IE20000052A1 - Nitric acid salts of B-blockers - Google Patents
Nitric acid salts of B-blockersInfo
- Publication number
- IE20000052A1 IE20000052A1 IE20000052A IE20000052A IE20000052A1 IE 20000052 A1 IE20000052 A1 IE 20000052A1 IE 20000052 A IE20000052 A IE 20000052A IE 20000052 A IE20000052 A IE 20000052A IE 20000052 A1 IE20000052 A1 IE 20000052A1
- Authority
- IE
- Ireland
- Prior art keywords
- nitric acid
- blockers
- bisoprolol
- blocker
- acid salts
- Prior art date
Links
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 229960002781 bisoprolol Drugs 0.000 claims abstract description 10
- VHYCDWMUTMEGQY-UHFFFAOYSA-N bisoprolol Chemical compound CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1 VHYCDWMUTMEGQY-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910002651 NO3 Inorganic materials 0.000 claims abstract description 6
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002876 beta blocker Substances 0.000 claims description 14
- 229940097320 beta blocking agent Drugs 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 229960002035 penbutolol Drugs 0.000 claims description 2
- KQXKVJAGOJTNJS-HNNXBMFYSA-N penbutolol Chemical compound CC(C)(C)NC[C@H](O)COC1=CC=CC=C1C1CCCC1 KQXKVJAGOJTNJS-HNNXBMFYSA-N 0.000 claims description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 claims 2
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 claims 1
- 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 claims 1
- 241001473992 Abax Species 0.000 claims 1
- 229960002274 atenolol Drugs 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229960002237 metoprolol Drugs 0.000 claims 1
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 claims 1
- 229960003712 propranolol Drugs 0.000 claims 1
- 229960004605 timolol Drugs 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 4
- 208000024172 Cardiovascular disease Diseases 0.000 abstract description 3
- 238000011321 prophylaxis Methods 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 150000002823 nitrates Chemical class 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 1
- HXKKHQJGJAFBHI-UHFFFAOYSA-N 1-aminopropan-2-ol Chemical class CC(O)CN HXKKHQJGJAFBHI-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- XILIYVSXLSWUAI-UHFFFAOYSA-N 2-(diethylamino)ethyl n'-phenylcarbamimidothioate;dihydrobromide Chemical compound Br.Br.CCN(CC)CCSC(N)=NC1=CC=CC=C1 XILIYVSXLSWUAI-UHFFFAOYSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004452 microanalysis Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
- C07D285/135—Nitrogen atoms
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
- C07C217/32—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
- C07C217/34—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
New nitric acid salts of B-blockers, especially Bisoprolol nitrate are useful in the prophylaxis and/or treatment of cardiovascular disease.
Description
This invention relates to beta-adrenergic blockers (β-blockers).
β-blockers are widely used in the prophylaxis and/or treatment of cardiovascular diseases. They are particularly important antihypertensives.
In general, β-blockers may be represented by the formula I:
OH
R1 and R2 may represent a wide range of substituents. The following is a table 15 giving the substituents for a selection of such compounds which are commercially available and widely used.
In general the compounds of formula I are amino-2-propanol derivatives in which R2 is iso-butyl, tert-butyl, iso-propyl or others.
I OPEN TO PUBLIC I VHOPR
I SECTION 2% ALL; RULE 23
I imt nt I )6j
IJNL.NO
404____..^muiaaueos’5 «ΟΟΟβββ T.
HO©®»»·»*0®·4'*’*'
IE000052
RUSS 19. C
Table 1
IE000052
RUSSI9/C
-3Most β-blockers of formula I are converted into pharmaceutically acceptable salts prior to formulation. The inorganic acids generally used are hydrochloric acid or sulphuric acid. The organic acids used are generally fumaric acid, maleic acid or tartaric acid.
There is however a need for improved pharmaceutically active salts of such βblockers which will have an equivalent or enhanced pharmacological profile, reduced side effects, increased purity and/or stability or which can be more efficiently produced than conventional salts of β-blockers.
This invention is therefore directed towards providing such a salt.
Statements of Invention
According to the invention there is provided nitric acid salts of β-blockers as defined in formula I and, particularly, in table 1 above.
In particular, the invention provides Bisoprolol Nitrate.
The invention further provides pharmaceutical formulations incorporating the compounds.
In addition, the invention also provides processes for preparing such compounds.
Detailed Description of the Invention
It has been found that β-blockers of formula I can be crystallised as their nitric acid salts.
IE000052
RUSSI9/C
-4-.
OH
(I)
The substituents R1 and R2 may be represented by groups as summarised in table 1 or others. Of particular interest are the nitrates of Bisoprolol II and Penbutolol
III.
The process for the preparation of such nitrates is simple and efficient. It may be performed under very mild conditions. The product is generally obtained in a good yield and is of high quality.
The invention will be more clearly understood from the following non-limiting examples.
IE000052
RUSS19/C
-5Example 1
Preparation of Bisoprolol Nitrate
.0 g (0.05 mol) of Bisoprolol base were dissolved in 50-100 ml of a suitable solvent such as ethyl acetate. One equivalent of cone, nitric acid was added and the mixture stirred, preferably at room temperature for approximately 15-20 min. The solvent was distilled off and remaining water may optionally be removed by treatment with toluene and subsequent azeotrop distillation. The product crystallises from the crude oil and may be recrystallised from a suitable solvent. Seeding material may be added to accelerate the crystallisation process. After filtration the product was dried preferably under vacuum. Typically a yield of >85% is obtained.
Figures 1, 2, 3 and 4 show the ^-NMR spectrum, 13C-spectrum, DEPT and the IR spectrum respectively.
Analytical data for Bisoprolol Nitrate:
Mp.: 57.5-58.5°C 'H-NMR (270 MHz, CDC13): δ = 1.16 (d; 6H, CH3), 1.38 (d; 6H, CH3), 3.15-3.40 (m; 2H, CH2), 3.56-3.63 (m; 6H, CH2, CH), 3.95-4.00 (m; 2H, CH2), 4.40-4.47 (m; 3H, CH2, CH), 5.22 (Sbr; 1H, OH), 6.81 (d; 2H, H^,), 7.22 (d; 2H, H^,), 8.00 (Sbr; 1H, NH2), 8.73 (Sbr, 1H, NH2), all OH and NH2-protons are exchangeable with D2O.
13C-NMR (67.5MHz, CDCL3): δ = 18.83, 19.03, 22.31 (CH3); 48.24 (CH2); 51.60, 66.00 (CH); 67.49, 69.73 (CH2); 71.90 (CH), 72.79 (CH2); 114.54, 129.5 (C^,), 131.49 (C^rC); 157.89 (Catyi-O).
FT-IR (KBr): v [cm'1] = 3414, 2973, '1612, 1513, 1334, 1245, 1108.
IE000052
RUSS19/C
- 6 Micro Analysis: C18H32N2O7 [388.46]
Calc.: C:55.66 H:8.30 N:7.21
Found: C:56.00 H:8.54 N:7.22
Example 2
Alternative preparation process for Bisoprolol Nitrate
.Og (0.027mol) of Bisoprolol Hydrochloride were dissolved in a suitable solvent such as acetonitrile. 4.70g (0.027mol) of silver nitrate were dissolved separately in the same solvent. The two solutions were mixed giving an immediate precipitate. The suspension was agitated, preferably at room temperature for 15-60 min. The precipitate was filtered off and the volume of the mother liquor was reduced producing an oil. The product precipitates from the oil on standing, preferably at a temperature below ambient. Optionally seeding material may be added to accelerate crystallisation. The product was filtered and dried. Typically a yield of >95% is obtained. The analytical data is as per example 1.
The compounds of the invention may be formulated in any suitable pharmaceutical compositions using conventional excipients or vehicles. Typically the composition is in a form for oral administration such as a tablet or capsule.
It will be appreciated that the compounds of the invention may be coadministered with one or more other pharmaceutically active compounds.
The compounds of the invention are useful in the prophylaxis and/or treatment of cardiovascular disease and are especially useful as antihypertensives.
The invention is not limited to the embodiments hereinbefore described which may be varied in detail.
IE000052
RUSSI9/C
Claims (7)
1. A nitric acid salt of a β-blocker. 5
2. A compound as claimed in claim 1 wherein the β-blocker is selected from bisoprolol, penbutolol, metoprolol, propranolol, atenolol and timolol.
3. Bisoprolol nitrate. 10
4. A pharmaceutical composition comprising a compound as claimed in any of claims 1 to 3 and a suitable pharmacologically acceptable carrier.
5. A nitric acid salt of a β-blocker substantially as hereinbefore described. 15
6. A pharmaceutical composition of a nitric acid salt of a β-blocker substantially as hereinbefore described.
7. A process for preparing a nitric acid salt of a β-blocker substantially as hereinbefore described. IE000052 'J 45 SI <23 ο ·Λ co Τ' O · J r». ο o -v 3 Aj . . r\, —. OO - : U O Q 3 uj j 1 a. ·< i a. — '.t li_ IE000052 •j ·υ ·-» .·« *» ο «Μ X X Ο Ο Ο Ώ η rs Ώ Τ. · Ο Ο Ο 7» · » ο ο *-> χ —· *-> '* af'4!\J · · ο -» <-> ο αΊ X ο ο u f-ι Ο ~ LTi Ο CJ ιΛ Ο Ο -» Ο .*» ./> »π · Ο © — ©ο rjo α □ υ Ο Ο Ζ tl r- r -rC.-JazO — X Zr- O.Z U Z □- X U— < —‘O ~ X > <α2£ίχαυΟυθ2ω j » O G lj — Ά c. < a. t i? O ',7 LU LL. cz co u e. uj ς·7 c3 » X X >I •ST) I U- IE000052 Ο Ο 0Q r“l Ο Αι • Ο Ο Ο · ο ο a ο '-ο a ·-* λ» · · -« *τ η ο cu ο ·, ο·· ο \ cr.-3 ο ζ < M3 * -□ ο ο : Ο£ Ο •J- χ ·. C3 X c «.Τι— X χζ.— < — ο C- UJ 4-1 <23 J X χ >. IE000052 A scans, 4.0cm-l, flat, abax PErtKIN
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IE20000052A IE20000052A1 (en) | 1999-04-29 | 2000-01-21 | Nitric acid salts of B-blockers |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IE990358 | 1999-04-29 | ||
| IE20000052A IE20000052A1 (en) | 1999-04-29 | 2000-01-21 | Nitric acid salts of B-blockers |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE20000052A1 true IE20000052A1 (en) | 2000-11-29 |
Family
ID=11042053
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE20000052A IE20000052A1 (en) | 1999-04-29 | 2000-01-21 | Nitric acid salts of B-blockers |
Country Status (2)
| Country | Link |
|---|---|
| GB (1) | GB2349386B (en) |
| IE (1) | IE20000052A1 (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1295694B1 (en) * | 1996-11-14 | 1999-05-27 | Nicox Sa | NITROXIS DERIVATIVES FOR THE PREPARATION OF MEDICATIONS WITH ANTI-THROMBINIC ACTIVITY |
-
2000
- 2000-01-21 IE IE20000052A patent/IE20000052A1/en not_active IP Right Cessation
- 2000-01-26 GB GB0001786A patent/GB2349386B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| GB0001786D0 (en) | 2000-03-22 |
| GB2349386A (en) | 2000-11-01 |
| GB2349386B (en) | 2004-02-25 |
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