IE913585A1 - Product for use in treating nephropathies - Google Patents
Product for use in treating nephropathiesInfo
- Publication number
- IE913585A1 IE913585A1 IE358591A IE358591A IE913585A1 IE 913585 A1 IE913585 A1 IE 913585A1 IE 358591 A IE358591 A IE 358591A IE 358591 A IE358591 A IE 358591A IE 913585 A1 IE913585 A1 IE 913585A1
- Authority
- IE
- Ireland
- Prior art keywords
- imidazol
- acid
- dihydro
- inhibitor
- aminoxypentanoic
- Prior art date
Links
- 208000017169 kidney disease Diseases 0.000 title claims abstract description 17
- 239000005541 ACE inhibitor Substances 0.000 claims abstract description 27
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims abstract description 26
- 239000003112 inhibitor Substances 0.000 claims abstract description 26
- 230000000694 effects Effects 0.000 claims abstract description 25
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 claims abstract description 24
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
- 238000011282 treatment Methods 0.000 claims abstract description 16
- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 claims abstract description 8
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- SWQFFLDVXJWKHS-UHFFFAOYSA-N 2-aminooxypentanoic acid Chemical compound CCCC(ON)C(O)=O SWQFFLDVXJWKHS-UHFFFAOYSA-N 0.000 claims description 22
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- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 claims description 18
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 claims description 16
- DQEDSIVMYUUZCK-UHFFFAOYSA-N 7-imidazol-1-yl-5,6-dihydronaphthalene-2-carboxylic acid Chemical compound C=1C2=CC(C(=O)O)=CC=C2CCC=1N1C=CN=C1 DQEDSIVMYUUZCK-UHFFFAOYSA-N 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 4
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
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- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- SXHUZJPIRVLMHY-AZPSIHDESA-N (z)-7-[(1r,3s,4s,5s)-3-[[(2r)-2-cyclopentyl-2-hydroxyacetyl]amino]-6,6-dimethyl-4-bicyclo[3.1.1]heptanyl]hept-5-enoic acid Chemical compound C1([C@@H](O)C(=O)N[C@@H]2[C@@H](C\C=C/CCCC(O)=O)[C@@H]3C[C@H](C2)C3(C)C)CCCC1 SXHUZJPIRVLMHY-AZPSIHDESA-N 0.000 claims description 2
- IULOBWFWYDMECP-UHFFFAOYSA-N 2-[4-[2-[(4-chlorophenyl)sulfonylamino]ethyl]phenyl]acetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1CCNS(=O)(=O)C1=CC=C(Cl)C=C1 IULOBWFWYDMECP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 2
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- FHHHOYXPRDYHEZ-COXVUDFISA-N Alacepril Chemical compound CC(=O)SC[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 FHHHOYXPRDYHEZ-COXVUDFISA-N 0.000 claims description 2
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- JZMNFXQHYSBCTC-UHFFFAOYSA-N ethyl 7-imidazol-1-yl-8-methyl-5,6-dihydronaphthalene-2-carboxylate Chemical compound CC=1C2=CC(C(=O)OCC)=CC=C2CCC=1N1C=CN=C1 JZMNFXQHYSBCTC-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
- A61K38/556—Angiotensin converting enzyme inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
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Abstract
A pharmaceutical composition containing an angiotensin converting enzyme inhibitor and an inhibitor of thromboxane A2 activity, or a pharmaceutically acceptable salt thereof, is useful in the treatment of nephropathies and hyperlipidaemia secondary to nephrotic syndrome.
Description
PRODUCT FOR USE IN TREATING NEPHROPATHIES The present invention relates to a product containing an angiotensin converting enzyme inhibitor (ACEI) and an inhibitor of thromboxane activity, useful in the treatment of nephropathies.
The use of inhibitors of the enzyme converting angiotensin I into angiotensin II (ACEI) in the treatment of hypertension is well consolidated. Of recent, these drugs have also been found to be useful in decreasing proteinuria of the various forms of renal desease both in animals and in man [ Nutritional and Pharmacological Strategies in Chronic Renal Failure. Contrib. Nephrol. Basel. Karger, 1990, vol 81, pp. 240-247; Kidney International, Vol. 31 (1987), pp 752-759].
However, it has been observed that prolonged administration of these inhibitors in the treatment of nephropathies at therapeutically effective doses is deleterious, especially in patients with vascular hypertension caused by stenosis of one or both of the renal arteries. In fact, prolonged inhibition of the formation of angiotensin II can lead to significant deterioration of renal function. [ Ferguson R. K., Vlasses P.H., eds. Angiotensin-converting enzyme inhibitors. Mount Kisco, NY: Futura Publishing, 1987:65-67; Am. J. Med. 1984; 77:43-51].
For these reasons it would be useful to reduce the dosage of ACE inhibitors during long-term treatment of nephropathies.
It has now been found that nephropathies in mammals, including man, can be treated by the combined use of an agent capable of inhibiting thromboxane A2 activity and an ACEI, at lower doses of ACEI, otherwise not therapeutically effective. It has also been found that with the combined use of an agent capable of inhibiting thromboxane activity and an ACEI, it is possible to obtain a therapeutic effect greater than that otherwise obtainable with the single agents when administered alone.
A first object of the present invention is therefore a pharmaceutical composition containing an ACEI and an inhibitor of thromboxane A2 activity, and a pharmaceutically acceptable carrier and/or diluent, useful in the treatment of nephropathies.
An object of the instant invention is also the use of an ACEI and of an inhibitor of thromboxane activity in the preparation of a pharmaceutical composition useful in the treatment of nephropathies.
A further object of the present invention is a product containing an angiotensin converting enzyme inhibitor and an inhibitor of thromboxane A2 activity as a combined preparation for simultaneous, separate or sequential use in the treatment of nephropathies.
Object of the present invention is also a combined method of treatment of nephropathies and hyperlipidaemia secondary to nephrotic syndrome in mammals, including humans, in need of such treatment, said method comprising administering 1) an angiotensin converting enzyme inhibitor (or a pharmaceutical composition containing it) and 2) an inhibitor of thomboxane A2 activity (or a pharmaceutical composition containing it), in amounts and close enough together in time sufficient to effect a useful therapeutical interaction.
The term combined method of treatment is meant to include both separate and substantially simultaneous administration of an ACEI or a pharmaceutical composition containing it and an inhibitor of thomboxane activity or a pharmaceutical composition containing it.
Examples of nephropathies that can be treated according to the present invention are diabetic nephropathy, nephropathy secondary to lupus erithematosus, glomerulosclerosis, Cyclosporin-A induced nephrosis, renal damages secondary to CHF (congestive heart failure) and the several forms of glomerular and tubular damages associated with proteinuria. Moreover, the products, according to the present invention, can be useful in the treatment of hyperlipidaemia secondary to nephrotic syndrome.
The term inhibitor of thromboxane A2 activity is meant to comprise both thromboxane synthase inhibitors, thromboxane receptor antagonists and compounds endowed with both said mechanisms of action.
Examples of inhibitors of thromboxane synthetase in accordance with the present invention, are for instance the imidazole derivatives described in the English patent GB-B-2122997, International patent application WO 90 0 3970 and English patent application GB 9004347.2. Λ Λ _ _ ___ ___ ic tn j58o Accordingly, preferred compounds among those described in GB-B-2122997 and WO 9003970 are those of following formula (I) H-Q^T^’n-O (I) wherein n is 0 or 1; R is COR,, in which R, is OH, NH2 or OR2 wherein R2 is C,-C„ alkyl; A is a group wherein R2 is hydrogen or C,-C„ alkyl, or a group CH2 II c / \ and the pharmaceutically acceptable salts thereof.
Specific examples of compounds of formula (I) are: ,6-dihydro-7- (1 H-imidazol-1-yl)-2-naphthalenecarboxy lie acid (FCE 22178); ethyl 5,6-dihydro-7-(1 H-imidazol-1 -yI)-2-naphthalenecarboxylate; 7,8-dihydro-6-( 1 H-imidazol-1-yl)-2-naphthalenecarboxylie acid; .6- dihydro-7- (1 H-imidazol-1 -y I) -2-naphthalenecarboxamide; .6- dihydro-7-( 1 H-imidazol-1-yI)-8-methyl-2-naphtalenecarboxylie acid; .6- dihydro-8-ethyl-7-| 1 H-imidazol-1-yI)-2-naphtalenecarboxylie acid; .6- dihydro-7-( 1 H-imidazol-1-y lmethy I )-8-methyl-2-naphthalenecarboxylic acid; I I Γ ,6,7,8-tetrahydro-7-(1 H-imidazol-1-y lmethyl )-8-methy I-2-naphthalenecarboxylic acid; ethyl 5,6-dihydro-7- (1 H-imidazol-1 -yl )-8-methyl-2-naphthalenecarboxylate; .6- dihydro-7-( 1 H-imidazol-1-y I )-8-methy I-2-naphthalenecarboxamide; ethyl 5,6-dihydro-7-( 1 H-imidazol-1-y lmethyl )-8-methyl-2-naphthalenecarboxylate; .6- dihydro-8-ethyl-7-( 1 H-imidazol-1-ylmethyl )-2-naphthalenecarboxylic acid; and 7,8-dihydro-6-( 1 H-imidazol- 1-ylmethy I)-5-methyl-2-naphthalenecarboxy lie acid; and the pharmaceutically acceptable salts thereof.
Preferred compounds among those described in the English patent application 9004347.2, are those of formula (II) (II) wherein Z is -CH2-,-CH(CH3)-, -CH2-CH2- or -CH(CH2Ph)- in which Ph means phenyl optionally substituted by a halogen atom; R3 is C5-C7 alkyl; a phenyl, pyridyl or thienyl ring unsubstituted or substituted by halogen, C,-Cu alkyl, C1-Cu alkoxy or trifluoromethyl; or a cyclohexyl or cycloheptyl ring; T is a C2-Cu alkylene or phenylene group x is a bond or a -0-CH2 group; Ru is hydrogen or C-,-Cu alkyl and the pharmaceutically salts thereof.
Specific examples of compounds of formula (II) are: Λ a Λ _ _ ic a ioooo -[1-pheny I-2-(imidazol-1-y I) ethylidene] aminoxypentanoic acid; ethyl 5-[ 1 -(3-trif luoromethylpheny I )-2-( imidazol-1-y I) ethylidene] aminoxypentanoate; -( 1-(3-trifluoromethy,phenyl )-2-(imidazol-l-yl) ethylidene] aminoxypentanoic acid; -(1-( 3-bromophenyI)-2{imidazol-1 -yI) ethylidene] aminoxypentanoic acid; 3-oxa-5-[1 -pheny 1-2-(imidazol-1 -yI)ethylidene]aminoxypentanoic acid; 3-oxa-5-( 1-( 3-trif luoromethylpheny I )-2-( imidazol-1-y I ) ethylidene] aminoxypentanoic acid; -( 1-cyclohexy I-2-(imidazol-1-y I) ethyl idene] aminoxypentanoic acid; -[1-pheny 1-2-(imidazol-1-yI)-2-methylethylidene]aminoxypentanoic acid; -(1-( n-hexyl )-2-( imidazol-1 -y I) ethyl idene] aminoxypentanoic acid; 3-oxa-5-[ 1-cyclohexy I-2-(imidazol-1-y I) ethyl idene] aminoxypentanoic acid; -[1-n-hepty 1-2-( imidazol-1-y I )ethylidene] aminoxypentanoic acid; -( 1-phenyl-2-(imidazol-1 -yI)-2-benzylethylidene]aminoxypentanoic acid; -(1 -cyclohexy 1-2-( imidazol-1-y I)-2-benzylethylidene] aminoxypentanoic acid; ethyl 5-( 1-pheny l-2-imidazol-1-y I)-2-benzylethylidene] aminoxypentanoate; ethyl 5- [ 1 -cyclohexyl-2- (imidazol-1 -y I) -2-benzylethylidene] aminoxypentanoate; I Λ A Ο·_Α Η __ ___ ___ it y u58o - [ 1 - (4-fluorophenyl) -2 - (imidazol-l-yl) - 2- (4-fluorobenzyl)ethylidene ] aminoxypentanoic acid; -[ 1 - cyclohexyl-2 - (imidazol-1 -yl) - 2 - (4-fluorobenzyl) ethylidene ] aminoxypentanoic acid; and 3- oxa-5- [ 1 -phenyl- 2 - (imidazol-l-yl )-2 -benzylethylidene ] aminoxypentanoic acid; and pharmaceutically acceptable salts thereof.
Further examples of inhibitors of thromboxane synthetase, in accordance with the present invention, are imidazo [1,5-a] pyridine-5-hexanoic acid [Ku et al. Biophys. Res. Comm. 112 (3)-889, 1983], RS-5186 (Thrombosis research, 51, 507, 1988): DP-1904 (J. Med. Chem. 32, 1326, 1989): and (E)-3,4-(l-imidazolylmethyl)phenyl-2-propenoic acid and their pharmaceutically acceptable salts.
Examples of antagonists of thromboxane receptors, in accordance with the present invention are: EP045 and EP092 (Armstrong et al., Br. J. Pharmacol. 84,595, 1985), 4- [2-(4-chloro-benzensulfonamido)-ethyl] phenylacetic acid (U.S. 4,443,477), 4-[2-(phenylsulphonylamino-ethyl] phenoxyacetic acid (U.S. 4,258,058); 5029548 (Ogletree et al., J. Pharmacol. Exp. Ther. 234, 435, 1985); ONO 3708 (Kutsura et al., Adv. pros. Thromb. LK. res. 11, 351, 1983); Bayu-3405 (Arzneimittel Forshung 39 (II) (12), 1525, 1989); GR-32191 (Circulation 80 (11), PO 197, 1989); S-145 (Thrombosis Research 50,365, 1988); and L-655240 (Eur. J. Pharmacol. 135, 193, 1987), and their pharmaceutically acceptable salts.
Examples of AC El, in accordance with the present invention are those described in EP-A-161801 and in EP-A-240366; in particular (+)-[(2S,6R)-6[(S)-l -ethoxy carbonyl - 3 -phenylpropyl ] amino - 5-oxo-2- (2 thienyl) perhydro-l-thiazepin-4-yl] acetic acid (CS-622) and their pharmaceutically acceptable salts. s s— πλ η <Γ_Ο γ _ _ _ 1C ΪΓΙΟΟΟΟ Other examples of ACEI are the following: captopril (Ondetti et al., Science, 196, 441, 1977), benazepril (Schaller et al., Eur. J. Clin. Pharm. 28,267, 1985), enalapril (Patchett et al., Nature, 288, 280, 1980), indolapril (Ryan et al., J. Pharmac. Exp. Ther. 288, 312, 1983), lisinopril (Haeq et al., Kidney Int., Vol. 36, 272, 1987), delapril, alacepril, cilazapril, spirapril and their pharmaceutically acceptable salts.
Pharmaceutically acceptable salts of the inhibitors of thromboxane activity and of ACEI, in accordance with the present invention, are the salts with physiologically acceptable bases and/or acids as well known to experts in the art of pharmaceutical technique.
The usefulness of the combined use of an agent capable of inhibiting thromboxane A2 activity with an ACEI in nephropathic treatment, in accordance with the present invention, has been tested for example by the following experimental data which illustrate but in no way intend limiting the scope of the present invention.
In order to test the afore-mentioned working hypothesis we developed an experimental model of nephropathy (MNS rats) which leads to spontaneous glomerulosclerosis, whose severity is related to age. In this model histologic damage is accompanied by severe proteinuria and deterioration of renal fuction.
We also demonstrated that an excessive intrarenal production of thromboxane plays a pivoted role in the development of renal pathology in MNS rats. -month-old MNS rats (at this age renal damage and proteinuria are already present) were treated as follows: Group 1: with the inhibitor of thromboxane synthase FCE 22178 (300 mg/kg p.o., n=10).
Group 2: with a low dose of ACEI CS-622 not capable of lowering systemic arterial pressure in the normotensive animals (3 mg/kg p.o., n=10).
Group 3: with a combination of the two compounds (FCE 22178, 300 mg/kg p.o. + CS-622 3 mg/kg p.o., n=9).
Group 4: control animals received only the vehicle, i.e. water, n=13).
The results obtained show that both FCE 22178 and CS-622 lower proteinuria observed in controls (470 + 35 mg/day, mean + SEM) when administered separately: CS-622 = 17 + 6% FCE 22178 = 28 + 5% but the two products administered in combination produce a greater reduction: CS-622 + FCE 22178 = 49 + 7%.
This effect occurs without modification of the hemodynamic parameters, i.e. systemic arterial pressure, total renal flow and glomerular filtration rate.
The control animals also showed hyperlidemia with high cholesterol (264 + 11 mg/dl) and trygliceride (285 + 36 mg/dl) values.
These values were reduced in the group that had received FCE 22178 alone (19.4% and 51.2% respectively) and in the group that received the combination (27.1% and 56% respectively). No effect was observed in the group given the ACEI, CS-622, alone.
These results show that it is possible to significantly reduce (49%) proteinuria combining a low dose of ACEI and an inhibitor of thromboxane synthase given at a dosage that inhibits the thromboxanesynthetase enzyme completely for 24 hours.
In addition, the combination has a beneficial effect on secondary hyperlipidemia which is not achieved with an ACEI alone.
The doses of ACEI and inhibitor of the thromboxane activity which can be administered in accordance with the present invention obviously depends on several factors, e.g. the administration route and the disease to be treated. In particular the exact dosage must be chosen on the basis of specific conditions of the patient under treatment in order to ensure the most suitable blood levels.
For example, in the case of the ACEI captopril, the drug can be administered to an adult at doses ranging between about 20 and about 100 mg p.o. per day. In the case of enalapril between about 2.5 and about 20 mg p.o., 1 to 3 times per day. In the case of CS-622 at doses ranging between about 0.5 to about 8 mg p.o. 1 or 2 times per day.
In the case of the inhibitor of thromboxane activity FCE 22178, the oral dose in an adult can vary from about 100 mg to about 800 mg per dose 1 to 3 times per day.
The pharmaceutical formulations of the present invention suitable for the oral administration can be prepared in the form of capsules, sugarcoated tablets, each containing a preestablished amount of active principle; or in the form of powder or granulates; or as solutions or suspensions in an aqueous or non aqueous liquid; or in the form of oil-in-water or water-in-oil emulsions.
The solutions or suspensions for subcutaneous administration can contain along with the active principle a pharmaceutically acceptable excipient and/or vehicle e.g. sterile water, olive oil, ethyl oleate, glycols, such as propylenic glycol.
The suppositories can contain along with the active principle a pharmaceutically acceptable vehicle such as cocoa butter, polyethylenic glycol or lecithin. ί>·_ s ouot> The following examples illustrate but do not intend limiting the present invention.
Example 1, capsules (100 mg) 5,6 - dihydro -7-(1 H -imidazolyl )-2- naphthalenecarhoxylic acid 100 mg lactose 248 mg corn starch 50 mg magnesium stearate 2 mg Total 400 mg Incapsulated in hard head-body gelatin capsules.
Example 2, film-coated tablets (2 mg) According to the usual pharmaceutical technique the foilwing pharmaceutical preparation can be obtained (+) -£( 2S, 6R ) -6 [ (S) -1 -ethoxycarbonyl-3-phenylpropyl ]amino-5 -oxo-2- (2- thienyl) perhydro-l-thiazepin-4-yl} acetic acid 2.0 mg low substituted hydroxypropylcellulose 12.0 mg hydroxypropylcellulose 4.5 mg lactose 100.3 mg magnesium stearate 1.2 mg titanium oxide 0.7 mg talc 0.7 mg hydroxypropylmethylcellulose 3.6 mg total 125.0 mg
Claims (3)
1. ) A pharmaceutical composition containing an angiotensin converting enzyme inhibitor, an inhibitor of thromboxane A 2 activity and a pharmaceutically acceptable carrier and/or diluent useful for the treatment of nephropathies and hyperlipidaemia secondary to nephrotic syndrome.
2. ) A pharmaceutical composition according to claim 1 wherein the inhibitor of thromboxane activity is a compound of formula (I) n-0 (I) wherein n is 0 or 1; R is COR,, in which R, is OH NH 2 or OR 2 wherein R 2 is C,-C u alkyl; A is a group wherein R 2 is hydrogen or C,-C„ alkyl, or CH, a group , or a pharmaceutically acceptable salt thereof. 3. A pharmaceutical composition according to claim 1 wherein the inhibitor of thromboxane activity is a compound of formula (II) =N-O-CH—T-X—00® 4 (II) iE 913585 wherein Z is -CH 2 ~, -CH(CHg)-, -CH 2 -CH 2 - or -CH 2 (CH 2 Ph)- in which Ph means phenyl optionally substituted by a halogen atom; R 3 is C^-C^ alkyl; a phenyl, pyridyl or thienyl ring unsubstituted or substituted by halogen, C^-C^ alkyl, C^-C^ alkoxy or trifluoromethyl; or a cyclohexyl or cycloheptyl ring; T is a C 2 ~C^ alkylene or phenylene group; X is a bond or a -O-CH 2 group; R4 is hydrogen or C-^-C^ alkyl or a pharmaceutically salt thereof. 4. A pharmaceutical composition according to claim 1, wherein the inhibitor of thromboxane activity is selected from imidazo [1,5-a] pyridine-5-hexanoic acid, RS5186, DP1904 and (E)-3,4-(1-imidazolyl- methyl) phenyl-2-propenoic acid or a pharmaceutically acceptable salt thereof. 5. A pharmaceutically composition, according to claim 1, wherein the inhibitor of thromboxane activity is selected from EP045, EP092 4-[2-(4-chloro-benzensulfonamido)-ethyl] phenylacetic acid, 4-[2-(phenylsulphonylamino-ethyl] phenoxyacetic acid, 5029548, ONO 3708, Bayu-3405, GR-32191, L-655240 and S-145 or a pharmaceutically acceptable salt thereof. 6. A pharmaceutical composition, according to claim 1, wherein the agiotensin converting enzyme inhibitor is selected from (+)-{(2S, 6R) -6 [ (S) -1 -ethoxycarbonyl-3-phenylpropyl]amino-5-oxo-2- (2thienyl) perhydro-l-thiazepin-4-yl} acetic acid (CS-622), captopril, elanapril, indolapril, lisinopril, spiraprilat, spirapril, delapril, alacepril and cilazapril or a pharmaceutically acceptable salt thereof. 7. A pharmaceutical composition according to claim 1 wherein the inhibitor of thromboxane activity is selected from: 5,6-dihydro-7-(lH-imidazol-yl)-2-naphthalenecarboxylic acid (FCE 22178; iE 913585 ethyl 5 z 6-dihydro-7- (1 H-imidazol-1-y I )-2-naphthalenecarboxylate; 7,8-dihydro-6-( 1H-imidazol-1-yl)-2-naphthalenecarboxyclic acid; 5.6- dihydro-7-(1 H-imidazol-1-y I )-2-naphthalenecarboxamide; 5.6- dihydro-7 (1 H-imidazol-1 -y I )-8-methyl-2-naphthalenecarboxy lie acid; 5.6- dihydro-8-ethy 1-7-(1 H-imidazol-1-y I)-2-naphthalenecarboxy lie acid; 5.6- dihydro-7-( 1 H-imidazol-1-ylmethyl )-8-methyl-2-naphthalenecarboxylic acid; 5.6.7.8- tetrahydro-7-( 1 H-imidazol-1 -y I-methyl )-8-methyl-2naphthalenecarboxylie acid; ethyl 5,6-dihydro-7-( 1 H-imidazol-1 -y I )-8-methy l-2-naphthalenecarboxylate; 5.6- dihydro-7- (1 H-imidazol-1 -yl )-8-methyl-2-naphthalene-carboxamide; ethyl 5,6-dihydro-7- (1 H-imidazol-1 -yl-methy I )-8-methy I-2naphthalenecarboxylate; 5.6- dihydro-8-ethyl-7-( 1 H-imidazol-1 -yl-methy I) ^naphthalenecarboxylic acid; 7.8- dihydro-6-( 1 H-imidazol-1 -yl-methy I )-5-methy I-2-naphthalenecarboxylic acid; 5-[ 1 -phenyl-2-1 imidazol-1-yl)ethylidene]aminoxypentanoic acid; ethyl 5-(1-( 3-trif luoromethylpheny I) -2- (imidazol-1 -y I Jethylidene] ami nox y pentanoate; 5-(1 - (3-bromophenyl )-2-( imidazol-1-y I) ethylidene] aminoxypentanoic acid; 3-oxa-5-( 1 -phenyl-2-( imidazol-1 -yl )ethylidene]aminoxypentanoic acid; 3-oxa-5- [1-( 3-trif luoromethylpheny I) -2- (imidazol-1 -y I) ethylidene] aminoxypentanoic acid; 5-(1 -cyclohexy I-2-(imidazol-1-y I ) ethy I idene] aminoxypentanoic acid; 5-(1 -phenyl-2- (imidazol-1 -yl) -2-methy lethylidenelaminoxypentanoic acid; 5-( 1 -(n-hexyl )-2-( imidazol-1-y I) ethy I idene] aminoxypentanoic acid; 3-oxa-5- [ 1 -cyclohexyl-2- (imidazol-1 -yl lethy, idene] aminoxypentanoic acid; 5-(1 -n-heptyl-2-(imidazol-1-yl)ethylidene]aminoxypentanoic acid; 5-(1 -pheny I-2- (imidazol-1 -y I) -2-benzy lethy I idene] aminoxypentanoic acid; 5-(1 -cyclohex y I-2-( imidazol-1-y I)-2-benzy lethy lidene] aminoxypentanoic acid; ethyl 5- [ 1 -pheny l-2-imidazol- 1-y I)-2-ben zy lethy I idene] aminox ypentanoate; ethyl 5-( 1-cyclohexy 1-2-( imidazol-1-y I)-2-benzy lethy lidene] aminoxypentanoate; 9. 9. 10. 10. 5-(1-( 4 -fluorophenyl )-2-( imidazol-1 -yl) - 2 - (4 -fluorobenzyl) ethylidene]aminoxypentanoic acid; 5-(1- cyclohexyl -2-( imidazol -1-yl )-2-(4 - fluoroben zyl) ethylidene ] aminoxypentanoic acid; and
3. -oxa- 5 - [ 1 -phenyl- 2-( imidazol-1 -yl) - 2 -benzylethylidene ] aminoxypentanoic acid; or a pharmaceutically acceptable salt thereof. The use of an ACEI and an inhibitor of thromboxane Ag activity in the preparation of a pharmaceutical composition useful in the treatment of nephropathies and hyperlipidaemia secondary to nephrotic syndrome. Products containing an angiotensin converting enzyme inhibitor and an inhibitor of thromboxane A 2 activity as a combined preparation for simultaneous, separate or sequential use in the treatment of nephropathies and hyperlipidaemia secondary to nephrotic syndrome. Products according to claim 9, wherein the inhibitor of thromboxane Ag is 5,6-dihydro-7-(lH-imidazolyl)-2-naphthalenecarboxylic acid and the angiotensin converting enzyme inhibitor is (+)-^2S,6R)-6[(S)-1 -ethoxy carbonyl- 3 -phenylpropyl ] amino- 5 -oxo- 2 -(2-thienyl) perhydro-l-thiazepin-4-ylJ acetic acid, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition according to Claim 1, substantially as described herein by way of Example.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT021757A IT9021757A1 (en) | 1990-10-16 | 1990-10-16 | PRODUCT FOR THE TREATMENT OF NEPHROPATHIES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE913585A1 true IE913585A1 (en) | 1992-04-22 |
Family
ID=11186438
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE358591A IE913585A1 (en) | 1990-10-16 | 1991-10-16 | Product for use in treating nephropathies |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0556204A1 (en) |
| JP (1) | JPH06501943A (en) |
| AU (1) | AU8725191A (en) |
| IE (1) | IE913585A1 (en) |
| IL (1) | IL99667A0 (en) |
| IT (1) | IT9021757A1 (en) |
| PT (1) | PT99238A (en) |
| WO (1) | WO1992006713A1 (en) |
| ZA (1) | ZA918038B (en) |
-
1990
- 1990-10-16 IT IT021757A patent/IT9021757A1/en unknown
-
1991
- 1991-10-08 ZA ZA918038A patent/ZA918038B/en unknown
- 1991-10-08 IL IL99667A patent/IL99667A0/en unknown
- 1991-10-15 PT PT99238A patent/PT99238A/en not_active Application Discontinuation
- 1991-10-16 IE IE358591A patent/IE913585A1/en unknown
- 1991-10-16 WO PCT/EP1991/001972 patent/WO1992006713A1/en not_active Application Discontinuation
- 1991-10-16 AU AU87251/91A patent/AU8725191A/en not_active Abandoned
- 1991-10-16 JP JP3516412A patent/JPH06501943A/en active Pending
- 1991-10-16 EP EP91918149A patent/EP0556204A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| WO1992006713A1 (en) | 1992-04-30 |
| IT9021757A1 (en) | 1992-04-17 |
| IL99667A0 (en) | 1992-08-18 |
| ZA918038B (en) | 1992-06-24 |
| EP0556204A1 (en) | 1993-08-25 |
| JPH06501943A (en) | 1994-03-03 |
| IT9021757A0 (en) | 1990-10-16 |
| AU8725191A (en) | 1992-05-20 |
| PT99238A (en) | 1992-09-30 |
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