WO1996033210A1 - Amines exhibiting analgesic action, their preparation and use - Google Patents
Amines exhibiting analgesic action, their preparation and use Download PDFInfo
- Publication number
- WO1996033210A1 WO1996033210A1 PCT/EP1996/001598 EP9601598W WO9633210A1 WO 1996033210 A1 WO1996033210 A1 WO 1996033210A1 EP 9601598 W EP9601598 W EP 9601598W WO 9633210 A1 WO9633210 A1 WO 9633210A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dproψ
- lysψ
- dicbz
- lys
- thr
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates to compounds of general formula (I)
- R 1 , R 2 , R 3 , R 4 are each selected from the group consisting of H, C 1-4 alkyl, aryl, aryl-C 1-4 alkyl-, an amine protective group;
- R 5 and R 6 are each selected from the group consisting of H, C 1-4 alkyl, aryl, aryl-C 1-4 alkyl-, or R 5 and R 6 with the carbon atom whereto they are bound form a CO group;
- R 7 is selected from the group consisting of: halogen; OR 8 ; NR 11 R 12 ; proteic amino acid, optionally protected, bound to Y by a nitrogen atom, where :
- R 8 is selected from the group consisting of H, C 1-4 alkyl, aryl, aryl- C 1-4 alkyl-, carboxyl-C 1-4 alkyl- and
- R 11 and R 12' identical or different, are each selected from the group consisting of H, C 1-4 alkyl, aryl, aryl-C 1-4 alkyl-, carboxyl-C 1-4 alkyl- or an ester thereof;
- x is a whole number from 1 to 10;
- n is a whole number from 1 to 5;
- C 1-4 alkyl means: methyl-, ethyl-, n-isopropyl-, n-iso-tert-butyl- group.
- Aryl means: phenyl group.
- Aryl- C 1-4 alkyl- means: benzyl-, phenyl-ethyl-, phenyl-propyl-, phenyl-butyl group.
- C 1-4 alcoxy means: methoxy-, ethoxy- propoxy-, butoxy group.
- Amine protective group preferably means: Boc, Cbz, CH 3 CO-.
- Halogen means: F, Cl, Br, I.
- n is preferably 3 or 4; x is 4, 5. 10.
- N,N'-diCbz-Lys-2-chloromethylpyrrolidine may be prepared by reactions already known, e.g.:
- the aldehyde, N,N'-diCbz-2,6-diaminohexanal, (3-75 g; 9.41 mmol) was solubilized in a 99:1 methanol-acetic acid mixture (40 ml).
- the solution obtained was added with 1.5 equivalent of D-proline at a time.
- the reaction mixture was added portionwise with NaBH 3 CN (1.77 g) over a period of 30 min.
- the reaction was maintained at room temperature for 30', the reaction solvent was partially evaporated and the residue was added with a sodium sulphate saturated solution (200 ml), acidified with sulphuric acid (1M in H 2 SO 4 ).
- reaction mixture was extracted at room temperature with ethyl acetate (300 ml) in 3 portions.
- the extracts were combined, dehydrated with anhydrous sodium sulphate and evaporated yielding a colourless oil which was initially purified by solubilization in ethyl acetate and two precipitations with n-hexane followed by solubilization in ethyl acetate and reprecipitation with ethyl ether.
- the product obtained was an oil, which then solidified.
- N,N'-diCbz-Lys ⁇ [CH 2 N]Pro (207 mg) was solubilized in methanol (5 ml) and subjected to catalytic hydrogenation at atmospheric pressure in the presence of 102% Pd-C.
- N,N'-diCbz-Lys ⁇ [CH 2 N]Pro 200 mg; 0.40 mol was solubilized in anhydrous THF (15 ml), added, in order, with N-ethylmorpholine (0.40 mmol) and ethyl chloroformate (0.40 mmol).
- the resulting turbid solution was allowed to stir at room temperature for a period of 30 min and, after ascertaining the formation of mixed anhydride by TLC, added with 5 equivalents of glycine ethyl ester hydrochloride, solubilized in a mixture of THF (10 ml) and DMF (1 ml) containing 5 equivalents of N-ethylmorpholine.
- reaction mixture was stirred at room temperature for additional 4 hrs and, after partial evaporation of the reaction solvent, added with a sodium bicarbonate saturated solution (200 ml).
- the suspension obtained was extracted portionwise with ethyl acetate (100 ml).
- the extracts were combined, washed with water, dehydrated, and evaporated to yield an oil (190 mg) which was purified by silica column chromatography (1.2 x 10 cm) eluting with chloroform-methanol, 98/2.
- Example 12 The product prepared as described in Example 12 (150 mg) was hydrogenated in a methanol solution at atmospheric pressure in the presence of 10% Pd-C catalyst for a period of 18 hrs. Once the catalyst had been removed, methanol was evaporated to give a colourless vitreous solid which was taken up with little H 2 O-0.1% TFA and purified by HPLC (reversed-phase C18; gradient H 2 O-0.1% TFA- methanol).
- Example 2 The compound prepared as described in Example 1 (900 mg) was suspended in anhydrous THF (70 ml). The resulting suspension was added with
- Boc-threonine(Bz) (1.070 g) was added at room temperature with TFA (3 ml). The solution was caused to react for 30', then the excess of TFA was distilled off under vacuum. The residue obtained was taken up with anhydrous THF (30 ml) containing 1 equivalent of N- ethylmorpholine and the solution was added to the above reaction mixture under stirring at room temperature.
- the product obtained (200 mg) was salified with HCl.
- Example 7 The product prepared as described in Example 7 (460 mg) was solubilized in methanol (20 ml) and hydrogenated at room temperature in the presence of 10% Pd-C catalyst for a period of 18 hrs. The solvent was evaporated and the resulting reaction product solution yielded a vitreous white solid, which was triturated in anhydrous ethyl ether, taken up with little H 2 O-0.1% TFA and purified by HPLC (isocratic, H 2 O-0.1% TFA) .
- Example 2 The compound prepared as described in Example 1 (350 mg; 0.6 mmol) was added with N-ethylmorpholine (180 ⁇ l; 1.4 mmol). The solution was cooled to 0oC and slowly added with ethyl chloroformate (70 ⁇ l; 0.7 mmol).
- reaction mixture was then added portionwise with sodium cyanoboron hydride (904 mg; 14.4 mmol) and stirred at room temperature for 4 hrs.
- the reaction solvent was evaporated, the residue was added with a sodium sulphate solution (250 ml) acidified with sulphuric acid and the suspension was extracted with ethyl acetate (200 ml) in 3 portions.
- reaction mixture was stirred for 3 hrs and, after ascertaining the formation of mixed anhydride, added with valine (703 mg; 6 mmol). The reaction was continued at room temperature for 18 hrs.
- N,N'-diCbz-Lys V[CH 2 N]Pro (1.2 g) was solubilized in anhydrous THF (100 ml).
- the resulting solution was added with N-ethylmorpholine (314 ⁇ l), cooled to 0oC and slowly added with ethyl chloroformate (186 ⁇ l), while the reaction mixture was allowed to stir for 1 hr.
- the mixture was then added with threonine(Bz) (1.088 g) solubilized in anhydrous THF (30 ml) containing 1 equivalent of N-ethylmorpholine.
- the solution was added to the above reaction mixture under stirring at room temperature.
- reaction was continued for 18 hrs, the reaction solvent was removed by evaporation, the residue was taken up with a sodium sulphate saturated solution acidified with sulphuric acid. The suspension was extracted portionwise with ethyl acetate (300 ml).
- reaction mixture was stirred at room temperature for 3 hrs, then added with a sodium sulphate solution (200 ml) acidified with sulphuric acid.
- a sodium sulphate solution 200 ml
- sulphuric acid 200 ml
- the resulting suspension was extracted with ethyl acetate (300 ml) in 3 portions.
- R 1 , R 3 , R 4 , R 5 , R 6 H;
- R 2 C(CH 3 ) 3 -O-CO-;
- R 7 OH;
- n 3;
- x 4;
- Y
- Example 10 The compound prepared as described in Example 10 ( 800 mg) was solubilized in methanol ( 15 ml ) . The resulting solution was subjected to catalytic hydrogenation at atmospheric pressure in the presence of 10% Pd-C .
- Example 13 The compound prepared as described in Example 13 (500 mg) was solubilized in methanol (15 ml) and hydrogenated at atmospheric pressure in the presence of 10% Pd-C as catalyst. The reaction was discontinued after 24 hrs, the solvent was evaporated and the vitreous solid residue was purified by HPLC (reversed phase, gradient H 2 O-0.1%
- the assigned product was recovered from the chromatographic fractions by partial evaporation followed by freeze-drying.
- N,N'-diCbz-Lys (1.5 g) was solubilized in a 10% DMF-DCM mixture containing N-hydroxysuccinimide (417 mg). The stirred solution was added with a 0.5M solution of N,N'-dicyclohexyl carbodiimide in DCM (7-5 ml). The resulting solution was allowed to stand at room temperature for 18 hrs.
- the dicyclohexylurea separated from the solution in the course of the reaction was filtered off.
- the protected lysine N-hydroxysuccinimide ester solution was evaporated to dryness to obtain complete DMF removal.
- the residue was taken up with DCM (10 ml) to give a turbid suspension.
- the active ester solution was slowly added to a prolinol solution (406 mg) under stirring at room temperature for 48 hrs.
- test animals mus rattus, mus musculus I
- oral or parenteral (i.p., i.e. v.) route do not affect, within a wide interval of doses, the physiological functions and behaviour of same, also in activation conditions (e.g. rota rod).
- said compounds exert potent selective antihyperalgesic.
- antiederaatous and antipyretic action obtained by peripheral administrations in the order of ⁇ g/kg bodyweight. Said action is evident in the case of hyperalgesia from interleukin-1 ⁇ (IL-1 ⁇ ) intraplantar administration and of edema from carrageenan intraplantar administration and is selective on inflamed tissue.
- IL-1 ⁇ interleukin-1 ⁇
- the claimed compounds do not reduce the response to mechanical stimulation of a normal paw injected with physiological saline solution. Conversely, said response is deeply modified by morphine.
- the anti-inflammatory activity does not depend on a direct antagonism of the drug on the receptor of IL-1 ⁇ (used in this study as a phlogogenic agent) as proved by binding tests with labelled agonist. Furthermore, it is not connected, in case to a slight degree, in its antihyperalgesic component, with an increase (release) in endogenous endorphins, as proved by its persistent effect in the animals pretreated with naloxone doses capable of suppressing the action of morphine.
- the action may therefore be related to a selective interference with the multifactorial route from IL-1 ⁇ receptor activation to tissual damage causing edema and pain, in which the activation of inducible cyclooxygenase ( cyclooxygenase 2 ) is the final fundamental moment .
- Said sequence has been clearly demonstrated by experimental studies carried out with IL-1 ⁇ and the "releasers" of same: prototypical is the LPS (lipopolysaccharide of bacterial origin).
- the activity is quantitatively connected with the chemical structure and is obtained with doses that, except for unexpected selective compartmentalization phenomena during distribution, cause concentrations in the organism fluids in the submicromolar order. Therefore, it is likely that the molecule of the drug interferes selectively with key factors (e.g. neurokinins, substance P) and receptors thereof on the phlogistic pain route.
- key factors e.g. neurokinins, substance P
- the doses that have been found to be active in and tolerated by test animals range from microgram fractions/kg bodyweight to 10 mg/kg bodyweight and may be varied according to the type of application for phlogistic pain control (e.g. local application to mucous membranes, systemic oral or i.v. administration, etc.) and depending on the pharmacokinetic and pharmacometabolic characteristics of the various compounds described herein.
- Carrageenan was injected 30' after drug administration. The test was carried out 3 hrs after carrageenan intraplantar administration.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP96914928A EP0825999A1 (en) | 1995-04-19 | 1996-04-17 | Amines exhibiting analgesic action, their preparation and use |
AU56889/96A AU5688996A (en) | 1995-04-19 | 1996-04-17 | Amines exhibiting analgesic action, their preparation and us e |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT95FI000073A IT1277841B1 (en) | 1995-04-19 | 1995-04-19 | AMMINES EQUIPPED WITH ANALGESIC ACTIVITY, THEIR PREPARATION AND USE |
ITFI95A000073 | 1995-04-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996033210A1 true WO1996033210A1 (en) | 1996-10-24 |
Family
ID=11351191
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1996/001598 WO1996033210A1 (en) | 1995-04-19 | 1996-04-17 | Amines exhibiting analgesic action, their preparation and use |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0825999A1 (en) |
AU (1) | AU5688996A (en) |
IT (1) | IT1277841B1 (en) |
WO (1) | WO1996033210A1 (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0335662A1 (en) * | 1988-03-28 | 1989-10-04 | Btg International Limited | Peptides |
-
1995
- 1995-04-19 IT IT95FI000073A patent/IT1277841B1/en active IP Right Grant
-
1996
- 1996-04-17 EP EP96914928A patent/EP0825999A1/en not_active Withdrawn
- 1996-04-17 AU AU56889/96A patent/AU5688996A/en not_active Abandoned
- 1996-04-17 WO PCT/EP1996/001598 patent/WO1996033210A1/en not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0335662A1 (en) * | 1988-03-28 | 1989-10-04 | Btg International Limited | Peptides |
Non-Patent Citations (3)
Title |
---|
DOULUT, S. ET AL.: "Reduced peptide bond pseudopeptide analogues of neurotensin", PEPTIDE RES., vol. 5, no. 1, 1992, pages 30 - 38, XP000577711 * |
NICOLAIDES, E.D. ET AL.: "Anti-writhing activity of some peptides related to neurotensin and tuftsin", INT. J. PEPTIDE PROTEIN RES., vol. 25, 1985, pages 435 - 441, XP000577690 * |
OLUYOMI, A.O. ET AL.: "Antinociceptive activity of peptides related to interleukin-1beta-(193-195), Lys-Pro-Thr", EUR. J. PHARMACOL., vol. 258, 1994, pages 131 - 138, XP000570480 * |
Also Published As
Publication number | Publication date |
---|---|
ITFI950073A1 (en) | 1996-10-19 |
AU5688996A (en) | 1996-11-07 |
IT1277841B1 (en) | 1997-11-12 |
ITFI950073A0 (en) | 1995-04-19 |
EP0825999A1 (en) | 1998-03-04 |
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