MXPA06006251A - Nitrooxyderivatives of antihypertensive drugs - Google Patents
Nitrooxyderivatives of antihypertensive drugsInfo
- Publication number
- MXPA06006251A MXPA06006251A MXPA/A/2006/006251A MXPA06006251A MXPA06006251A MX PA06006251 A MXPA06006251 A MX PA06006251A MX PA06006251 A MXPA06006251 A MX PA06006251A MX PA06006251 A MXPA06006251 A MX PA06006251A
- Authority
- MX
- Mexico
- Prior art keywords
- enantiomers
- pharmaceutically acceptable
- integer
- diastereoisomers
- acceptable salts
- Prior art date
Links
- 239000002220 antihypertensive agent Substances 0.000 title 1
- 239000011780 sodium chloride Substances 0.000 claims abstract description 62
- 150000003839 salts Chemical class 0.000 claims abstract description 59
- 229910004679 ONO2 Inorganic materials 0.000 claims abstract description 13
- 208000008787 Cardiovascular Disease Diseases 0.000 claims abstract description 7
- 206010020772 Hypertension Diseases 0.000 claims abstract description 6
- 208000010412 Glaucoma Diseases 0.000 claims abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 143
- 229910052760 oxygen Inorganic materials 0.000 claims description 43
- 229910052717 sulfur Inorganic materials 0.000 claims description 39
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 31
- 239000001301 oxygen Substances 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 27
- 239000011593 sulfur Chemical group 0.000 claims description 27
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 22
- -1 NHCOCH3 Chemical group 0.000 claims description 19
- 125000001893 nitrooxy group Chemical group [O-][N+](=O)O* 0.000 claims description 18
- 125000005843 halogen group Chemical group 0.000 claims description 17
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 16
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 16
- 125000002947 alkylene group Chemical group 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 13
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 12
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 7
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- 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 5
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 229940079593 drugs Drugs 0.000 claims description 4
- 230000004410 intraocular pressure Effects 0.000 claims description 4
- 125000004430 oxygen atoms Chemical group O* 0.000 claims description 3
- 201000011528 vascular disease Diseases 0.000 claims description 3
- 230000000069 prophylaxis Effects 0.000 claims description 2
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 2
- 125000006832 (C1-C10) alkylene group Chemical group 0.000 claims 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 125000005842 heteroatoms Chemical group 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical group [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 claims 1
- 206010027599 Migraine Diseases 0.000 abstract description 3
- 208000008085 Migraine Disorders Diseases 0.000 abstract description 3
- 206010027603 Migraine headache Diseases 0.000 abstract description 3
- 201000010099 disease Diseases 0.000 abstract description 2
- 239000000674 adrenergic antagonist Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- SQGYOTSLMSWVJD-UHFFFAOYSA-N Silver nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 31
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 150000003254 radicals Chemical class 0.000 description 24
- 239000000243 solution Substances 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 16
- 239000002876 beta blocker Substances 0.000 description 14
- 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
- 239000003960 organic solvent Substances 0.000 description 12
- 229910001961 silver nitrate Inorganic materials 0.000 description 12
- 230000000903 blocking Effects 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 8
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Carbodicyclohexylimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 210000004027 cells Anatomy 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 229910052801 chlorine Inorganic materials 0.000 description 8
- 230000000875 corresponding Effects 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 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 7
- OKDQKPLMQBXTNH-UHFFFAOYSA-N N,N-dimethyl-2H-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 7
- 238000009835 boiling Methods 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 230000002829 reduced Effects 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 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
- 206010034800 Phaeochromocytoma Diseases 0.000 description 5
- 125000006242 amine protecting group Chemical group 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 229960004605 timolol Drugs 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 4
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 4
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 4
- 125000004429 atoms Chemical group 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 239000012024 dehydrating agents Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 230000001681 protective Effects 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 210000004204 Blood Vessels Anatomy 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 3
- 241001435619 Lile Species 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000005755 formation reaction Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
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- 229910052709 silver Inorganic materials 0.000 description 3
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- FWFUSMMVFVVERM-UHFFFAOYSA-N 2-(1,4-dioxan-2-yl)acetic acid Chemical compound OC(=O)CC1COCCO1 FWFUSMMVFVVERM-UHFFFAOYSA-N 0.000 description 2
- OITNBJHJJGMFBN-UHFFFAOYSA-N 4-(chloromethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(CCl)C=C1 OITNBJHJJGMFBN-UHFFFAOYSA-N 0.000 description 2
- RCOVTJVRTZGSBP-UHFFFAOYSA-N 4-(chloromethyl)benzoyl chloride Chemical compound ClCC1=CC=C(C(Cl)=O)C=C1 RCOVTJVRTZGSBP-UHFFFAOYSA-N 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M Tetra-n-butylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
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- 125000001309 chloro group Chemical group Cl* 0.000 description 2
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- 231100000730 tolerability Toxicity 0.000 description 2
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 media Substances 0.000 description 1
- 150000002829 nitrogen Chemical group 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 210000000056 organs Anatomy 0.000 description 1
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- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
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- 239000006187 pill Substances 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention relates to&bgr;-adrenergic blockers nitrooxyderivatives of general formula (I):A-(Y-ONO2)s and enantiomers and diastereoisomers and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them and their use for the treatment of hypertension, cardiovascular diseases, glaucoma, migraine headache andvascular diseases.
Description
N1TROOXIDERIVADOS OF ANTIHYPERTHENTICAL DRUGS
DESCRIPTIVE MEMORY
The present invention relates to derivatives of β-adrenergic blockers. More particularly, the present invention relates to nitrooxiderivatives of β-adrenergic blockers, to pharmaceutical compositions containing them and to their use for the treatment of hypertension, cardiovascular diseases, glaucoma, migraine headache, vascular diseases and high 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 on receptor sites in the heart, but they differ somewhat in their ability to block receptors in blood vessels and lungs. The selective β-blockers exert their main action on the heart, some others are weak stimulators of the β-receptor while they still block the main action of the catecholamines, some block both ßi and β2 receptors in the heart and those of the blood vessels and do not they have stimulatory activity and some block other catecholamine receptors that can cause other vascular effects on the blood vessels.
With this class of drugs are associated several side effects, such as muscle fatigue, sleep disturbances, decreased heart rate, hypotension, cold extremities, bronchospasm in asthmatic patients, hypoglycemia, increased plasma lipids. In addition, abrupt discontinuation should be avoided after a long-term treatment with β-blockers, because a greater sensitivity to the β-adrenergic system develops. US Patent No. 6,242,432 describes derivatives of the formula A- (XrN02) to having an antithrombotic activity, where A is the residue of a β-adrenergic blocker, Xi is a bivalent binding bridge and t0 is 1 or 2. The invention is limited to particular meanings of the bivalent binding bridge X. U.S. Patent No. 5,502,237 and U.S. Patent No. 5,639,904 describe derivatives of the formula RrAr-O-CH2-CH (OH) -CH2-NH-CH (CH3) 2 which are used for the treatment of cardiovascular diseases, where Ri is a chain having at least one nitrooxy group as a substituent. U.S. Patent No. 4,801, 596 discloses aminopropanol derivatives of the formula:
(OJvIO nBXN (R,) - A - i,? -0-CHz-CH (0H3-CH2-NH-R3 R2 that can be used for the prophylaxis and / or treatment of cardiac and circulatory diseases, where R3 is a An alkyl or nitrooxyalkyl radical containing between 3 and 8 carbon atoms It is an object of the present invention to provide new nitrooxiderivatives of β-adrenergic blockers with a significantly improved total pharmacological profile compared to the original β-blockers which are capable not only of of eliminating or at least reducing the side effects that are associated with their original compounds, but also having improved pharmacological activity and tolerability.Surprisingly, it has been found that the nitrooxiderivatives of β-adrenergic blockers of the present invention have a better pharmacological activity and properties of protection to the organs, improved effects as anti-inflammatory, and on the renal functions. n effective in other pathologies that include atherosclerosis, diabetes, peripheral vascular diseases (PVD) and high intraocular pressure. In particular, it has been recognized that, unlike the previous compounds mentioned in the prior art, the ß-adrenergic blockade nitrooxiderívados of the present invention show an improved activity on the cardiovascular system and a better tolerability and can be used to treat or prevent hypertension, cardiovascular diseases, glaucoma, migraine headache, vascular diseases and high intraocular pressure.
An object of the present invention are nitrooxiderivatives of β-adrenergic blockers of the general formula (I): A- (Y-ON02) s and enantiomers and diastereoisomers and pharmaceutically acceptable salts thereof, wherein s is an integer equal to 1 or 2, preferably s is 2; A is selected from the following β-adrenergic blocking residues of the formula (II):
(Or where Ri is selected from the group consisting of:
(lio) (Hp) (Hq)
(Mr) (lis) (llt) (llu) (Hv) (llw)
(i "y) (iiz): R2 is selected from the group comprising: -CH (CH3) 2, -C (CH3) 3
(li le) when the radical Ri is selected from the formulas (No), (llp), (llt), (llu), (llv), (lly) or (llz), R2 is -CH (CH3) 2; when the radical Ri is selected from the formulas (llq), (lys) or (llw), R2 is -C (CH3) 3; when the radical R-i is (llr), R2 is (lile);
Z is H or is a group capable of joining Y selected from the group consisting of: -C (O) -, -C (0) 0- or
OR R? OR
where R 'and R "are the same or different, and are H or straight or branched C4 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; when s is 2, Z or Z-i are preferably - C (O) -; Y is a bivalent radical with the following meaning: a) straight or branched alkylene of CrC2o, preferably CrC10, which is optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, -ONO2 or T , where T is -OC (0) (CrC10 alkyl) -ONO2, -0 (CrC10 alkyl) -ONp2; b) - cycloalkylene of from 5 to 7 carbon atoms in the cycloalkylene ring, where the ring is optionally substituted with Ti side chains, where Ti is straight or branched alkyl of 1 to 10 carbon atoms, Ti is preferably CH 3;
(IV) wherein: n is an integer from 0 to 20, preferably n is an integer from 0 to 10, more preferably n is 0, and n1 is an integer from 1 to 20, preferably from 1 to 10; 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 between 0 to 20, preferably na is equal to 0; XT is -WC (O) - or -C (0) W-, where W is oxygen, sulfur or NH, preferably W is oxygen; with the proviso that: when s of the formula (I) is 1, Z is - (CO) - and in the formula (IV) of the bivalent radical Y n2, n3, n4, n5 are equal to 0 then n is 0 and n1 is 1; when s of the formula (I) is 1, Z is - (CO) - and in the formula (IV) of the bivalent radical Y n2, n3, n5 are equal to 0, n4 is 1 then n and n1 are different to 1;
(V)
wherein: n1 is an integer from 1 to 20, preferably from 1 to 10; XT is -WC (O) - or -C (0) W-, where W is oxygen, sulfur or NH, preferably W is sulfur; n6 is an integer from 1 to 20, n7 is an integer from 0 to 20, R5 and R5 R6 and Rd 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 in c) -d), the -ON02 group is attached to a group - (CH2) ni-; with the proviso that when s of the formula (I) is 1 and Z is - (CO) -, then the bivalent radical Y does not have the meanings in a), b) and d);
and)
(SAW)
• Cr. For CH-X, - [(CH2) n ^ - CH-XJ- (CH2) n 2-CH-R '11a R' 1n to R11 a
(VII) where X2 is O or S, n10a, n10 and n12 are integers selected independently from 0 to 20, n 10a is preferably selected from 0 to 10, n10 and n12 are preferably selected from 1 to 10, and n11 is an integer between 0 and 6, preferably 0 to 4, R11 is H, CH3 or nitrooxy group, preferably R11 is H, R11a is CH3 or nitrooxy group; with the proviso that when in the formula (I) s is 1, in the formula (II) Z is - (CO) -, in the formula (VI) of the bivalent radical Y n10a, n10, n12 are equal to 1 then X can not be an oxygen atom;
where n8 is an integer from 0 to 10; n9 is an integer from 1 to 10; R9, R10, R8, R7 are identical or different, and are H or straight or branched dC4 alkyl, preferably R9, R10, R8, R7 are H; where the group -ON02 is linked to 15
- [C] n 9
where n9 is as defined above; Y2 is a 5 or 6 membered saturated, unsaturated or aromatic heterocyclic ring containing 1 or more heterogeneous atoms selected from nitrogen, oxygen, sulfur, and is selected from the group consisting of:
(Y1) (Y2) (Y3) (Y4) (Y5)
(Y1 1) (Y12) (Y13) One embodiment of the present invention comprises compounds of the formula (I) wherein s is 2, A is a β-adrenergic blocking residue of the formula (II) as defined above: Z is a group capable of linking Y selected from the group consisting of: -C (0) -, -C (0) 0- or
where R 'and R "are identical or different, and are H or C4 straight or branched alkyl, Z is -C (O) -, preferably Z and Zi are -C (O) -; Y is a radical bivalent has the following meaning: a) - alkylene C straight or branched C2o, preferably d- C10, which is optionally substituted with one or more substituents selected from the group consisting of: halogen atoms, hydroxy, - ON02 or T, where T is -OC (0) (C 10 alkyl) -ONO 2, -O (d-C 10 alkyl) -ONO 2; b) -cycloalkylene of between 5 to 7 carbon atoms in the cycloalkylene ring, where the ring is optionally substituted with Ti side chains, where Ti is straight or branched alkyl of 1 to 10 carbon atoms, Ti is preferably CH 3; c)
(IV) where: n is an integer from 0 to 20, preferably n is an integer from 0 to 10, more preferably n is 0, and n1 is an integer from 1 to 20, preferably from 1 to 10; 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 between 0 to 20, preferably na is equal to 0; Xi is -WC (O) - or -C (0) W-, where 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; X ^ is -WC (O) - or -C (O) W-, where W is oxygen, sulfur or NH, preferably W is sulfur; 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; with the proviso that when Y is selected from the divalent radicals mentioned in c) -d), the group -ON02 is linked to a group - (CH2) n-;
and)
(SAW)
(VII) where X2 is O or S, n10a, n10 and n12 are integers selected independently from 0 to 20, n 10a is preferably selected from 0 to 10, n10 and n12 are preferably selected from 1 to 10, and n11 is an integer between 0 and 6, preferably 0 to 4, R11 is H, CH3 or nitrooxy group, preferably R11 is H, R11a is CH3 or nitrooxy group;
'R9 R8
n9 R10 T
(VI I I) 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 C4 alkyl, preferably R9, R10, R8, R7 are H; where the group -ONO2 is linked to
- [C] | n g
where n9 is as defined above; Y2 is a 5 or 6 membered saturated, unsaturated or aromatic heterocyclic ring containing or more heterogeneous atoms selected from nitrogen, oxygen, sulfur, and is selected from the group consisting of:
(Y6) (Y7) (Y8) (Y9) (Y10)
(Y1 1) (Y12) (Y13) Another embodiment 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; Y is a bivalent radical having the following meaning: a) straight or branched alkylene of d-do, preferably d-do, which is optionally substituted with one or more of the substituents selected from the group consisting: halogen atoms, hydroxy, -ON02 or T, where T is -OC (0) (C1-C1o alkyl) -ON02l -O (C? -Co alkyl) -ON02; b) cycloalkylene of from 5 to 7 carbon atoms in the cycloalkylene ring, where the ring is optionally substituted with Ti side chains, where Ti is straight or branched alkyl of 1 to 10 carbon atoms, Ti is preferably CH 3; c) (iv) where: n is an integer from 0 to 20, preferably n is an integer from 0 to 10, more preferably n is 0, and n1 is an integer from 1 to 20, preferably from 1 to 10; 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 - (CH) na-CH = CH- where na is an integer from 0 to 20, preferably na is equal to 0; Xi is -WC (O) - or -C (O) W-, where W is oxygen, sulfur or NH, preferably W is oxygen;
(V) wherein: n1 is an integer from 1 to 20, preferably from 1 to 10; X-i is -WC (O) - or -C (0) W-, where W is oxygen, sulfur or NH, preferably W is sulfur; 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, CH3l 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 in c) -d), the -ONO2 group is attached to a group - (CH2) n? -; and)
(SAW)
-ÍCK.WJG CH-X, - Í (CH2) GIW- CH- < 2] n r (H2) p _-CH R11a R1 l a R 11 a
(VII) where X2 is O or S, n10a, n10 and n12 are integers selected independently from 0 to 20, n10a is preferably selected from 0 to 10, n10 and n12 are preferably selected from 1 to 10, and n11 is a whole between 0 and 6, preferably 0 to 4, R11 is H, CH3 or nitrooxy group, preferably R11 is H, R11a is CH3 or nitrooxy group;
F)
"(VIII) wherein 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 dC4 alkyl, preferably R9, R10, R8, R7 are H, wherein the -ONO group is attached to
• [C] n g
where n9 is as defined above; Y2 is a 5 or 6 membered saturated, unsaturated or aromatic heterocyclic ring containing 1 or more heterogeneous atoms selected from nitrogen, oxygen, sulfur, and is selected from the group consisting of:
(Y1) (Y2) (Y3) (Y4) (Y5) (Yß) (Y7) (Y8) (Y9) (Y10)
(Y1 1) (Y12) (Y13)
Another embodiment comprises compounds of the formula (I) wherein s is 1, A is a β-adrenergic blocker residue of the formula (II) as defined above: Z1 is H; Z is a group capable of linking to Y selected from the group consisting of: -C (O) -, -C (0) 0- or
Where R 'and R "are identical or different, and are H, or straight or branched d-d alkyl;
Preferably Z is -C (0) -; And it's a bivalent radical that has the following meaning: c) /
(IV) where: n is an integer from 0 to 20, preferably n is an integer from 0 to 10, more preferably n is 0, and n1 is an integer from 1 to 20, preferably from 1 to 10; 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 -CH- or - (CH2) na-CH = CH- where na is an integer from 0 to 20, preferably na is equal to 0; Xi is -WC (O) - or -C (0) W-, where W is oxygen, sulfur or NH, preferably W is oxygen; with the proviso that Z is -C (O) -; in the bivalent radical Y of formula (IV) n2, n3, n4, n5 are equal to 0 then n is 0 and n1 is 1 in the bivalent radical Y of formula (IV) n2, n3, n5 are equal to 0 , n4 is 1 then n and n1 are different from 1;
(SAW)
(VII) where X2 is O or S, n10a, n10 and n12 are integers selected independently from 0 to 20, n10a is preferably selected from 0 to 10, n10 and n12 are preferably selected from 1 to 10, and n1 1 is an integer between 0 and 6, preferably 0 to 4, R11 is H, CH3 or nitrooxy group, preferably R11 is H, R11a is CH3 or nitrooxy group; with the proviso that Z is -C (O) - and in the formula (VI) of the divalent radical Y n10a, n10, n12 are equal to 1 then X can not be an oxygen atom;
(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 dC4 alkyl, preferably R9, R10, R8, R7 are H; where the -ON02 group is attached to- [C]
where n9 is as defined above; Y2 is a 5 or 6 membered saturated, unsaturated or aromatic heterocyclic ring containing 1 or more heterogeneous atoms selected from nitrogen, oxygen, sulfur, and is selected from the group consisting of:
(YD (Y2) (Y3) (Y4) (Y5) (Yß) (Y7) (Y8) (Y9) (Y10)
(Y11) (Y12) (Y13) Preferred compounds are those of the formula (I) wherein s is 1A is a β-adrenergic blocking residue of the formula (II) as defined above, Z is H and Z- , is -C (O) -, and the bivalent radical Y has the following meaning: a) straight CrC10 alkylene preferably C3-C6 alkylene; c)
(IV) where the group -ON02 is linked to (CH2) n .; 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; or n, n2, n5 are 1, n3 and n4 are equal to 0, and n1 is an integer between 1 and 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) Another group of preferred compounds are those of the formula
(I) where s is 1, A is a β-adrenergic blocking residue of the formula
(II) as defined above, and the bivalent radical Y has the following meaning: (IV) where the group -ONO2 is attached to (CH2) n ?; n, n2, n3, n4, n5 are equal to 0, n1 is 1 and the group - (CH2) n1- is linked 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 between 1 and 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 linked to the phenyl ring through [C] 4, R4 is CH3 and the group (OR4) is attached to the phenyl ring through [C] 3; d)
(VI) where X2 is O or S, and n10a and n11 are 0, n12 is 1 and R11 is H and the group -ON02 is linked to (CH2) n12; Another group of preferred compounds are those of the formula (I) wherein s is 2, A is a β-adrenergic blocking residue of the formula (II) as defined above, Z. and Z are -C (O) -, and the bivalent radical Y has the following meaning: a) straight d-do alkylene, preferably C3-C6 alkylene;
(IV) where the group -ON02 is linked to (CH2) n ?; n, n2, n3, n4, n5 are equal to 0, n1 is 1 and the group - (CH2) nr is linked 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 between 1 and 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], R is CH3 and the group (OR) is attached to the phenyl ring through the
[C d)
() - (Xi) - ÍCH2) ', n1 (V) wherein the -ON02 is linked to the group - (CH2) nr; n1 is an integer between 1 and 10, n6 and n7 are 1, XT is -WC (O) - where W is sulfur, R5, R5 'and R6' are H, R6 is NHCOCH3; The preferred compounds of the formula (I) according to the present invention are the following:
(1) (2) (3) 5 (4) (5) (6)
(7) (8) (9) Examples of "straight or branched d-C2o alkylene" include, but are not limited to, methylene, ethylene, propylene, isopropylene, n-butylene, pentylene, n-hexylene, and the like. As stated, the invention also includes pharmaceutically acceptable salts of the compounds of the formula (I) and stereoisomers thereof. Examples of pharmaceutically acceptable salts 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 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 acids, tartaric, maleic, succinic, citric. 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, pure diastereomers, mixtures of enantiomers, mixtures of diastereomers, racemic mixtures of enantiomers, racemates or mixtures of racemates. All the isomers, stereoisomers and their possible mixtures of the compounds of the formula (I) are also included within the scope of the invention. The compounds and compositions of the present invention can be administered through any available and effective delivery system including, but not limited to, oral, buccal, parenteral, inhalation vaporizer, topical, injection, transdermal or rectal ( for example through the use of suppositories) in unit administration formulations containing conventional, non-toxic vehicles, adjuvants and vehicles acceptable for pharmaceutical use. The parenteral route includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion technique.
Solid dosage forms for oral administration may include for example capsules, tablets, pills, powders, granules and gel. In such administration forms, the active compounds can be mixed with at least one inert diluent such as sucrose, lactose or starch. Said administration form may also comprise, as a normal procedure, additional substances other than inert diluents, for example, lubricating agents such as for example magnesium stearate. Injectable preparations, for example sterile injectable aqueous or oily suspensions, may be formulated according to the known art using suitable dispersing agents, wetting agents and / or suspending agents. The composition of this invention may further include conventional excipients, i.e., organic or inorganic substances acceptable for pharmaceutical use that do not adversely react with the active compounds. The doses of nitrooxide derivatives of β-adrenergic blockers can be determined by standard clinical technique and are in the same ranges or lower than those described for compounds commercially available in: Physics Desk Reference, Medical Economics Company, Inc., Oradell, NJ, 58th Ed., 2004; The pharmacological basis of therapeutics, Goodman and Gilman, J. G. Hardman, L. e. Limbird, 20th Ed.
EXPERIMENTS Synthesis procedure
The compounds of the invention can be synthesized as shown in Schemes 1 to 6. The compounds of the general formula (I) A- (Y-ONO2) s, which are defined in Schemes 1-3 as compounds of the formula D, where s is 1, Y is as defined and A is a β-adrenergic blocking residue of the formula (II), where Z is -C (O) - and Z-? is H, the enantiomers, diastereoisomers and a pharmaceutically acceptable salt thereof can be prepared as outlined in Schemes 1-3.
SCHEME 1
(A) (F) (G!
() (¡) (H)
R,, R,
O -Z-Y-ONO- < D > The compounds of the formula (I) wherein Ri, R2, Z and Y are as defined, Pi is an amine protecting group such as tert-butyloxycarbonyl ester (t-Boc) and X3 is a halogen atom preferably of Cl, Br and I, are converted to compounds of the formula (L) wherein R1, R2, P1, Z and Y are as defined, by reaction with AgNO3 in an appropriate organic solvent such as acetonitrile or tetrahydrofuran, preferably using a molar excess of silver nitrate and carrying out the reaction in the dark, at a temperature between room temperature and 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 (a strong acid, such as HCl in dioxane or trifluoroacetic acid, is used to remove a t-butyl carbamate). Other preferred methods for removing the amine protecting groups are described in TW Greene "Protective groups in organic synthesis", Harvard University Press, 1980. The compounds of the formula (H) wherein Ri, R2, Z, P1 and Y are as defined above, are converted to the esters of the formula (i) wherein Ri, R2, Y, Z, X3 and P1 are as defined, by reaction with an appropriate acid (Q1) of the formula X3-Y-COOH where Y and X3 are as defined above. In general, the reaction is carried out in an inert organic solvent such as for example N, N'-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, or a polyhalogenated aliphatic hydrocarbon at a temperature between 0 ° C and 50 ° C in the presence of a dehydrating agent such as for example dicyclohexylcarbodiimide DCC or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDAC HCl) with a catalyst, such as for example 4-N, N-dimethylaminopyridine (DMAP). The compounds of the formula (H) wherein Ri, R2 and Pi are as defined above, can be obtained by deprotecting the hydroxyl group of the compounds of the formula (G) wherein Ri, R2 are as defined and P is a protecting group hydroxylic such as silyl ethers, such as for example trimethylsilyl or tert-butyl-dimethylsilyl and those described in T. W. Greene "Protective groups in organic synthesis", Harvard University Press, 1980. The preferred method for removing the silyl ether protecting group is fluoride. The compounds of the formula (G) wherein Ri, R2, P and P1 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 protecting group of appropriate amine (P1) as described. The alcohol group of the compounds of the formula (A) wherein R-i,
R2 are as defined, protected to give the compounds of the formula (F) where Ri, R2 are as defined. Preferred protective groups for the alcohol unit are the alkyl ethers, for example trimethylsilyl or tert-butyl-dimethylsilyl. The compounds (A) wherein R-, R2 are as defined and are commercially available, the acids of the formula X3-Y-COOH where X3 is as defined, and are commercially available.
SCHEME 2
(A) < B) (D)
The compounds of the formula (B) wherein R1 (R2, Z, y are as defined and X3 is a halogen atom, such as for example Cl, Br and I, are converted to compounds of the formula (D) where R- ,, R2, Z and y are as defined, by reaction with AgN03 in an appropriate organic solvent such as for example acetonitrile or tetrahydrofuran, preferably using a molar excess of silver nitrate and carrying out the reaction in the dark, at a temperature between the ambient temperature and the boiling temperature of the solvent The compounds of the formula (B) wherein Ri, R2, Z, y and X3 are as defined can be obtained by reacting the compounds of the formula (A) with a Suitable acyl (Q) of the formula X3-YC (0) CI, where X3 is selected from chlorine, bromine, and Y is as defined The esterification is carried out in an inert organic solvent such as N, N ' -dimethylformamide, tetrahydrofuran, benzene, toluene, chloroform in the presence of a e as triethylamine or pyridine at a temperature between room temperature and 50 ° C. The reaction is completed at a time within the range of 30 minutes and 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'-dlmethylformamide, tetrahydrofuran, benzene, toluene, dioxane, or a polyhalogenated aliphatic hydrocarbon at a temperature between 0 ° C and 50 ° C. The reaction is completed at a time within the scale between 30 minutes to 36 hours. Compounds of the formula (Q1), wherein X3 is a halogen atom can be obtained commercially or can be obtained from the corresponding commercially available hydroxy acid using well-known reactions, for example by reaction with thionyl or oxalyl chloride, halides of P1"or Pv in inert solvents such as toluene, chloroform, DMF, etc. Compounds (A) where Ri, R2 are as defined can be obtained commercially.
SCHEME 3
(A) (D)
Alternatively, the compounds of the formula (D) can be obtained as described below. The compounds of the formula A are converted to the compounds (D) by reaction of the hydroxy group with a nitrooxiderivative, containing an activated acylating group, of the formula CI (0) C-Y-ON02. The nitrooxicompuestos can be obtained from the corresponding alcohols of the formula CI (0) CY-OH by reaction with nitric acid and acetic anhydride at a temperature within the range between -50 ° C to 0 ° C or from the corresponding halogenated derivatives of the formula CI (0) CY-Hal by reaction with silver nitrate in the presence of an inert solvent such as acetonitrile or tetrahydrofuran, preferably using a molar excess of silver nitrate and carrying out the reaction in the dark, a temperature between the boiling temperature and the ambient temperature. The reaction is completed at a time within the scale between 30 minutes to 3 days. The compounds of the general formula (I) A- (Y-ON02) s, which are defined in Scheme 4 as compounds of the formula (D1), where s is 1, Y is as defined and A is a blocking residue β-adrenergic of the formula (II), wherein Z is -C (0) 0- and Zi is H, the enantiomers, diastereomers and a pharmaceutically acceptable salt thereof, can be prepared as mentioned in Scheme 4.
SCHEME 4
(A) (B1) (DI)
The compounds of the formula (B1) wherein R1 (R2, and are as defined and X3 is a halogen atom, such as for example Cl, Br and I, are converted to compounds of the formula (D1) where Ri, R2, and Y are as defined, by reaction with AgN03 in an appropriate organic solvent such as for example acetonitrile or tetrahydrofuran, preferably using a molar excess of silver nitrate and carrying out the reaction in the dark, at a temperature between room temperature and the boiling temperature of the solvent The compounds of the formula (A) wherein Ri and R2 are as defined above and converted to the compounds (B1) by reaction with an appropriate compound (Q2) of the formula X3-Y-OC (0) CI where X3 is Cl, Br or I, and Y is as defined In general, the reaction is carried out in the presence of a base in a polar or non-polar aprotic solvent such as THF or CH2Cl2 at a temperature within the scale between 0 ° -65 ° C or in a two-phase system H20 / Et 0 at a temperature within the range 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 (I) A- (Y-ON02) s, which are defined in Scheme 5 as compounds of the formula (D), wherein s is 1, Y is as defined and A is a blocking residue β-adrenergic agent of the formula (II), wherein Z is
where R 'and R "are as defined and Z-, is H, the enantiomers, diastereoisomers and the pharmaceutically acceptable salts thereof may be prepared as summarized in Scheme 5:
SCHEME 5
(M O _-V-0NO, ¿- .. and-OHO.
The compounds of the formula (I) wherein Ri, R2, Z and Y are as defined, 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, by reaction with AgN03 in an appropriate organic solvent such as for example acetonitrile or tetrahydrofuran, preferably using a molar excess of silver nitrate and carrying out the reaction in the dark, at a temperature between room temperature and 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 (a strong acid, such as for example HCl in dioxane or trifluoroacetic acid, is used to remove a t-butyl carbamate). Other preferred methods for removing the amine protecting groups are described in TW 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, they can be obtained by reacting the compounds of the formula (M) wherein Ri, R2, Pi, R ', R "and X3 are as defined, with an acid (Q1) of the formula X3-Y-COOH where X3 is a halogen atom and Y is as defined The reaction is carried out in an inert organic solvent such as N, N'-dimemethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon in a range of temperature between 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 for example 4-N , N-dimethylaminopyridine (DMAP).
The reaction is completed at a time within the scale between 30 minutes to 24 hours. The compounds of the formula (M) wherein Ri, R2, Pi, R ', R "and X3 are as defined, can be obtained by reacting compounds of the formula (H) with an acyl compound (S) of the formula X3 -C (R ') (R ") - 0C (0) X3 where 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, or acetonitrile at a temperature within the range of -5 ° C to 60 ° C or in a two-phase system in accordance with well-known methods in the literature. The amine group of the compounds (A) is protected to give the compounds of the formula (H) wherein P-j is an appropriate amine protecting group such as, for example, tert-butyloxycarbonyl ester (t-Boc). The compounds (S) are commercially available. The compounds of the general formula (I) A- (Y-ON02) s, are defined in Scheme 6 as compounds of the formula (E), where s is 2, Y is as defined and A is a β-adrenergic blocking residue of the formula (II), where Zi and Z are -C ( O) -, the enantiomers, diastereomers and a salt thereof acceptable for pharmaceutical use, can be synthesized as shown in Scheme 6.
SCHEME 6
(A) (C) < AND)
The compounds of the formula (C) wherein R1, R2, Z, Z1 and y are as defined and X3 is a halogen atom, such as Cl, Br and I, are converted to compounds of the formula (E) where Ri, R2, Z and Y are as defined, by reaction with AgN03 in an appropriate organic solvent such as for example acetonitrile or tetrahydrofuran, preferably using a molar excess of silver nitrate and carrying out the reaction in the dark, at a temperature between 50 ° C. ambient temperature and the boiling temperature of the solvent. The compounds of the formula (C) wherein Ri, R2, Z, Z- ?, Y and X3 are as defined above can be obtained by reaction of compounds of the formula (A) with an appropriate acid (Q) chloride of the formula X3-YC (0) CI, where X3 is selected from chlorine, bromine, and Y is as defined. 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 or pyridine at a temperature between room temperature and 50 ° C. The reaction is completed at a time within the scale between 30 minutes to 24 hours. Alternatively, the compounds of the formula (C) can be obtained by reacting 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-dimethylaminopropy!) - 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, or a polyhalogenated aliphatic hydrocarbon at a temperature between 0 ° C to 50 ° C. The reaction is completed at a time within the scale between 30 minutes to 36 hours. The compounds of the formula (Q1), wherein X3 is a commercially available halogen atom or can be obtained from commercially available hydroxyl acids using well-known reactions, for example by reaction with thionyl or oxaliium chloride, halides of P1"or Pv in inert solvents such as toluene, chloroform, DMF, etc. The compounds (A) wherein R-, R are as defined and are commercially available The compounds of the formula (D) can also be obtained as described The compounds of the formula A are then converted to the compounds (E) by reaction with a nitrooxiderivative of the formula CI (0) CY-ON02 containing an activated acylating group The nitrooxy-compounds can be obtained from the corresponding alcohols of the formula C! (0) CY-OH by reaction with nitric acid and acetic anhydride at a temperature within the range between -50 ° C to 0 ° C or from the corresponding halo derivatives Octanes of the formula CI (0) CY-Hal by reaction with silver nitrate in the presence of an inert solvent such as acetonitrile or tetrahydrofuran, preferably using a molar excess of silver nitrate and carrying out the reaction in the dark, a temperature between the boiling temperature and the ambient temperature. The reaction is completed at a time within the scale between 30 minutes and 3 days.
EXAMPLES
The following non-limiting examples describe the invention in greater detail and allow one skilled in the art to make and use.
EXAMPLE 1 Maleate salt of (S) -1-rf1,1-dimethylethyl) amino-3- (4- (4- morpholinyl) -1,5,5-thiadiazol-3-ipoxp-2-propanoate 4- ( nitrooxymethyl) benzoic
1a. (S) -1 - [(1,1-dimethylethyl) amino] -3 - [[4- (4-morpholinyl) -1,2,5-thiadiazol-3-yl] oxy] -2-propanoic acid 4 - (chloromethyl) benzoic To a solution of timolol (3.5 g, 11 mmol) in chloroform (200 ml) were added 4-chloromethylbenzoic acid (1.9 g, 11 mmol), EDAC (3.6 g,
16. 5 mmole) and N, N-dimethylaminopyridine (catalytic amount). The reaction was stirred for 12 hours at room temperature. The solution was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with chloroform / isopropanol 10 / 0.5 to give the title compound (3 g) as a white powder. 1 B. (S) -1 - [(1,1-dimethylethyl) amino] -3 - [[4- (4-morpholinyl) -1,5,5-thiadiazol-3-l! Oxy] -2-propanoic acid 4 - (nitrooxymethyl) benzoic A solution of the product of Example 1 a (1 g, 2.1 mmol) and silver nitrate (0.71 g, 4.21 mmol) in acetonitrile (50 ml) was stirred at 60 ° C, in the dark, for 36 hours . The precipitate (silver salts) was removed by filtration and the solvent was evaporated under vacuum. The residue was treated with chloroform and water. The organic phase was dried over sodium sulfate and the solvent was evaporated. The residue was purified by flash chromatography, eluting with chloroform / isopropanol 10 / 0.5 to give the title compound (0.6 g) as a white powder. 1 C. Maleate salt of (S) -1 - [(1,1-dimethylethyl) amino] -3 - [[4- (4-morpholinyl) -1,5,5-thiadiazol-3-yl] oxy] -2-propanoate of 4- (Nitrooxymethyl) benzoic acid To a solution of the product of Example 1b (0.6 g, 1.2 mmol) in acetone (100 ml) was added maleic acid (0.14 g, 1.2 mmol). The reaction was stirred at room temperature for 1 hour. The precipitate was filtered, washed with acetone and dried under vacuum to give the title compound (0.6 g) as a white powder. P.f. = 160 ° C 1 H-NMR (CDCl 3) d (ppm): 7.99 (2H, d); 7.42 (2H, d); 5.93 (2H, s); 5.87 (1 H, m); 5.46 (2H, s); 4.82 (1H, dd); 4.71 (1 H, dd); 3.73 (4H, m); 3.44 (4H, m); 1.49 (9H, s).
EXAMPLE 2 (S) -1-f (1,1-dimethylethyl) f (4-nitrooxymethyl) benzoyl] aminol-3-fr4- (4-morpholinyl) -1,2,5-thiadiazole-3-ppoxp -2- propanoate of 4- (nitrooxymethyl) benzoic acid
2a. (S) -1 - [(1,1-dimethylethyl) [(4-chloromethyl) benzoyl] amino] -3 - [[4- (4-morpholinyl) -1,2,5-thiadiazol-3-yl] oxl ] -2- propanoate of 4- (chloromethyl) benzoic acid
To a solution of timolol hydrochloride (8 g, 22.66 mmol) in chloroform (130 ml) was added a mixture of 4-chloromethylbenzoyl chloride (4.28 g, 22.66 mmol) and triethylamine (6.2 ml, 44.66 mmol) in chloroform (70 ml). by drip The reaction was stirred for 24 hours at room temperature. The solution was treated with water and diethyl ether, the organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with chloroform / isopropanol 10 / 0.3 to give the title compound (3 g) as a powder. 2b. (S) -1 - [(1,1-dimethylethyl) [(4-nitrooxymethyl) benzoyl] amino] -3 - [[4- (4-morpholinyl) -1,2,5-thiadiazol-3-yl] oxy] ] -2- 4- (Nitrooxymethyl) benzoic acid propanoate A solution of the product of Example 2a (1.5 g, 2.4 mmol) and silver nitrate (1.23 g, 7.2 mmol) in acetonitrile (100 ml) was stirred at 60 ° C. , in the dark, for 36 hours. The precipitate (silver salts) was removed by filtration and the filtrate was concentrated. The residue was treated with chloroform and water and the organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 10/2 chloroform / isopropanol to give the title product (0.95 g) as a yellow powder. P.f. = 44-46 ° C 1 H-NMR (CDCl 3) d (ppm): 7.95 (2H, d); 7.50 (2H, d); 7.38 (4H, s);
. 79 (1 H, m); 5.75 (2H, s), 5.74 (2H, s); 4.50 (1 H, dd); 4.30 (1 H, dd); 3.95 (1 H, dd); 3.85 (1 H, dd); 3.59 (4H, m); 3.34 (4H, m); 1.60 (9H, s).
EXAMPLE 3 (S) -1 - [(1,1-dimethylethyl) f (4-nitrooxymethyl) benzoinamino1-3-fr4- (4-morpholinyl) -1,2,5-thiadiazol-3-ipoxp-2-propanol
3a. (S) -1 - [(1,1-dimethylethyl) amino] -3 - [[4- (4-morpholinyl) -1,5,5-thiadiazol-3-yl] oxy] -2-propan-1 - tert-butyldimethylsilylether To a solution of timolol (2 g, 6.32 mmol) in N, N-dimethylformamide (10 ml) were added tert-butyldimethylsilyl chloride (1.15 g, 7.58 mmol) and imidazole (1 g, 15.8 mmol). The reaction was stirred for 2 hours at room temperature. The solution was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with chloroform / isopropanol 10 / 0.3 to give the title compound (1.5 g). 3b. (S) -1 - [(1,1-dimethylethyl) [(4-chloromethyl) benzoyl] amino] -3 - [[4- (4-morpholinyl) -1,2,5-tlad-azoi-3-yl] ] oxy] -2-propan-1-tert-butyldimethylsilyl ether. To a solution of the product of Examples 3a (0.7 g, 1.62 mmol) in chloroform (50 ml) were added 4-chloromethylbenzoylchloride (0.46 g, 2.44 mmol) and triethylamine (0.39 ml, 2.44 mmol). The reaction was stirred for 24 hours at room temperature. The solution was treated with water and diethyl ether, the organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with n-hexane / ethyl acetate 7/3 to give the title product (0.7
g). 3c. (S) -1 - [(1,1-dimethylethyl) [(4-chloromethyl) benzoyl] amino] -3 - [[4- (4-morfoylinyl) -1,2,5-thiadiazol-3-yl] oxy] ] -2-propanol To a solution of the product from Example 3b (0.6 g, 1.03 mmol) in tetrahydrofuran (50 ml) cooled to 0 ° C, a solution of tetrabutylammonium fluoride in 1 M tetrahydrofuran (0.54 ml, 2.05 mmol) was added. ). The reaction was stirred for 30 minutes at room temperature. The solution was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with n-hexane / ethyl acetate 1/1 to give the title product (0.2 g). 3d (S) -1 - [(1-Dimethylethyl) [(4-nitrooxymethyl) benzoyl] amino] -3 - [[4- (4-morpholinyl) -1,2,5-thiadiazol-3-yl] oxy] - 2-propanoi A solution of the product of Example 3c (0.15 g, 0.32 mmol) and silver nitrate (0.11 g, 0.64 mmol) in acetonitrile (50 ml) was stirred at 65 ° C., in the dark, for 32 hours. The precipitate (silver salts) was removed by filtration and the filtrate was concentrated. The residue was treated with methylene chloride and water and the organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with n-hexane / ethyl acetate 45/65 to give the title compound 0.65g as a white powder. P.f. = 50-54 ° C H-NMR (CDCl 3) d (ppm): 7.40 (4H, s); 5.44 (2H, s); 4.33-4.18 (3H, m), 3.79 (4H, dd); 3.64-3.50 ((2H, m); 4.46 (4H, dd); 3.00 (1H, s); 1.53 (9H, s).
EXAMPLES 4
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 related to serious cardiovascular diseases such as hypertension, diabetic complications, atherosclerosis, and tissue infarction. Therefore, the extent of cGMP formation caused by the compounds of the invention in the rat pheochromocytoma (PC12) cell line was evaluated.
Compounds tested 1) Timolol (original compound) 2) (S) -1 - [(1,1-dimethylethyl) [(4-nitrooxymethyl) benzoyl] amino} -3-. { [4- (4- Morpholinyl) -1,5,5-thiadiazol-3-yl] oxy] -2-propanoate of 4- (Nitrooxymethyl) benzoic acid (compound of Example 1) 3) (S) -1- [ (1,1-dimethylethyl) [(4-nitrooxymethyl) benzoyl] amino} -3-. { [4- (4- Morpholinyl) -1,5,5-thiadiazol-3-yl] ox] -2-propanoate of 4- (Nitrooxymethyl) benzoic acid (compound of Example 2) 4) (S) -1 - [(1,1-dimethylethyl) [(4-nitrooxymethyl) benzoyl] amino} -3-. { [4- (4-morpholinyl) -1,5,5-thiadiazol-3-yl] oxy] -2-propanol (compound of Example 3)
Method The cells were maintained at 37 ° C in DMEM medium enriched with 10% horse serum and 5% fetal bovine serum under an atmosphere with 5% CO2. At the time of the experiments the cells were washed eleven with Hank's balanced salt solution (HBSS) supplemented with 0.05% ascorbic acid and preincubated in the same pH buffer for 10 minutes floating in a water bath. After the preincubation step, the cells were exposed for another 45 minutes under both control conditions and increasing concentrations of test compounds varying within the range between 0.1 and 25 μM, in the presence of the phosphodiesterase inhibitor, IBMX (100 μM) and the soluble independent activator of guanylyl cyclase NO, YC-1 (20μM). The reaction was terminated by removing the buffer solution in incubation and by the consecutive addition of 100 μl of absolute ethanoi. The organic extracts were then evaporated to dryness and the residues were dissolved in aqueous buffer solution for quantitative determination of the intracellular levels of cGMP using the cGMP enzyme immunoassay kit. The results obtained from Table 1 are reported as EC50 (μM) and Emax efficiency (% of vehicle). As shown in the table, the nitroderivatives of carvedilol induced a consistent increase in the intracellular formation of cGMP in the PC12 cell line. On the contrary, the original compound did not share this effect
TABLE 1 Effects of nitrooxiderivatives of timolol and ann of timolol on the formation of cGMP in PC12 cells
NOVELTY OF THE INVENTION
CLAIMS
1. A compound of the general formula (I) A- (Y-ONO2) s and the enantiomers, diastereomers and pharmaceutically acceptable salts thereof, wherein s is an integer equal to 1 or 2; A is selected from the following β-adrenergic blocking residues of the formula (II):
(ID where R- is selected from the group comprising:
(lly) (llz); R2 is selected from the group consisting of: -CH (CH3) 2, -C (CH3) 3 or
(lile) when the radical Ri is selected from the formulas (lio), (llp), (llt), (llu), (llv), (lly) or (llz), R2 is -CH (CH3) 2; when the radical Ri is selected from the formulas (llq), (lys) or (llw), R2 is -C (CH3) 3; when the radical R is (llr), R2 is (lile); Z is H or is a group capable of joining Y selected from the group comprising: -C (O) -, -C (0) O- or
Claims (49)
- where R 'and R "are the same or different, and are H or straight or branched CC alkyl, Z-? is H or a group -C (O) - capable of binding to Y, with the proviso that when s the formula (I) is 1, Z or Z-, is H; Y is a bivalent radical with the following meaning: a) straight or branched C 2 or C 2 alkylene which is optionally substituted with one or more of the substituents selected from the group comprising halogen atoms, hydroxy, -0N02 or T, where T is -OC (0) (CrC10 alkyl) -ON? 2, -O (CrC10 alkyl) -ONO2; b) -cycloalkylene with between 5 and 7 carbon atoms in the cycloalkylene ring, wherein the ring is optionally substituted with Ti side chains, where Ti is straight or branched alkyl having 1 to 10 carbon atoms; (IV) where: n is an integer between 0 to 20, and n1 is an integer between 1 and 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 between 0 to 20; X-i is -WC (O) - or -C (0) W-, where W is oxygen, sulfur or NH; with the proviso that: - when s of the formula (I) is 1, Z is - (CO) - and in the formula (IV) of the bivalent radical Y n2, n3, n4, n5 are equal to 0 then n is 0 and n1 is 1; - when s of the formula (I) is 1, Z is - (CO) - and in the formula (IV) of the bivalent radical Y n2, n3, n5 are equal to 0, n4 is 1 then n and n1 are different from 1; d) ) p- (Xl? - (CH2) p- (V) where: n1 is an integer between 1 to 20; Xi is -WC (O) - or - C (0) W-, where W is oxygen, sulfur or NH; n6 is an integer between 1 to 20 and n7 is an integer from 0 to 20, R5 and R5 'R6 and R6' are independently selected from the group comprising 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 among the divalent radicals mentioned in c) -d), the -ON02 group is attached to a group - (CH2) -; with the proviso that when s of the formula (I) is 1 and Z is - (CO) -, then the bivalent radical Y does not have the meanings mentioned in a), b) and d); and) (SAW) (VII) where X2 is 0 or S, n10a, n10 and n12 are integers selected independently from 0 to 20, n11 is an integer from 0 to 6, R11 is H, CH3 or nitrooxy group; with the proviso that when in the formula (I) s is 1, in the formula (II) Z is - (CO) -, in the formula (VI) of the bivalent radical Y n10a, n10, n12 are equal to 1, then X can not be an oxygen atom; F) (VIII) where: nd is an integer between 0 to 10; n9 is an integer between 1 to 10; R9, R10, R8, R7 are the same or different, and are H or straight or branched C4 alkyl; where the group -ON02 is linked to l - [C] I pg where n9 is as already defined; Y2 is a saturated, unsaturated or aromatic 5 or 6 membered heterocyclic ring, with one or more heteroatoms selected nitrogen, oxygen, sulfur, and is selected from the group that includes: (Y1) (Y2) (Y3) (Y4) (Y5) (Y6) (Y7) (Y8) (Y9) (Y10) (Y11) (Y12) (Y13) 2. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 1, further characterized in that: s equals 1 and Z-? is H. 3. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 2, further characterized in that Z is -C (0) -. 4. The compound and enantiomers and diastereomers and their pharmaceutically acceptable salts according to claim 3, further characterized in that Y is (IV) wherein n, n2, n3, n4 and n5 are equal to 0; n1 is an integer equal to 1 5. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 3, further characterized in that: Y is (iv) where n, n2, n5 are 1, n3 and n4 are equal to 0, n1 is an integer between 1 and 10, Y1 is - (CH2) na-CH = CH- where na is 0, X is - WC (O) - where W is oxygen and Xi 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. 6. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 3, further characterized in that: Y is (VI) (VII) where X2 is O or S, n10a, n10 and n12 are selected integers independently from 2 to 20; n1 1 is an integer from 0 to 6; R11 is H, CH3 or a nitrooxy group; R11 a is CH3 or a nitrooxy group. 7. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to the claim 2, further characterized in that Z is -C (0) 0-. 8. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 7, further characterized in that: Y is a straight or branched C20 alkylene that is optionally substituted with one or more of the substituents selected from the group consisting of group comprising halogen atoms, hydroxy, -0N02 or T, where T is -OC (0) (CrC10 alkyl) -ON? 2, -0 (CrC10 alkyl) -ONO2. 9. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to the claim 8, further characterized in that: Y is a straight or branched CrC 0 alkylene. 10. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 7, 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- where na is an integer from 0 to 20; Xi is -WC (O) - or -C (0) W-, where W is oxygen, sulfur or NH. 11. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 10, 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. 12. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 7, further characterized in that: Y is (VI) (VII) where: X2 is O or S, n10a, n10 and n12 are integers selected independently from 0 to 20; n11 is an integer between 0 to 6; R11 is H, CH3 or a nitrooxy group; R11a is CH3 or a nitrooxy group. 13. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 12, further characterized in that: Y is (VI) where: X2 is O or S, n10a and n11 are 0, n12 is 1 and R11 is H; where the group -ON02 is linked to the group - (CH2) ni2-- 14.- The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to the claim 7, further characterized because: Y is (V) where: n1 is an integer between 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 comprising: 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. 15. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 2, further characterized in that Z is 16. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 15, further characterized in that: Y is a straight or branched C 2 or C 2 alkylene which is optionally substituted with one or more of the substituents selected from the group it comprises halogen atoms, hydroxy, -ON02 or T, where T is -OC (0) (C? -C-? o alkyl) -ON02, -0 (C10 alkyl) -ONO2. 17. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 16, further characterized in that: Y is a straight or branched C C? Alkylene. 18. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 15, 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- where na is an integer from 0 to 20; X1 is -WC (O) - or -C (0) W-, where W is oxygen, sulfur or NH. 19. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 18, 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. 20. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 1, further characterized in that Z and Zi are -C (O) -. 21. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to the claim 20, further characterized in that: Y is a straight or branched C 2 C alkylene which is optionally substituted with one or more of the substituents selected from the group comprising halogen atoms, hydroxy, -ON02 or T, where T is -OC ( 0) (CC 0 alkyl) -ONO 2, -0 (C 10 alkyl) -ONO 2. 22. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to the claim 21, further characterized in that Y is a straight or branched C1-C10 alkylene. 23. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 20, further characterized in that: Y is (IV) where: n is an integer between 0 to 20, n1 is an integer between 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 selected independently between H or CH3; Y1 is -CH2- or - (CH2) na- CH = CH- where na is an integer from 0 to 20; X is -WC (O) - or -C (0) W-, where W is oxygen, sulfur or NH. 24. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 23, 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. 25. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 23, 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, Xi is -WC (O) - where W is oxygen and Xi is linked to the phenyl ring through [C], R4 is CH3 and the group (OR4) is attached to the phenyl ring through [C] 3. 26. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 20, further characterized in that: Y is (SAW) (VII) where: X2 is O or S, n10a, n10 and n12 are integers selected independently from 0 to 20; n11 is an integer from 0 to 6; R11 is H, CH3 or a nitrooxy group; R11a is CH3 or a nitrooxy group. 27. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 26, further characterized in that: Y is (VI) where: X is O or S, n10a and n11 are 0, n12 is 1, R11 is H; where the group -ONO2 is attached to the group - (CH2) ni2-. 28. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts in accordance with the claim 20, further characterized because: Y is (V) where: 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 comprising: 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. 29. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 28, 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 -ON0 is linked to the group - (CH2) n? -. 30. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 1, further characterized in that s is 1, Z is H and Z1 are -C (O) -. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 30, further characterized in that: Y is a straight or branched C 1 -C 20 alkylene which is optionally substituted with one or more of the substituents selected from the group comprising halogen atoms, hydroxy, -ON02 or T, where T is -OC (0) (C10 alkyl) -ON? 2, -0 (CC? oalkyl) -ONO2. 32. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 31, further characterized in that Y is a straight or branched C C? Alkylene. 33. - The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 30, further characterized in that: Y is (IV) where: n is an integer between 0 to 20, n1 is an integer between 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; X1 is -WC (O) - or -C (0) W-, where W is oxygen, sulfur or NH. 34. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 33, 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 their pharmaceutically acceptable salts according to claim 33, further characterized in that: n, n2, n5 are 1, n3 and n4 are equal to 0, n1 is an integer between 1 to 10 , Y1 is - (CH2) na-CH = CH- where na is 0, Xi is -WC (O) -, where W is oxygen and Xi is attached to the phenyl ring through [C], R4 is CH3 and group (OR4) is attached to the phenyl ring through [C] 3. 36. - The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 30, further characterized in that: Y is (SAW) (VII) where: X2 is O or S, n10a, n10 and n12 are integers selected independently from 0 to 20; n11 is an integer from 0 to 6; R11 is H, CH3 or a nitrooxy group; R11a is CH3 or a nitrooxy group. 37.- The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts in accordance with the claim 36, further characterized because: Y is (VI) where: X2 is O or S, n10a and n11 are 0, n12 is 1, R11 is H, where the group -ON02 is linked to the group - (CH2) ni2--38.- The compound and the enantiomers , diastereoisomers and their pharmaceutically acceptable salts according to claim 30, 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 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. 39.- The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts in accordance with the claim 38, further characterized because: 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 -ON02 is linked to the - (CH2) nr. The compounds and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 3 and claim 4, further characterized in that the compounds are: (1) (2) (3) 41.- The compounds and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 20 and claim 24, further characterized in that the compounds are: (4) (5) (6) 42.- The compounds and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 30 and claim 34, further characterized in that the compounds are: (7) (8) (9) 43.- The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 1 and claim 4, further characterized in that it is maleate salt of (S) -1- [ (1, 1 -dimethylethyl) amino] -3 - [[4- (4-morpholinyl) -1,5,5-thiadiazol-3-yl] oxy] -2-propanoic acid 4- (nitrooxymethyl) )benzoic. The compound and the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to claim 1 and claim 24, further characterized in that it is (S) -1 - [(1,1-dimethylethyl) [(4-nitrooxymethyl) l) benzoyl] amino] -3 - [[4- (4-morpholinyl) -1,5,5-thiadiazol-3-yl] oxy] -2-propanoate of 4- (nitrooxymethyl) benzoic acid. 45.- The compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts according to claim 1 and claim 34, further characterized in that it is (S) -1 - [(1,1-dimethylethyl) [(4-nitrooxymethyl) benzoyl] amino] -3 - [[4- (4-morpholinyl) -1,5,5-thiadiazol-3-yl] oxy] -2-propanol. 46. The compound of the formula (I) and / or the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to any of claims 1 to 45, further characterized in that it is for use as a medicament. 47.- The use of a compound of the formula (I) and / or the enantiomers, diastereoisomers and their pharmaceutically acceptable salts according to any of claims 1 to 45, further characterized in that it is for preparing a drug that can be used in the treatment or prophylaxis of hypertension, cardiovascular and vascular diseases. 48. The use of a compound of the formula (I) and / or the enantiomers, diastereoisomers and their pharmaceutically acceptable salts as defined in any of claims 1 to 45, for preparing a drug that can be used in the treatment of glaucoma. and high intraocular pressure. 49.- 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 45 and a pharmaceutically acceptable carrier thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP03104485.2 | 2003-12-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA06006251A true MXPA06006251A (en) | 2006-10-17 |
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