0 alkyl) -ONO 2, -O (C 1 -C 0 alkyl) -ONO 2. 59. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof in accordance with the claim 58, further characterized in that Y is a straight or branched chain C3-C6 alkylene. 60.- The compound and the enantiomers, diastereomers and pharmaceutically acceptable salts thereof according to claim 57, further characterized in that Y is (IV) where n is an integer from 0 to 20, n1 is an integer from 1 to 20; n2, n3, n4 and n5 are integers equal or different from each other, equal to 0 or 1; R3 and R4 are independently selected from H or CH3; Y1 is -CH2- or - (CH2) na-CH = CH-wherein na is an integer from 0 to 20; X. is -WC (O) - or -C (0) W-, where W is oxygen, sulfur or NH. 61.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 60, further characterized in that n2, n3, n4, n5 are equal to 0, n1 is 1, n is an integer from 0 to 10 , Y1 is CH2. 62.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 60, further characterized in that n, n2, n5 are 1, n3 and n4 are equal to 0, and n1 is an integer of 1 to 10, Y1 is - (CH2) na-CH = CH-wherein na is 0, Xi is -WC (O) - wherein W is oxygen and Xi is linked to the phenyl ring through [C] 4, R4 is CH3 and the group (OR4) is linked to the phenyl ring through [C] 3. 63.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 57, further characterized in that Y is (SAW) (VII) where X2 is O or S, n10a, n10 and n12 are integers independently selected from 0 to 20; n11 is an integer from 0 to 6; R11 is H, CH3 or a nitroxy group; R11a is CH3 or a nitroxy group. 64.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 63, further characterized in that Y is (VI) where X2 is O or S, n10a and n11 are 0, n12 is 1, R11 is H; where the group -ONO2 is linked to group - (CH2) n12-. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 57, further characterized in that Y is (V) where: n1 is an integer from 1 to 20; Xi is -WC (O) - or a -C (0) W-, where W is oxygen, sulfur or NH, n6 is an integer from 1 to 20, n7 is an integer from 0 to 20, R5, R5, R6 and R6 are independently selected from the group consisting of: H, CH3, OH, NH2, NHCOCH3, COOH, CH2SH and C (CH3) 2SH; when the bond between the carbon atoms CA and CB is a double bond, R5 and R6 or R6 'and R5 are absent. 66.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof in accordance with the claim 65, further characterized in that n1 is an integer from 1 to 10, n6 and n7 are 1; Xi is -WC (O) - where W is sulfur; R5, R5 'and R6' are H, R6 is NHCOCH3; with the proviso that the -ON02 group is linked to - (CH2) n? -. 67.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof in accordance with the claim 36, further characterized in that s is 1, Zi is H and Z-C (O) O-. 68.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof in accordance with the claim 67, further characterized in that Y is a straight or branched chain C? -C20 alkylene being optionally substituted with one or more of the substituents selected from the group consisting of halogen atoms, hydroxy, -ON02 or T, wherein T is -OC (0) (CC-alkyl) -ON02, -C (C? -C? Alkyl) -ONO2. 69.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof in accordance with the claim 68, further characterized in that Y is straight or branched chain C1-C10 alkylene. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 67, further characterized in that Y is (IV) wherein n is an integer from 0 to 20, n1 is an integer from 1 to 20; n2, n3, n4 and n5 are integers equal or different from each other, equal to 0 or 1; R3 and R4 are independently selected from H or CH3; Y1 is -CH2-o- (CH2) na-CH = CH-wherein na is an integer from 0 to 20; Xi is -WC (O) - or -C (0) W-, where W is oxygen, sulfur or NH. 71.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 70, further characterized in that n2, n3, n4, n5 are equal to 0, n1 is 1, n is an integer from 0 to 10 , Y1 is CH2. 72. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 70, further characterized in that n, n2, n5 are 1, n3 and n4 are equal to 0, n1 is an integer from 1 to 10 , Y1 is - (CH2) pa-CH = CH- where na is 0, Xi is -WC (O) -where W is oxygen and Xi is linked to the phenyl ring through [C] 4, R4 is CH3 and the group (OR4) is linked to the phenyl ring through [C] 3. 73.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 67, further characterized in that Y is (VI) ' (VII) wherein X2 is O or S, n10a, n10 and n12 are integers independently selected from 0 to 20; n11 is an integer from 0 to 6; R11 is H, CH3 or a nitroxy group; R11a is CH3 or a nitroxy group. 74.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts of! same according to claim 73, further characterized because Y is (VI) wherein X2 is O or S, n10a is 0 or 1, n11 is 0 or 1, n12 is 1 or 2, R11 is H; wherein the group -ONO2 is linked to group - (CH2) n? 2-. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 67, further characterized in that Y is (V) wherein: n1 is an integer from 1 to 20; Xi is -WC (O) - or a -C (O) W-, where W is oxygen, sulfur or NH, n6 is an integer from 1 to 20, n7 is an integer from 0 to 20, R5, R5 ' , R6 and R6 'are independently selected from the group consisting of: H, CH3, OH, NH2, NHCOCH3, COOH, CH2SH and C (CH3) 2SH; when the bond between the carbons CA and CB is a double bond R5 and R6 or R6 'and R5' are absent. 76.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof in accordance with the claim 75, further characterized in that n1 is an integer from 1 to 10, n6 and n7 are 1; Xi is -WC (O) - where W is sulfur; R5, R5 'and R6' are H, R6 is NHCOCH3; with the proviso that the -ONO2 group is linked to - (CH2) n? -. 77.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claims 36 further characterized because s is 1, Zi is H and Z is 78. - The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 77, further characterized in that Y is (IV) where n is an integer from 0 to 20, n1 is an integer from 1 to 20; n2, n3, n4 and n5 are equal to 0; Y1 is -CH2. 79. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 10 78, further characterized in that n is 0 and n1 is 1. 80.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts of the same according to claim 77, further characterized in that Y is T 5 (VI) wherein X2 is O or S, n10a and n11 are 0, n12 is 1, R11 is H; where the group -ON02 is linked to group - (CH2) ni2-. 81. The compounds and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to any of claims 36 and 57 to 67, further characterized in that the compounds are: (27) 82. - The compounds and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to any of claims 12 to 17, further characterized in that the compounds are: (49) (49) (57) (58) (62) (56) (67) (71) (75) (94) (98) (102) (106) 83. The compounds and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to any of claims 36 and 67 to 76, further characterized in that the compounds are: (21) (22) (23) (24) (25) 84. - The compounds and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to any of claims 36 to 46, further characterized in that the compounds are: (5) (10) (2) (11) (13) (26) (28) 85.- The compounds and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to any of claims 2 to 11, further characterized in that the compounds are: (33) (37) (41) (50) (51) (60) (63) (68) (69) (78) (82) (103) (104) (107) 86. The compounds and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to any of claims 36 and 47 to 55 further characterized in that the compounds are : (3) (6) (12) (14) (15) (112) (113) (17) (19) (29) 87. The compounds and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to any of claims 26 to 35, further characterized in that the compounds are: (34) (35) (38) (43) (44) (47) (52) (55) (56) (61) (70) (88) (80) (83) (105) (108) (109) 8d.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claims 36 and 47, further characterized in that it is 1- (9H-carbazol-4-yloxy) -3 - [[2- (2- methoxyphenoxy) ethyl] amino] -2-propanoate of 4- (nitroxomethyl) benzoic acid. d9.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claims 36 and 57, further characterized in that it is 1- (9H-carbazol-4-yloxy) -3 - [[2- (2- methoxyphenoxy) ethyl] [(4-nitroxymethyl) benzoyl] amino-2-propanoate of 4- (nitroxymethyl) benzoic acid. 90.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claims 36 and 47, further characterized in that it is 1- (9H-carbazol-4-yloxy) -3 - [[2- (2- methoxyphenoxy) ethyl] - [(4-nitroxymethyl) benzoyl] amino] -2-propanol. 91.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claims 36 and 47, further characterized in that it is 1- (9H-carbazol-4-yloxy) -3 - [[2- (2- methoxyphenoxy) ethyl] amino] -2-propanol hydrochloride 6- (nitroxy) hexanoic acid. 92. The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claims 36 and 47, further characterized in that it is 1- (9H-carbazoI-4-yloxy) -3 - [[2- (2- methoxyphenoxy) ethyl] - [(6-nitroxyhexanoyl] amino] -2-propanol of 6- (nitroxy) hexanoic acid 93.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claims 36 and 47 , further characterized in that it is 1- (9H-carbazol-4-yloxy) -3 - [[2- (2-methoxyphenoxy) ethyl] [(6-nitroxyhexanoyl) amino] -2-propanol. enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claims 36 and 47, further characterized in that it is 1- (9H-carbazol-4-yloxy) -3 - [[2- (2-methoxyphenoxy) ethyl] [(3 -nitroxypropanoyl) amino] -2-propanol. 95. The compound of the formula (I) and / or the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to any of claims 1 to 94, for use as a medicament. The use of a compound of the formula (I) and / or the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof as claimed in any of claims 1 to 94, for preparing a drug that can be used in the treatment or prophylaxis of hypertension, cardiovascular diseases and vascular diseases. 97. The use of a compound of the formula (I) and / or the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof as claimed in any of claims 1 to 94, for preparing a drug that can be used in the treatment of glaucoma and elevated intraocular pressure. 98. A pharmaceutical composition comprising a compound of the formula (I) and / or the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to any of claims 1 to 94, and at least one pharmaceutically acceptable carrier.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP03104484.5 | 2003-12-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA06006193A true MXPA06006193A (en) | 2006-10-17 |
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