IE20000052A1 - Nitric acid salts of B-blockers - Google Patents

Nitric acid salts of B-blockers

Info

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
Application number
IE20000052A
Inventor
Helmut Schickaneder
Aggelos Nikolopoulos
Original Assignee
Russinsky Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Russinsky Ltd filed Critical Russinsky Ltd
Priority to IE20000052A priority Critical patent/IE20000052A1/en
Publication of IE20000052A1 publication Critical patent/IE20000052A1/en

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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

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
IE20000052A 1999-04-29 2000-01-21 Nitric acid salts of B-blockers IE20000052A1 (en)

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

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IE20000052A1 true IE20000052A1 (en) 2000-11-29

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IE (1) IE20000052A1 (en)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
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

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GB2349386A (en) 2000-11-01
GB0001786D0 (en) 2000-03-22

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