JPS63165317A - Pharmaceutical product - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to pharmaceutical products with antihypertensive activity.

[Conventional technology]

European Patent Publication No. 173,848 discloses potassium channel activators (potassium channel activators) useful in the treatment of cardiovascular disorders.
assium ehann@l aetivatori
) describes various Beynobilan compounds that have already been disclosed as antihypertensive agents.

European Patent Publication No. 205292 describes hypertension,
A class of pyranopyridines is disclosed that are useful potassium channel activators for the treatment of cardiovascular disorders and disorders associated with smooth muscle contraction.

GB 1489879 discloses the compound N1-cyano-N-4-pyridyl-N'-1,2,2-trimethyl-propylguanidine and the method by which it is prepared in Example 47. The compound pinacidil, referred to herein by its common name, is described in patents as an antihypertensive compound. "Drugs of the Future"
re) J■ (3) Vol. 149.1981, pinacidil is described as a vasodilator. Pinacidil is known to be a potassium channel activator.

Ninara grill, Rinnopril and cut grill are formula (4)
), ω) and C): angiotensin converting enzyme (A
CE) inhibitor
ertlgenzym@1nhibltors)
and "Drugs J 31" respectively.
, (1986): rDruglas op Zahieuteyer J 10 (11)% 948 (1985): and 'Disclosed in J 6 (11), 731 (1981).

[Summary of the invention]

potassium channel activators antihypertensive agents such as the aforementioned pinacidil or benzobirane or pyranoviridi/and ACE
It has been found that combinations of inhibitors antihypertensive agents such as compounds of formula (4), (B) or (C) or any of the pharmaceutically acceptable salts described above have good antihypertensive activity. The effectiveness of the combination is much greater than could be predicted on the basis of the antihypertensive activity of the individual components, and synergism is likely to occur.

Accordingly, the present invention provides a combination of potassium channel activators and antihypertensive agents such as pinacidil or the formula (R2, where Y is N and R2 is hydrogen) as a combined preparation to be used simultaneously or sequentially in the treatment of hypertension. Is there? Or Y
is C-R1 and one of R1 and R7 is hydrogen and the other is C1-.

Alkylcarbonyl%C, -@alkoxycarbonyl5
C1-@alkylcarbonyloxy, CI-@alkylhydroxymethyl, nitro, cyano, salt i.

Trifluoromethyl & CI-+1 alkylsulfinyl, CI-・alkylsulfonyl, CI-a alkoxysulfinyl, CI-・alkoxysulfonyl, CI-
- Alkylcarbonylamino %C1-. Alkoxycarbonylamino 1, c, +ll ruthiocal=s
C*-sFlukoxythiocarbonyl % C1-1 Alkyl theocarbonyl quine, l-mercapto C2-malol, formyl or aminosulfinyl, aminosulfonyl or aminocarbonyl (these amino moieties optionally contain 1 or 2 c, -II (optionally substituted with an alkyl group) or cl-, alkylsulfinylamino, C
1-@alkylsulfonylamino %C1-.alcokynesulfinylamino or C2-, alkoxysulfonylamino, or C,+@ethylenyl terminally substituted by alkylcarbonyl, nitro or cyano, or -C(Ct- s 7 k kill) NOR or -C (C
or R
one of 1 and R8 is nitro, cyano or at-S alkylcarbonyl and the other is meth or 1 or 2
C,+@amino optionally substituted by alkyl or cm -v alkanoyl: R, or R2O one is hydrogen or C1-, alkyl and the other is C8-, alkyl or R1 and R
, together with C2-, polymethylene; R1 is hydrogen, hydroxyl S C, +@alco or C0-, afluoxy; and R6 is hydrogen: or R, and R6 are together 9; R? is hydrogen, or hydroxyl% CI-alcoquine
C1-@alkoxycarbonyl or C,+@alkyl optionally substituted with carboxy, 0-fold alkyl polysubstituted with halogen, or C,-alkenyl; C1-alkoxy, hydroxyl , halogen, trifluoromethyl, nitro, cyano% cx
-tt Aryl or heteroaryl optionally substituted by one or more groups or atoms selected from the group of acyl carboxylates, or optionally substituted by one or two C1-.alkyl groups. optionally amino or aminocarbonyl; and R1 is hydrogen or C,-alkyl; or R1 and R are joined together to form C1-, polymethylene or -
CH, -(CH,)n-Z-(CH,'')m- (in the formula m
and n is an integer from O to 2, and rn+n is 1 or 2, and 2 is oxygen, sulfur, or NR1 (in the formula, R9 is hydrogen h C1
-@Alkyls CR-1 Phenyl which is alkanoyl or optionally substituted with 1 or 2 OC,--alkyl%C1-alkoxy or halogen in the phenyl or naphthyl ringC,,furthyl,naphthyl carbonyl, phenylcarbonyl or benzylcarbonyl: monocyclic or bicyclic heteroarylcarbonyl)
X is oxygen or sulfur; and R, NCXR, the moiety is R, is hydroxylyl, CI-.

7 in alkoxy or Ct-V acyl is trans to the R1 group] or a pharmaceutically acceptable salt thereof Further ACE inhibitor antihypertensive agents such as formula (4), (B) or (C): A pharmaceutical product comprising a compound of the present invention is provided.

In a preferred embodiment, the active ingredients of the product are administered simultaneously.

The present invention further provides a potassium channel activator antihypertensive agent such as binandil or a compound of formula (1) or a pharmaceutically acceptable salt thereof and an ACI inhibitor antihypertensive agent such as formula (4) in combination with a pharmaceutically acceptable carrier. , (B) or C
) is provided.

The present invention further provides a potassium channel active antihypertensive agent such as pinacidil or a compound of formula (1) or a pharmaceutically acceptable salt thereof in the preparation of a combined product for simultaneous, separate or sequential use in the treatment of hypertension. ACE
Uses of the compounds of (B) or (C) as inhibitors of antihypertensive agents, such as antihypertensive agents, are provided.

Suitable and preferred groups or atoms in formula (1) are described in European Patent Publication No. 76075.917.
48.93535,95316.107423゜120
426%120427%126311.126350.
126367.138134 and 205292.

The corresponding U.S. patent references are U.S. Patent No. 4446, respectively.
113.4542149.4510152.44812
14.4496565.4555509.461099
2.4571406%4629734.4575511
%4,677,116 and US Patent Application No. 8,71,711.

A particularly preferred compound of formula (1) is R3-6-dia-2-3<4-dihydro-2,2-dimethyl-trans- which is the compound of Example 1 of European Patent Publication No. 76075 and US Pat. 4-(2-oxo-1-pyrrolidinyl)-2H-benzo(5)pyran-
It is 3-ol.

Examples of pharmaceutically acceptable salts are described in the European patent documents mentioned above, the subject matter of which is cited herein.

The aforementioned products and compositions have good blood pressure lowering activity and may be useful in the treatment of hypertension.

Compounds of formula (1) and their salts are described in the European and US patent literature mentioned above.

Pinacidil and its salts are described in the aforementioned British patent specifications.

The products of the invention are administered orally to humans and are formed into syrups, tablets or capsules for separate, sequential or simultaneous administration.

However, they may be adapted for other modes of administration, such as parenteral administration for patients with heart disease. Other alternative modes of administration include sublingual or transdermal administration.

In general, pinacidil or a compound of formula (1) or a pharmaceutically acceptable salt thereof 0.5-25 q of formula (4
).

Compositions containing compounds (B) or (C) are effective depending on the activity of the potassium channel activator.

Preferably, the compositions of the invention are in unit dosage form to maintain consistency of dosing. Suitable unit dosage forms include tablets, capsules and powders in packs or vials. Such unit dosage forms contain a total of 9.5-100q of active compound of the invention and more usually 0.5-5
0sv e.g. 0.5-20q e.g. 0.5, 1.2%3
．． 5. May contain 10% 15% 201q. Such compositions are administered 1 to 6 times per day, and more commonly 2 to 4 times per day, with a daily dose of 0.000 kg for an adult of 70 Kf.
5~20011? and even more particularly 0.5-25 II
It is I.

No adverse toxicological effects have been demonstrated with the compounds of the present invention within the above-mentioned dosage range.

The compositions of the present invention may contain conventional additives such as fillers, disintegrants,
It may be formulated with binders, lubricants, and flavoring agents. They are prescribed in conventional formulations similar to those used for antihypertensive agents, for example.

Potassium channel active antihypertensive agents such as pinacidil or a compound of formula (1) or a pharmaceutically acceptable salt thereof and A
CE inhibitor antihypertensive agent such as formula (4), CB) or (
It is highly preferred that the compound of C) is administered in the form of a focally administered composition, such as a unit dose oral or parenteral composition.

Such compositions are prepared by admixture and are preferably adapted for oral or parenteral administration and are themselves tablets,
It may be in the form of capsules, oral liquid preparations, powders, granules, troches, redissolveable powders, solutions or suspensions for injection and perfusion, or suppositories. Orally administrable compositions, particularly shaped oral compositions, are preferred as they are more convenient for general use.

Tablets and capsules for oral administration are usually presented in unit doses and may contain conventional excipients such as binders, fillers, diluents, tabletting agents, lubricants, disintegrants, colorants, flavoring agents, wetting agents. including. The tablets are coated by methods well known to those skilled in the art.

Preferred fillers for use are cellulose, mannitol,
Contains lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone, starch inhibitors such as sodium starch glycolate.

Suitable lubricants include, for example, Magnesium stearate. A suitable pharmaceutically acceptable wetting agent includes sodium 9-murauryl sulfate.

These solid oral compositions may be manufactured by conventional methods of mixing, filling or tabletting. Repeated mixing operations are used to distribute the active agent in these compositions employing large amounts of filler. These operations are, of course, well known to those skilled in the art. Oral solutions may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be reconstituted with water or other suitable vehicle before use. Provided as a dry product to be dissolved. Such liquid compositions are prepared by adding conventional additives such as suspending agents such as nlubitol, syrup, methylcellulose, gelatin, hydroxylcellulose, carboquine methylcellulose, aluminum stearate gel, hydrogenated edible fats, emulsifying agents such as lecithin, sorbitan monomer, etc. Olate, polyglycerol or gum arabic: aqueous or non-aqueous medium (including edible oils) such as almond oil, fractionated coconut oil, oily esters such as esters of glycerin or hapropylene glycol or ethyl alcohol, glycerin, water or normal brine preservatives such as methyl or hapropyl p-hydroxybenzoate or sorbic acid; and, if desired, conventional flavorings or colorants.

Oral formulations also include conventional sustained release formulations such as & tablets or granules with soluble coatings.

For parenteral administration, liquid unit dosage forms (containing a compound of the invention and a pacifying vehicle) are prepared.

Depending on the vehicle and concentration, the compound may be suspended or dissolved. Parenteral solutions are usually prepared by dissolving the compound in a vehicle, filtering sterilization, then filling and sealing a suitable vial or ampoule. Advantageously, auxiliary agents such as local anesthetics, preservatives and buffers are also dissolved in the vehicle.

To ensure stability, the composition is frozen after filling into vials and the water is removed in vacuo.

Parenteral suspensions are prepared with a substantially similar formulation except that the compound is suspended in the vehicle instead of being dissolved and the compound is sterilized by exposure to ethylene chloride prior to suspension in the sterile vehicle. . Advantageously, a surfactant or wetting agent is included in the composition to aid in uniform distribution of the compound of the invention.

Furthermore, such compositions may also contain active agents such as other classes of antihypertensive agents and diuretics.

It will be appreciated that, as in common practice, the compositions are usually accompanied by handwritten or printed inserts used for the medical treatment concerned.It will be appreciated that each component of the product of the invention may be administered by different routes.

The present invention further provides a method of treating hypertension in mammals, including humans, which comprises administering potassium channel activity in combination with an antihypertensive effective amount of a pharmaceutically acceptable carrier to the diseased mammal. Antihypertensive agents such as pinacidil or a compound of formula (1) or a pharmaceutically acceptable salt thereof and ACE inhibitor antihypertensive agents such as formula (4), (B) or (C
).

〔Example〕

The following pharmacological data illustrate the invention.

Compound 1 is 6-dia2-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzobilan-3-ol (European Patent Publication Rg7607!l and U.S. Pat. No. 4446113
Compound 2 is trans-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidin-1-yl)-2H
-pyrano(3,2-e)pyridin-3-ol (compound of Example 1 of EP 205 292); Compound 3 is 6-cyano-3,4-dihydro-2,2- Dimethyl-trans-4-(N-5-methyltetrahydro-2-pyrimidone)-2H-pesozo(b) bilane-3-
Compound 4 is trans-4-N-acetylamino-6-cyano-3,4-dihydro-2, 2-Dimethyl-2H-benzobilan-3-ol (European Patent Publication No. 93)
No. 535 and Example 2 of US Pat. No. 4,448,214).

Pharmacology An enhanced antihypertensive response to the compound was observed in conscious male spontaneously hypertensive rats (SHR) when the above data compound was combined with the angiotensin convertase inhibitor enalapril.

For the purpose of the experiment, 36 rats were randomly divided into 4 groups with 9 rats in each group. Inflatable tail cuff (Inflatable@
Systolic pressure (SBP) using the tail cuff method
The protocol for non-invasively measuring the number of pretexts is as follows.

po pO 8BP was measured for each rat before the treatment described above and then
．． 75. Measurements were made again at 2.75 and 4.75 hours, and the results were as shown in Table 1. The results for compounds 2 to 4 were as shown below.

Compound 2 0246±6244±6247±3246±40.75
-3±2 1±2 -9±1
-8±11.75-4±2-20±2-22±2-
45±52.75-2±3-12±3-14±3-32
±44.75-8±2-11±2-16±2-31±3
Compound 3 0251±5253±6254±4255±30.75
0±2 0±3 -8±2
-13±21.75 0th2-20±3-10±3
-44±52.75 2±2-22±3-12±4-4
8±44.75-6±3-21±3-21±3-48±
3 Compound 4 0275±4281±5280±5285±10.75
-2±10±2-4±2-6±21.75-6th2-
26±4-9±2-42±4(7)2.75-6±1-
23±4-12±3-41±24.75 -2±1
-13±2 -14±2 -32±2
The experimental results regarding pinacidil were unsuccessful in the following manner.

1% methylcellulose SEP in 11F water was measured in each rat before the above treatment and then 1.75
．． Measurements were taken at 2.75 and 4.75 hours. The results were as shown in Part ① Thorn.

Voluntary procedure assistance January 17, 1985

Claims (11)

[Claims] (1) A pharmaceutical product comprising a potassium channel activator antihypertensive agent and an ACE inhibitor antihypertensive agent as a combined formulation for simultaneous, separate or sequential use in the treatment of hypertension. (2) The potassium channel activator antihypertensive agent is pinacidil or the formula (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, Y is N and R_2 is hydrogen; or Y is C-R_1, and one of R_1 and R_2 is hydrogen, and the other is C_
1_-_6 alkylcarbonyl, C_1_-_6 alkoxycarbonyl, C_1_-_6 alkylcarbonyloxy, C_1_-_6 alkylhydroxymethyl, nitro, cyano, chlorine, trifluoromethyl, C_1_-_
6 alkylsulfinyl, C_1_-_6 alkylsulfonyl, C_1_-_6 alkoxysulfinyl, C_
1_-_6 alkoxysulfonyl, C_1_-6 alkylcarbonylamino, C_1_-_6 alkoxycarbonylamino, C_1_-_6 alkyl-thiocarnyl,
C_1_-_6 alkoxy-thiocarbonyl, C_1_
-_6 alkyl-thiocarbonyloxy, 1-mercapto C_2_-_7 alkyl, formyl, or aminosulfinyl, aminosulfonyl or aminocarbonyl (these amino moieties optionally contain 1 or 2 C_1_-_6
optionally substituted with an alkyl group), or C_1_-
_6 alkylsulfinylamino, C_1_-_6 alkylsulfonylamino, C_1-_6 alkoxysulfinylamino or C, -, alkoxysulfonylamino, or ethylenyl terminally substituted by C_1-_6 alkylcarbonyl, nitro or cyano, or - C(C_1-_6 alkyl)NOH or -C(C_1
___6 alkyl) NNH_2; or one of R_1 and R_2 is nitro, cyano or C_1
____2 alkylcarbonyl and the other by methoxy or 1 or 2 C_1_-_6 alkyl or C
_2_-_7 is amino optionally substituted by alkanoyl; one of R_3 or R_4 is hydrogen or C_1_-_4 alkyl and the other is C_1_-_4 alkyl; or R_3 and R_4 together Become C_2_-_5
is polymethylene; R_5 is hydrogen, hydroxyl, C_1_-_6 alkoxy or C_1_-_7 acyloxy; and R_
Either 6 is hydrogen; or R_8 and R_6 together are a bond; R_7 is hydrogen or optionally substituted by hydroxyl, C_1_-_6 alkoxy, C_1_-_6 alkoxycarbonyl or carboxy C_1_-_
6 alkyl, C_1_-_6 substituted by halogen
Is it alkyl or C_2_-_6 alkenyl; C
_1_-_6 alkoxy, hydroxyl, halogen, trifluoromethyl, nitro, cyano, C_1_-_1_
Aryl or heteroaryl optionally substituted with one or more groups or atoms selected from the group of acyl dicarboxylate, or 1 or 2 C_1_-_
and R_8 is hydrogen or C_1_-_6 alkyl; or R_7 and R_8 are joined together to form C_3_-_4
Polymethylene or -CH_2-(CH_2)_n-Z-
(CH_2)_m-{where m and n are integers from 0 to 2, m+n is 1 or 2, and Z is oxygen, sulfur or NR
_9 (in the formula, R_9 is hydrogen, C_1_-_9 alkyl, C
phenyl C_1_-_4 alkyl, naphthylcarbonyl, phenylcarbonyl which is _2_-_7 alkanoyl or optionally substituted by 1 or 2 C_1_-_6 alkyl, C_1_-_6 alkoxy or halogen in the phenyl or naphthyl ring; or benzylcarbonyl; monocyclic or bicyclic heteroarylcarbonyl}; X is oxygen or sulfur; and the R_6NCXR_7 moiety is R_8 is hydroxyl, C_
1_-_6 alkoxy or C_1_-_7 acyloxy is trans to the R_5 group] or a pharmaceutically acceptable salt thereof, and the ACE inhibitor antihypertensive agent is a compound of formula (A), (B) or (C)
: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (A) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (B) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (C) 1) The product described in section 1). (3) Potassium channel activator antihypertensive agent has the formula (I
) [wherein Y is N or C-R_1 (wherein R_1 is nitro, cyano, or C_1_-_3 alkylcarbonyl) and R_2 is hydrogen]. ). (4) The product according to claim (2) or (3), wherein R_3 and R_4 are both methyl groups. (5) R_7 and R_8 are combined together to form C_3_-_
4 polymethylene or -CH_2-(CH_2)_n-Z
-(CH_2)_m-, where m, n and z are as defined in claim (2); or R_8 is hydrogen or methyl and R_7 is ethyl;
methyl, hydrogen or phenyl optionally substituted by 1, 2, 3 or 4 groups or atoms selected from methyl, methoxy, hydroxyl, fluorine and chlorine A product according to any one of paragraphs (2), (3) and (4). (6) The compound of formula (I) is (±)-6-cyano-3,
4-dihydro-2,2-dimethyl-trans-4-(2
The product according to claim 5, which is 2H-benzo[b]pyran-3-ol (oxo-1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol. (7) The potassium channel activator antihypertensive agent according to any one of claims (1) to (6) in combination with a pharmaceutically acceptable carrier;
A pharmaceutical composition comprising the ACE inhibitor antihypertensive agent according to any one of items 1) to (6). (8) The potassium channel activator antihypertensive agent is pinacidil or a compound of formula (I) according to claim (2) or a pharmaceutically acceptable salt thereof, and ACE
The composition according to claim (7), wherein the inhibitor antihypertensive agent is a compound of formula (A), (B) or (C) according to claim (2). (9) 0.5-25 mg of formula (A) per mg of pinacidil or a compound of formula (I) or a pharmaceutically acceptable salt thereof;
), (B) or (C). (10) Claim No. 1 concerning the manufacture of a combination preparation for simultaneous, separate or sequential use in the treatment of hypertension.
- Use of a product or pharmaceutical composition according to any one of paragraphs (9). (11) Claim No. (1) used for the treatment of hypertension
A product or pharmaceutical composition according to any one of items 1) to (10).