US3720768A - Aspergillic acid as an antihypertensive agent - Google Patents
Aspergillic acid as an antihypertensive agent Download PDFInfo
- Publication number
- US3720768A US3720768A US00201176A US3720768DA US3720768A US 3720768 A US3720768 A US 3720768A US 00201176 A US00201176 A US 00201176A US 3720768D A US3720768D A US 3720768DA US 3720768 A US3720768 A US 3720768A
- Authority
- US
- United States
- Prior art keywords
- pyridone
- pyrazinone
- hydroxy
- antihypertensive agent
- ethyl
- 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 - Lifetime
Links
- IUZCDJYHMMWBBE-VIFPVBQESA-N 6-[(2S)-butan-2-yl]-1-hydroxy-3-(2-methylpropyl)pyrazin-2-one Chemical compound CC[C@H](C)C1=CN=C(CC(C)C)C(=O)N1O IUZCDJYHMMWBBE-VIFPVBQESA-N 0.000 title description 4
- 239000002220 antihypertensive agent Substances 0.000 title description 3
- 229940030600 antihypertensive agent Drugs 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 abstract description 9
- 206010020772 Hypertension Diseases 0.000 abstract description 8
- 230000001631 hypertensive effect Effects 0.000 abstract description 5
- 238000000034 method Methods 0.000 abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 3
- 239000001257 hydrogen Substances 0.000 abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- -1 5-cyclohexyl-3-methyl-2- 1H -pyrazinone Chemical compound 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 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
- 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
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 150000003216 pyrazines Chemical class 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/18—Oxygen or sulfur atoms
Definitions
- R R R and R each are hydrogen, alkyl, cycloalkyl or aryl with the limitation that R; is present only when X is C.
- the antihypertensive activity of the compounds useful in the practice of this invention was first established in the spontaneously hypertensive rate using standard procedures.
- the compounds are effective as antihypertensive agents at dosages of from 60 to 200 mg./kg. of body Weight daily.
- the compounds are administered to hypertensive patients, preferably by the oral route, in divided dosages, i.e., three to four times daily. They may also be co-administered with, for example, diuretics or tranquilizers in treating hypertension.
- the compounds can be administered alone, that is, as the sole component of a filled capsule, it is preferred to formulate the compound in various dosage forms for oral or parenteral administration such as tablets, syrups, sterile aqueous or non-aqueous suspension and the like.
- the oral dosage forms are prepared by methods well known in the art (as are the parenteral) and generally in clude a pharmaceutically acceptable carrier or diluent such as lactose, starch or sucrose along with lubricating agents such as magnesium stearate and flavoring and sweetening agents and the like.
- a method of reducing blood pressure in hypertensive patients which comprises administering to said patients an antihypertensively effective amount of aspergillic acid.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
METHOD OF TREATING HYPERTENSION BY ADMINISTERING TO A HYPERTENSIVE PATIENT A THERAPWUTICALLY EFFECTIVE AMOUNT OF A COMPOUND OF THE FORMULA
O=N<(=C(-OH)-(R3-)C=X(-R4)-(R1-)C=C(-R2)-) OR
HO-N<(-C(=O)-(R3-)C=X(-R4)-(R1-)C=C(-R2)-)
WHEREIN X IIS C OR N; AND R1, R2, R3 AND R4 EACH ARE HYDROGEN, ALKYL, CYCLOALKYL OR ARYL, WITH THE LIMITATION THAT R4 IS PRESENT ONLY WHEN X IS C.
O=N<(=C(-OH)-(R3-)C=X(-R4)-(R1-)C=C(-R2)-) OR
HO-N<(-C(=O)-(R3-)C=X(-R4)-(R1-)C=C(-R2)-)
WHEREIN X IIS C OR N; AND R1, R2, R3 AND R4 EACH ARE HYDROGEN, ALKYL, CYCLOALKYL OR ARYL, WITH THE LIMITATION THAT R4 IS PRESENT ONLY WHEN X IS C.
Description
United States Patent O 3,720,768 ASPERGILLIC ACID AS AN ANTI- HYPERTENSIVE AGENT Peter Hadley Jones, Lake Forest, and Yvonne Connolly Martin, Waukegan, 111., assignors to Abbott Laboratories, North Chicago, Ill. No Drawing. Filed Nov. 22, 1971, Ser. No. 201,176 Int. Cl. A61k 27/00 U.S. Cl. 424-250 1 Claim ABSTRACT OF THE DISCLOSURE Method of treating hypertension by administering to a hypertensive patient a therapeutically effective amount of a compound of the Formula wherein X is C or N; and R R R and R each are hydrogen, alkyl, cycloalkyl or aryl, with the limitation that R; is present only when X is C.
DETAILED DESCRIPTION OF THE INVENTION wherein X is C or N; and R R R and R each are hydrogen, alkyl, cycloalkyl or aryl with the limitation that R; is present only when X is C.
Representative compounds which are represented by the above formula include:
3-n-pentyl-1-hydroxy-2-( 1H) -pyrazinone 5 -n-pentyll-hydroxy-2-( 1H) -pyrazinone 6-n-pentyl-1-hydroxy-2-( 1H) -pyrazinone 3,6-diethyl-l-hydroxy-2- 1H) -pyrazinone 3-ethyl-6-n-butyl-2- 1H) -pyrazinone 5-ethyl-6-propyl-2- 1H) -pyrazinone 5-ethyl-6-isopropyl-2-( 1H) -pyrazinone 3,5 ,6-triethy1-2- 1H) -pyrazinone 3,5 -diethyl-6-propy1-2- 1H) -pyrazinone 5-phenyl-6methyl-2-( 1H)-pyrazinone 5-cyclohexyl-3-methyl-2- 1H -pyrazinone 5-n-butyl-1-hydroxy-2-( 1H)-pyridone 3-n-butyll-hydroxy-2-( 1H -pyridone 4-n-butyl-1-hydroxy-2-( 1H) -pyridone 6-n-butyl-1-hydroxy-2-( 1H)-pyridone 6-ethyl3-propyl-2-( 1H)-pyridone 6-ethyl-3-isopropyl-2- 1H -pyridone 4-isobutyl-1-hydroxy-2- 1H) -pyridone 3-isobutyl-6sec-butyl-2- 1H -pyridone 5-cyclohexyl-3-methyl-2-( 1H -pyridone 4-cyclopentyl- 6-ethyl-2-( 1H) -pyridone 5 -phenyl-3-ethyl-2-( 1H -pyridone 3-phenyl-6-ethyl-2- 1H) -pyridone The compounds useful in the practice of this invention can be prepared by methods well known in the art. See, for example, Dunn et al., Pyrazine Derivatives XI Synthesis of Cyclic Hydroxarnic Acids Related to Aspergillic Acid J. Chem. Soc., 1949, 2707-l2; U.S. 2,666,054; France 2,022,146 and GB. 1,238,106.
The antihypertensive activity of the compounds useful in the practice of this invention was first established in the spontaneously hypertensive rate using standard procedures. The compounds are effective as antihypertensive agents at dosages of from 60 to 200 mg./kg. of body Weight daily.
In the practice of this invention, the compounds are administered to hypertensive patients, preferably by the oral route, in divided dosages, i.e., three to four times daily. They may also be co-administered with, for example, diuretics or tranquilizers in treating hypertension.
While the compounds can be administered alone, that is, as the sole component of a filled capsule, it is preferred to formulate the compound in various dosage forms for oral or parenteral administration such as tablets, syrups, sterile aqueous or non-aqueous suspension and the like. The oral dosage forms are prepared by methods well known in the art (as are the parenteral) and generally in clude a pharmaceutically acceptable carrier or diluent such as lactose, starch or sucrose along with lubricating agents such as magnesium stearate and flavoring and sweetening agents and the like.
We claim:
1. A method of reducing blood pressure in hypertensive patients which comprises administering to said patients an antihypertensively effective amount of aspergillic acid.
References Cited UNITED STATES PATENTS 2,666,054 1/1954 Safir 260-250 FOREIGN PATENTS 2,022,146 7/ 1970 France. 1,238,106 7/1971 Great Britain.
OTHER REFERENCES Dunn et al. J. Chem. Soc. (1949) pp. 2707-2712.
JEROME D. GOLDBERG, Primary Examiner A. J. ROBINSON, Assistant Examiner U.S. C1. X.R. 424-263
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US20117671A | 1971-11-22 | 1971-11-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3720768A true US3720768A (en) | 1973-03-13 |
Family
ID=22744781
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US00201176A Expired - Lifetime US3720768A (en) | 1971-11-22 | 1971-11-22 | Aspergillic acid as an antihypertensive agent |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3720768A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4292318A (en) * | 1979-07-10 | 1981-09-29 | Grissman Chemicals Limited | Product and method for combating swine dysentery |
| US4721713A (en) * | 1986-02-20 | 1988-01-26 | Toyo Jozo Kabushiki Kaisha | Process for inhibiting blood platelet aggregation and promoting vasodilation |
| EP0477829A2 (en) * | 1990-09-25 | 1992-04-01 | Lonza Ag | Microbiological process for the preparation of hydroxylated heterocyclic compounds |
| EP0484908A2 (en) * | 1990-11-08 | 1992-05-13 | Lonza A.G. | Microbiological process for the preparation of hydroxylated Pyrazinederivatives |
-
1971
- 1971-11-22 US US00201176A patent/US3720768A/en not_active Expired - Lifetime
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4292318A (en) * | 1979-07-10 | 1981-09-29 | Grissman Chemicals Limited | Product and method for combating swine dysentery |
| US4721713A (en) * | 1986-02-20 | 1988-01-26 | Toyo Jozo Kabushiki Kaisha | Process for inhibiting blood platelet aggregation and promoting vasodilation |
| EP0291594A1 (en) * | 1986-02-20 | 1988-11-23 | Toyo Jozo Kabushiki Kaisha | Pyrazine for use in the treatment of haemodynamic and metabolic disorders |
| EP0477829A2 (en) * | 1990-09-25 | 1992-04-01 | Lonza Ag | Microbiological process for the preparation of hydroxylated heterocyclic compounds |
| EP0477829A3 (en) * | 1990-09-25 | 1993-04-07 | Lonza Ag | Microbiological process for the preparation of hydroxylated heterocyclic compounds |
| EP0484908A2 (en) * | 1990-11-08 | 1992-05-13 | Lonza A.G. | Microbiological process for the preparation of hydroxylated Pyrazinederivatives |
| EP0484908A3 (en) * | 1990-11-08 | 1993-04-07 | Lonza A.G. | Microbiological process for the preparation of hydroxylated pyrazinederivatives |
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