IL41662A - Cis and trans n1-piperonyl-n4-farnesyl-piperazine its preparation and pharmaceutical compositions containing it - Google Patents
Cis and trans n1-piperonyl-n4-farnesyl-piperazine its preparation and pharmaceutical compositions containing itInfo
- Publication number
- IL41662A IL41662A IL41662A IL4166273A IL41662A IL 41662 A IL41662 A IL 41662A IL 41662 A IL41662 A IL 41662A IL 4166273 A IL4166273 A IL 4166273A IL 41662 A IL41662 A IL 41662A
- Authority
- IL
- Israel
- Prior art keywords
- isomers
- trans
- mixture
- compound
- cis
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
Cia and trans N^-piperonyl-W -farnesyl-^ plperazine Nits preparation and pharmaceutical compositions containing it. ,1*TK"IS*S/- - »3nS¾- jj1 omen o»s miK m son mnpn manym maon1? τ^ηη ! The present invention relates to novel nitrogen containing acyclic isoprenoid compounds which display remarkable pharmacodynamic activity.
The compounds of the present invention show £. poor toxicity and a remarkable activity as inhibitors of the gastric secretion; also the anti-ulcer action is very good.
Moreover, they show also a spasmolytic action of the papaverinic type, and an analgesic-anti-inflammatory activity.
It must also be noted that these products exhibit anti-secretive and anti-ulcer activity in absence of anti-cholinergic properties, proving therefore very interesting from the therapeutical viewpoint. The compounds of the present invention are represented by the following formula wherein the presence Of three double carbon-carbon bonds makes possible the existence of geometric isomers with the following possibilities: ;acid addition salts thereof.
;The compounds of the present invention can be prepared by employing hrarious processes and methods already known in the art, some of which can be summarized as follows 1) A suitable acyclic isoprenoid halide is reacted with a monosub- stituted piperazine according to the following scheme, wherein the group 2) A suitable acyclic isoprenoid halide is reacted with piperazine- carboixa ldehyde and, after alkaline hydrolysis, the resulting 1- -acyclic isoprenoidpiperazine is reacted with a suitable R-halide wherein R has the meaning stated above, according to the foolow-i ing scheme: 1 3 ) A suitable acyclic isoprendid halide is reacted with p-tosylpipe- razine and the resulting sulphonamide is reacted with Na in liquid ammonia to give a secondary amine which, by treatment with a R-halide (R has the meaning stated above) gives the desired product, according to the following scheme: \ Hal . + NH N-SO \ The products of the present invention show?' as mentioned above, a remarkable interesting pharmacological activit as it appears from the following description, wherein i.p. = intraperitoneally i.d. = intraduodenally i.v. = intravenously ce of the tesf¾d products was found not hinder Clinical experimentation. are reported in the table. d no particular symptomatology at high dosages, or at the dosages which the tested products caused slight the isolated organs (segments of he tested pr On the the products evidenced a spasmolytic action of the papaverinic type, inhibiting the spasm induced by BaCl . f In this case the concentrations which resulted active, are in the same range as evidenced for the specific antagonist (papaverine 1 - 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 G¾tased- 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, i 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, immobilisation ulcer, phenylbutazone ulcer and Shay ulcerogenic test).
The products displayed also analgesic and anti-inflammatory actions and the active doses proved to be from ζθ to 200 mg./Kg. p.o.
With regard to the anti-cholinergic activity, said products resulted 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 resulted to be highly active already at doses of 0.5 - 1 Moreover, other conventional pharmacological tests were utilized during the investigations, but they are not rejSrted because no conclusive results have been adieved.
From the table, it results that the products ^H i g the highest toxicity are 2,2 '-bipyridine and atropine-sulp &te, whereas the products according to the present invention (indicated as: toxicity by oral route.
I On the Qsm ra^y, the most active product is atropine-sulphate, whereas ; 2,2 '-b show a very close activity φ I 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.
ACUTE TOXICITY IN MICE INHIBITION OF COMPOUNDS LD50 (mg./Kg.) i.p. P.O. Volume \ / a) trans ^-C^ trans 300 b) cis C -C . trans C.-C 600 26 2 3» 6 7 .. c) mixture of a) + b) 400 2000 20 d) cis C2-C3)cis C6-C7 500 26 e) trans C -C , cis C .-C 250 10- 2 3 6 7 f) mixture of d) + e) 350 - 2000 20 g) mixture of a)-h¾) <¾J>¾¾^.-v... 400 2000 ) Atropine Sulphate 200 800 2,5 - 5 ) 2,2'-Bipyridine 250 330 10 The following non-limitative Examples illustrate the products and processes of the present invention.
A solution of 45 mmoles of l-bromo-3 ,7> ll-trimethyl-2 , 6, 10-dodeca-; triene (obtained from synthetic famesol, commercially available and containing four isomers) in 10 ml. of benzene was added drop-: wise at 0°C to a stirred solution of 45 mmoles of piperonylpipera- zine in 60 ml. of benzene containing 5 g. of triethylamine.
The mixture was stirred for 2 hours and then the precipitated tri- ethylammonium bromide was filtered off.
The benzene solution was wafched first with water and then with K„C0 2 3 solution and finally dried (K CO ). 2 3 Removal of benzene under reduced pressure gave a crude oily residue which ./as dissolved in acetone and treated at ¾-8°C with a slight excess of 37% HC1 solution. The precipitated hydrochloride was filtered, washed with acetone and with absolute ethaiiol. 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 sol- vent system ethyiacetate-petrol /ether 1:1.
Gas liquid chromatography showed three peaks indicating the presence of four possible isomers.
Pure product was a colourless oil: the NMR showed the following si-; nals in < : 1.55 - 1.80 (m, 12H, CH -C=) , 1.95 - 2.20 (m, 8H, CH -C=), ; 3 1 2.48 (s, 8H, CH2-N)y 3.00 (d, 2H, J^7cps , -CH2~C=) , ; 3.41 (s, 2H, CH -arom), 4.90 - 5. 50 (m, 3H, CH=C), [ 5.91 (s, 2H, 0-CH2-0) , 6.75 - 6.90 (3H,arom).
EXAMPLE II The procedure of Example I was carried out with 45 mmoles of formyl- piperazine instead of piperonylpiperazine. The oily residue obtained b evaporation of the benzene solution was chromatographed on silica gel column (elution with cHbroform-methanol) to afford the pure base. The NMR showed '-;he following signals in J : EXAMPLE III ; 317 ■> 1l-trimethyl-2 ,6,10-dodecatrienylpiperazine. (four isomers mixture).
A solution of 47.09 mmoles of the N^-formyl derivative (see Ex. II) in 50 ml. ethanol :.was: refluxed for 20 hours with 7.5 g. of NaOH in :.EXAMPLE V : N^-tosyl-N^-^ ,7, ll-trimethyl-2 ,6,10-dodecatrienyljpiperazine. : (four isomers mixture). ' To a cold solution (0°C) of 21.6 mmoles of tosylpiperazine in 8ml. of absolute ethanol containing 1.2 g. of anhydrous KOH, 23.8 mmoles of l-bromo-3i7jll-trimethyl-2,6,10-dodecatriene .were added dropwise ; under stirring. The mixture was stirred for 1 hour at room temperature and filtered to remover KBr.
Concentration of the solution gave a crude oily residue which was treated with $% KOH, extracted with methylene dichloride, washed with water and dried (K CO )·. Evaporation to dryness in vacuo gave " 3 an oil which was chromatographed on silica gel using ethylacetate- -petrol ether as eluants.
Ir (neat) 1345 SO^ and 1160 cm"1 ( SO^ .
EXAMPLE VI 3,7, ll-trimethyl-2 ,6yl0-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 g. of ammonium chloride was added in one portion and I j the blue colour was immediately discharged. The mixture was stirred I j for additional 10 min. and then 100 ml, of toluene were added drop-; wise allowing ammonia to evjlporate over a 2 hours period. The orga- Inic solution was washed with water, dried (K„C0 and concentrated |: ' 2 3' ί under reduced pressure, IPurification by chromatography over silica gel (chloroform-methanol j eluants) afforded the pure base.
[For NMR signals see Example III. 10.5 ml. of anhydrous pyridine are added to a solution of 100 g. (0.45 moles) of commercially available pure trans-rierolidol in 300 ml. petroleum ether and then, under stirring and maintaining the temperature between -5 and ^IOOC, a solution of 53 g. (0.2 moles) of PBr^in 70 ml. petroleum ether are added thereto.
When the addition is completed, stirring at -2 - 0°C, then the solution is washed neutrality, and then with cold saturated NaHCO solution.
After drying orTN^SO and then ρηΤ'anhydrous K.CO , the solvent is eliminated and the remaining oil is treated · .th 100 ml. benzene. The so obtained solution (l-bromo-3,7ill-tri':'¾thyl-2,6,10-dodeca-triene) is added under stirring at 0°C to a Solution of 99 g. (0.45 moles) of N-piperonylpiperazine dissolved iii 500 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 solu- 2 3 tion 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% aqueous HC1, maintaining the temperature below +10°C. "ft 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,-C and trans C -C , trans C,-C . ^ o 7 3 0 Chromatography of 15 g. of the product on 3 Kg. Silica gel (160 x 9.5 cm. column), using 25% benzene in ethy^acetate as eluant, resulted in complete separation of the two isomers.
The first eluted product is the pure cis C-'-C' trans C,-C„ isomer. 2 3' 6 7 Thin layer chromatography on silica gel gave one spot in the system e zene-ethyl|acetate 25 : 75· ' "" >·■ i.
Gas liquid chromatography showed only one peak on OV 17 - 5% on Chromosorb G AW-DMCS 80-100 mesh, 6 m. len¾A 1.6 mm. inlet diameter.
EXAMPLE VIII I^-piperonyl-N4-^ ,7 ,ll-trimethyl-2 ,6 , 10-dodecatrienyipiperasine.
The procedure of Example VII, is carried out with 0.45 moles of cis--nerolidol (from commercially available mixtur of cis and trans--nerolidols the separation was achieved on 5. silver nitrate impregnated silica gel column with benzene-ethyiscetate 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 . 3' 6 7 2 3 ) 6 7 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 chroma- & 3 ' o 7 tography and gas liquid chromatography.
After separation of the pure isomer cis C^-C^jCis 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. 2 3 » 6 7 Thj-π layer chromatography on silica gel gave one spot in the system benzene-ethylk etate 25 :75.
Gas liquid chromatography showed only one peak.
EXAMPLE XI Preparation of 1000 tablets, each containing 50 mg. of the active substance. -pi eronyl-N -3 , 7 , 11 - 1rimethyl-2 , 6, 10 -dodecatrienyj iperazine g. 50 Colloidal silicic acid g. 150 Starch ' g. ISO Lactose s- 40 Talc g. 8 Magnesium Stearate g. 2 Procedure v The active substance is dissolved in ethano.'. and the resulting solution is adsorbed by colloidal silicic acid using a suitable mixer.
The mixture i« dried in stove under vacuum at 40°C.
Starch, lactose and the half of the lubricants are added to the dried mixture which, after accurate mixing, is compressed in slugs which are afterwards granulated. The remaining quantity of lubricants is added to the obtained granulate and the mixture is then compressed into tablets of 400 mg., each containing 50 mg. of active substance.
EXAMPLE XII Preparation of enteric-coated tablets.
The ingredients and the procedures described in Example II are used. At the end, the tablets are covered with a cellulose aceto-phtalate-film. \ EXAMPLE XIII Preparation of 1000 tablets; bf soft-gelatine capsules, each containing 50 mg. of active substance. . sly mixed capsules.
EXAMPLE XIV Gastro-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-resis':ance.
Claims (1)
1. C L M S The compound dodecatrienylpiperazine and therapeutically acceptable acid addition salts The trans trans of compound of claim The isomer cis trans of compound of claim The isomer cis cis of compound of claim The isomer trans of compound of claim The compound of claim 1 constituted by a mixture of the isomers of claims 2 and The compound of claim 1 constituted by a mixture of the isomers of claims 4 and The compound of claim 1 constituted by a mixture of the isomers of claims 4 and Pharmaceutical compositions in dosage unit form possessing gastric antisecretory and activity comprising pharmaceutical carriers and N A process for the preparation of the new of the formula in the form of its geometric isomers or as an V and its acid addition characterized in that mixture of isomers of a is reacted or a mixture of isomers of reacted pi eronyllchloride and such mixture of isomers are separated into the isomers if the pure isomers or such of isomers converted are into a oxic acid addition Process as claimed in claim the substituted piperazine Process as claimed in vherein the Process as in vherein the halide is Process as claimed in claim wherein the halide is dated 28th 19T3 insufficientOCRQuality
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB934872A GB1387324A (en) | 1972-02-29 | 1972-02-29 | Nitrogen containing isoprenoid compounds |
Publications (2)
Publication Number | Publication Date |
---|---|
IL41662A0 IL41662A0 (en) | 1973-05-31 |
IL41662A true IL41662A (en) | 1977-10-31 |
Family
ID=9870216
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IL41662A IL41662A (en) | 1972-02-29 | 1973-02-28 | Cis and trans n1-piperonyl-n4-farnesyl-piperazine its preparation and pharmaceutical compositions containing it |
Country Status (31)
Country | Link |
---|---|
JP (1) | JPS5335078B2 (en) |
AR (1) | AR198301A1 (en) |
AT (1) | AT333285B (en) |
AU (1) | AU474791B2 (en) |
BE (1) | BE796036A (en) |
BR (1) | BR7301392D0 (en) |
CA (1) | CA992084A (en) |
CH (1) | CH569010A5 (en) |
CS (2) | CS179411B2 (en) |
CY (1) | CY867A (en) |
DE (1) | DE2310044A1 (en) |
DK (1) | DK144012C (en) |
ES (1) | ES411984A1 (en) |
FI (1) | FI56178C (en) |
FR (1) | FR2181757B1 (en) |
GB (1) | GB1387324A (en) |
HK (1) | HK51476A (en) |
HU (1) | HU165112B (en) |
IE (1) | IE37317B1 (en) |
IL (1) | IL41662A (en) |
IN (1) | IN138638B (en) |
KE (1) | KE2650A (en) |
MX (1) | MX3448E (en) |
MY (1) | MY7600279A (en) |
NL (1) | NL7302525A (en) |
NO (1) | NO137388C (en) |
PL (1) | PL92977B1 (en) |
RO (2) | RO71992A (en) |
SE (1) | SE397978B (en) |
YU (1) | YU35366B (en) |
ZA (1) | ZA731182B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2062940B1 (en) * | 1993-03-11 | 1995-06-16 | Vita Invest Sa | GASTROCINETIC AGENT, PROCESS FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN IT. |
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1972
- 1972-02-29 GB GB934872A patent/GB1387324A/en not_active Expired
-
1973
- 1973-02-15 MX MX004906U patent/MX3448E/en unknown
- 1973-02-19 AU AU52309/73A patent/AU474791B2/en not_active Expired
- 1973-02-20 ZA ZA731182A patent/ZA731182B/en unknown
- 1973-02-20 FI FI506/73A patent/FI56178C/en active
- 1973-02-20 IN IN385/CAL/73A patent/IN138638B/en unknown
- 1973-02-20 AR AR246682A patent/AR198301A1/en active
- 1973-02-21 CY CY867A patent/CY867A/en unknown
- 1973-02-22 FR FR7306245A patent/FR2181757B1/fr not_active Expired
- 1973-02-23 NL NL7302525A patent/NL7302525A/xx not_active Application Discontinuation
- 1973-02-23 IE IE284/73A patent/IE37317B1/en unknown
- 1973-02-23 ES ES411984A patent/ES411984A1/en not_active Expired
- 1973-02-24 CS CS7300001348A patent/CS179411B2/en unknown
- 1973-02-24 CS CS7600002329A patent/CS179450B2/en unknown
- 1973-02-26 BR BR731392A patent/BR7301392D0/en unknown
- 1973-02-27 NO NO800/73A patent/NO137388C/en unknown
- 1973-02-27 DK DK103873A patent/DK144012C/en active
- 1973-02-27 CA CA164,748A patent/CA992084A/en not_active Expired
- 1973-02-27 YU YU499/73A patent/YU35366B/en unknown
- 1973-02-27 SE SE7302708A patent/SE397978B/en unknown
- 1973-02-27 HU HUPI378A patent/HU165112B/hu unknown
- 1973-02-27 CH CH281773A patent/CH569010A5/xx not_active IP Right Cessation
- 1973-02-27 BE BE128167A patent/BE796036A/en not_active IP Right Cessation
- 1973-02-28 DE DE19732310044 patent/DE2310044A1/en not_active Ceased
- 1973-02-28 PL PL1973160969A patent/PL92977B1/pl unknown
- 1973-02-28 AT AT178473A patent/AT333285B/en not_active IP Right Cessation
- 1973-02-28 IL IL41662A patent/IL41662A/en unknown
- 1973-02-28 RO RO7374009A patent/RO71992A/en unknown
- 1973-02-28 RO RO7382295A patent/RO76582A/en unknown
- 1973-02-28 JP JP2420373A patent/JPS5335078B2/ja not_active Expired
-
1976
- 1976-07-19 KE KE2650*UA patent/KE2650A/en unknown
- 1976-08-12 HK HK514/76*UA patent/HK51476A/en unknown
- 1976-12-31 MY MY1976279A patent/MY7600279A/en unknown
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