GB2028324A - Pyrazolidine-dione derivatives and their preparation and use in therapy - Google Patents
Pyrazolidine-dione derivatives and their preparation and use in therapy Download PDFInfo
- Publication number
- GB2028324A GB2028324A GB7927472A GB7927472A GB2028324A GB 2028324 A GB2028324 A GB 2028324A GB 7927472 A GB7927472 A GB 7927472A GB 7927472 A GB7927472 A GB 7927472A GB 2028324 A GB2028324 A GB 2028324A
- Authority
- GB
- United Kingdom
- Prior art keywords
- pyrazolidine
- formula
- dione
- compound
- therapy
- 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.)
- Withdrawn
Links
- CYMJPJKHCSDSRG-UHFFFAOYSA-N pyrazolidine-3,4-dione Chemical class O=C1CNNC1=O CYMJPJKHCSDSRG-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 238000002560 therapeutic procedure Methods 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 208000010110 spontaneous platelet aggregation Diseases 0.000 claims abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000001424 substituent group Chemical group 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 18
- -1 morpholino, piperazino, piperidino Chemical group 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 102000008186 Collagen Human genes 0.000 claims description 4
- 108010035532 Collagen Proteins 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229920001436 collagen Polymers 0.000 claims description 4
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 239000013638 trimer Substances 0.000 claims description 4
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 230000004931 aggregating effect Effects 0.000 claims description 2
- 238000004458 analytical method Methods 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 235000019256 formaldehyde Nutrition 0.000 claims description 2
- 229960004279 formaldehyde Drugs 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 238000000338 in vitro Methods 0.000 claims description 2
- 238000002329 infrared spectrum Methods 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 230000005764 inhibitory process Effects 0.000 claims description 2
- 239000002198 insoluble material Substances 0.000 claims description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 2
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 230000000144 pharmacologic effect Effects 0.000 claims description 2
- 125000006413 ring segment Chemical group 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 238000006683 Mannich reaction Methods 0.000 abstract 1
- 239000003112 inhibitor Substances 0.000 abstract 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or 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
- C07D231/28—Two oxygen or sulfur atoms
- C07D231/30—Two oxygen or sulfur atoms attached in positions 3 and 5
- C07D231/32—Oxygen atoms
- C07D231/36—Oxygen atoms with hydrocarbon radicals, substituted by hetero atoms, attached in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (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
Pyrazolidine-dione derivatives of the formula <IMAGE> in which R1 and R2 are the same or different and each is hydrogen or alkyl of 1 to 6 carbon atoms, or R1 and R2 together with the nitrogen to which they are attached form a heterocyclic ring which may or may not contain another hetero-atom which can itself carry a substituent, are useful in therapy as inhibitors of platelet aggregation. They may be made from the corresponding unsubstituted pyrazolidine-dione by a Mannich reaction.
Description
SPECIFICATION
Pyrazolidine - dione derivatives and their preparation and use in therapy
The present invention relates to pyrazolidine dione derivatives, their preparation and their use in therapy.
The compounds of the invention are those of the formula:
in which R1 and R2 are the same or different and each is hydrogen or alkyl of 1 to 6 carbon atoms, or R1 and
R2 together with the nitrogen to which they are attached for a heterocyclic ring, preferably containing 5-to 7 ring atoms, which may or may not contain another hetero-atom which can itself carry a substituent, e.g. an oxygen or sulphur atom, or an > NR3 radical where R3 is hydrogen, or alkyl of 1 to 4 carbon atoms. Examples of such heterocyclic radicals are morpholino, piperazino, piperidino, and more, particularly, the 4 - methyl - piperazino - 1 radical.
According to a feature of the invention, the compounds of formula I are prepared by reacting the pyrazolidine - dione of formula:
with formaldehyde, as such or as its trimer, and an amine of the formula
The following Example illustrates the invention.
The analyses and IR and NMR spectra confirm the structure of the product.
Example
1, 2 - Diphenyl - 4 - (2 - phenylsulphinyl - ethyl) - 4 [(4- methylpiperazino) - methyl] - pyrazolidine- 3, 5dione.
A solution of 4.044 g (0.01 mol) of 1,2 - diphenyl - 4 - (2 - phenylsulphinyl - ethyl) - pyrazolidine - 3, 5 done, 10 cm3 of isopropanol, 1.048 cm3 of formal- dehyde and 1.23 cm3 (0.0111 mol) of N - methyl piperazine is stirred. The temperature rises to + 29"C. The mixture is heated at the reflux temperature for 2 hours 30 minutes. The solvent is evaporated, the residue is taken up in chloroform and the mixture is dried over anhydrous MgSO4. The chloroform is evaporated and the residue is dissolved in ether under reflux. The insoluble material is separated and the ether is evaporated. A white product is obtained, m.p. 139"C., which is the desired product.
Pharmacological experiments carried out on the compounds of the invention show that they are active as agents for inhibiting platelet aggregation.
The inhibition of platelet aggregation was measured on rabbit platelets, in vitro, in accordance with the test of Born and Cross, J. Physiol. 1963, 168-178,
ADP and collagen being used as aggregating agents.
In the presence of ADP, the EC 50, expressed in ,ag/ml, I, is about 400 for the compound of the inven- tion, studied by way of example. In the presence of collagen, the EC 50 is about 135 ,ag/ml.
The compounds of the invention can be used in therapy to prevent platelet aggregation.
The invention therefore includes within its scope pharmaceutical compositions containing at least one compound of formula (I) as the active principle, in association with excipients suitable for the intended route of administration, which is preferably oral but may also be endorectal or parenteral.
1. Pyrazolidine-dione derivatives of the formula
in which R1 and R3 are the same or different and each is hydrogen or alkyl of 1 to 6 carbon atoms, or R, and
R2 together with the nitrogen to which they are attached form a heterocyclic ring which may or may not contain another hetero-atom which can itself carry a substituent.
2. 1, 2 - Diphenyl - 4 - (2 - phenylsulphinyl - ethyl) -4-[(4- methylpiperazino) - methyl] - pyrazolidine3, 5 - dione.
3. Process for the preparation of a compound as claimed in claim 1, which comprises reacting the pyrazolidine-dione of formula:
with formaldehyde, as such or as its trimer, and an amine of formula:
4. Process according to claim 3 substantially as described in the Example.
5. A compound as claimed in claim 1 or 2 when prepared by the process claimed in claim 3 or 4.
6. A pharmaceutical composition comprising a compound as claimed in claim 1,2 or 5 in association with a compatible pharmaceutical carrier.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (6)
1. Pyrazolidine-dione derivatives of the formula
in which R1 and R3 are the same or different and each is hydrogen or alkyl of 1 to 6 carbon atoms, or R, and
R2 together with the nitrogen to which they are attached form a heterocyclic ring which may or may not contain another hetero-atom which can itself carry a substituent.
2. 1, 2 - Diphenyl - 4 - (2 - phenylsulphinyl - ethyl) -4-[(4- methylpiperazino) - methyl] - pyrazolidine3, 5 - dione.
3. Process for the preparation of a compound as claimed in claim 1, which comprises reacting the pyrazolidine-dione of formula:
with formaldehyde, as such or as its trimer, and an amine of formula:
4. Process according to claim 3 substantially as described in the Example.
5. A compound as claimed in claim 1 or 2 when prepared by the process claimed in claim 3 or 4.
6. A pharmaceutical composition comprising a compound as claimed in claim 1,2 or 5 in association with a compatible pharmaceutical carrier.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7823438A FR2433020A1 (en) | 1978-08-09 | 1978-08-09 | PYRAZOLIDINE-DIONE DERIVATIVES AND THEIR THERAPEUTIC APPLICATION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB2028324A true GB2028324A (en) | 1980-03-05 |
Family
ID=9211717
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB7927472A Withdrawn GB2028324A (en) | 1978-08-09 | 1979-08-07 | Pyrazolidine-dione derivatives and their preparation and use in therapy |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JPS5524200A (en) |
| AT (1) | AT369735B (en) |
| BE (1) | BE878158A (en) |
| DE (1) | DE2932054A1 (en) |
| ES (1) | ES483236A1 (en) |
| FR (1) | FR2433020A1 (en) |
| GB (1) | GB2028324A (en) |
| IT (1) | IT1122740B (en) |
| LU (1) | LU81582A1 (en) |
| NL (1) | NL7906029A (en) |
| PT (1) | PT70042A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0106251A1 (en) * | 1982-10-15 | 1984-04-25 | Edmond Pharma Srl | Pyrazolidinedione derivative having vasodilating, antiaggregating and hypocholesterolemic activities |
-
1978
- 1978-08-09 FR FR7823438A patent/FR2433020A1/en active Granted
-
1979
- 1979-08-07 DE DE19792932054 patent/DE2932054A1/en not_active Withdrawn
- 1979-08-07 NL NL7906029A patent/NL7906029A/en not_active Application Discontinuation
- 1979-08-07 GB GB7927472A patent/GB2028324A/en not_active Withdrawn
- 1979-08-07 AT AT0539279A patent/AT369735B/en not_active IP Right Cessation
- 1979-08-08 PT PT70042A patent/PT70042A/en unknown
- 1979-08-08 JP JP10178979A patent/JPS5524200A/en active Pending
- 1979-08-08 LU LU81582A patent/LU81582A1/en unknown
- 1979-08-08 ES ES483236A patent/ES483236A1/en not_active Expired
- 1979-08-08 IT IT24997/79A patent/IT1122740B/en active
- 1979-08-09 BE BE0/196660A patent/BE878158A/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0106251A1 (en) * | 1982-10-15 | 1984-04-25 | Edmond Pharma Srl | Pyrazolidinedione derivative having vasodilating, antiaggregating and hypocholesterolemic activities |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2433020B1 (en) | 1980-12-05 |
| IT1122740B (en) | 1986-04-23 |
| PT70042A (en) | 1979-09-01 |
| LU81582A1 (en) | 1981-03-24 |
| NL7906029A (en) | 1980-02-12 |
| ES483236A1 (en) | 1980-05-16 |
| AT369735B (en) | 1983-01-25 |
| ATA539279A (en) | 1982-06-15 |
| IT7924997A0 (en) | 1979-08-08 |
| BE878158A (en) | 1980-02-11 |
| FR2433020A1 (en) | 1980-03-07 |
| DE2932054A1 (en) | 1980-02-21 |
| JPS5524200A (en) | 1980-02-21 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |