IL154395A - Security element for hinge-side of door - Google Patents

Description

153176/2 0J11 Ώ^ ηη ηι ρι > w.>m wvirt o»j N*iA>a JD New phenylpiperazines and pharmaceutical compositions comprising them Solvay Pharmaceuticals B.V.

C.142180 New phenylpiperazines The invention relates to novel phenylpiperaztne derivatives of the formula (1 ): wherein: - R is a group of the formula (a) or (b) and salts thereof.

It has been found that the compounds according to the invention show high affinity for both the dopamine D2 receptor and the serotonin reuptake site. This combination is useful for the treatment of psychotic disorders like schizophrenia (treating both positive and negative symptoms), and other psychiatric disorders.

The compounds show activity as (partial) agonists which makes them suited as well for the treatment of Parkinson's disease.

The compounds show antagonist activity at dopamine D2 receptors as they antagonize apomorphine-induced climbing behaviour in mice. The compounds also show activity as inhibitors of serotonin reuptake as they potentiate 5-HTP induced behaviour in mice.

The compounds are active in therapeutic models sensitive to clinically relevant antipsychotics (e.g. the conditioned avoidance response; Van der Heyden & Bradford, Behav. Brain Res., 1988, 31 :61-67) and antidepressants or anxiolytics (e.g. suppression of stress-induced vocalization; van der Poel et a!., Psychopharmacology, 1989, 97: 147-148).

The compounds are active in clinically relevant models for Parkinson's disease (e.g. turning rat behaviour, U. Ungerstedt, Acta Physiol. Scand., 1971 , 82 (suppl. 367): 69-93).

In contrast to clinically relevant dopamine D2 receptor antagonists the described compounds have a low propensity to induce catalepsy in rodents and as such are likely to induce less extrapyrimidal side effects than existing antipsychotic agents.

The inhibitory activity of serotonin reuptake inherent in these compounds may be responsible for the therapeutic effects observed in behavioural models sensitive to either antidepressants or anxiolytics.

The compounds can be used for the treatment of affections or diseases of the central nervous system caused by disturbances in either the dopaminergic or serotonergic systems, for example: aggression, anxiety disorders, autism, vertigo, depression, disturbances of cognition or memory, Parkinson's disease and in schizophrenia and other psychotic disorders.

Pharmacologically acceptable acids with, which the compounds of the invention can form suitable acid addition salts are for example hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, and organic acids such as citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, benzoic acid, p-toluene · sulphonic acid, methanesulphonic acid and naphthalene sulphonic acid.

The compounds and their acid addition salts can be brought into forms suitable for administration by means of suitable processes using auxiliary substances such as liquid and solid carrier materials.

The compounds having formula (1 ) can be prepared by reaction. of a compound of the formula under basic conditions with a compound of the formula L - (a) or L - (b) in which formulae (a) and (b) have the meanings given above, and L is a so-called leaving group such as a halogen atom or a mesylate group.

The piperazine compound having formula (2) can be obtained as described in EP 0189612.

The starting materials of the formula L - (a) can be obtained according to the following scheme: t 6 1 p5 1 p4 Scheme A Compound 1 p2 can be obtained from 1 p1 in the same manner as compound 2p4, i.e. compound L - (b) wherein L is the mesylate group, from compound 2p3 (see Scheme B below).

Scheme B The invention is illustrated by means of the following Examples.

Example 1 18.1 g (0.1 mol) of 2p1 was dissolved in 250 ml of CH2C12 and brought to 0 °C. A solution, made from 50 ml of concentrated sulfuric acid poured on 200 g of ice, was added to the CH2CIZ solution. The resulting mixture was maintained at 0 °C by applying an ice/acetone cooling bath. To the latter solution, 8.3 g (0.12 mol) of NaN02 dissolved in 50 ml of water, was added dropwise, while the temperature was kept below 2 °C. Stirring was continued for 1 hour. Subsequently, the organic layer was separated, the water layer extracted (CH2Cl2) once, the combined organic fractions were dried on MgS0 . Removal of the drying agent by filtration and concentration in vacuo of the fillrate yielded 17.8 g (99%) of crude dark yellow 2p2. Under a nitrogen atmosphere, a solution of 17.8 g (0.099 moi) of 2p2 in 100 ml of dry THF was added dropwise very carefully to a suspension of LiAIH4 (9.75 g, 244 mmol) in refluxlng dry THF. After the addition was complete, the resulting mixture was allowed to react for another 40 minutes. The reaction mixture was brought to room temperature and further cooled by an ice/ethanol cooling bath. Subsequently were added: 9.75 ml of water/THF (1/1 ), 18.5 m! of 2N NaOH(aq) and 18.5 ml of water. The resulting mixture was brought to reflux for 20 minutes. After cooling down, the reaction mixture was filtered (Hyflo), the resulting filtrate was concentrated in vacuo, yielding 15.9 g of residue. The latter was dissolved in 98 ml of 1N HCI in EtOAc, the resulting precipitate was filtered yielding 17.5 g (87%) of 2p3.HCI. 17.5 g {86 mmol) of 2p3.HCI were dissolved in a mixture 190 ml of ethyleneglycol and 90 ml of water, the resulting solution was heated to 95 °C. Subsequently 7.96 g (94.6 mmol) of (3,4)-dihydro-2H-pyran carefully was added dropwise. After the addition was complete, stirring was continued for 3 hours at 95 °C. After the reaction mixture reached room temperature, water and some brine were added and extraction was performed with EtOAc (3x). The combined organic fractions were washed with water, NaHS03(aq), water, NaHC03(aq), NaCI(aq) respectively after which the organic fraction was dried on NazS04. Removal of the drying agent and solvent yielded a residue which was purified by column chromatogaphy (Si02, eluent MeOH/CH2CI2 3/97), resulting in 12 g (63%) of a dark red oil containing the corresponding alcohol of 2p4 which solidified on standing. Subsequently the alcohol was converted into its mesylate by standard procedures (MsCI, diisopropylethylamine in CH2CI2, 0 °C) yielding 2p4 (98% yield).

The phenylpiperazine having formula (2) was reacted with 2p4 according to the procedure mentioned in EP 0900792. yielding compound (1 ) wherein R is the group of formula (b); (m.p.: 182-5 °C).

Example 2 1 p1 was converted into 1p2 analogously to the preparation of 2p4 (in Example 1 ). 1p2 was converted into 1 p3 (98%) according to the procedure described in RajanBabu et.al., J.Org.Chem. 51 , (1986), 1704.

Under a nitrogen atmosphere, 31.9 g (103 mmol) of 1p3 were dissolved in 49 ml of DMF. The resulting solution was added slowly to a solution containing 5.88 g (134 mmol, 1.3 eq) of an oily suspension containing 55% of NaH in 148 ml of DMF, after which stirring was continued for one hour at room temperature, after which the reaction mixture was cooled (ice/water), To the latter solution, 8.34 ml (19.02 g, 134 mmol, 1.3 eq) of Mel diluted in 49 ml of DMF, were added dropwise. The reaction mixture was stirred for an additional 16 hours at room temperature. To the latter, water was added and extraction performed; Et20 (2x), the organic fraction was washed with water (2x) and brine (1 ), and eventually dried on MgS04. After removal of the drying agent and solvent in vacuo, the residu was subjected to column chromatography (Si02, eluent: CH2CI2/hexane 3/1 ) yielding 26.2 g (79%) of 1p4 as a yellowish oil.

Under a nitrogen atmosphere, 25.03 g (78 mmol) of 1 p4 were dissolved in 1 10 ml of THF after which 93 ml (0.93 mmol, 1.2 eq.) of 1 N (nBut)4N+F" in THF were added. After one hour of stirring, Et20 was added, and the resulting mixture washed with water (3x) and brine (1 x). The organic layer was dried on Na2S04. After removal of the drying agent and the solvent, the residue was taken up in toluene and subsequently concentrated in vacuo to remove traces of (tert. )butyltrirnethylsilylfluoride. The residu was subjected to flashchromatography (Si02, eiuent Et20). eventually yielding 14.8 g (92%) of 1 p5. 1.69 g (6.45 mmol) of PPh3 and 0.44 g (6.44 mmol) of imidazole were dissolved in 20 ml of CH2CI2, after which 1.64 g (6.45 mmol) of iodine were added portionwise. The reaction mixture was stirred for another 30 minutes at room temperature. To the fatter mixture 1.07 g (5.16 mmol) of tp5 dissolved in 10 ml of CH2CI2 were added slowly. After 30 minutes the reaction mixture was washed with NaHC03(aq), NaHS03(aq) and brine, the remaining organic fraction dried on Na2S04. After removal of the drying agent and the solvent in vacuo, the residu was dissolved in Et20, the precipitate which formed (Ph3PO) was removed by filtration. The filtrate was concentrated in vacuo, the residue purified by flash chromatography (Si02), eiuent CH2CI2/hexane 1/1), yielding 1.45 g (88%) of the desired iodide 1 p6.

The phenylpiperazine having formula (2) was reacted with 1 p6 according to the procedure described in EP 0900792, yielding compound 1 wherein R is group (a) (m.p.: 202-4 °C). 1 53 176/2 7 Claims . Phenylpiperazine derivatives having formula (1) wherein is a group of the formula (a) or (b) and salts thereof.

Method for the preparation of a compound as claimed in claim 1 , characterized in that a compound having formula (2) (2) - 8 - 153176/2 is reacted under basic conditions with a compound of the formula L-(a) or L-(b) in which formulae L is a leaving group and (a) and (b) have the meaning given in claim 1. 3. A pharmaceutical composition containing at least one compound as claimed in claim 1 as the active component. 4. A compound as claimed in claim 1 , or a salt thereof, for use as a medicament.

. Use of a compound as claimed in claim 1 for the preparation of a pharmaceutical composition for the treatment of Parkinson Disease. 6. Use of a compound as claimed in claim 1 for the preparation of a pharmaceutical composition for the treatment of CNS-disorders such as schizophrenia, anxiety and depression.

For the Applicants, REINHOLD COHN AND PARTNERS

Claims (10)

SECURITY ELEMENT FOR HINGE-SIDE OF DOOR 1274RAV-IL 1 154395/2 SECURITY ELEMENT FOR HINGE-SIDE OF DOOR FIELD OF THE INVENTION The present invention relates generally to doors and particularly to a security element that helps prevent unauthorized forced entry at the hinge side of a door. BACKGROUN D OF THE INVENTION Many kinds of security doors are known that are designed to withstand the brute force of crowbars, clubs, pickaxes and the like of unauthorized persons attempting to gain forced entry through the door. It is also know that one of the weaker points of entry of the door is the side of the hinges, because the hinge side does not have the locki ng bolts and latches of the lock side of the door. Attempts have been made in the prior art to bolster the hinge side with locking elements but there is still much room for improvement. One example is described in publication number EP 1223279, which describes hook fingers attached to a door next to the hinges. The hook fingers fit into sockets on the doorpost. Another example is US Patent 4,704,767 to Carter et al ., which describes a door hinging system, wherein the door hinge comprises locking elements in the shape of circular posts on each hinge leaf. Lock engaging means in the form of apertures are located on the door and the doorframe to engage the locking elements of the hinge. The locking elements and the lock engaging means cooperate when the door is in the closed position to secure the door to the door frame in the event the conventional mounting screws become inoperable, as when excessive force is appl ied to the door hinge area. SUMMARY OF THE INVENTION The present invention seeks to provide a novel security element that helps prevent unauthorized forced entry at the hinge side of a door, as is described more in detail hereinbelow. There is thus provided in accordance with an embodiment of the present invention apparatus comprising a door comprising a sti ffener disposed between a lock side and a hinge side of the door and between front and rear panels of the door, a security element installed in the door, the security element comprising a first portion that protrudes outwards of a hinge-side surface of the door and a second portion that extends to the stiffener such that the stiffener limits deflection of the second portion. The stiffener may extend along a height of the door. 2 154395/2 The security element may be received in or pass through an aperture formed in the stiffener. Additionally or alternatively, the security element may be attached to the stiffener. The second portion of the security element may be chamfered. In accordance with an embodiment of the present invention the first portion of the security element comprises a hook receivable in a recess formed in a doorframe. Further in accordance with an embodiment of the present invention the first portion of the security element comprises a flange secured to the hinge side of the door. Still further in accordance with an embodiment of the present invention the security element is stiffer against bending about a height axis of the door than about a width axis of the door. BRIEF DESCRI PTION OF THE DRAWINGS The present invention will be understood and appreciated more fully from the following detailed description, taken in conjunction with the drawings in which: Fig. 1 is a simplified pictorial illustration of a security element installed in the hinge side of a door, constructed and operative in accordance with an embodiment of the present invention; and Figs. 2 and 3 are simplified top-view illustrations of the security element of Fig. J , respectively before and after the security element is received in an aperture formed in a doorframe, in accordance with an embodiment of the present invention. DETAILED DESCRI PTION OF A PREFERRED EMBODIM ENT Reference is now made to Figs. 1 -3, which illustrate a security element 10 constructed and operative in accordance with an embodiment of the present invention. Security element 10 may be installed in a door 12 that comprises front and rear panels 14 and 16, a lock side 18 (where a mortise lock or the like may be installed - not shown) and a hinge side 20. Hinges 22 of any kind may be mounted on hinge side 20 of door 1.2. A sti ffener 24 may be disposed between lock side 18 and hinge side 20 of door 12. Stiffener 24 may be a vertical stiffener (also called rail), which extends along a height of door 12. Door 12 and its components may be made of steel, but the invention is not limited to this material. A security element 26 may be installed in door 12. Security element 26 may comprise a first portion 28 that protrudes outwards of a hinge-side surface 29 of door 12, and a second portion 30 that extends to stiffener 24. Security element 26 may be received in or pass through an aperture 32 (Fig. 1 ) formed in stiffener 24. Alternatively or additionally, security element 26 may be attached to stiffener 24 by means such as, but not l imited 3 154395/2 to, welding, brazing, soldering, screws or rivets. The second portion 30 of security element 26 may be cham fered (as seen clearly in Figs. 2 and 3) to facilitate insertion through aperture 32. Referring particularly to Fig. 1, stiffener 24 may limit the deflection of second portion 30 in the front or rear direction (as indicated by arrows 34) and/or in the sideways direction (as indicated by arrows 36). Security element 26 may be stiffer against bending about a height axis 38 of door 1.2 (as indicated by arrows 39) than about a width axis 40 of door 12 (as indicated by arrows 4 1 ). This may be accompl ished by making security element 26 with a longer dimension in the front-rear direction than a thickness in the vertical direction. The first portion 28 of security element 26 may comprise a hook that may be received in a recess (or socket, the terms being used interchangeably) 42 formed in a doorframe (or doorpost, the terms being used interchangeably) 44. I n addition, the first portion 28 may comprise a flange 46 secured to the hinge side 20 of door 12, such as but not limited to, by means of rivets or screws. Any attempt to pry open door 12, such as by means of a crowbar (not shown), may be defeated by any combination of the shape of doorframe 44 which blocks direct access to the hinges 22, and by security element 26 being held in recess 42 and blocked by sti ffener 24. It will be appreciated by persons skilled in the art that the present invention is not limited by what has been particularly shown and described hereinabove. Rather the scope of the present invention includes both combinations and subcombinations of the features described hereinabove as well as modifications and variations thereof which would occur to a person of skill in the art upon reading the foregoing description and which are not in the prior art. CLAIMS What is claimed is:

1. A device comprising: a door comprising a stiffener disposed between a lock side and a hinge side of said door and between front and rear panels of said door; a security element installed in said door, said security element comprising a first portion that protrudes outwards of a hinge-side surface of said door and a second portion that extends to said stiffener such that said stiffener limits deflection of said second portion.

2. The device according to claim 1, wherein said security element is received in an aperture formed in said stiffener.

3. The device according to claim 1, wherein said security element passes through an aperture formed in said stiffener.

4. The device according to claim 1, wherein said security element is attached to said stiffener.

5. The device according to claim 1, wherein said second portion of said security element is chamfered.

6. The device according to claim 1, wherein said first portion of said security element comprises a hook receivable in a recess formed in a doorframe.

7. The device according to claim 1, wherein said first portion of said security element comprises a flange secured to said hinge side of said door.

8. The device according to claim 1, wherein said security element is stiffer against bending about a height axis of said door than about a width axis of said door.

9. The device according to claim 1, wherein said stiffener extends along a height of said door.

10. The device according to any one of claims 1-9 and substantially as shown and described hereinabove.