WO2003013499A2 - Drugs for vasculopaties - Google Patents
Drugs for vasculopaties Download PDFInfo
- Publication number
- WO2003013499A2 WO2003013499A2 PCT/EP2002/008374 EP0208374W WO03013499A2 WO 2003013499 A2 WO2003013499 A2 WO 2003013499A2 EP 0208374 W EP0208374 W EP 0208374W WO 03013499 A2 WO03013499 A2 WO 03013499A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acid
- methyl
- nitrooxy
- alpha
- formula
- Prior art date
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- 239000003814 drug Substances 0.000 title claims description 17
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- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 claims description 8
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- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
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- 206010038923 Retinopathy Diseases 0.000 description 1
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
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- 230000007574 infarction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
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- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
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- 239000001301 oxygen Substances 0.000 description 1
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- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
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- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
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- 230000003331 prothrombotic effect Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000003439 radiotherapeutic effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
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- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- the present invention relates to the use of drugs in the prevention and/or treatment of vasculopathies .
- vascular cells cells of the vasal smooth musculature ceils, endothelial cells
- haematic cells platelets, leucocytes, monocytes/macrophages, etc.
- Vasculopathies and diseases related thereto are pathological conditions associated to an altered haematochemical and clinical picture, which shows itself with hyperglycemia and/or hyperinsulinemia, hyperlipide ia and/or hydric-saline retention and/or hyperproliferation of vasal and/or tu oral cells, and/or prothrombotic and procoagulant activity, etc.
- Vasculopathies can facilitate the growth of other pathologies such obesity, diabetes and cardiovascular diseases such for example myocardial, cerebral and/or peripheral ischaemias, retinopathies, polyneuropathies, gastroenteropathies, ne- phropa-thies, etc., hypertension (general and local at pulmonary, coronary, portal, renal level, etc.) atherosclerosis, Alzheimer disease, cancer.
- cardiovascular diseases such for example myocardial, cerebral and/or peripheral ischaemias, retinopathies, polyneuropathies, gastroenteropathies, ne- phropa-thies, etc.
- hypertension generally and local at pulmonary, coronary, portal, renal level, etc.
- Alzheimer disease cancer.
- vasculopathies Also particular pathologies such as the X syndrome (or insulin resistance) and the vasculopathy from drugs are comprised in vasculopathies.
- the ideal approach is to operate on the various cell processes, i.e. to prevent the pathological activation of the aforesaid cells, which causes the growth and the progress of the pathological process affecting the cardiovascular system.
- Statines, rapamycin and the radiotherapeutic treatment are active only on the smooth musculature but not on the other cell populations.
- the results obtained with said pharmacological treatments and with the radiotherapy are only partially satisfactory and therefore it is necessary to increase dosages with consequent even serious side effects.
- An object of the present invention is therefore the use in vasculopathies of drugs, or salts thereof, having the following general formula (I) :
- R is the radical of formula (All)
- Ri is phenyl, or a 2, 6-dichlorophenylamino- group; R 6 is hydrogen or one halogen atom, preferably fluorine; or Ri and R 6 form together the radical of formula (Ala);
- the precursor compound of B being selected from the following: aminoacids, selected from the following: L- carnosirie, anserine, selenocysteine, selenome- thionine, penicillamine, N-acetylpenicillamine, cysteine, N-acetylcysteine, glutathione or its esters, preferably ethyl or isopropyl ester; hydroxyacids, selected from the following: gallic acid, ferulic acaid, gentisic acid, citric acid, caffeic, dihydrocaffeic acid, p-cumaric acid, vanillic acid; aromatic and hetrocyclic polyalcohols, selected from the following: nordihydroguai
- Y is :
- nIX is an integer comprised between 0 and 3, preferably 1
- nllX is an integer comprised between 1 and 3, preferably 1;
- R TIX , RTIX', T I IX ⁇ R II '/ equal to or different from each other are H or linear or branched C ⁇ -C 4 alkyl; preferably R TIX , R T ⁇ x ' , R T nx, RTIIX' are H.
- Y 3 is a saturated, unsaturated or aromatic heterocy-rod ring containing one or two nitrogen atoms, having 5 or 6 atoms, or Y can be: Yo, selected from the following: an alkylenoxy group R'O wherein R' is a linear or branched when possible C ⁇ -C 20 , preferably having from 2 to 6 carbon atoms, or a cycloal- kylene having from 5 to 7 carbon atoms, in the cycloalkylene ring one or more carbon atoms can be substituted by heteroatoms, the ring can have side chains of R' type, R' being as above; or one of the following groups: -(CH 2 - CH 2 O)'nf
- nf ' is an integer from 1 to 6 preferably from 1 to 4 ;
- R if H, CH 3 and nf is an integer from 1 to
- Y is Y AR and is selected from the following:
- n3 is an integer from 0 to 3 and n3 ' is an integer from 1 to 3;
- YAR2 is an integer from 0 to 3 and n3 ' is an integer from 1 to 3;
- n3 and n3 ' have the above meaning.
- R AI is CH 3
- Ri is the phenyl group in position 4 of the ring
- R 6 F in position 3
- the so defined radical is that of the precursor drug Flurbiprofen
- R A ⁇ is CH 3
- Ri and R 6 are in position 4 and 5 of the ring and form together the radical of formula (Ala)
- the so defined radical is that of the precursor drug Naproxen
- R A ⁇ is H
- Ri is the 2,6- dichlorophenylamino group and is in position 2 of the ring
- R 6 H
- the so defined radical is that of the precursor drug Diclofenac.
- Y 3 is selected from the following:
- Y 3 is an aromatic ring having 6 atoms, containing one nitrogen atom, said aromatic ring having the two free valences in position 2 and 6.
- Y 3 is Y12 (pyridyl) substituted in position 2 and 6.
- the bonds can also be in an asymmetric position, for example Y12 (pyridyl) can be substituted also in position 2 and 3; Yl (pyrazol) can be 3, 5-disubstituted.
- the precursors of Y p wherein the oxygen free valence is saturated with H and the free valence of the end carbon is saturated either with a carboxylic or an hydroxyl group, are compounds available on the market or can be obtained by meth ⁇ ods known in the prior art .
- the functional linking groups between, respectively, R and X 2 , between X 2 and Y, or between R and Y, can be ester, am- ideor thioester.
- the precursor compounds of B of the above groups are pre- pard according to the methods known in the prior art and described for example in "The Merck Index", 12th Ed. (1996), herein incorporated by reference.
- the preferred compounds of formula (I) are the following: 2-Fluoro- ⁇ -methyl [1, 1' -biphenyl] -4-acetic acid 4- (nitrooxy) butyl ester (V)
- the compounds of formula (I) are generally obtained by methods known in the prior art, see for example patent applications WO 00/61537, WO 00/51988, WO 95/30641, in the name of the Applicant .
- the compounds of formula (I) usable in the present invention have one or more chiral centres, they can be in a race ic form or as mixtures of diastereoisomers, as single en- antiomers or single diastereoisomers; when they show a geometric asymmetry, the compounds in the cis or trans form can be used.
- a salifiable functional group for example an aminic or heterocyclic nitrogen
- organic solvent such as for example acetonitrile, tetrahy- drofuran, with an equimolar amount of the corresponding organic or inorganic acid.
- usable organic acids are the following: ox ⁇ alic, tartaric, maleic, succinic, citric acids.
- Examples of usable inorganic acids are the following: nitric, hydrochloric, sulphuric, phosphoric acids. Nitric and hydrochloric acids are preferred.
- the vasculopathy is significantly reduced and in particular the restenosis process which can grow in people subjected to angioplasty and in particular , in those more at risk such as old people, diabetic, hyperlipidemic people.
- the amount on a molar basis of the active principle in said formulations is equal to or lower than the maximum posol- ogy indicated for the precursor drugs. Also higher doses can be used considering their very good tolerability.
- the daily doses of the precursor drugs can be found in the publications of the prior art, such as for example in "Physician's Desk reference".
- Wistar male rats of 300-350 g weight were anaesthetized by intraperitoneal injection of ketamine (100 g/kg) and xylazine (5 mg/kg) and subjected to angioplasty according to the procedure described by Indolfi et Al . , Circulation 1995 92 1230-1235, by using a little balloon catheter.
- the balloon was first introduced in the aortic arch through the right carotid, then swollen and passed three times forth and back in the duct lumen.
- the animals were divided in the two groups indicated below and subjected for 14 days to the pharmacological treatment as described ereunder: one group was treated by os by means of a gastric cannula with NO-Flurbiprofen at the dose of 10 mg/kg dissolved in polyethylene glycol (PEG 400), and the other group (control) received only the carrier (PEG 400, 0.2 ml/rat).
- one group was treated by os by means of a gastric cannula with NO-Flurbiprofen at the dose of 10 mg/kg dissolved in polyethylene glycol (PEG 400), and the other group (control) received only the carrier (PEG 400, 0.2 ml/rat).
- the animals were sacrificed and the carotids removed. For each artery no. 6 sections having a thickness of 6 ⁇ m were obtained. Stomachs were also removed and inspected to evaluate damages to the gastric mucosa. Areas of both bleeding lesions and non bleeding lesions were determined.
- the thicknesses, respectively, of the middle and neoin- tima tunica, and of the duct wall were measured.
- the results reported in Table 1 are expressed as percentage of restenosis and have been calculated as a ratio between the thickness of the neointima tunica to that of the middle tunica (M/N) measured in the sections of the various groups, assuming equal to 100 the N/M ratio of the control group.
- Example FI is repeated but using NO-Flurbiprofen at the dose of 30 mg/Kg. The results are reported in Table 1.
- Example FI is repeated but using Flurbiprofen at the dose of 7 mg/Kg. The results are reported in Table 1.
- Example FI is repeated but using Flurbiprofen at the dose of 21 mg/Kg. The results are reported in Table 1.
- Example FI is repeated but using NO-Ketorolac at the dose of 10 mg/Kg. Comments on Table 1
- NO-Ketorolac appears not very effective with respect to NO-Flurbiprofen and at effective doses it produces gastric lesions .
Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2002333276A AU2002333276A1 (en) | 2001-08-09 | 2002-07-26 | Drugs for vasculopaties |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT2001MI001744A ITMI20011744A1 (en) | 2001-08-09 | 2001-08-09 | DRUGS FOR VASCULOPATHIES |
ITMI01A001744 | 2001-08-09 |
Publications (2)
Publication Number | Publication Date |
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WO2003013499A2 true WO2003013499A2 (en) | 2003-02-20 |
WO2003013499A3 WO2003013499A3 (en) | 2003-12-31 |
Family
ID=11448261
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/EP2002/008374 WO2003013499A2 (en) | 2001-08-09 | 2002-07-26 | Drugs for vasculopaties |
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AU (1) | AU2002333276A1 (en) |
IT (1) | ITMI20011744A1 (en) |
WO (1) | WO2003013499A2 (en) |
Cited By (8)
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WO2005011646A2 (en) * | 2003-07-31 | 2005-02-10 | Nicox S.A. | Nitrooxy derivatives of losartan, valsatan, candesartan, telmisartan, eprosartan and olmesartan as angiotensin-ii receptor blockers for the treatment of cardiovascular diseases |
EP1709155A2 (en) * | 2003-12-31 | 2006-10-11 | Khosrow Kashfi | Compounds and compositions for treating dysproliferative diseases, and methods of use thereof |
US7163958B2 (en) * | 2002-07-03 | 2007-01-16 | Nitromed Inc. | Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use |
US7220749B2 (en) | 2002-06-11 | 2007-05-22 | Nitromed, Inc. | Nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use |
EP2075011A2 (en) | 2004-08-26 | 2009-07-01 | Piramal Life Sciences Limited | Prodrugs Containing Bio-Cleavable Linkers |
EP2266623A2 (en) | 2004-08-26 | 2010-12-29 | Piramal Life Sciences Limited | Prodrugs containing novel bio-cleavable linkers |
US8236820B2 (en) | 2007-08-10 | 2012-08-07 | Basil Rigas | Anti-inflammatory compounds and uses thereof |
RU2560144C2 (en) * | 2006-02-03 | 2015-08-20 | Никокс Сайенс Ирландия | Nitrogen oxide-releasing compounds |
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- 2002-07-26 WO PCT/EP2002/008374 patent/WO2003013499A2/en not_active Application Discontinuation
- 2002-07-26 AU AU2002333276A patent/AU2002333276A1/en not_active Abandoned
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AU2002333276A1 (en) | 2003-02-24 |
WO2003013499A3 (en) | 2003-12-31 |
ITMI20011744A0 (en) | 2001-08-09 |
ITMI20011744A1 (en) | 2003-02-09 |
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