CA1171789A - Therapeutic agents - Google Patents
Therapeutic agentsInfo
- Publication number
- CA1171789A CA1171789A CA000415369A CA415369A CA1171789A CA 1171789 A CA1171789 A CA 1171789A CA 000415369 A CA000415369 A CA 000415369A CA 415369 A CA415369 A CA 415369A CA 1171789 A CA1171789 A CA 1171789A
- Authority
- CA
- Canada
- Prior art keywords
- quinolone
- compositions
- methyl
- ethyl
- administration
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Abstract
Abstract Therapeutic Agents Therapeutic compositions which comprise as an active ingredient a quinolone of the general formula I
wherein n is 0, 1 or 2 and either (a) R2 is hydrogen and R1 is methyl or ethyl, or (b) R2 is methyl and R1 is ethyl, provided that, when R1 is ethyl, n is 1 or 2, together with a pharmaceutically acceptable carrier.
The compositions have antihypertensive activity and may be used for treating hypertension in warm blooded animals including man. Administration may be enteral or parenteral; enteral administration, especially oral administration, is preferred.
wherein n is 0, 1 or 2 and either (a) R2 is hydrogen and R1 is methyl or ethyl, or (b) R2 is methyl and R1 is ethyl, provided that, when R1 is ethyl, n is 1 or 2, together with a pharmaceutically acceptable carrier.
The compositions have antihypertensive activity and may be used for treating hypertension in warm blooded animals including man. Administration may be enteral or parenteral; enteral administration, especially oral administration, is preferred.
Description
~ 1 7 1 7 ~ ~
Therapeutic Compositions This invention relates to therapeutic compositions containing certain quinolone compounds which we have found to possess antihypertensive activity. More particularly, the present invention provides therapeutic compositions which comprise as an active ingredient a quinolone of the general formula ' O
Rz ~ S(O)nCH3 wherein n is 0, 1 or 2 and either (a) R2 is hydrogen and Rl is methyl or ethyl, or (b) R2 is methyl and Rl is ethyl, provided that, when Rl is ethyl, n is 1 or 2, together with a pharmaceutically acceptable carrier.
We have found that the compounds of general formula I have valuable antihypertensive activity.
When administ~red to warm blooded animals in non-toxic doses the compounds are effective in reducing elevated blood pressure.
,~
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The compounds of general forn~ula I have been described in the literature, but no therapeutic activity has been ascribed to them. Thus, for example, the individual compounds within the scope of general 5 formula I and methods for their preparation have been described in one or more of the following publications:
Van Leusen and Taylor, J. Org. Chem., Vol. 33, pp.
66-70 (1968) Albrecht, Chimie Therapeutique, 1973, No. 1, pp. 45-48.
10 Connor et al., J. Heterocyclic Chem., Vol. 15, pp.
113-114 (1978) Connor et al., J. Heterocyclic Chem., Vol. 15 pp.
115-117 (1978) As used hereinafter, the term 'active compound' 15 denotes a quinolone compound of general formula I. In therapeutic use, the active compound may be administered orally, rectally or parenterally, preferably orally. Thus the therapeutic compositions of the present invention may take the form of any of 20 the known pharmaceutical compositions for oral, rectal or parenteral administration. Pharmaceutically acceptable carriers suitable for use in such compositions are well-known in the art of pharmacy.
The compositions of the invention suitable contain 25 0.1-90% by weight of active compound. The compositions of the invention are generally prepared in unit dosage form.
Compositions for oral administration are the preferred compositions of the invention and these are 30 the known pharmaceutical forms for such administration, for example tablets, capsules, syrups and aqueous or oily suspensions. The excipients used in the preparation of these compounds are the excipients known in the pharmacists' art. Tablets may be prepared by B
1 1.'~' 1 7~
~ixing the active compound with an inert diluent such as calcium phosphate in the presence of disintegrating agents, for example maize starch, and lubricating agents, or example magnesium stearate, and tableting the mixture by known methods. Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate. Similarly capsules, for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by conventional means and, if desired, provided with enteric coatings in a known manner. The tablets and capsules may conveniently each contain 5-500 mg. of the active compound. Other compositions for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions containing a compound of the present invention, in a suitable vegetable oil, for example arachis oil.
Compositions of the invention suitable for rectal administration are the known pharmaceutical forms for such administration, for example suppositories with cocoa butter or polyethylene glycol bases.
Compositions of the invention suitable for parenteral administration are the known pharmaceutical forms for such administration, for example sterile suspension in aqueous and oily media or sterile solutions in a suitable solvent.
In some formulations it may be beneficial to use the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
. D
In the compositions of the present in~ention the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.
The therapeutic activity of the quinolones of general formula I has been demonstrated by tests which include (A) the oral administration of the compounds to a strain of spontaneously hypertensive rat and (B) the intraduodenal administration of the compounds to a strain of normotensive rat. These tests were carried out in the following way:
Test A
Female rats weight range 180-240 g., of the Aoki-Okamoto strain of spontaneously hypertensive rat were used. The rats in groups of four were fasted overnight before administration of the test compound.
Blood pressure was determined in the following way.
The rats were placed in a cabinet kept at 38C with their tails protruding through holes in the cabinet.
After 30 minutes in the cabinet blood pressure was measured using an inflatable cuff placed round the base of the tail and arterial pulsations monitored with a pneumatic pulse transducer. A pressure, greater than the expected blood pressure, was applied to the cuff, and this pressure was slowly reduced. The pressure in the cuff at which arterial pulsations reappeared was ~aken as the blood pressure. The rats were removed from the cabinet and each group orally dosed with a given dose of the test compound given as a solution or suspension in 0.25% aqueous carboxymethylcellulose. In addition to the pre-dose reading, blood pressure was measured at 1.5 and 5.0 hours after dosing. A compound was designated as active if it gave a reduction of blood pressure of 20% or greater at either of these time intervals.
D
Test B
Male normotensive rats (Wistar strain) of weight range 210-240 g. were used. The rats were anaesthetised and cannulae placed in a carotid artery and in the duodenum. Blood pressure was recorded electronically by means of a pressure transducer connected to the arterial cannula. The test compound was administered into the duodenum as a solution or suspension in 0.25% aqueous carboxymethylcellulose.
Blood pressure was recorded before dosing and for 30 minutes afterwards. Results were obtained as the mean of determinations in three rats per dosage level.
Compounds which caused a fall in blood pressure of lO%
or greater during the 30 minute post-dose period were designated as active.
The following compounds were found to be active in one or both of the tests at a dosage of 90 mg./kg. or less.
l-methyl-3-methylsulphinyl-4-quinolone 1-ethyl-3-methylsulphinyl-4-quinolone l-methyl-3-methylthio-4-quinolone l-methyl-3-methylsulphonyl-4-quinolone The present invention provides a method of reducing blood pressure in a hypertensive warm blooded animal which comprises the administration of a quinolone compound of the hereinbefore defined general formula I. Administration may be enteral or parenteral; enteral administration, especially oral administration, is preferred. A suitable dosage for treating hypertension in warm blooded animals, including man, is generally within the range 0.1-100 mg./kg./day, more usually 0.5-75 mg./kg./day and especially 1-50 mg./kg./day, given in single or divided .B
.7 doses. Unit dosage forms suitably contain 1-500 mg., especially 5-500 mg., of the active compound.
The invention is illustrated by the following non-limitative Examples.
1 l ~'1 7 Example 1 In the preparation of tablets, the following mixture is dry granulated and compressed in a tableting machine to give tablets containing 10 mg. of active ingredient:
Active Ingredient 10 g.
Lactose 5 g-Calcium Phosphate 5 g.
Maize Starch 5 g.
In a similar manner tablets are prepared containing 25 mg. of active ingredient.
Example 2 In a similar manner to that described in Example 1, there are prepared tablets containing 10 mg. or 25 mg. of 1-methyl-3-methylsulphinyl-4-quinolone as the active ingredient.
Example 3 In the preparation of enteric coated tablets, the tablets described in Examples 1 and 2 are given a thin coat of shellac varnish, followed by 20 coats of cellulose acetate phthalate.
Exam~le 4 In the preparation of capsules, a mixture of equal parts by weight of active ingredient and calcium phosphate is encapsulated in hard gelatin capsules, each capsule containing 10 mg. of active ingredient.
i~
Capsules containing 25 mg. of active ingredient are prepared in a similar manner.
Example 5 In a similar manner to that described in Example 4, there are prepared capsules containing 10 mg. or 25 mg. of l-methyl-3-methylsulphinyl-4-quinolone as the active ingredient.
Example 6 In the preparation of enteric coated capsules, the capsules of Examples 4 and 5 are coated with cellulose acetate phthalate in a conventional manner.
Example 7 Suppositories weighing 1 g. and containing 25 mg.
active ingredient are prepared in a conventional manner using a base consisting of:
Polyethylene glycol 4000 33%
Polyethylene glycol 6000 47%
Water 20%
Suitable active ingredients include that listed in Example 2.
r~
~S~
.
Therapeutic Compositions This invention relates to therapeutic compositions containing certain quinolone compounds which we have found to possess antihypertensive activity. More particularly, the present invention provides therapeutic compositions which comprise as an active ingredient a quinolone of the general formula ' O
Rz ~ S(O)nCH3 wherein n is 0, 1 or 2 and either (a) R2 is hydrogen and Rl is methyl or ethyl, or (b) R2 is methyl and Rl is ethyl, provided that, when Rl is ethyl, n is 1 or 2, together with a pharmaceutically acceptable carrier.
We have found that the compounds of general formula I have valuable antihypertensive activity.
When administ~red to warm blooded animals in non-toxic doses the compounds are effective in reducing elevated blood pressure.
,~
B
11,~7~
The compounds of general forn~ula I have been described in the literature, but no therapeutic activity has been ascribed to them. Thus, for example, the individual compounds within the scope of general 5 formula I and methods for their preparation have been described in one or more of the following publications:
Van Leusen and Taylor, J. Org. Chem., Vol. 33, pp.
66-70 (1968) Albrecht, Chimie Therapeutique, 1973, No. 1, pp. 45-48.
10 Connor et al., J. Heterocyclic Chem., Vol. 15, pp.
113-114 (1978) Connor et al., J. Heterocyclic Chem., Vol. 15 pp.
115-117 (1978) As used hereinafter, the term 'active compound' 15 denotes a quinolone compound of general formula I. In therapeutic use, the active compound may be administered orally, rectally or parenterally, preferably orally. Thus the therapeutic compositions of the present invention may take the form of any of 20 the known pharmaceutical compositions for oral, rectal or parenteral administration. Pharmaceutically acceptable carriers suitable for use in such compositions are well-known in the art of pharmacy.
The compositions of the invention suitable contain 25 0.1-90% by weight of active compound. The compositions of the invention are generally prepared in unit dosage form.
Compositions for oral administration are the preferred compositions of the invention and these are 30 the known pharmaceutical forms for such administration, for example tablets, capsules, syrups and aqueous or oily suspensions. The excipients used in the preparation of these compounds are the excipients known in the pharmacists' art. Tablets may be prepared by B
1 1.'~' 1 7~
~ixing the active compound with an inert diluent such as calcium phosphate in the presence of disintegrating agents, for example maize starch, and lubricating agents, or example magnesium stearate, and tableting the mixture by known methods. Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate. Similarly capsules, for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by conventional means and, if desired, provided with enteric coatings in a known manner. The tablets and capsules may conveniently each contain 5-500 mg. of the active compound. Other compositions for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions containing a compound of the present invention, in a suitable vegetable oil, for example arachis oil.
Compositions of the invention suitable for rectal administration are the known pharmaceutical forms for such administration, for example suppositories with cocoa butter or polyethylene glycol bases.
Compositions of the invention suitable for parenteral administration are the known pharmaceutical forms for such administration, for example sterile suspension in aqueous and oily media or sterile solutions in a suitable solvent.
In some formulations it may be beneficial to use the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
. D
In the compositions of the present in~ention the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.
The therapeutic activity of the quinolones of general formula I has been demonstrated by tests which include (A) the oral administration of the compounds to a strain of spontaneously hypertensive rat and (B) the intraduodenal administration of the compounds to a strain of normotensive rat. These tests were carried out in the following way:
Test A
Female rats weight range 180-240 g., of the Aoki-Okamoto strain of spontaneously hypertensive rat were used. The rats in groups of four were fasted overnight before administration of the test compound.
Blood pressure was determined in the following way.
The rats were placed in a cabinet kept at 38C with their tails protruding through holes in the cabinet.
After 30 minutes in the cabinet blood pressure was measured using an inflatable cuff placed round the base of the tail and arterial pulsations monitored with a pneumatic pulse transducer. A pressure, greater than the expected blood pressure, was applied to the cuff, and this pressure was slowly reduced. The pressure in the cuff at which arterial pulsations reappeared was ~aken as the blood pressure. The rats were removed from the cabinet and each group orally dosed with a given dose of the test compound given as a solution or suspension in 0.25% aqueous carboxymethylcellulose. In addition to the pre-dose reading, blood pressure was measured at 1.5 and 5.0 hours after dosing. A compound was designated as active if it gave a reduction of blood pressure of 20% or greater at either of these time intervals.
D
Test B
Male normotensive rats (Wistar strain) of weight range 210-240 g. were used. The rats were anaesthetised and cannulae placed in a carotid artery and in the duodenum. Blood pressure was recorded electronically by means of a pressure transducer connected to the arterial cannula. The test compound was administered into the duodenum as a solution or suspension in 0.25% aqueous carboxymethylcellulose.
Blood pressure was recorded before dosing and for 30 minutes afterwards. Results were obtained as the mean of determinations in three rats per dosage level.
Compounds which caused a fall in blood pressure of lO%
or greater during the 30 minute post-dose period were designated as active.
The following compounds were found to be active in one or both of the tests at a dosage of 90 mg./kg. or less.
l-methyl-3-methylsulphinyl-4-quinolone 1-ethyl-3-methylsulphinyl-4-quinolone l-methyl-3-methylthio-4-quinolone l-methyl-3-methylsulphonyl-4-quinolone The present invention provides a method of reducing blood pressure in a hypertensive warm blooded animal which comprises the administration of a quinolone compound of the hereinbefore defined general formula I. Administration may be enteral or parenteral; enteral administration, especially oral administration, is preferred. A suitable dosage for treating hypertension in warm blooded animals, including man, is generally within the range 0.1-100 mg./kg./day, more usually 0.5-75 mg./kg./day and especially 1-50 mg./kg./day, given in single or divided .B
.7 doses. Unit dosage forms suitably contain 1-500 mg., especially 5-500 mg., of the active compound.
The invention is illustrated by the following non-limitative Examples.
1 l ~'1 7 Example 1 In the preparation of tablets, the following mixture is dry granulated and compressed in a tableting machine to give tablets containing 10 mg. of active ingredient:
Active Ingredient 10 g.
Lactose 5 g-Calcium Phosphate 5 g.
Maize Starch 5 g.
In a similar manner tablets are prepared containing 25 mg. of active ingredient.
Example 2 In a similar manner to that described in Example 1, there are prepared tablets containing 10 mg. or 25 mg. of 1-methyl-3-methylsulphinyl-4-quinolone as the active ingredient.
Example 3 In the preparation of enteric coated tablets, the tablets described in Examples 1 and 2 are given a thin coat of shellac varnish, followed by 20 coats of cellulose acetate phthalate.
Exam~le 4 In the preparation of capsules, a mixture of equal parts by weight of active ingredient and calcium phosphate is encapsulated in hard gelatin capsules, each capsule containing 10 mg. of active ingredient.
i~
Capsules containing 25 mg. of active ingredient are prepared in a similar manner.
Example 5 In a similar manner to that described in Example 4, there are prepared capsules containing 10 mg. or 25 mg. of l-methyl-3-methylsulphinyl-4-quinolone as the active ingredient.
Example 6 In the preparation of enteric coated capsules, the capsules of Examples 4 and 5 are coated with cellulose acetate phthalate in a conventional manner.
Example 7 Suppositories weighing 1 g. and containing 25 mg.
active ingredient are prepared in a conventional manner using a base consisting of:
Polyethylene glycol 4000 33%
Polyethylene glycol 6000 47%
Water 20%
Suitable active ingredients include that listed in Example 2.
r~
~S~
.
Claims (7)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Therapeutic compositions which comprise as an active ingredient a quinolone of the general formula wherein n is 0, 1 or 2 and either (a) R2 is hydrogen and R1 is methyl or ethyl, or (b) R2 is methyl and R1 is ethyl, provided that, when R1 is ethyl, n is 1 or 2, together with a pharmaceutically acceptable carrier.
2. Compositions as claimed in claim 1 in unit dosage form.
3. Compositions as claimed in claim 2 in the form of tablets, capsules or suppositories.
4. Compositions as claimed in claim 1, claim 2 or claim 3, wherein the quinolone is 1-methyl-3-methylsulphinyl-4-quinolone.
5. Compositions as claimed in claim 1, claim 2 or claim 3, wherein the quinolone is 1-methyl-3-methylthio-4-quinolone.
6. Compositions as claimed in claim 1, claim 2 or claim 3, wherein the quinolone is 1-ethyl-3-methylsulphinyl-4-quinolone.
7. Compositions as claimed in claim 1, claim 2 or claim 3, wherein the quinolone is 1-methyl-3-methylsulphonyl-4-quinolone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000415369A CA1171789A (en) | 1979-03-27 | 1982-11-10 | Therapeutic agents |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7910558 | 1979-03-27 | ||
| GB7910558 | 1979-03-27 | ||
| GB7939505 | 1979-11-15 | ||
| GB7939505 | 1979-11-15 | ||
| CA000348520A CA1151652A (en) | 1979-03-27 | 1980-03-26 | 3-(alkylthio, alkylsulphinyl or alkylsulphonyl)-4- quinolones |
| CA000415369A CA1171789A (en) | 1979-03-27 | 1982-11-10 | Therapeutic agents |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000348520A Division CA1151652A (en) | 1979-03-27 | 1980-03-26 | 3-(alkylthio, alkylsulphinyl or alkylsulphonyl)-4- quinolones |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1171789A true CA1171789A (en) | 1984-07-31 |
Family
ID=27426228
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000415369A Expired CA1171789A (en) | 1979-03-27 | 1982-11-10 | Therapeutic agents |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1171789A (en) |
-
1982
- 1982-11-10 CA CA000415369A patent/CA1171789A/en not_active Expired
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |