Patent Publication Number: US-3875163-A

Title: Nitrogen containing acyclic isoprenoid compounds

Description:
United States Patent Zumin et al.  
 [ 1 Apr. 1, 1975 NITROGEN CONTAINING ACYCLIC (52] U.S. Cl. 260/268 BC, 260/268 C, 260/268 S,  
 ISOPRENOID COMPOUNDS 424/250 I T Z C I51] Int. Cl C07d 51/70 nvemors- 58 Field of Search 260/268 BC Marlo Riva, Monza; Giuseppe Iafolla, Milan, all of Italy [56] References Cited Assignee: Pierrel S.p.A., Milan, Italy UNITED STATES PATENTS Filed: Mar. 27, 1973 3,188,313 6/1965 Archer 260/268 BC Appl&#39; No; 345,256 Primary Examiner-Alton D. Rollins Assistant Eszmziner-Jose Tovar Attorney, Agent, or FirmBacon &amp; Thomas Related U.S. Application Data Continuation-impart of Ser. No. 271,067, July 12, [57] ABSTRACT 1972, abandoned. Novel compounds of the formula:  
  O-CH- CH. 4 3 C=CH- (CH2) ,)C(CH3)=CH% (CI-I?)2C {CH3-=CH--CH7N/ N-CHZ 0 Foreign Application Priority Data and their pharmaceutically acceptable acid addition salts. The compounds are useful for their Feb. 29, 1972 United Kingdom 9348/72 Feb. 21, 1973 United Kingdom 9348/72 analgesic-anti-inflammatory activity and anti-ulcer action. They also inhibit gastric secretion.  
 8 Claims, N0 Drawings 1 a 2 NITROGEN CONTAINING ACYCLIC ISOPRENOID The compounds of the present invention can be pre- 1 COMPOUNDS pared by employing various processes and methods al- 1 ready known in the art, some of which can be summa- This application is a continuation-in-part of US. aprized as follows: plication Ser. No. 271,067 filed July 12, 1972, now 5 l. A suitable acyclic isoprenoid halide is reacted with abandoned. a monosubstituted piperazine according to the follow- The present invention relates to novel nitrogen coning scheme, wherein the group /C=CH (CH2) 2C (CH3 =CH- (CH2) 2-C (CH3 =CH-CH2 CH3 taining acyclic isoprenoid compounds which display is n i n lly cated as A nd O-(IIH2 R=CH -C -o A-Hal H6 N: -R AL N-R remarkable pharmac dynamic i i y. 2. A suitable acyclic isoprenoid halide is reacted with The compounds of the Present invention Show a low piperazinecarboxaldehyde and, after alkaline hydrolytoxicity and a remarkable activity as inhibitors of the i the resulting l-acyclic isoprenoidpiperazi i gastric secretion; also the anti-ulcer action is very good. d i h a i bl R h ]id h i R h h mean- Moreover, y Show also a spasmoiytie action of the ing stated above, according to the following scheme:  
 papaverinic type, and an analgesic-anti-inflammatory 3. A suitable acyclic isoprenoid halide is reacted with activity. It must also be noted that these products exp-tosylpiperazine and the resulting sulphonamide is rehibit anti-secretive and anti-ulcer activity in absence of acted with Na in liquid ammonia to give a secondary anti-cholinergic properties, proving therefore very inamine which, by treatment with a R-halide (R has the teiestihg from the therapehtieai Viewpeihtmeaning stated above) gives the desired product, ac-  
 The compounds of the present invention are repredi to h f ll i h sented by the following formula:  
 wherein the presence of three double carbon-carbon The products of the present invention show, as menbonds make possible the existence of geometric isotioned above, a remarkable interesting pharmacologmers with the following possibilities: ical activity as will be apparent from the following dea. the sole configuration trans C -C trans C -C i ti wherei b. the sole configuration cis C -C trans C -C c. a mixture of the two above-mentioned geometric htttaperitohealiy isomers f t i id. mtraduodenally d. the sole configuration cis C -C cis C -C lhttaveheusiy e. the sole configuration trans C -C cis C -C 6O P- P 05 f. a mixture of the two last-mentioned geometric iso- -so Lethai O 50 mers of triene; E.D. Effective dose 50 g. a mixture of the four mentioned geometric isomers The acute toxicity on male mice of the ested prodof triene. ucts was found to be very low and such as to not hinder The compounds of the present invention (sole isomer Clinical expefimehtation- The pp f e 50 or mixture ofvarious isomers, as explained before) are ties are p e in the table Behaviour investigation available in the form of free bases or in the form of Proved no particular eymptomatoiogy at low dosages,  
 pharmaceutically acceptable non-toxic acid addition Whereas at y g g of at the dosages ich salts thereof, e.g. hydrochlorides, sulphates, acetat s, caused the death of animals, the tested products caused maleates, citrates, etc. slight convulsions.  
  With regard to the effects on the isolated organs (segments of Guinea pig ileum) no one of the tested products possesses -a remarkable antagonist action either to acetylcholine or histamine. In fact, an inhibiting action was evidenced only with concentrations at least 100 5 times higher than the ones necessary to obtain an approximate E.D. with the control substances (atropine sulphate 0,006 &#39;y/mL; diphenhydramine 0,007 &#39;y/ml.).  
  On the contrary, the products evidenced a spasmolytic action of the papaverinic type, inhibiting the spasm induced by BaCl In this case the concentrations which proved active, are in the same range as evidenced for the specific antagonist (papaverine 1-10 &#39;y/ml.).  
  When administered in cats narcotized with chloralose (80 mg./Kg.i.v.b.w.), even at high dosages (100 mg./Kg.i.d.b.w.), no one of the tested products caused remarkable variations on the blood pressure and breathing. The tested products showed a remarkable activity in inhibiting the gastric secretion on the 4 hrs. Shay test in the rat. The approximate E.D. by i.d. route are reported in the table. Moreover, the products displayed significant anti-ulcer properties in the various experimental conditions in rat at dosages between 50 and 200 mg./Kg.i.p. (reserpine ulcer, immobilization ulcer, phenylbutazone ulcer and Shay ulcerogenic test).  
  The products displayed also analgesic and antiinflammatory actions and the active doses proved to be from 50 to 200 mg./Kg.p.o. With regard to the anticholinergic activity, said products proved to be completely inactive up to doses of 200 mg./Kg.i.p. in the oxotremorine test in the mouse, as well as in the chromodacryorrhea test in the rat.  
  In the same tests, under the same experimental conditions, atropine sulphate proved to be highly active already at doses of 0.5-1 mg./Kg. i.p.b.w.  
  From the table, it results thatthe products showing the highest toxicity are 2,2&#39;-bipyridine and atropinesulphate, whereas the products according to the present invention (indicated as:  
 show a very low toxicity by oral route.  
  The most active product is atropine-sulphate, whereas 2,2-bypyridine and show a very close activity level. It is known, however that atropine-sulphate, at the active dose, shows marked undesired effects of anticholinergic type (mydriasis etc.).  
  The action of the products according to the present invention remains practically unchanged when administering the products as such, as well as when administering their pharmacologically acceptable non-toxic acid addition salts. The products of the invention may be administered by the same general mode as known for administering the known pharmaceutical compositions, in effective amounts for treatment of the particular condition for which the compounds are active, but with less danger of toxic or undesirable side effects than with the known compositions. They may be prepared in tablet or capsule form, in which a representative dosage unit may be mg., administered once or several times per day. However, smaller or larger dosage units may be prepared as desired, the only reservation being that a reasonable degree of safety before the toxic limit be observed.  
 Comp rative values of Acute Toxicity and Gastric Antisccrctory Activity (Shay test) of invention compounds -N N-R Atropine Sulphate, 2,2&#39;-llipyri\l.ilic.  
  ACUTE TOXICITY IN NICE INHIBITION OI&#34; GASTRIC Sl-IGIGII&#39;I&#39;ON IN RATS conr&#39;ouxns L0 (mg./Kg.)  
 &#39; 1. p.0- Volume Fx&#39;cc acid output E0 (mg./Kg, i.d.) E0 (mg./Kg.i.d.)  
 a) t s c243 trans 0 97 300 14 9 b) cis C -C3,trans 0 -07 I 600 26 15 c) mixture of a.) b) 400 2000 20 14 d) cis c -c ,cis 0 -0 500 26 15 e) trans c -c cis 0 -0 250 1o- 6 1) mixture of d) e) 350 2000 20 13 a) mixture of 400 2000 16 9 2) Atropine Sulphate 200 800 ,5 5 ,5  
 3) 2, 2 &#39;-Bipyridine 250 330 10 10 The following non-limitative Examples illustrate the products and processes of the present invention.  
 EXAMPLE I N -piperonyl-N -3,7,1 1-trimethy1-2,6,l0- dodecatrienylpiperazine (four isomers mixture) A solution of 45 mmoles of l-bromo-3,7,l l-trimethyl-2,6,l0-dodecatriene (obtained from synthetic farnesol, commercially available and containing four isomers) in ml. of benzene was added dropwise at 0C to a stirred solution of 45 mmoles of piperonylpiperazine in 60 ml. of benzene containing 5 g. of triethylam-.  
 ine. The mixture was stirred for 2 hours and then the precipitated triethylammonium bromide was filtered off. The benzene solution was washed first with water and then with K CO solution and finally dried (K CO Removal of benzene under reduced pressure I gave a crude oily residue which was dissolved in acetone and treated at 5-8C with a slight excess of 37 percent HCl solution. The precipitated hydrochloride was filtered, washed with acetone and with absolute ethanol. The corresponding base was purified on a silica gel column and the purity of all fractions was checked by thin layer chromatography and gas liquid chromatography. Thin layer chromatography on silica gel gave three spots in the solvent system ethylacetatepetrol ether 1:1 Gas liquid chromatography showed three peaks indicating the presence of four possible isomers. The pure product was a colourless oil: the NMR showed the following signals in 6: 1.55-1.80 (m, 12H, cH, c= 1.95-2.20(m,8H,Cl-1 CH N), 3.00 (cl, 2H, J=7cps, NCH -C=), 3.41 (s, 2H, CH arom), 4.90-5.50 (m, 3H, Cl-l=C), 5.91 (s, 2H, O-CH O), 6.75-6.90 (3H, arom).  
 EXAMPLE 1] N -formyl-N -3 ,7,1 l-trimethyl-2,6, l O-dodecatrienylpiperazine (four isomers mixture) 4.95-5.45 (m, 3H, CH=C), 8.00  
 EXAMPLE n1 3,7,1 l-trimethyl-2,6,10-dodecatrienylpiperazine (four isomers mixture) A solution of 47.09 mmoles of the N-formyl derivative (see Ex. 11) in 50 ml. ethanol was refluxed for 20 hours with 7.5 g. of NaOH in 50 ml. water and then the ethanol was evaporated in vacuo. An ethylether extract of the reaction mixture was washed with water, dried (Na SO and concentrated to an oil, a solution of which was purified on silica gel column. Structure was confirmed by analyses. The NMR showed the following signals in 8: l.55l.80 (m, 121-1, CH C=), l.95-2.20 (m, 8H, CH C=), 2.30-2.60 (m, 4H, CH N), 2.42 (s, 1H, NH), 2.80-3.10 (m, 6H, CH N), 4.95-5.50 (m, 3H, Cl-l=C).  
 EXAMPLE 1V N -piperonyl-N -3,7,1 l-trimethyl-2,6, l 0- dodecatrienylpiperazine (four isomers mixture) The title compound is prepared condensing 45 mmoles of piperonylchloride with 45 mmoles of 3,7,1 1- trimethyl,2,6,lO-dodecatrienylpiperazine following the procedure described in Example 1.  
 EXAMPLE V N-tosyl-N-3,7,l 1-trimethyl-2,6,IO-dodecatrienylpiperazine (four isomers mixture) To a cold solution (0C) of 21.6 mmoles of tosylpiperazine in 8 ml. of absolute ethanol containing 1.2 g. of anhydrous KOH, 23.8 mmles of 1-bromo-3,7,1 1- trimethyl-2,6,l0-dodecatriene were added dropwise under stirring. The mixture was stirred for 1 hour at room temperature and filtered to remove KBr. Concentration of the solution gave a crude oily residue which was treated with 5 percent KOH, extracted with methylene dichloride, washed with water and dried (K CO Evaporation to dryness in vacuo gave an oil which was chromatographed on silica gel using ethylacetate-petrol ether as eluants.  
 lr (neat) 1345 (w $0 and 1160 cm (1 S0 EXAMPLE VI 3,7,11-trimethyl-2,6,10-dodecatrienylpiperazine (four isomers mixture) A solution of 4.9 mmoles of the tosyl derivative in 10 ml. of toluene was slowly added to 100 ml. of liquid ammonia and the resulting suspension was treated with about 250 mg. (10.9 mg.-atoms) of sodium in small portions until a deep blue colour persisted for 15 min. Then 1.0 gfof ammonium chloride was added in one portion and the blue colour was immediately discharged. The mixture was stirred for additional 10 min. and then 100 ml. of toluene were added dropwise a1- lowing ammonia to evaporate over a 2 hours period.  
 EXAMPLE VII N -piperonyl-N-3,7,l l-trimethyl-2,6,ldodecatrienylpiperazine (cis C -C trans C C 10.5 ml. of anhydrous pyridine are added to a solution of 100 g. (0.45 moles) of commercially available pure transnerolidol in 300 ml. petroleum ether and then, under stirring and maintaining the temperature between -5 and C, a solution of 53 g. (0.2 moles) of PBr in 70 ml. petroleum ether are added thereto. When the addition is completed, stirring is maintained for 2 hours at 2 to 0C, then the solution is washed first with water-ice up to neutrality, and then with cold satuated NaI-ICO solution. After drying on Na-,,SO and then on anhydrous K CO the solvent is eliminated and the remaining oil is treated with 100 ml. benzene. The so obtained solution (l-bromo-3,7,l l-trimethyl- 2,6,l0-dodecatriene) is added under stirring at 0C to a solution of 99 g. (0.45 moles) of N-piperonylpiperazine dissolved in 600 ml. of benzene containing 50 g. of triethylamine. When the addition is completed, stirring is maintained for 2 hours then the precipitated triethylammonium bromide is filtered off and the solution is washed first with water and then with K CO solution and finally dried. Afterwards, the solvent is evaporated under vacuum and the oily residue is dissolved in acetone and treated with a slight excess of 37 percent aqueous I-ICl, maintaining the temperature below +l0C. The precipitated hydrochloride is filtered, washed with acetone and with absolute ethanol. The corresponding base is the expected mixture of the two isomers cis C -C trans C and trans C -C trans C C Chromatography of g. of the product on 3 Kg. Silica gel 160 X 9.5 cm. column), using 25 percent benzene in ethylacetate as eluant, resulted in complete separation of the two isomers. The first eluted product is the pure cis C C trans C -C isomer. Thin layer chromatography on silica gel gave one spot in the system benzene-ethylacetate 25:75. Gas liquid chromatography showed only one peak on OV l7 5 percent on Chromosorb G AW-DMCS 80-100 mesh, 6 m. length, 1.6 mm. inlet diameter.  
 EXAMPLE VIII N-piperonyl-N -3,7,l l-trimethyl-2,6,l0- dodecatrienylpiperazine (trans C -C trans C.,C  
  After separation of the pure isomer cis C -C trans C -C of Example VII, some fractions are obtained which contain the isomer mixture. At the end, the pure isomer trans C -C trans C -C is eluted. Thin layer chromatography on silica gel gave one spot in the system benzene-ethylacetate 25:75. Gas liquid&#39;chromatography showed only one peak.  
 EXAMPLE IX -N-piperonyl-N-3,7,l1-trimethyl-2,6,l0- dodecatrienylpiperazine (cis C -C cis C C The procedure of Example VII is carried out with 0.45 moles of cis-nerolidol (from commercially available mixture of cis and trans-nerolidols; the separation was achieved on 5 percent silver nitrate impregnated silica gel column with benzene-ethylacetate 70:30 as eluant). The obtained base is the expected mixture of the two isomers cis C -C cis C -C and trans C -C cis C,,C,. After chromatography as in Example VII, the first eluted product is the pure cis C -C cis C C isomer, as showed by thin layer chromatography and gas liquid chromatography.  
 EXAMPLE X N-piperonyl-N -3,7,l l-trimethyl-2,6,10- dodecatrienylpiperazine (trans C -C cis C -C After separation of the pure isomer cis C -C cis C -C of Example IX, some fractions are obtained which contain the isomer mixture. At the end, the pure isomer trans C -C cis C -C is eluted. Thin layer chromatography on silica gel gave one spot in the system benzene-ethylacetate 25:75. Gas liquid chromatography showed only one peak.  
 EXAMPLE XI Preparation of 1000 tablets, each containing 50 mg. of  
 the active substance dodecatrienylpiperazine g. 50 Colloidal silicic acid g. I50 Starch g. 150 Lactose g. 40 Talc g. 8 Magnesium Stearate g. 2  
 PROCEDURE EXAMPLE XII Preparation of enteric-coated tablets The ingredients and the procedures described in Example XI are used. At the end, the tablets are covered with a cellulose acetophtalate-film.  
 EXAMPLE XIII Preparation of 1000 tablets of soft-gelatine capsules, each containing 50 mg. of active substance N&#34;piperonyl-N-3,7,l l-trimethyl-2,6, l 0- -dodecatrien ylpiperazine g. 50 Vegetable oil g.  
 PROCEDURE The active substance and the vegetable oil are homogeneously mixed proceeding thereafter to the preparation of Scherer type capsules. Each capsule contains 50 mg. of active substance.  
 EXAMPLE XIV Castro-resistant soft-gelatine capsules The same ingredients and procedures of Example XIII are used. The capsules, at the end, undergo a treatment with formalin in order to obtain gastro-resistance.  
  What we claim is: 1. A compound selected from the group consisting of N-piperonyl-N -3,7,l l-trimethyl-2,6,l-  
 dodecatrienylpiperazine and therapeutically acceptable nontoxic acid addition salts thereof.  
  2. The isomer trans C -C trans C -C of the compound of claim 1.  
  3. The isomer cis C -C trans C -C of the compound of claim 1.  
  4. The isomer cis C -C cis C -C of the compound of claim 1.  
 C C cis C -C of the compound of claim l.