WO2008134840A2 - Compound with anesthetics activity, methods for its production an pharmaceutical compositions comprising the same - Google Patents
Compound with anesthetics activity, methods for its production an pharmaceutical compositions comprising the same Download PDFInfo
- Publication number
- WO2008134840A2 WO2008134840A2 PCT/BR2008/000145 BR2008000145W WO2008134840A2 WO 2008134840 A2 WO2008134840 A2 WO 2008134840A2 BR 2008000145 W BR2008000145 W BR 2008000145W WO 2008134840 A2 WO2008134840 A2 WO 2008134840A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- lpsf
- activity
- fact
- girsupan
- Prior art date
Links
- 0 *c1cccc(*)c1CCl Chemical compound *c1cccc(*)c1CCl 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
Definitions
- the present invention is related to a new series of chemical compounds, namely 3-benzyl-imidazolidine-2,4-dione substituted in the position 2 and/or 6 of benzyl ring by halogens as presented to the molecule named LPSF-PT-31, GIRSUPAN and its therapeutic use as drug with analgesic, sedative and adjuvant of anesthetics activities.
- the invention is also related to a process for production of said compounds as well as pharmaceutical compositions comprising them.
- NSAID non-steroidal anti-inflammatory drugs
- salicylates which mechanism of action is located in the peripheral sites
- hypnotic-analgesics which action is focused in the central nervous system.
- the NSAIDs are a group of compounds widely used and well tolerate due to low incidence of severe side effects.
- the NSAID are very effective for regulating peripheral somatic pain, especially related to inflammatory processes.
- NSAIDs Due to the mechanism of action based on inhibition of ciclooxigenase enzymes type 1 (Nature New Biology, 2001, 231:232-235) and type 2 (PNAS, 1991, 88:2692-2696) the efficacy of NSAIDs for treatment of pains such as colic caused by obstruction, trauma, nerve compression or central nervous system pain, is limited. Few drugs are available for treatment of this modality of pain.
- the pharmacological group recommended for the control of high intensity pain is the opioid, which the prototype compound is morphine, and even in this group few drugs are available.
- Clinical use of morphine and related drugs is not dissociated of several side effects as nausea, vomiting, itching and respiratory depression, which frequently interrupts the treatment.
- a therapeutic protocol to increase the potency of a drug based on association of an adjuvant compound with a main compound has been developed for treatment of patients with sustained pain.
- the adjuvant compound is directed to increase the efficacy and also the duration of the effect of drug like morphine for pain treatment.
- the main advantage of simultaneously use an adjuvant compound is the reduction of dose and frequency of administration of the main active drug, thus reducing side effects.
- an adjuvant compound also potentiates the intensity and duration of anesthesia induced by intrathecal administration of local anesthetics. This procedure is frequently recommended for abdominal lower surgery and for patients with chronic pain.
- a drug such as morphine
- an adjuvant compound also potentiates the intensity and duration of anesthesia induced by intrathecal administration of local anesthetics. This procedure is frequently recommended for abdominal lower surgery and for patients with chronic pain.
- One group of compounds that has been used for this purpose is the alpha-2 adrenoceptor agonists, such as clonidine.
- the efficacy of alpha-2 adrenoceptor agonists as analgesic is lower than the morphine, however, the ability for increasing the intensity and duration of analgesia of this drug in combination with other drugs is significant (Anesthesiology 1994, 80:837).
- alpha-2 adrenoceptor agonists are sedative and hypnotic effects (Anesthesiology 1988, 69:818-823). Although the efficacy as a hypnotic by itself is not as high as the barbiturates, alpha-2 adrenoceptor agonists are useful as pre-anesthetics drugs agent and as adjuvants for intravenous (Br. J. Anaesth. 1990, 65:157-163) and inhalation general anesthetics (Anesthesiology 1987, 67:11-19). Hypotension is the main side effect related to the administration of alpha-
- alpha-2 adrenoceptors agonists used as adjuvants of analgesic and hypnotic compounds may cause decreasing of blood pressure, it is important to find new drugs with properties similar to clonidine but hemodynamically more stable. Finding new prototype with central nervous system analgesic effect and adjuvant for anesthesia is clinically relevant due to limited number of drugs with these properties.
- Clonidine was one of the few drugs available (US 4,094,964), and, more recently the isomer of medetomidine, dexmedetomidine, is also available (US 5,091,402) both with alpha-2 adrenoceptor agonist activity.
- the present finding introduces a new series of compound with analgesic and sedative profile which effect results from activation of alpha-2 adrenoceptor demonstrated by complete reversion of the effect by the specific antagonist yohimbine.
- the analgesic activity can be demonstrated by both systemic and intrathecal administration of a preferred compound, LPSF-PT-31 , GIRSUPAN. Part of the effect is also reversed by naloxone, a specific the antagonist of opioid receptor, however, the intensity of this effect is smaller when compared to the alpha-2 adrenoceptor.
- Activity of the same molecule on more than one pharmacological target is revealed in several compounds due to similarity of arrangement of the macromolecule receptor and the dynamic of the molecules.
- the main advantage of LPSF-PT-31, GIRSUPAN, the compound found in this study in comparison to other compounds such as clonidine is the stability of blood pressure and heartbeat rate.
- X and Y are, each independently, selected from the group consisting of H 1 F, Cl, Br, I; and pharmaceutically acceptable salts, solvates, hydrates and isomers thereof.
- X and Y are, each independently, selected from the group consisting of H, F, Cl, Br 1 1; with imidazolidine-2,4-dione.
- composition comprising: a) a compound with anesthetics activity according to the formula (I) below:
- the pharmaceutical composition comprise an additional anesthetic, sedative and/or analgesic compound.
- Figure 2 shows the reversion of anestethic activity of LPSF-PT-31 by yohimbine.
- Figure 3 shows the isobologram for LPSF-PT-31 and morphine Figure 4 shows the reduction of pain reaction after intrathecal administration in a dose-dependent manner.
- Figure 5 shows the reduction of motor activity caused by LPSF-PT-31 , GIRSUPANI.
- pharmaceutically acceptable should be understood as compounds, materials, compositions and/or dosage forms which are proper for use in humans and/or animals, without triggering any irritation, allergic or toxic response, or any other problem or complication, without any reasonable ratio between risk/benefit.
- X and Y are, each independently, selected from the group consisting of H, F 1 Cl 1 Br 1 1; and pharmaceutically acceptable salts, solvates, hydrates and isomers thereof.
- pharmaceutically acceptable salts includes the compounds from the general formula (I) above which are modified by the addition of acids and/or bases. Examples include, without limitation, mineral or organic salts of basic residues such as amines, alkaline or organic salts or acid residues such as carboxylic acids.
- the pharmaceutically acceptable salts include conventional non-toxic salts, such as quaternary ammonium salts, and derivatives from inorganic acids, such as hydrochloridric acid, bromidric acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid; and organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, rnaleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanylic, sulphonic, oxalic, among others.
- inorganic acids such as hydrochloridric acid, bromidric acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid
- organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, r
- a preferred embodiment include the compound 3-(2-chloro-6-fluoro- benzyl)-imidazolidine-2,4-dione (LPSF-PT-31, GIRSUPAN) presenting the atoms of chlorine and fluorine in X and Y position, which leverage the activities found.
- Other suitable compounds include 3-(2,6-difluoro-benzyl)-imidazolidine- 2,4-dione (LPSF-PT-122) and 3-(2,6-dichloro-benzyl)-imidazolidine-2 ,4-dione (LPSF-PT-123).
- the process of production of the anesthetics of the present invention comprises the step of reacting a benzyl chloride of formula (II):
- X and Y are, each independently, selected from the group consisting of H, F, Cl, Br, I; with imidazolidine-2,4-dione.
- the reaction mixture is heated and the formation of di-ortho substituted benzyl- imidazolidinediones is accompanied by thin layer chromatography.
- the product formed is filtered and purified by crystallizations or column chromatography on silica in /?-hexane:ethyl acetate 8:2 system.
- the LPSF-PT-31 presented a yield of 36% and a melting point of 155-156°C
- the LPSF-PT-122 presented a yield of 32% and a melting point of 150-152 0 C
- LPSF-PT-123 presented a yield of 23% and a melting point of 160-1 0 C.
- LPSF-PT-31, LPSF-PT-122 and LPSF-PT- 123 synthesized was performed by the infrared spectra recorded at 66 Bruker IFS unit in tablet of KBr, the nuclear magnetic resonance spectra of proton made in a spectrophotometer device Bruker AC P 300, using the DMSO-d ⁇ as solvent and the mass spectra.
- the spectroscopic features in the infrared, nuclear magnetic resonance of the protons and mass spectra of prepared compounds are in accordance with the structure.
- mass spectrometry the fragmentation observed and the intensity of the peaks of isotopes after electron impact are also in agreement with the proposed structures.
- compositions comprising: a) a compound with anesthetics activity according to the formula (I) below:
- the pharmaceutical composition comprises an additional active principle.
- the additional active principle has a synergistic effect with the compound of the present invention, so as to achieve the same level of sedation with a lower dose.
- Suitable active principles include, without limitation, the anesthetics of the state of the art, such as morphine, codeine, sevoflurane, halothane, among others. o
- the in vivo tests performed in animals show that the compound LPSF- PT-31 GIRSUPAN has an analgesic and sedative activities and also potentiates the anesthetic activity.
- the analgesic effect was demonstrated using a specific and validated method described as Hot Plate Test.
- the activity of several compounds with action in central nervous system as opioids, which the main drug is morphine, and the alpha-2 adrenoceptor agonist as clonidine have been identified by this method.
- the analgesic activity of LPSF-PT-31, GIRSUPAN demonstrated in this invention was completely reversed by exposure of the animals to yohimbine a compound identified as antagonist of alpha-2 adrenoceptor (J Pharm Pharmacol 2005, 57).
- the sedative activity of LPSF-PT-31, GIRSUPAN was demonstrated by measuring the motor activity of animals followed by an automated device. Decreasing of motor activity measured in this equipment suggest that the tested compound has a sedative effect.
- the effect of LPSF-PT-31, GIRSUPAN in decreasing the motor activity was completely reversed by yohimbine sustaining the hypothesis that the target of this compound is the alpha-2 adrenoceptor.
- the analgesic activity of LPSF-PT-31 , GIRSUPAN was investigated in male Swiss mice weighting 18-24 grams using the Hot Plate Test method (Brain Res. 1983, 245-252).
- the animals were positioned on a hot plate stabilized at 52° C using the equipment Analgesic Meter - Letica LE 7406.
- the time between positioning the animals on the plate and lick the paw was the latency of the pain reaction.
- the maximal time (cut-off) allowed to the animals staying on the hot plate was three times the latency time measured on the control. The cut-off was very important to avoid skin damage of the paw.
- the experimental protocol used to test the analgesic effect of the compound LPSF-PT-31, GIRSUPAN 1 consisted to measure the AA in the control condition (before drug administration) and after (i.p.) intraperitoneal administration of increasing dose (1, 5, 10 and 15 mg.kg "1 ).
- GIRSUPAN increased the % AA in a dose-dependent manner.
- the maximal effect observed with dose of 15 mg.kg "1 was about 80% AA.
- the plateau of effect was sustained for 40-50 min and then began to decay until a complete recovery from the analgesic effect at about 100-120 min.
- the adjuvant of analgesic effect of LPSF-PT-31, GIRSUPAN was investigated in a protocol, which the main elected analgesic compound was morphine.
- DE50 for the analgesic effect of LPSF-PT-31, GIRSUPAN was also calculated. Fraction of association of DE50 of each drug was administrated and the DE50 of combination was determined.
- a isobolographic analysis (Figure 3) using the DE50 of each drug and of the combination was performed using a computer program ⁇ Life Sd 1989 45: 947-961) to determine the type of interaction.
- Sevoflurane was the elected anesthetic due to low blood solubility causing a fast induction and recovery of anesthesia.
- LPSF-PT-31 GIRSUPAN
- AA activity started to measure from 10 minutes.
- LPSF-PT-31 GIRSUPAN reduces the pain reaction after intrathecal administration in a dose-dependent manner.
- the maximal analgesic effect measured by Hot Plate was ca. 40% sustained by 180 minutes.
- This intensity of analgesic effect is observed with alpha-2 adrenoceptor agonist as clonidine.
- This experimental protocol demonstrated that LPSF-PT-31, GIRSUPAN cause analgesic effect after intrathecal administration suggestion a activation of alpha-2 adrenoceptor.
- LPSF-PT-31 10 mg/kg was injected trough external jugular vein in a single dose in awaked animals. The blood pressure and the heart rate were not changed showing that LPSF-PT-31 , GIRSUPAN is a stable compound for the cardiovascular system differently that occurs with clonidine.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Anesthesiology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BRPI0810737-8A2A BRPI0810737A2 (en) | 2007-05-03 | 2008-05-05 | ANALGESIC ACTIVITY COMPOSITION, PRODUCTION PROCESS AND PHARMACEUTICAL COMPOSITION |
US12/598,347 US8217068B2 (en) | 2007-05-03 | 2008-05-05 | Compound with anesthetics activity, methods for its production and pharmaceutical compositions comprising the same |
EP08748070A EP2167475A2 (en) | 2007-05-03 | 2008-05-05 | Compound with anesthetics activity, methods for its production an pharmaceutical compositions comprising the same |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BRPI0701016-8 | 2007-05-03 | ||
BRPI0701016-8A BRPI0701016B1 (en) | 2007-05-03 | 2007-05-03 | MOLECULES WITH ANALGESIC, SEDATIVE AND ANESTHETIC ADJUVANT ACTIVITY |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2008134840A2 true WO2008134840A2 (en) | 2008-11-13 |
WO2008134840A3 WO2008134840A3 (en) | 2009-01-29 |
Family
ID=39944056
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/BR2008/000145 WO2008134840A2 (en) | 2007-05-03 | 2008-05-05 | Compound with anesthetics activity, methods for its production an pharmaceutical compositions comprising the same |
Country Status (4)
Country | Link |
---|---|
US (1) | US8217068B2 (en) |
EP (1) | EP2167475A2 (en) |
BR (2) | BRPI0701016B1 (en) |
WO (1) | WO2008134840A2 (en) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2759002A (en) * | 1954-03-24 | 1956-08-14 | Abbott Lab | 3-benzyl hydantoin and process |
EP0545478A1 (en) * | 1991-12-03 | 1993-06-09 | MERCK SHARP & DOHME LTD. | Heterocyclic compounds as tachykinin antagonists |
GB2386892A (en) * | 2002-03-28 | 2003-10-01 | Pantherix Ltd | Carboxy containing (phenyl-/heterocyclyl-)methylene substituted azole & azine derivatives and their therapeutic use as antibacterials |
WO2004010950A2 (en) * | 2002-07-31 | 2004-02-05 | Euro-Celtique S.A. | Aryl substituted hydantoin compounds and their use as sodium channel blockers |
-
2007
- 2007-05-03 BR BRPI0701016-8A patent/BRPI0701016B1/en active IP Right Grant
-
2008
- 2008-05-05 BR BRPI0810737-8A2A patent/BRPI0810737A2/en not_active Application Discontinuation
- 2008-05-05 US US12/598,347 patent/US8217068B2/en not_active Expired - Fee Related
- 2008-05-05 WO PCT/BR2008/000145 patent/WO2008134840A2/en active Application Filing
- 2008-05-05 EP EP08748070A patent/EP2167475A2/en not_active Withdrawn
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2759002A (en) * | 1954-03-24 | 1956-08-14 | Abbott Lab | 3-benzyl hydantoin and process |
EP0545478A1 (en) * | 1991-12-03 | 1993-06-09 | MERCK SHARP & DOHME LTD. | Heterocyclic compounds as tachykinin antagonists |
GB2386892A (en) * | 2002-03-28 | 2003-10-01 | Pantherix Ltd | Carboxy containing (phenyl-/heterocyclyl-)methylene substituted azole & azine derivatives and their therapeutic use as antibacterials |
WO2004010950A2 (en) * | 2002-07-31 | 2004-02-05 | Euro-Celtique S.A. | Aryl substituted hydantoin compounds and their use as sodium channel blockers |
Also Published As
Publication number | Publication date |
---|---|
US20100130575A1 (en) | 2010-05-27 |
BRPI0701016A2 (en) | 2008-12-16 |
EP2167475A2 (en) | 2010-03-31 |
BRPI0701016B1 (en) | 2021-10-26 |
WO2008134840A3 (en) | 2009-01-29 |
BRPI0810737A2 (en) | 2014-10-21 |
US8217068B2 (en) | 2012-07-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6196986B2 (en) | Anesthetic compounds and related methods of use | |
RU2559888C2 (en) | Etomidate analogues which do not inhibit synthesis of adrenocorticosteroids | |
US20130303540A1 (en) | 5-methyl-1-(naphthalen-2-yl)-1h-pyrazole derivatives and their use in potentiating the effect of opioid analgesics | |
JP2016523276A (en) | Use of Sigma Ligand for Prevention and Treatment of Pain Associated with Interstitial Cystitis / Bladder Pain Syndrome (IC / BPS) | |
US20150093435A1 (en) | Treatment of length dependent neuropathy | |
US8217068B2 (en) | Compound with anesthetics activity, methods for its production and pharmaceutical compositions comprising the same | |
JP2004517947A (en) | Use of a MGLUR5 antagonist for the treatment of pruritus | |
AU2010214659B2 (en) | Treatment of length dependent neuropathy | |
EP2246055A1 (en) | The use of aryl piperazine derivatives in manufacturing medicants for treating pain | |
US9745275B2 (en) | Pain-related compound and medical composition | |
US20190099412A1 (en) | Analgesic compositions | |
KR20230147351A (en) | Quinoxaline carboxamide derivatives and pharmaceutical composition for prevention or treatment of glioblastoma containing the same as an active ingredient | |
NZ515513A (en) | Method for treating chronic obstructive pulmonary disease using an endothelin A receptor antagonist | |
US20090163571A1 (en) | Pharmaceutical for use in the treatment of ureterolithiasis | |
AU2012202326A1 (en) | Treatment of length dependent neuropathy |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 08748070 Country of ref document: EP Kind code of ref document: A2 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12598347 Country of ref document: US |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2008748070 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: PI0810737 Country of ref document: BR Kind code of ref document: A2 Effective date: 20091103 |