PINNA GERARD AIME (IT)
CIGNARELLA GIORGIO (IT)
PINNA GERARD AIME (IT)
| US5672601A | 1997-09-30 |
BARLOCCO, D. ET AL.: "Synthesis and mu-opioid receptor affinity pf a new series of nitro substituted 3,8-diazabicyclo(3.2.1)octane derivatives", IL FARMACO, vol. 53, 1998, pages 557 - 562, XP001000529
BALLABIO M ET AL: "2,2,6- and 2,3,5-Trimethylpiperazines as Monocyclic Analogues of the mu-Opioid Agonist 3,8-Diazabicyclo[3.2.1]octanes: Synthesis, Modeling, and Activity", TETRAHEDRON, vol. 53, no. 4, 27 January 1997 (1997-01-27), pages 1481 - 1490, XP004105235, ISSN: 0040-4020
BARLOCCO, D. ET AL.: "Computer-aided structure-affinity relationship ...", J. COMPUTER-AIDEDMOLECULAR DESIGN, vol. 7, 1993, pages 557 - 571, XP001000932
CIGNARELLA, G. ET AL.: "Trasposizione intramoleculare acilica nella serie del 3,9-diazabiciclo(3.3.1)nonano", GAZZ. CHIM. ITAL., vol. 93, 1963, pages 320 - 325, XP001000561
| 1. | Compounds of formula 1 : wherein R and Ri, which are different from each other, are a straight or branched C2C8 acyl group ; a group of formula wherein : B is a C6Clo aryl group, optionally substituted at the ortho, metaor para positions with one or more substituents, which are the same or different, selected from the group consisting of ClC3 alkoxy, CC2 halo alkyl, C1C3 alkyl, halogens, carboxy, cyano, nitro, CONHR3 ; a C5C7 cycloalkyl group, a 5 or 6 membered heterocyclic aromatic group, optionally benzofused, having at least one heteroatom selected from nitrogen, oxygen, sulfur ; said heterocyclic group optionally having one or more substituents as described above for the aryl group ; R2 is hydrogen, CiC4 alkyl, CsCy cycloalkyl or a phenyl group optionally substituted as indicated above ; and the pharmaceutically acceptable salts thereof. |
| 2. | Compounds as claimed in claim 1 wherein R or Ri are an acyl group as defined in claim 1 or a group of formula and B is an optionally substituted phenyl group as defined in claim 1, or a naphthyl group or a benzofused heterocyclic group. |
| 3. | Compounds as claimed in claim 1 wherein R, is an acyl group as defined in claim 1 and R is the group of formula. |
| 4. | Compounds as claimed in claims 13 as central analgesic agents. |
| 5. | The use of the compounds of claims 13 for the preparation of analgesic medicaments. |
In particular, the invention relates to compounds of general formula (I) wherein R and RI, which are different from each other, are a straight or branched C2-C8 acyl group ; a group of formula wherein : B is a C6-Clo aryl group, optionally substituted at the ortho-, meta-or para-positions with one or more substituents, which are the same or different, selected from the group consisting of Cl-C3 alkoxy, Cl-C2 halo alkyl, C-C3 alkyl, halogens, carboxy, cyano, nitro, CONHR3 ; a C5-C7 cycloalkyl group, a 5 or 6 membered heterocyclic aromatic group, optionally benzofused, having at least one heteroatom selected from nitrogen, oxygen, sulfur ; said heterocyclic group optionally having one or more substituents as described above for the aryl group ; R2 is hydrogen, Cl-C4 alkyl, CS-C7 cycloalkyl or a phenyl group
optionally substituted as indicated above, and the pharmaceutically acceptable salts thereof.
Examples of Cl-C8 acyl groups are acetyl, propionyl, isopropionyl, butyryl, isobutiryl, valeryl, isovaleryl, pivaloyl, caproyl.
Examples of heterocyclic groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyridine, pyrimidine, pyridazine, pyrazine, benzothienyl.
Examples of pharmaceutically acceptable salts are those with halohydric acids, such as hydrochloric acid, hydrobromic acid ; mineral acids, such as sulfuric and phosphoric acids ; organic acids, such as acetic, propionic, succinic, glutaric, benzoic, salicylic acids. Any carboxylic groups can be in the salified form with alkali or alkaline-earth metal bases, such as sodium, potassium, calcium, magnesium ; bases of non toxic metals ; non toxic organic amines.
Preferred are compounds of formula (I) wherein R or Rl are an acyl group as defined above or a group of formula and B is a phenyl group, optionally substituted, as defined above, a naphthyl or a heterocyclic group.
Also preferred are compounds of formula (I) wherein Ri is an acyl group as defined above and R is the group of formula 3, 8-Diazabicyclo [3. 2. 1.] octane derivatives with analgesic activity are disclosed in EP 0 746 560.
It has now been found that the compounds of formula (I) have central analgesic activity comparable to that of morphine and higher than that of 3, 8-diazabicyclo [3. 2. 1.] octane, are"substantially free"from withdrawal
symptoms and less liable than morphine to induce tolerance or physical dependence after chronic treatment.
"Substantially free"herein means an activity 3 to 20 times lower than that of morphine in the mouse jumping test, after chronic administration three times a day for 7 consecutive days of analgesically equipotent dosages.
The present invention also relates to the compounds of general formula (I) as agents with central analgesic activity.
A further object of the present invention are the processes for the preparation of said compounds.
Still a further object of the present invention is the use of the compounds of formula (I) for the preparation of a medicament useful to induce analgesia on central nervous system in a mammal, particularly in humans, requiring such treatment.
Still a further object of the invention are pharmaceutical compositions containing a therapeutically effective amount of at least one compound of formula (I) in mixture with conventional carriers and excipients.
The compounds of the invention can be prepared by reaction of intermediates of formula (IIa) or (IIb) ils alb wherein R'is a straight or branched C2-C8 acyl group with a compound of formula
wherein R2'and B'have the same meanings as R2 and B or are groups which can be transformed into R2 and B, and X is a leaving group, for example a halogen atom, mesyl, tosyl and the like.
The reactions described above are carried out according to conventional techniques known to those skilled in the art. Reagents are usually present in stoichiometric or slightly different ratios, depending on the reactivity of the specific reagent.
The acylation of the nitrogen at 3 or at 9 is usually carried out with acid chlorides in an inert reaction medium, such as an open or closed chain ether, a ketone, an optionally halogenated hydrocarbon, preferably in the presence of a proton acceptor, such as a tertiary amine. Alternatively, the acylating agent can be a carboxylic acid anhydride.
The intermediates of formulae (IIa) and (IIb) can be obtained by acylation, according to conventional methods, of a compound of formula (IVa) or (IVb) IVa IVb wherein Ra is an amino-protecting group, and subsequent removal of the protective group. Compound of formula (IVa) in which Ra is benzyl is known from Gazzetta Chimica Italiana, 1963, 226-227, and can be prepared according to the following scheme 1 Scheme 1 v VII cis VII trans Vill
IVa Meso-dimethyl-a, a-dibromopimelate (VI) obtained by bromination of pimelic acid (V), is condensed with benzylamine in benzene under reflux to give N-benzyl-2, 6-dicarbomethoxy-piperidine (VII) as cis and trans isomeric mixture, which is reacted with benzylamine in xylene under reflux for 18 hours and then, after evaporation of the solvent, for a further 4 hours a 160- 170°C The resulting compound (VIII) is recovered as hydrochloride from the
reaction product by dissolution in ethanol and precipitation with HCI, then is hydrogenolysed to give the compound (IX) which is reduced with metal hydrides such as LiAlH4, to yield compound (IVa).
Compounds (IVb) can be obtained from compounds (IVa) through thermal rearrangement, analogously to what published for the homologous diazabicyclooctanes (Tetrahedron, 1963, 9, 143-148).
Intermediates of formula (III) are known or can be prepared with known methods, for example by reducing suitable arylacryl acids or esters thereof with metal hydrides and subsequently transforming the resulting alcohol into halide, with conventional methods, according to Scheme 2 reported in the following, concerning compounds (III) in which B is optionally substituted phenyl and R2 is hydrogen. Other compounds of formula (III) can be obtained with similar methods.
In Scheme, R3 represents the substituents listed for the aryl group Ruz.
Scheme 2 Compounds (I) and the salts thereof with pharmaceutically acceptable acids can be advantageously used as active principles in medicaments having central analgesic activity, as well as poor liability to induce tolerance and withdrawal symptoms which are the most serious restrictions to the use of
morphine.
For the envisaged therapeutical uses, compounds (I) or the salts thereof will be formulated in a therapeutically effective amount in suitable pharmaceutical formulations according to conventional techniques and excipients, such as those described in"Remington's Pharmaceutical Sciences Handbook"XVII Ed. Mack Pub., N. Y., USA.
Examples of pharmaceutical compositions are tablets, capsules, granulates, powders soluble, drops, elixirs, syrups, injectable forms, suppositories.
The dosages and posology will be defined by the physician depending on the severity of the disease, the conditions of the patient and any possible interactions with other medicaments.
The following examples further illustrate the invention.
Preparation 1 3-Propionyl-3. 9-diazabicyclo [3. 3. llnonane.
9-Propionyl-3, 9-diazabicyclo [3. 3. 1.] nonane (IVa) (0. 83 g, 4. 56 mmol) obtained according to Gazzetta Chimica Italiana 1963, 226-227 was heated at 150°C for 2 hours. The crude product was chromatographed (silica gel) eluting with CHC13-CH30H/8 : 2.
The title product was recovered from the fraction with Rf 0. 29 as oil, b. p. 125-130°C/0. 4 mmHg. IR (film, cm-1) v : 1630 (C=O), 2920 (NH) ; 'H-NMR (CDC13) 8H : 1. 16 (t, 3H), 1. 50-1. 70 (iris, 2H), 1. 80-2. 20 (m, 4H), 2. 35 (q, 2H), 3. 15 (dd, 1H), 3. 33 (br s, 2H), 3. 65 (dd, 1H), 3. 88 (d, 1H), 4. 79 (br s, 1H exch. with D20).'3C-NMR (CDC13) 8c : 9. 05 (CH3), 18. 24, 26. 64, 29. 48, 29. 49, 45. 08 and 49. 22 (CH2x6), 46. 53 and 46. 61 (CHx2), 172. 58 (C=O) from DEFT (135°C) and HETCOR.
Ex. R Yield m. p. Formula IRC'H-NMR<BR> % °C (Analysisb) v cm~l 6 ppm<BR> 8. H 36 oil Cl9H26N20 1525, 1635 1. 19 (t, 3H) ; 1. 46-1. 66 (m, 2H) ; 1. 72-2. 20 (m, 4H) ; 2. 21-<BR> (C, H, N) 2. 40 (m, 2H) ; 2. 92 (br s, 2H) ; 3. 18 (dd, 1H) ; 3. 50-3. 80<BR> (m, 4H) ; 4. 40 (d, 1H) ; 6. 20-6. 30 (dt, 1H) ; 6. 60 (d, 1H) ;<BR> 7. 20-7. 40 (m, 5H).<BR> <P>9 4'-NO2 22 oil C,9H25N303 1360, 1515 1. 19 (t, 3H) ; 1. 47-1. 70 (m, 2H) ; 1. 72-2. 20 (m, 4H) ; 2. 21-2. 40<BR> (C, H, N) 1630 (m, 2H) ; 3. 01 (br s, 2H) ; 3. 50-3. 70 (m, 5H) ; 4. 37 (d, 1H) ;<BR> 6. 30-6. 40 (dt, 1H) ; 6. 60 (d, lI- ; 7. 50 (d, 1H) ; 8. 20 (d, 2H).<BR> <P>10 3'-Cl 27 oil CCHO 1630 1. 17 (t, 3H) ; 1. 40-1. 60 (m, 2H) ; 1. 70-2. 20 (m, 4H) ; 2. 30-<BR> (C, H, N) 2. 50 (m, 2H) ; 2. 98 (br s, 2H) ; 3. 10 (dd, 1H) ; 3. 40-3. 60 (m,<BR> 4H) ; 4. 40 (d, 1H) ; 6. 20-6. 40 (dt, 1H) ; 6. 45 (d, 1H) ; 7. 01-<BR> 7. 40 (m, 4H).<BR> <P>11 3', 4'-CI2 36 oil Cl9H24C12N20 1635 1. 17 (t, 3H) ; 1. 40-1. 60 (m, 2H) ; 1. 70-2. 10 (m, 4H) ; 2. 20-<BR> (C, H, N) 2. 40 (m, 2H) ; 2. 89 (br s, 2H) ; 3. 40-3. 60 (m, 5H) ; 4. 20 (d,<BR> 1H) ; 6. 20-6. 30 (dt, 1H) ; 6. 40 (d, 1H) ; 7. 10-7. 20 (m, 1H) ;<BR> 7. 30-7. 50 (m, 2H).<BR> <P>12 3'-NO2, 4'-CI 60 oil C19H24CIN303 1330, 1520 1. 19 (t, 3H) ; 1. 42-1. 62 (m, 2H) ; 1. 70-2. 20 (m, 4H) ; 2. 20-<BR> (C, H, N) 1630 2. 40 (m, 2H) ; 2. 92 (br s, 2H) ; 3. 15 (dd, 1H) ; 3. 40-3. 60 (m,<BR> 4H) ; 4. 40 (d, 1H) ; 6. 20-6. 40 (dt, 1H) ; 6. 52 (d, 1H) ; 7. 40-<BR> 7. 60 (m, 2H) ; 7. 80 (s, 1H).<BR> <P>13 2'-NO2, S'-cul 25 130 (dec) a C » H24C1N303'HCl 1340, 1520 1. 17 (t, 3H) ; 1. 42-1. 65 (m, 2H) ; 1. 70-2. 20 (m, 4H) ; 2. 37<BR> (C, H, N) 1635 (q, 2H) ; 2. 93 (br s, 2H) ; 3. 12 (dd, 1H) ; 3. 50-3. 75 (m, 4H) ;<BR> 4. 40 (d, 1H) ; 6. 15-6. 30 (dt, 1H) ; 7. 01 (d, 1H) ; 7. 30 (dd,<BR> 1H) ; 7. 56 (d, 1H) ; 7. 92 (d, 1H).<BR> <P>14 2'-Cl, 5'-N02 30 24fa Cl9H24CIN303HCl 1340, 1520 1. 17 (t, 3H) ; 1. 48-1. 68 (m, 2H) ; 1. 72-2. 18 (m, 4H) ; 2. 34<BR> (C, H, N) 1560, 1635 (dq, 2H) ; 2. 93 (br s, 2H) ; 3. 15 (dd, 1H) ; 3. 42-3. 78 (m,<BR> 4H) ; 4. 40 (d, 1H) ; 6. 30-6. 50 (dt, 1H) ; 7. 01 (d, 1H) ; 7. 65<BR> (d, 1H) ; 8. 05 (dd, 1H) ; 8. 42 (d, 1H).
Ex. R Yield m. p. Formula IR'H-NMR<BR> % °C (Analysisb) v cm~ 8 ppm<BR> H 72 oil Cl9H26N2O 1635 1. 16 (t, 3H) ; 1. 40-1. 60 (m, 1H) ; 1. 70-1. 95 (m, 4H) ;<BR> (C, H, N) 2. 20-2. 40 (m, 4H) ; 2. 70-3. 15 (m, 5H) ; 3. 88 (br s, 1H) ;<BR> 4. 70 (br, s, 1H) ; 6. 20-6. 40 (dt, 1H) ; 6. 50 (d, 1H) ; 7. 20-<BR> 7. 40 (m, 5H).<BR> <P>2 4'-NO2 34 oil Cl9H25N303 1350-1510 1. 17 (t, 3H) ; 1. 50-1. 70 (m, 1H) ; 1. 70-1. 92 (m, 4H) ;<BR> (C, H, N) 1620 2. 20-2. 40 (m, 4H) ; 2. 65-3. 20 (m, 5H) ; 3. 95 (br s, 1H) ; 4. 73<BR> (br, s, 1H) ; 6. 40-6. 60 (m, 2H) ; 7. 55 (d, 2H) ; 8. 20 (d, 2H).<BR> <P>3 3'-C1 64 oil Cl9H25CIN20 1640 1. 18 (t, 3H) ; 1. 40-1. 60 (m, 1H) ; 1. 70-1. 93 (m, 4H) ; 2. 20-<BR> (C, H, N) 2. 40 (m, 4H) ; 2. 80-3. 10 (m, 5H) ; 3. 88 (br s, 1H) ; 4. 68 (br,<BR> s, 1H) ; 6. 10-6. 30 (dt, 1H) ; 6. 50 (d, 1H) ; 7. 20-7. 30 (m, 4H).<BR> <P>4 3'4'-CI2 72 oil C, 9H24C12N2O 1635 l. ll (t ; 3H) ; 1. 42-1. 63 (m, lu) ; 1. 70-1. 90 (m, 4H) ; 2. 20-<BR> (C, H, N) 2. 40 (m, 4H) ; 2. 80-3. 10 (m, 5H) ; 4. 05 (br s, 1H) ; 4. 65 (br,<BR> s, 1H) ; 6. 10-6. 30 (dt, 1H) ; 6. 40 (d, 1H) ; 7. 10-7. 50 (m, 3H).<BR> <P>5 3'-NO2, 4'-Cl 76 oil Cl9H24CIN303 1335, 1524 1. 15 (t, 3H) ; 1. 50-1. 70 (m, lH) ; 1. 75-1. 95 (m, 4H) ; 2. 22-<BR> (C, H, N) 1630 2. 42 (m, 4H) ; 2. 85-3. 25 (m, 5H) ; 3. 89 (br s, 1H) ; 4. 73 (br,<BR> s, 1H) ; 6. 15-6. 24 (dt, 1H) ; 6. 40-6. 50 (m, 2H) ; 7. 40 (br s,<BR> 2H) ; 7. 80 (s, 1H).<BR> <P>6 2'-NO2, 5'-Cl 25 130-134a C,9H24CIN303HC 1340, 1520 1. 17 (t, 3H) ; 1. 50-1. 70 (m, 1H) ; 1. 70-1. 95 (m, 4H) ; 2. 23-<BR> (C, H, N) 1630 2. 45 (m, 4H) ; 2. 65-3. 20 (m, 5H) ; 3. 90 (br s, 1H) ; 4. 72 (br,<BR> s, 1H) ; 6. 17-6. 24 (dt, 1H) ; 7. 05 (d, 1H) ; 7. 30 (dd, 1H) ;<BR> 7. 56 (d, 1H) ; 7. 92 (d, 1H).<BR> <P>7 2'-CI, 5'-NO2 31 208-210a Cl9H24CIN303HC 1345, 1525 1. 17 (t, 3H) ; 1. 50-1. 70 (m, 1H) ; 1. 70-1. 95 (m, 4H) ; 2. 25-<BR> (C, H, N) 1640 2. 45 (m, 4H) ; 2. 80-3. 20 (m, 5H) ; 3. 95 (br s, 1H) ; 4. 72 (br,<BR> s, 1H) ; 6. 34-6. 48 (dt, 1H) ; 6. 95 (d, 1H) ; 7. 53 (d, 1H) ; 8. 03<BR> (dd, 1H) ; 8. 40 (d, 1H).
Ex. R Yield m. p. Formula IRC'H-NMR<BR> % °C (Analysisb) v cm-1 8 ppm<BR> 15 54 102-lOSa C25H3oN2HCl 1650 1. 17 (t, 3H) ; 1. 40-1. 60 (m, 2H) ; 1. 70-2. 10 (m, 4H) ; 2. 20-<BR> (C, H, N) 2. 40 (m, 2H) ; 2. 89 (br s, 2H) ; 3. 40-3. 60 (m, 4H) ; 4. 26 (d,<BR> 2H) ; 6. 18 (t, 1H) ; 7. 00-7. 50 (m, I OH).
Ex. Yield m. p.<BR> <P>% °C<BR> 16 59 55-57
General procedure A mixture of compounds (IVa) or (IVb) (2. 30 mmol), the desired cinnamyl halide (2. 30 mmol) and K2CO3 (2. 30 mmol) in acetone or butanone (13. 5 ml) was refluxed for 4-12 hours. Inorganic salts were filtered off, the filtrate was evaporated and the oily residue was purified by flash chromatography (eluent CH2Cl3 : acetone/9 : 1) to give the compounds reported in the following tables as oils or as hydrochlorides.
Examples 17-30 According to similar procedures, the following compounds were prepared : Ex. R m. p.
110° 141° 125-30° 130-5° oil 22 23 oil 153°
Ex. R m. p.
138° 143° 128-32° 134-38° oil 29 30
Example 31 Pharmacological activity Binding studies on the opioid receptors were carried out on mouse brain homogenates, in the presence of [3H]-DAMGO for p [3H]- DELTORPHINE (II) for 5. [3H]-U69, 593 was used on guinea pigs homogenates to evaluate the K binding. Morphine was used as the reference compound.
The results are reported in the following tables.
Table 1 Binding affinity to, 8 and K receptors Compound of Ex. Binding affinities (Ki nM) a K 1 292. 0 120001152 >50000 8 131. 5 1750144 2000180
aEach value is the mean SEM of independent tests, each of them carried out in triplicate (n=3).
Table 2 Inhibition constants towards g opioid receptors Compound of Ex. [H]-DAMGO (Ki nM) a 2 29. 0 3 70. 0 4 48. 33 8 13. 0 9 7. 66 10 8. 66 11 5. 83 12 18. 0 13 6. 0 14 6. 0 aValues of Ki were calculated based on Kd values of InM for [3H]- DAMGO. Values are the mean from two experiments.