IE55364B1 - Synergistic antihypertensive pharmaceutical composition - Google Patents
Synergistic antihypertensive pharmaceutical compositionInfo
- Publication number
- IE55364B1 IE55364B1 IE1597/83A IE159783A IE55364B1 IE 55364 B1 IE55364 B1 IE 55364B1 IE 1597/83 A IE1597/83 A IE 1597/83A IE 159783 A IE159783 A IE 159783A IE 55364 B1 IE55364 B1 IE 55364B1
- Authority
- IE
- Ireland
- Prior art keywords
- indapamide
- thiochroman
- salt
- pharmaceutical preparation
- physiologically tolerable
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 12
- 230000002195 synergetic effect Effects 0.000 title claims abstract description 7
- 230000003276 anti-hypertensive effect Effects 0.000 title description 2
- NDDAHWYSQHTHNT-UHFFFAOYSA-N indapamide Chemical compound CC1CC2=CC=CC=C2N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 NDDAHWYSQHTHNT-UHFFFAOYSA-N 0.000 claims abstract description 32
- 229960004569 indapamide Drugs 0.000 claims abstract description 32
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 13
- 206010020772 Hypertension Diseases 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract 6
- WPWNEKFMGCWNPR-UHFFFAOYSA-N 3,4-dihydro-2h-thiochromene Chemical compound C1=CC=C2CCCSC2=C1 WPWNEKFMGCWNPR-UHFFFAOYSA-N 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 6
- 230000003287 optical effect Effects 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 9
- 102000030621 adenylate cyclase Human genes 0.000 description 8
- 108060000200 adenylate cyclase Proteins 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 7
- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 description 7
- 229940095074 cyclic amp Drugs 0.000 description 7
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 208000013403 hyperactivity Diseases 0.000 description 4
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 241000272201 Columbiformes Species 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 2
- DRBBFCLWYRJSJZ-UHFFFAOYSA-N N-phosphocreatine Chemical compound OC(=O)CN(C)C(=N)NP(O)(O)=O DRBBFCLWYRJSJZ-UHFFFAOYSA-N 0.000 description 2
- 208000037849 arterial hypertension Diseases 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 239000002934 diuretic Substances 0.000 description 2
- 230000001882 diuretic effect Effects 0.000 description 2
- 210000003617 erythrocyte membrane Anatomy 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 229940039009 isoproterenol Drugs 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000011775 sodium fluoride Substances 0.000 description 2
- 235000013024 sodium fluoride Nutrition 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- 210000001685 thyroid gland Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- -1 3-amino-2-hydroxypropyloxy Chemical group 0.000 description 1
- AJVBPNRMKNARPG-UHFFFAOYSA-N 3-sulfamoylbenzamide Chemical compound NC(=O)C1=CC=CC(S(N)(=O)=O)=C1 AJVBPNRMKNARPG-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 101100294102 Caenorhabditis elegans nhr-2 gene Proteins 0.000 description 1
- 102000004420 Creatine Kinase Human genes 0.000 description 1
- 108010042126 Creatine kinase Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000009454 functional inhibition Effects 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229940082173 indapamide 1.25 mg Drugs 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 210000003975 mesenteric artery Anatomy 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 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
- 229950007002 phosphocreatine Drugs 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000010414 supernatant solution Substances 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
- A61P7/10—Antioedematous agents; Diuretics
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention provides pharmaceutical compositions and preparations comprising a combination of indapamide and certain thiachromans, especially 8-(3-tert.-butylamino-2- hydroxypropoxy)-thiachroman, or a physiologically tolerable acid addition salt thereof. Each of the two components may be in the racemic form or in the form of an optical isomer. The components in combination have unexpected synergistic properties and can be used for treating hypertension.
[GB2123293A]
Description
-2- $5364 The present invention relates to a pharmaceutical composition comprising a combination of active substances.
Indapamide, or N-(3-su1phamoyl-4-chlorobenzamido)-2-methyl-indoline, also known as 4-chloro-N-(2-methyl-l-indolinyl)-5 3-sulphamoylbenzamide, has been described in Example 1 of GB 1,203,691 (FR 69.06023; published under No. 2,003,311) as a diuretic that can be used especially for the treatment of arterial hypertension.
GB Patent 1,308,191 (FR 71.11445; published under No. 2,092,004) describes and claims (3-amino-2-hydroxypropyloxy) thiochromans of the general formula 0 - CH2 - CH0H - CH2 NHR2 (I) wherein A represents a hydrogen or halogen atom, R-] represents a hydrogen atom or an alkyl radical having from 1 to 5 carbon atoms, and R2 represents an alkyl radical having from 1 to 5 carbon atoms or a cycloalkyl radical having from 3 to 6 carbon atoms, -3- and salts thereof with mineral and organic acids.
This patent mentions cardiovascular properties, especially beta-blocking properties. 8-(3-tert.-butyl-amino-2-(hydroxypropoxy)-thiochroman (and the hydrochloride salt thereof) is described in Example 2 of the above British Patent. For the sake of convenience, 8-(3-tert.-butylami no-2-hydroxypropoxy)-thiochroman will be referred to hereinafter as "THPT".
We have now found that combinations of the above-mentioned compounds, in particular indapamide and THPT, have unexpected synergistic properties.
The combinations may be used for the treatment of hypertension.
The present invention provides a pharmaceutical composition which comprises indapamide and a thiochroman of the general formula I shown above, wherein A represents a hydrogen or halogen atom, R.j represents a hydrogen atom or an alkyl radical having from 1 to 5 carbon atoms, and Rg represents an alkyl radical having from 1 to 5 carbon atoms or a cycloalkyl radical having from 3 to 6 carbon atoms, or a physiologically tolerable addition salt thereof.
Preferably the thiochroman of the general formula I is THPT.
Accordingly, the present invention especially provides a pharmaceutical composition which comprises a combination of indapamide and THPT or a physiologically tolerable addition salt thereof.
The composition may be a simple admixture of compounds, or the active ingredients may, for example, be formulated with a pharmaceutically suitable carrier into a form suitable for direct administration.
Thus, the present invention also provides a pharmaceut-10 ical preparation which comprises indapamide in admixture or conjunction with a thiochroman of the general formula I given above, especially THPT, or a physiologically tolerable addition salt thereof, and in admixture or conjunction with a pharmaceutically suitable carrier. The 15 pharmaceutical preparation may, for example, be in dosage unit form.
One or more of the thiochromans may be present in the composition or preparation.
Each of the active ingredients, independently of the 20 other(s) may be in racemic form or in the form of an optical isomer, and indapamide, for example, may be in the form of its hemi-hydrate. The thiochroman may also be in the form of a salt of addition with a mineral or organic acid.
Suitably the ratio of indapamide to the thiochronian or salt thereof (preferably THPT or salt thereof) is, for example, from 1:15 to 1:1 by weight, more especially substantially 1:4.
The pharmaceutical compositions or preparations of the present invention are preferably administered by the oral route and may be, for example, in the form of tablets, coated tablets, capsules or suspensions. Preferably they contain from 0.8 to 3 mg of indapamide and from 10 3 to 12 mg of the thiochroman, especially THPT, or a physiologically tolerable addition salt thereof. Excipients or carriers customary for oral forms may, for example, be used. The combinations may be administered for example in one or two daily doses.
Although the indapamide and the thiochroman are preferably administered simultaneously, they may be taken one immediately after the other or, having regard, for example, to the half-life in vivo after absorption, at intervals such that a synergistic action of the two components in the body 20 is achieved. For this, the components may be brought together in the form of a pack, which comprises a container or other support member holding the indapamide and the thiochroman specified above, or a physiologically tolerable salt thereof, together with indications and/or 25 instructions to indicate or facilitate one or more treatments each comprising the administration of indapamide -6- and the thiochroman or salt thereof simultaneously or at close intervals sufficient to obtain a synergistic effect. In the pack there may be pharmaceutical preparations containing a combination of the active ingredients 5 or preparations containing the two ingredients separately.
The following test illustrates the synergistic effect of a combination of the present invention.
Pharmacological Study Indapamide and THPT were tested, alone and in combination, 10 for functional inhibition of membrane adenylate cyclase.
The red corpuscles of pigeons have been known for their considerable adenylate cyclase activity since the studies of SUTHERLAND et al_. (Adenyl cyclase 1. Distribution, preparation and properties, 0. Biol. Chem. (1962) 237 : 1220-15 1227). The experiments were carried out on erythrocyte ghosts (open cells) prepared from the blood of Strasser pigeons according to the method of SALESSE R. and GARNIER J., "Effects of drugs on pigeon erythrocyte membrane and asymmetric control of adenylate cyclase by the lipid 20 bilayer" (Biochem. Biophys. Acta (1979) 554 : 102-103).
The suspensions obtained were incubated for twenty minutes in hypotonic buffer with a volume of the tested product at the final concentration desired. The adenylate cyclase activity was determined according to the method -7- of BIRNBAUMER L. et al_. (J. Biol. Chem. (1969) 244 (13) : 3468-3476) and RAMACHANDRAN J.; LEE V. (Biochem. Biophys. Res. Commun. (1970) 41 : 358-366).
The final concentrations of reagents were ATP 2 nM 32 5 having IpCi of |a- JP ATP, theophylline 4 mM, phos-phocreatine 10 mM, creatine kinase 0.5 g/litre, MgC12 7.5 mM, tromethamine HC1 ("TRIS" HC1) 10 mM, pH = 7.4.
The total volume was 75 microlitres and the number of O cells per tube was approximately 10 .
The production of cyclic AMP (cAMP) was stimulated either by 0.05 mM of isoproterenol in the presence of 0.1 mM of GTP, or by 10 mM of sodium fluoride. The compound was added to the final concentration required.
The reaction was stopped after 15 minutes at 37°C by adding 300 microlitres of 0.5 N hydrochloric acid and by placing the mixture over a boiling water bath for 3 minutes. The tubes were then removed from the water bath and the contents were neutralised by 300 microlitres of 1.65 N 20 imidazole.
After centrifugation (10 minutes, 4000 g), 500 microlitres of the supernatant solution were poured into a neutral activated alumina column and were eluted with 8- 2.6 ml of imidazole, 10 mM, pH = 7.5. These columns had a yield of cAMP of 95¾.
The radioactivity of the samples was measured in a scintillation counter "Packard Tricarb'1 (Trade Mark), 5 using the Cerenkov effect after adding 10 ml of 1¾ aqueous solution of 7-amino-l,3-naphthalenedisulphonic acid to the eluate (counting yield 65¾).
According to a logarithmic scale, there were determined three concentrations above and three concentrations below 10 the concentration for which, i_n vitro, on the mesenteric artery of rats an inhibition of half of the vasoconstriction induced by noradrenaline could be observed.
The results were calculated as the average of three tests in pi comoles of cyclic AMP produced per minute and 15 per milligramme of membrane phospholipids.
It was seen that the indapamide and THPT subjected to this test inhibited the activation of adenylate cyclase stimulated by isoproterenol or sodium fluoride since the quantity of cAMP produced decreased. The nature of the 20 effect on the production of cAMP which was observed was dependent on the concentration of the compound used.
The active concentration of each compound producing an inhibition of 25¾ (AC2g) and 50¾ (ACg0) was determined -9- graphically. These concentrations were as follows: Indapamide (ra.w. = 365.89) : AC25 = 9 x 10"5 mole/litre ACgp = 3 x 10‘4 mole/litre THPT HC1 (m.w. = 331.90) : AC2g = 1.2 x 10'5 mole/litre 5 ^50 = 7 x 10~® mole/litre The inhibition produced by the mixtures of the two compounds at those concentrations was then measured. The following Table shows the percentage inhibition obtained with each of the 4 mixtures: TABLE Indapamide 25¾ Indapamide 50¾ THPT 25¾ 45¾ 62% THPT 50¾ 62¾ 75% It can be seen that the inhibition obtained with the 15 mixture of the two compounds is clearly superior to that obtained with each compound separately. For example, with -5 a mixture at the concentrations of 9 x 10 mole/litre of indapamide and 1.2 x 10'5 mole/litre of THPT, 45¾ inhibition is obtained, whereas with the single ingredients 20 this inhibition is only achieved by 2.5 x 10-4 mole/litre _C of indapamide or by 5 x 10 mole/litre of THPT; that is -10- approximately 3 to 4 tines the quantity is necessary for each of the compounds taken separately. The two effects corresponding to 25¾ inhibition are therefore multiplied in their global effect and result in a 45¾ inhibition of the activity of the enzyme.
Discussion: Since THPT is known as a beta-blocker, its inhibitory activity on adenyl cyclase associated with an extracellular beta-receptor might be foreseen. However, it was not to be expected that an anti-hypertensive diuretic such as indapamide would have a similar activity and that, above all, the activity of these two compounds would be combined: in fact, the dose/activity curve of these compounds, and especially their ACgg and ACgg, show that they act in multiplying synergism. cAMP is a second intracellular messenger triggering the start of cellular functions. By inhibiting adenyl cyclase, all states of cellular hyperactivity, such as those existing in hyperactivity of the thyroid, hypertension, hypersensitivity, etc., are slowed down. As a result, the combination of the two compounds acting in synergism according to the invention is indicated especially for treating states of beta-dependent hyperactivity such as are encountered in hypertension, especially in cases of severe arterial hypertension together with renal insufficiency, or in disorders such as hyperactivity of the -11- thyroid.
The present invention also provides a pharmaceutical composition comprising indapamide and the thiochroman specified above, or a physiologically tolerable salt 5 thereof, especially indapamide and THPT or physiologically tolerable salt thereof, for use in treating hypertension.
The following Example illustrates the composition of a pharmaceutical preparation of the present invention.
EXAMPLE: 90 mg TABLET Indapamide 1.25 mg 8-(3-tert.-butylami no-2-hydroxypropoxy) - thiochroman hydrochloride 5.00 mg stearic acid 0.90 mg 15 sodium carboxymethyl starch 3.00 mg microcrystalline cellulose 33.38 mg lactose 35.75 mg calcium hydrogen phosphate 10.00 mg colloidal silica 0.27 mg 20 magnesium stearate 0.45 mg This tablet may be coated.
Claims (13)
1. A pharmaceutical composition which comprises (i) indapamide, and (ii) a thiochroman of the general formula wherein A represents a hydrogen or halogen atom, R.j represents a hydrogen atom or an alkyl radical 10 having from 1 to 5 carbon atoms, and R2 represents an alkyl radical having from 1 to 5 carbon atoms or a cycloalkyl radical having from 3 to 6 carbon atoms, or a physiologically tolerable acid addition salt thereof. 15
2. A pharmaceutical composition which comprises (i) indapamide, and (i i) 8-(3-tert.-butyl ami no-2-hydroxyprop oxy)-thiochroman or a physiologically tolerable acid addition salt thereof. 20
3. A pharmaceutical composition as claimed in claim 1 or claim 2, wherein the ratio of indapamide to thiochroman or salt thereof is from 1:15 to 1:1 by weight. -13-
4. A pharmaceutical composition as claimed in claim 3, wherein the ratio of indapamide to thiochroman or salt thereof is substantially 1:4 by weight.
5. A pharmaceutical preparation which comprises (i) indapamide, in admixture or conjunction with (ii) a thiochroman of the general formula I specified in claim 1, wherein A, R1 and have the meanings given in claim 1, or a physiologically tolerable acid addition salt thereof, and in admixture or conjunction with a pharmaceutically suitable carrier.
6. A pharmaceutical preparation which comprises (i) indapamide, and (i i) 8-(3-tert.-butyl ami no-2-hydroxypropoxy)-thiochro man or a physiologically tolerable acid addition salt thereof, in admixture or conjunction with a pharmaceutically suitable carrier.
7. A pharmaceutical preparation as claimed in claim 5 or claim 6, wherein the ratio of component (i) to component (ii) is as specified in claim 3 or claim 4.
8. A pharmaceutical preparation as claimed in any one of claims 5 to 7, which is in a form suitable for oral administration. -14-
9. A pharmaceutical preparation as claimed in any one of claims 5 to 8, which is in dosage unit form.
10. A pharmaceutical preparation as claimed in claim 9, which contains from 0.8 to 3 mg of indapamide and 5 from 3 to 12 mg of 8-(3-tert.-butylamino-2-hydroxyprop-oxy)-thiochroman or salt thereof.
11. A pharmaceutical preparation as claimed in claim 10, which contains substantially 1.25 mg of indapamide and substantially 5 mg of 8-(3-tert.-butylamino-2-hydroxy- 10 propoxy)-thiochroman or salt thereof.
12. A pharmaceutical preparation as claimed in claim 5, substantially as described in the Example herein. 13. A pack which comprises a container or other support member holding indapamide and a thiochroman of the general 15 formula I shown in claim 1, in which A, and Rg have the meanings given in claim 1, or a physiologically tolerable acid addition salt thereof, together with indications and/ or instructions to indicate or facilitate one or more treatments each comprising administration of indapamide 20 and the thiochroman or salt thereof simultaneously or at close intervals sufficient to obtain a synergistic effect. 14. A pack as claimed in claim 13, wherein the thiochroman or salt thereof is 8-(3-tert.-butylamino-2-hydroxy- -15- propoxy)-thiochroman or a physiologically tolerable salt thereof. 15. A pharmaceutical composition as claimed in claim 1, for use in the treatment of hypertension. 16. A pharmaceutical compostion as claimed in claim 2, for use in the treatment of hypertension. Dated this 8th day of July 1983 CRUICKSHANK & C0.s Agents for the Applicant Youghal House,
13. Trinity Street, Dublin 2.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8212058A FR2529785A1 (en) | 1982-07-09 | 1982-07-09 | PHARMACEUTICAL COMPOSITION BASED ON INDAPAMIDE AND 8- (3-TERTBUTYLAMINO 2-HYDROXYPROPOXY) THIACHROMAN |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE831597L IE831597L (en) | 1984-01-09 |
| IE55364B1 true IE55364B1 (en) | 1990-08-29 |
Family
ID=9275835
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE1597/83A IE55364B1 (en) | 1982-07-09 | 1983-07-08 | Synergistic antihypertensive pharmaceutical composition |
Country Status (16)
| Country | Link |
|---|---|
| JP (1) | JPS5927813A (en) |
| AU (1) | AU557601B2 (en) |
| BE (1) | BE897251A (en) |
| CA (1) | CA1197191A (en) |
| CH (1) | CH655007A5 (en) |
| DE (1) | DE3324785C2 (en) |
| FR (1) | FR2529785A1 (en) |
| GB (1) | GB2123293B (en) |
| IE (1) | IE55364B1 (en) |
| IT (1) | IT1173729B (en) |
| LU (1) | LU84902A1 (en) |
| NL (1) | NL8302435A (en) |
| NZ (1) | NZ204849A (en) |
| OA (1) | OA07489A (en) |
| SE (1) | SE8303886L (en) |
| ZA (1) | ZA834978B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU196125B (en) * | 1985-02-05 | 1988-10-28 | Sandoz Ag | Process for producing pharmaceutical comprising 3-(aminopropoxy)-indole derivatives combined with diuretic |
| PL193976B1 (en) | 2002-07-01 | 2007-04-30 | Pliva Krakow | Prolonged effect containing indapamide and method of manufacture of prolonged effect tablets containing indapamide |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1203691A (en) * | 1968-03-06 | 1970-09-03 | Science Union & Cie | New disubstituted n-amino indoline derivatives and process for preparing them |
| GB1308191A (en) * | 1970-04-06 | 1973-02-21 | Science Union & Cie | Thiochroman derivatives and a process for preparing them |
| DE2227423A1 (en) * | 1971-06-15 | 1972-12-21 | Ciba-Geigy Ag, Basel (Schweiz) | New pharmaceutical preparations |
-
1982
- 1982-07-09 FR FR8212058A patent/FR2529785A1/en active Granted
-
1983
- 1983-07-06 LU LU84902A patent/LU84902A1/en unknown
- 1983-07-07 IT IT48641/83A patent/IT1173729B/en active
- 1983-07-07 SE SE8303886A patent/SE8303886L/en not_active Application Discontinuation
- 1983-07-07 ZA ZA834978A patent/ZA834978B/en unknown
- 1983-07-08 NL NL8302435A patent/NL8302435A/en not_active Application Discontinuation
- 1983-07-08 NZ NZ204849A patent/NZ204849A/en unknown
- 1983-07-08 IE IE1597/83A patent/IE55364B1/en unknown
- 1983-07-08 JP JP58124582A patent/JPS5927813A/en active Granted
- 1983-07-08 AU AU16702/83A patent/AU557601B2/en not_active Ceased
- 1983-07-08 OA OA58056A patent/OA07489A/en unknown
- 1983-07-08 BE BE0/211143A patent/BE897251A/en not_active IP Right Cessation
- 1983-07-08 CH CH3786/83A patent/CH655007A5/en not_active IP Right Cessation
- 1983-07-08 GB GB08318512A patent/GB2123293B/en not_active Expired
- 1983-07-08 DE DE3324785A patent/DE3324785C2/en not_active Expired
- 1983-07-08 CA CA000432068A patent/CA1197191A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| DE3324785C2 (en) | 1986-10-09 |
| FR2529785A1 (en) | 1984-01-13 |
| OA07489A (en) | 1985-03-31 |
| GB2123293A (en) | 1984-02-01 |
| SE8303886L (en) | 1984-01-10 |
| JPH0250084B2 (en) | 1990-11-01 |
| CH655007A5 (en) | 1986-03-27 |
| GB8318512D0 (en) | 1983-08-10 |
| AU557601B2 (en) | 1986-12-24 |
| SE8303886D0 (en) | 1983-07-07 |
| IT1173729B (en) | 1987-06-24 |
| IT8348641A0 (en) | 1983-07-07 |
| BE897251A (en) | 1984-01-09 |
| LU84902A1 (en) | 1984-03-22 |
| CA1197191A (en) | 1985-11-26 |
| DE3324785A1 (en) | 1984-01-12 |
| NL8302435A (en) | 1984-02-01 |
| AU1670283A (en) | 1984-01-12 |
| NZ204849A (en) | 1986-04-11 |
| IE831597L (en) | 1984-01-09 |
| GB2123293B (en) | 1985-10-09 |
| FR2529785B1 (en) | 1984-12-07 |
| JPS5927813A (en) | 1984-02-14 |
| ZA834978B (en) | 1984-03-28 |
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