WO2004000300A1 - Cyclooxygenase-2 inhibitors - Google Patents
Cyclooxygenase-2 inhibitors Download PDFInfo
- Publication number
- WO2004000300A1 WO2004000300A1 PCT/EP2003/006651 EP0306651W WO2004000300A1 WO 2004000300 A1 WO2004000300 A1 WO 2004000300A1 EP 0306651 W EP0306651 W EP 0306651W WO 2004000300 A1 WO2004000300 A1 WO 2004000300A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acid
- methyl
- formula
- nitrooxypropyl
- integer
- Prior art date
Links
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 229940079593 drug Drugs 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 229940111134 coxibs Drugs 0.000 claims abstract description 6
- 238000011282 treatment Methods 0.000 claims abstract description 6
- -1 R2 is H Chemical group 0.000 claims description 23
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 claims description 18
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 claims description 17
- 150000002148 esters Chemical class 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 230000002757 inflammatory effect Effects 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 235000018417 cysteine Nutrition 0.000 claims description 6
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
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- 229910010280 TiOH Inorganic materials 0.000 claims description 5
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- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims description 5
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
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- DDSFKIFGAPZBSR-UHFFFAOYSA-N 2-[(2-acetyloxyphenyl)-oxomethoxy]benzoic acid Chemical compound CC(=O)OC1=CC=CC=C1C(=O)OC1=CC=CC=C1C(O)=O DDSFKIFGAPZBSR-UHFFFAOYSA-N 0.000 claims description 3
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 3
- SBDNJUWAMKYJOX-UHFFFAOYSA-N Meclofenamic Acid Chemical compound CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C(O)=O)=C1Cl SBDNJUWAMKYJOX-UHFFFAOYSA-N 0.000 claims description 3
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- 229910004679 ONO2 Inorganic materials 0.000 claims description 3
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- 229960001138 acetylsalicylic acid Drugs 0.000 claims description 3
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
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- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 claims description 3
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- MELAUZDORKBWNM-UHFFFAOYSA-N 3-[4-(3-nitrooxypropyl)piperazin-1-yl]propyl 2-[4-(2-methylpropyl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(CC(C)C)=CC=C1C(C)C(=O)OCCCN1CCN(CCCO[N+]([O-])=O)CC1 MELAUZDORKBWNM-UHFFFAOYSA-N 0.000 claims 2
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- LPVFOGFYUMHSAV-UHFFFAOYSA-N 3-[4-(3-nitrooxypropyl)piperidin-1-yl]propyl 2-[2-(2,6-dichloroanilino)phenyl]acetate;hydrochloride Chemical compound Cl.C1CC(CCCO[N+](=O)[O-])CCN1CCCOC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl LPVFOGFYUMHSAV-UHFFFAOYSA-N 0.000 claims 1
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- 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
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to compounds able to inhibit selectively the enzyme COX- 2 without inhibiting substantially the enzyme COX-1.
- non-steroidal anti-inflammatory compounds which are able to inhibit selectively the enzyme COX-2.
- non-steroidal anti-inflammatory drugs are widely used as analgesics, antipyretics and in the treatment of pathologies that have an inflammatory origin.
- the use of NSAIDs is limited by serious side-effects at gastrointestinal and renal levels and by haemorrhagic complications that appear after prolonged treatments with these drugs.
- the inflammatory process originates from the activation of two isoforms of the enzyme cyclooxygenase (COX), which are involved in the activation of a series of biochemical processes, known as arachidonic acid cascade.
- COX cyclooxygenase
- the two isoforms of the enzyme cyclooxygenase are identified as cyclooxygenase- 1 or COX-1 and cyclooxygenase-2 or COX-2 respectively (Annu. Rev. Pharmacol. Toxicol. 1998 38, 97-120).
- the COX-2 produced after inflammatory stimuli represents the form of the enzyme cyclooxygenase responsible for the production of inflammatory and pro-algogenic prostanoids.
- the COX-2 activates a series of factors that maintain and amplify the inflammatory process.
- drugs that inhibit selectively COX-2 without inhibiting substantially COX-1 have been proposed.
- the COX-2 inhibitor drugs celecoxib, rofecoxib, etc., can be mentioned. (Drugs of Future 1998, 23 (12) 1287-1296).
- Another drawback of these drugs is that the analgesic activity is not optimal.
- the need was felt to have available drugs showing an improved COX-1/ COX-2 pharmacological performance, and being able to inhibit both the activity and expression of the enzyme COX-2 without presenting the aforesaid side-effects.
- the Applicant has surprisingly and unexpectedly found drugs that are able to solve the aforementioned technical problem.
- An object of the present invention is the use of compounds of formula (I) or salts thereof with an anti-inflammatory activity that are able to inhibit selectively the enzyme COX-2 without inhibiting substantially the enzyme COX-1, without showing side- effects, in particular at gastrointestinal, renal levels, and without damaging the cardiovascular apparatus:
- R-Tj- is a radical deriving from a non steroidal anti-inflammatory drug of formula R- TiOH or R-TiH wherein R is defined hereunder, Ti is CO or X, wherein X is O, S,
- R ⁇ C is H or a linear or branched C ⁇ -C 5 alkyl
- cO is an integer equal to 0 or 1
- s is an integer equal to 1 or 2, preferably 2;
- B is a bivalent linker of formula (III) -T B -X 2 -TBI-
- T B and T ⁇ t are equal or different and are CO or X wherein X is as defined above;
- X2 is a bivalent bridging group and is selected from the following compounds: a)
- nl and n2 are integers 0 or 1; R 2 and R 3 are independently selected from H or CH ; b)
- n4 is an integer from 1 to 20 and n5 is an integer from 0 to 20, R 4 and R 4 R 5 and R 5 are independently selected from H, CH 3 , OH, NH 2 , NHCOCH 3 , COOH; when the bond bbeetlween the C A and C B carbons is a double bond R 4 and R 5 or R4' and R 5 are absent d)
- nIX is an integer from 0 to 10, preferably from 1 to 5
- nlLX is an integer from 1 to 10, preferably from 1 to 5;
- R TIX , R TIX ', R TIIX , R TIIX ', are the same or different, and are H or straight or branched
- RTIX, RTIX-, RTIIX, RTIIX- are H
- Y 3 is a saturated, unsaturated or aromatic heterocyclic ring having 5 or 6 atoms, containing one or more heteroatoms selected from nitrogen, oxygen, sulphur, and selected from:
- Y15 preferably Y are: (Yl), having the two free valences in ortho position to the nitrogen atom, (Y4), (Y10);
- C is the bivalent radical -T c -Y- wherein:
- T c is CO or X, wherein X is as above defined;
- Y is a bivalent radical having the following meaning: e) an alkylenoxy group -R' O- wherein R' is linear or when possible branched C i -C 20 , alkylene preferably having from 2 to 6 carbon atoms, or a cycloalkylene having from 5 to 7 carbon atoms, in the cycloalkylenic ring one or more carbon atoms can be substituted b y h eteroatoms, the ring c an have s ide chains o fR' type wherein R 'is as above defined; f)
- m is an integer from 1 to 6, preferably from 1 to 4, Rj f is H or CH 3 ; g)
- n3 is an integer from 0 to 3 and n3' is an integer from 1 to 3; with the proviso that: when Ti is CO then T B is X wherein X is as defined above; when Ti is X wherein X is as defined above, then T B is CO; when cO is 1, T c is CO when T BI is X wherein X is as above defined; when cO is 1, T c is X wherein X is as above defined, when T B ⁇ is CO; when cO is 0, T BI has the only meaning of O; the radical R, deriving from the non steroidal anti-inflammatory drugs o f formula R-
- TiOH when Ti is CO, or R-TiH, when T t is X, is selected from:
- Ri is H or -OCOR wherein R 3 is methyl, ethyl or linear or branched C 3 -C alkyl, R 2 is H, hydroxy, halogen atom, nitro, amino, mono- or di-(d-C 4 ) alkylamino, linear or when possible branched C ⁇ -C alkyl, linear or branched when possible C ⁇ -C 4 alkoxy, a linear or when possible branched C ⁇ -C 4 perfluoroalkyl, for example trifluoromethyl; with the proviso that in formula (la) Riand R 2 cannot contemporaneously be H, preferably when Ri is H, R 2 is OH;
- R6 is H, CH 3 , an halogen atom preferably Cl,; R4 is H, CF , CH or an halogen atom preferably Cl,; R5 is H, an halogen atom preferably Cl; when M is CH, R6 and R5 are H, R4 is CF 3 , (Ic) is the residue of flufenamic acid; when M is CH, R6 and R5 are Cl, R4 is CH 3 , (Ic) is the residue of meclofenamic acid; when M is CH, R6 and R4 are CH , R5 is H, (Ic) is the residue of mefenamic acid; when M is CH, R6 is CH 3 , R5 is H, R4 is Cl, (Ic) is the residue of tolfenamic acid; when M is N, R6 and R5 are H, R4 is CF , (Ic) is the residue of niflumic acid; when M is N, R6 is CH , R5 is H, R4
- R F1 and R F2 are independently selected from H or Cl, Br, F, R G is hydrogen or , C ⁇ -C 6 linear or branched alkyl, preferably R G is methyl; when R F1 and R F2 are Cl and R G is hydrogen the compound of formula (Ila) represents the residue of dichlophenac;
- NSAIDs of formulas R-TiOH and R-TiH are commercially available compounds or can be prepared according to the known methods described in the prior art, for example, in "The Merck Index” 12a Ed. (1996), herein incorporated by reference.
- Example of anti-inflammatory compounds for use in the present inventions are: Aspirin, Salicylic acid, Mesalamine, Acetylsalicylsalicylic acid, 5-amino- acetylsalicylic acid, Flunixin, Ketorolac, Tolfenamic acid, Niflumic acid, Mefenamic acid, Meclofenamic acid, Flufenamic acid, Enfenamic acid, Etodolac, Pirazolac, Tolmetin, Bromefenac, Fenbufen, Mofezolac, Diclofenac, Pemedolac, Sulindac, Indomethacin, Suprofen, Ketoprofen, Tiaprofenic acid, Fenoprofen, Indoprofen, Carprofen, Naproxen, Loxoprofen, Ibuprofen, Pranoprofen, Bermoprofen, CS-670, Zaltoprofen, Flurbiprofen, Ten
- Example of precursor compounds of the bivalent radical B of formula (III), wherein the free valences of T B and T BI can be saturated with OH or H, for use in the present invention are: penicillamine, N-acetylpenicillamine, cysteine, N-acetylcysteine, aspartic acid, gallic acid, ferulic acid, gentisic acid, citric acid, caffeic acid, dihydrocaffeic, p- coumaric acid, vanillic acid, dihydroxymaleic acid, glycolic acid, lactic acid, fumaric acid, 3-3'-thiodipropionic acid, p-coumaric alcohol, 4-hydroxyphenethylalcohol, conyferyl alcohol
- Compounds of the present invention which have one or more asymmetric atoms can exist as the optically pure enantiomers, pure diastereoisomers, mixture of enantiomers, mixture of diastereoisomers, racemic mixtures of enantiomers, diasteroeisomeric racemates o r m ixtures o f d iastereoisomeric r acemates. It i s t o b e u nderstood t hat t he present invention anticipates and includes within its scope all such isomers or mixtures thereof.
- the compounds according to the present invention when at least a functional group salifiable with acids is present, for example an amino group, can be transformed into the corresponding salts.
- a method to form salts is the following: when in the molecule one basic nitrogen atom is present, it is reacted in organic solvent as, for instance, acetonitrile, tetrahydrofuran, with an equimolecular amount of the corresponding organic or inorganic acid.
- organic acids are: oxalic, tartaric, maleic, succinic, citric, trifluoroacetic acids.
- inorganic acids are: nitric, hydrochloric, sulphuric, phosphoric acids.
- the compounds object of the present invention are formulated in the corresponding pharmaceutical compositions, even at delayed release, for parental, oral and topic use, as for example inhalatory, suppository, transdermal, enema use, according to the well known methods in the art, together with the usual excipients; see for example the volume “Remington's Pharmaceutical Sciences", 15a Ed.
- the amount on molar basis of the active principle in these formulations is generally the same, or lower, in comparison with that of the corresponding precursor drug.
- the daily administrable doses are those of the precursor drugs, or in the case lower.
- the daily doses can be found in the publications of the field, such as for example in "Physician's Desk Reference".
- the compounds of the invention can inhibit substantially selectively COX-2 without showing a marked inhibitory effect on COX-1. These results are even more surprising if it is considered the fact that the precursors are not selective COX-2 inhibitors. Moreover, even the same compounds of the invention but without the presence of the bivalent linker -B-of formula (III) have resulted non- selective towards the COX-2. See the comparative examples. Furthermore, the compounds of the present invention do not present any side- effect at gastric, cardiovascular and renal levels, and at the same time they also show a good analgesic activity.
- the compounds of the present invention can be used for the treatment of diseases having an inflammatory origin, osteoarthritis, rheumatoid arthritis, dysmenorrhea, pain, fever, and for the treatment and / or the prevention of troubles caused by high levels of COX-2.
- N'-(3-chloropropyl)-N-Boc-piperazine (1.7 g).
- N'-(3-chloropropyl)-N-Boc-piperazine was dissolved in HCl/ethyl acetate(10 ml), the solution was cooled at 0 °C in an ice bath and stirred for 1 hour at 0 °C then it is left to return to room temperature. The solvent was eliminated and the residue was treated with diethyl ether and the obtained solid product was filtered and used without any further purification..
- the plates were treated with calcium ionophore A23187 (50 ⁇ M) and after 30 minutes with dichlophenac to inhibit the enzyme COX-1 (1 mM). 15 minutes after, the cells were centrifuged and the plasma removed.
- the COX-2 activity of the tested compounds was determined as concentration of PGE2 present in the samples, determined by a radioimmunologic method (Amersham, Oakville, Ontario Canada). Results are reported in Table I and are expressed as the dose inhibiting 50% of COX activity (IC 50 ).
- the compounds used are the following:
- Rats weighing 20 g were treated i.p. with acetic acid (2% w/v in saline solution pH 2.7, 10 ml /kg) and after 15 minutes the animals were treated p.o. with the tested compounds at doses as indicated in Table 2 or with the carrier (carboxymethylcellulose 0.5 % w/ v; 10 ml/ kg) and immediately set in single cages where the number of abdominal contractions were calculated for 30 minutes.
- the results reported in Table are expressed as inhibition percentage of the abdominal contractions induced by acetic acid in comparison with non-treated controls.
- Celecoxib and precursor drugs cause an elevation of pressure, while the drugs of the present invention do not influence the cardiovascular parameters.
- Table 1
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Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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AU2003238042A AU2003238042A1 (en) | 2002-06-25 | 2003-06-24 | Cyclooxygenase-2 inhibitors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT2002MI001399A ITMI20021399A1 (en) | 2002-06-25 | 2002-06-25 | CYCLOOXYGENASE INHIBITORS 2 |
ITMI2002A001399 | 2002-06-25 |
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Publication Number | Publication Date |
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WO2004000300A1 true WO2004000300A1 (en) | 2003-12-31 |
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PCT/EP2003/006651 WO2004000300A1 (en) | 2002-06-25 | 2003-06-24 | Cyclooxygenase-2 inhibitors |
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AU (1) | AU2003238042A1 (en) |
IT (1) | ITMI20021399A1 (en) |
WO (1) | WO2004000300A1 (en) |
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EP1539729A2 (en) * | 2002-07-03 | 2005-06-15 | Nitromed, Inc. | Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use |
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CN102964250A (en) * | 2012-11-19 | 2013-03-13 | 吉林大学 | Flurbiprofen eugenol ester medical compound and preparation and preparation method thereof |
US20140275033A1 (en) * | 2013-03-13 | 2014-09-18 | Boston Biomedical, Inc. | Inhibitors of kinases and cancer stem cells, and methods of preparation and use thereof |
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US9227962B2 (en) | 2013-03-13 | 2016-01-05 | Boston Biomedical, Inc. | Heterocyclic substituted-3-heteroarylidenyl-2-indolinone derivative |
Also Published As
Publication number | Publication date |
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AU2003238042A1 (en) | 2004-01-06 |
ITMI20021399A0 (en) | 2002-06-25 |
ITMI20021399A1 (en) | 2003-12-29 |
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