US3752891A - Method for producing antihypertensive activity - Google Patents
Method for producing antihypertensive activity Download PDFInfo
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- US3752891A US3752891A US00150203A US3752891DA US3752891A US 3752891 A US3752891 A US 3752891A US 00150203 A US00150203 A US 00150203A US 3752891D A US3752891D A US 3752891DA US 3752891 A US3752891 A US 3752891A
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- 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
Definitions
- the present invention relates to a method for producing antihypertensive activity in a hypertensive mammal by the administration of a compound of the formula: I
- R is hydrogen, lower alkyl or phenyl lower alkyl.
- the present invention relates to a novel method and more particularly the present invention relates to a novel method in lowering blood pressure in a mammal suffering from hypertension by the administration of a compound of the formula:
- R is hydrogen, lower alkyl or phenyl lower alkyl.
- lower alkyl is meant to contain from 1 to 7 carbon atoms such as methyl, ethyl, propyl, isopropyl and the like.
- Hypertension has been defined as being a condition whereby there is a persistent elevation of blood pressure or, as otherwise stated, an increased resistance to blood flow. It is well known that if hypertension is not treated, it will place an extra burden on the cardiovascular system and will generally predispose the hypertensive mammal to other complications; for example, congestive heart failure, myocardial infarction and the like.
- drugs available to treat hypertension, these drugs depend for their antihypertensive activity on their various pharmacological action; for example, the well known drug guanathidine acts by inhibiting the responses to sympathetic adrenergic nerve activity.
- guanathidine acts by inhibiting the responses to sympathetic adrenergic nerve activity.
- hydralazine acts to produce the antihypertensive efliect by providing peripheral vaso dilatation.
- the compounds of this invention exhibit pronounced hypotensive effect in mammals who are sufiering from renal and/or spontaneous hypertension.
- the renal hypertensions in these animals are experimentally induced by procedures known to the art.
- rats were induced to become hypertensive by the Grollman procedure. See Grollman, Proc. Soc. Exper. Biol. Med. 57, 102 (1944). I
- these compounds are combined with a pharmaceutical carrier such as lactose, mannitol and granulated with a granulating agent such as water or gelatin solution into granules. These granules are then compressed into tablets containing the active ingredient from about 1-100 mg. per dosage unit. They can also be combined with vehicles such as syrup or water with a suitable suspending agent such as tragacanth, with the active ingredient being present from 1-100 mg. per dosage unit.
- the compounds are suspended in vehicles such as peanut oil and sterilized by conventional procedure into dosage forms suitable for injection.
- a dosage range of about 5 to mg. orally is recommended to a mammalian host having an average body weight of about 70 kg.
- This dosage regimen can be repeated up to three times daily.
- the described dosage regimen can be varied depending on the age, sex, species of the mammal and the condition of the mammal being treated by well known clinical procedures.
- EXAMPLE 2 3 -hydrazino-S-methyl-SH-as-triazino [5, 6-b] indole 3
- EXAMPLE 3 5 -benzyl-3-hydrazine-5 H-as-triazino [5 ,6-b] indole
- a solution of 15.3 g. (0.05 mole) of S-benzyl-e-(methylthio) -5H-as-triazino[5,6-b]indole in 50 ml. of hydrazine hydrate was refluxed for four hours, poured over crushed ice and filtered to give 12.9 g. (0.045 mole, 88.9%) of crude material. Recrystallization from DMF gave yellow crystals, M.P. 215-217".
- EXAMPLE 5 5-n-propyl-3-hydrazino-5H-as-triazino[5,6-b]indole The material was prepared in 88% yield in a manner similar to preparation of 5-benzyl-3-hydrazino5H-as-tri- -azino[5,6-b]indole. Recrystallization from DMF gave yellow-orange solid, M.P. 168-170" (dec).
- Example 1 The compound of Example 1 was found to produce a pronounced blood pressure reduction at a dosage of 10 50 mg./kg.
- a compound of Example 2 was found to produce a pronounced blood pressure reduction at a dosage of 10- 50 mg./kg.
- a compound of Example 3 was found to produce a pronounced blood pressure reduction at a dosage of 20- mg./kg.
- Example 4 The compound of Example 4 was found to produce a pronounced blood pressure reduction at a dosage of 10- 50 mg./kg.
- Example 5 The compound of Example 5 was found to produce a pronounced blood pressure reduction at a dosage of 10- 50 mg./kg.
- Example 6 The compound of Example 6 was found to produce a pronounced blood pressure reduction at a dosage of 10- 50 mg./kg.
- R is hydrogen, lower alkyl or benzyl.
- R is methyl. 4. A method according to claim 1 wherein R is ethyl. 5. A method according to claim 1 wherein R is propyl. 6. A method according to claim 1 wherein R is butyl. 7. A method according to claim 1 wherein R is benzyl. 8. A method according to claim 1 wherein said compound is administered at a dose of about 10-100 mg./kg.
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Abstract
THE PRESENT INVENTION RELATES TO A METHOD FOR PRODUCING ANTIHYPERTENSIVE ACTIVITY IN A HYPERTENSIVE MAMMAL BY THE ADMINISTRATION OF A COMPOUND OF THE FORMULA:
3-(NH2-NH-),5-R1-5H-AS-TRIAZINO(5,6-B)INDOLE
WHEREIN R1 IS HYDROGEN, LOWER ALKYL OR PHENYL LOWER ALKYL.
3-(NH2-NH-),5-R1-5H-AS-TRIAZINO(5,6-B)INDOLE
WHEREIN R1 IS HYDROGEN, LOWER ALKYL OR PHENYL LOWER ALKYL.
Description
United States Patent ABSTRACT OF THE DISCLOSURE The present invention relates to a method for producing antihypertensive activity in a hypertensive mammal by the administration of a compound of the formula: I
wherein R is hydrogen, lower alkyl or phenyl lower alkyl.
The present invention relates to a novel method and more particularly the present invention relates to a novel method in lowering blood pressure in a mammal suffering from hypertension by the administration of a compound of the formula:
wherein R is hydrogen, lower alkyl or phenyl lower alkyl.
As used in this specification and in the claims, lower alkyl is meant to contain from 1 to 7 carbon atoms such as methyl, ethyl, propyl, isopropyl and the like.
Hypertension has been defined as being a condition whereby there is a persistent elevation of blood pressure or, as otherwise stated, an increased resistance to blood flow. It is well known that if hypertension is not treated, it will place an extra burden on the cardiovascular system and will generally predispose the hypertensive mammal to other complications; for example, congestive heart failure, myocardial infarction and the like.
Although there are many types of drugs available to treat hypertension, these drugs depend for their antihypertensive activity on their various pharmacological action; for example, the well known drug guanathidine acts by inhibiting the responses to sympathetic adrenergic nerve activity. On the other hand, hydralazine acts to produce the antihypertensive efliect by providing peripheral vaso dilatation.
It has now been found that the desired anti-hypertensive eifect can be achieved by the administration of a compound corresponding to Structure I above which acts unlike the known agents. These compounds are known compounds, the preparation of which is described in U.S. Pat. No. 3,510,482. These compounds are described as having antiviral activity in said U.S. patent. It is therefore quite surprising that these compounds can be used to produce the desired antihypertensive elfect by the practice of the present invention as described below.
Broadly speaking, the compounds of this invention exhibit pronounced hypotensive effect in mammals who are sufiering from renal and/or spontaneous hypertension. The renal hypertensions in these animals are experimentally induced by procedures known to the art. Thus, for example, rats were induced to become hypertensive by the Grollman procedure. See Grollman, Proc. Soc. Exper. Biol. Med. 57, 102 (1944). I
By the administration of Compound I, it was found that at a dose of about 5-100 mg. per kg. these compounds are capable of causing pronounced falls in blood pressure with the duration of action greater than four hours. On the other hand, when the same compound was administered to nonhypertensive hosts, there was no appreciable decrease in blood pressure.
In order to use these compounds, they are combined with a pharmaceutical carrier such as lactose, mannitol and granulated with a granulating agent such as water or gelatin solution into granules. These granules are then compressed into tablets containing the active ingredient from about 1-100 mg. per dosage unit. They can also be combined with vehicles such as syrup or water with a suitable suspending agent such as tragacanth, with the active ingredient being present from 1-100 mg. per dosage unit.
For dosage forms suitable for parenteral administration the compounds are suspended in vehicles such as peanut oil and sterilized by conventional procedure into dosage forms suitable for injection.
Generally speaking, a dosage range of about 5 to mg. orally is recommended to a mammalian host having an average body weight of about 70 kg. This dosage regimen can be repeated up to three times daily. As it will become obvious to those skilled in the art, the described dosage regimen can be varied depending on the age, sex, species of the mammal and the condition of the mammal being treated by well known clinical procedures.
In order to further illustrate the practice of this invention, the following examples are given.
EXAMPLE 1 NHNH 3-hydrazino-5-as-triazino [5,6-b]indole A solution of 10.8 g. (0.05 mole) of 3-(methylthio)- SH-as-triazino[5,6-b]indole in 50 g. (1 mole) of hydrazine hydrate was refluxed for 2 hours and poured over crushed ice. The precipitated solid was filtered to give 3.5 g. (35%) of crude material. Recrystallization from aqueous DMF gave a yellow crystalline material, M.P. 27 8-279 (dec).
Analysis.-Calcd. for C H N (percent): C, 53.99;"H, N, 41.98. Found (percent): C, 54.19; H, 4.17; N,
EXAMPLE 2 3 -hydrazino-S-methyl-SH-as-triazino [5, 6-b] indole 3 EXAMPLE 3 5 -benzyl-3-hydrazine-5 H-as-triazino [5 ,6-b] indole A solution of 15.3 g. (0.05 mole) of S-benzyl-e-(methylthio) -5H-as-triazino[5,6-b]indole in 50 ml. of hydrazine hydrate was refluxed for four hours, poured over crushed ice and filtered to give 12.9 g. (0.045 mole, 88.9%) of crude material. Recrystallization from DMF gave yellow crystals, M.P. 215-217".
Analysis.Calcd. for C W N (percent): C, 66.19; W, 9.86; N, 28.95. Found (percent): C, 65.93; W, 4.70; N, 28.76.
EXAMPLE 4 N W \F NHNH N \N 3 CHa 5-ethyl-3-hydrazino-5H-as-triazino[5,6-b1indo1e The material was prepared in 86.3% yield in a manner similar to preparation of S-benzyl-B-hydrazino-SH-as-triazino-[5,6-b]indole. Recrystallization from DMF gave an orange-brown solid, M.P. 161-162 (dec).
Analysis.Calcd. for C H N (percent): C, 57.88; H, 5.30; N, 36.82. Found (percent): C, 57.89; H, 5.46; N, 36.86.
EXAMPLE 5 5-n-propyl-3-hydrazino-5H-as-triazino[5,6-b]indole The material was prepared in 88% yield in a manner similar to preparation of 5-benzyl-3-hydrazino5H-as-tri- -azino[5,6-b]indole. Recrystallization from DMF gave yellow-orange solid, M.P. 168-170" (dec).
Analysis.Ca1cd. for C H N (percent): C, 59.48; H, 5.82; N, 34.69. Found (percent): C, 59.44; H, 5.94; N, 34.96.
4 EXAMPLE 6 The material was prepared in 76.5% yield in a manner similar to the preparation of 5-benzyl-3-hydrazino-5H-astriazino[5,6-b]indole.
Recrystallization from aqueous DMF gave light tan crystals, M.P. 179-180 C.
Analysis.--Calcd. for C H N (percent): C, 60.92; H, 6.29; N, 32.79. Found (percent): C, 60.99; H, 6.22; N, 33.09.
EXAMPLE 7 The above compounds were also evaluated in Grollman hypertensive rats, op-cit; the following results were obtained:
The compound of Example 1 was found to produce a pronounced blood pressure reduction at a dosage of 10 50 mg./kg.
A compound of Example 2 was found to produce a pronounced blood pressure reduction at a dosage of 10- 50 mg./kg.
A compound of Example 3 was found to produce a pronounced blood pressure reduction at a dosage of 20- mg./kg.
The compound of Example 4 was found to produce a pronounced blood pressure reduction at a dosage of 10- 50 mg./kg.
The compound of Example 5 was found to produce a pronounced blood pressure reduction at a dosage of 10- 50 mg./kg.
The compound of Example 6 was found to produce a pronounced blood pressure reduction at a dosage of 10- 50 mg./kg.
I claim:
1. A method for producing an antihypertensive effect in a mammal suffering from hypertension which comprises the administration to said mammal of an antihypertensively eflective amount of a compound of the formula:
wherein R is hydrogen, lower alkyl or benzyl.
2. A method according to claim 1 wherein R is hydrogen.
3. A method according to claim 1 wherein R is methyl. 4. A method according to claim 1 wherein R is ethyl. 5. A method according to claim 1 wherein R is propyl. 6. A method according to claim 1 wherein R is butyl. 7. A method according to claim 1 wherein R is benzyl. 8. A method according to claim 1 wherein said compound is administered at a dose of about 10-100 mg./kg.
References Cited UNITED STATES PATENTS 3,510,482 5/ 1970 Gladych et a1 424-249 JEROME D. GOLDBERG, Primary Examiner
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US15020371A | 1971-06-04 | 1971-06-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3752891A true US3752891A (en) | 1973-08-14 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US00150203A Expired - Lifetime US3752891A (en) | 1971-06-04 | 1971-06-04 | Method for producing antihypertensive activity |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5830894A (en) * | 1997-02-21 | 1998-11-03 | Viropharma Incorporated | Methods for preventing and treating pestivirus infection and associated diseases |
| US6541472B1 (en) | 1997-02-21 | 2003-04-01 | Viropharma Incorporated | Compounds, compositions and methods for preventing and treating pestivirus infection and associated diseases |
-
1971
- 1971-06-04 US US00150203A patent/US3752891A/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5830894A (en) * | 1997-02-21 | 1998-11-03 | Viropharma Incorporated | Methods for preventing and treating pestivirus infection and associated diseases |
| US6541472B1 (en) | 1997-02-21 | 2003-04-01 | Viropharma Incorporated | Compounds, compositions and methods for preventing and treating pestivirus infection and associated diseases |
| US20040127499A1 (en) * | 1997-02-21 | 2004-07-01 | Pevear Daniel C | Compounds, compositions and methods for preventing and treating pestivirus infection and associated diseases |
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