GB2349386A - Nitric acid salts of beta-blockers - Google Patents

Nitric acid salts of beta-blockers Download PDF

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Publication number
GB2349386A
GB2349386A GB0001786A GB0001786A GB2349386A GB 2349386 A GB2349386 A GB 2349386A GB 0001786 A GB0001786 A GB 0001786A GB 0001786 A GB0001786 A GB 0001786A GB 2349386 A GB2349386 A GB 2349386A
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United Kingdom
Prior art keywords
blockers
nitric acid
bisoprolol
acid salts
beta
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Granted
Application number
GB0001786A
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GB0001786D0 (en
GB2349386B (en
Inventor
Helmut Schickaneder
Angelo Nikolopoulos
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Russinsky Ltd
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Russinsky Ltd
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Publication of GB2349386A publication Critical patent/GB2349386A/en
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Publication of GB2349386B publication Critical patent/GB2349386B/en
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    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

New nitric acid salts of …-blockers, especially Bisoprolol nitrate, are useful in the prophylaxis and/or treatment of cardiovascular disease. They have equivalent or enhanced pharmacological profile, reduced side effects, increased purity and/or stability or can be more efficiently produced than conventional salts of …-blockers.

Description

"A Compound" Introduction This invention relates to beta-adrenergic blockers ( (3-blockers).
(3-blockers are widely used in the prophylaxis and/or treatment of cardiovascular diseases. They are particularly important antihypertensives.
In general, (3-blockers may be represented by the formula I:
R'and Ruz mamy represent a wide range of substituents. The following is a table 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 W is iso-butyl, tert-butyl, iso-propyl or others.
r Product R1 R2 Bisoprolol < 0 Ti lSO butyl 3 CH CH3 Penbutolol tert.-butyl I I Metoprolol iso-butyl , hic Propranolol iso-butyl han HzN Atenolol iso-butyl a ' N N Timolol N tert.-butyl ou i O i Table 1 Most (3-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 (3blockers 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 (3-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 (3-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 0.-blockers of formula I can be crystallised as their nitric acid salts.
The substituents R'and R'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.
Example 1 Preparation of Bisoprolol Nitrate 15.0 g (0.05 mol) of Bisoprolol base were dissolved in 50-100 ml of a suitable solvent such as ethyl acetate. One equivalent of conc. 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 tH-NMR spectrum,'3C-spectrum, DEPT and the IR spectrum respectively.
Analytical data for Bisoprolol Nitrate: Mp.: 57.5-58.5 C 'H-NMR (270 MHz, CDC13) : 5 = 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, Heu), 7.22 (d; 2H, Heu), 8.00 (Sbr ; 1H, NH2), 8.73 (Sbr 1H, NH2), all OH and NH2-protons are exchangeable with D20.
"C-NMR (67.5MHz, CDCL3) : 5 =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 (Caryl), 131.49 (C.,-C) ; 157.89 (Cel-O).
FT-IR (KBr) : v ['] = 3414, 2973,1612,1513,1334,1245,1108.
Micro Analysis: Cl8H32N207 [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 I O. 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 co- administered 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.

Claims (7)

  1. Claims 1. A nitric acid salt of a (3-blocker.
  2. 2. A compound as claimed in claim 1 wherein the (3-blocker is selected from bisoprolol, penbutolol, metoprolol, propranolol, atenolol and timolol.
  3. 3. Bisoprolol nitrate.
  4. 4. A pharmaceutical composition comprising a compound as claimed in any of claims 1 to 3 and a suitable pharmacologically acceptable carrier.
  5. 5. A nitric acid salt of a-blocker substantially as hereinbefore described.
  6. 6. A pharmaceutical composition of a nitric acid salt of a-blocker substantially as hereinbefore described.
  7. 7. A process for preparing a nitric acid salt of a-blocker substantially as hereinbefore described.
GB0001786A 1999-04-29 2000-01-26 A compound Expired - Fee Related GB2349386B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
IE990358 1999-04-29

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GB0001786D0 GB0001786D0 (en) 2000-03-22
GB2349386A true GB2349386A (en) 2000-11-01
GB2349386B GB2349386B (en) 2004-02-25

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* 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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GB0001786D0 (en) 2000-03-22
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PCNP Patent ceased through non-payment of renewal fee

Effective date: 20050126