00124495
`
`are prep a red by
`
`5
`
`NH
`2
`is H2N~
`c) Salts of the formula I wherein A
`the strong base
`treating omeprazole with
`NH2
`
`H N-C....,..........NH2
`2
`
`'-NH
`5 dissolved in a solvent, for example an alcohol.
`
`10
`
`d) A salt of formula I may be converted to another salt of the same
`formula by exchanging the cation. When both the starting material and
`the salt obtained as final product are sufficiently soluble, such an ex(cid:173)
`change may be performed by using a cation-exchange resin saturated
`with the cation desired in the product. The exchange may also be per(cid:173)
`formed by utilizing the low solubility of a desired salt. By this
`15 principle, for example, Na+ as a counter ion may be exchanged for
`2+
`2+
`Ca
`or Mg
`.
`
`e) The reaction between the compounds (i) and (ii) may also be carried
`out by ion-pair extraction.For example, tetrabutylammonium salts of
`the invention may be prepared by dissolving the Na+-sal't in water con(cid:173)
`taining tetrabutylammonium sulfate followed by extraction of the tetra(cid:173)
`butylammonium salt I into a methylene chloride phase, and subsequent
`isolation of the tetrabutylammonium salt I. In this manner also other
`tetraalkylammonium salts I may be prepared.
`
`20
`
`25
`
`Illustrative examples of the radical Rare CH3, c2H5, n-c3H7, n-C4H9,
`i-C4H9, sec.-c4H9 and tert.-c4H9.
`
`The invention also relates to pharmaceutical compositions containing a
`30 novel salt of omeprazole as active ingredient; to the use of the novel
`omeprazolesalts for providing gastrointestinal cytoprotective effects
`in mammals and man; to the use of the novel omeprazole salts in the
`prevention and treatment of gastrointestinal inflammatory diseases in
`mammals and man; to the use of the novel omeprazole salts for inhibit-
`ing gastric acid secretion in mammals and man; to a method for inhibit(cid:173)
`ing gastric acid secretion in mammals and man by administering a com(cid:173)
`pound of the formula I; to a method for the treatment of gastrointesti-
`
`35
`
`

`

`00124495
`
`6
`
`nal inflammatory diseases in mammals and man by administering a com(cid:173)
`pound of the formula I; and to a method for providing gastrointesti(cid:173)
`nal cytoprotective effects in mammals and man by administering a
`compound of the formula I.
`
`5
`
`For clinical use the compounds of the invention are formulated into
`pharmaceutical formulations for oral, rectal, parenteral or other
`mode of administration. The pharmaceutical formulation contains a
`compound of the invention in combination with a pharmaceutically
`10 acceptable carrier. The carrier may be in the form of a solid, semi(cid:173)
`solid or liquid diluent, or a capsule. These pharmaceutical prepara(cid:173)
`tions are a further object of the invention. Usually the amount of
`active compound is between 0.1-95% by weight of the preparation, between
`0.2-20% by weight in preparations for parenteral use and between 1 and
`15 50% by weight in preparations for oral administration.
`
`In the preparation of pharmaceutical formulations containing a compound
`of the present invention in the form of dosage units for oral admini(cid:173)
`stration the compound selected may be mixed with a solid, powdered
`20 carrier, e.g.
`lactose, saccharose, sorbitol, mannitol, starch, amylo-
`pectin, cellulose derivatives or gelatin, as well as with lubricating
`agents e.g.
`magnesium stearate, calcium stearate, sodium steryl fuma-
`rate and polyethylene glycol waxes. The mixture is then processed into
`granules or pressed into tablets. Since the.compounds of the invention
`25 are susceptible to degradation in acid to neutral media, the above-men(cid:173)
`tioned granules or tablets are preferably coated with an enteric coating
`which protects the active compound from acid degradation as long as the
`dosage form remains in the stomach. The enteric coating is chosen among
`pharmaceutically acceptable enteric-coating materials e.g. beeswax,
`30 shellac or anionic film-forming polymers such as cellulose acetate
`phthalate, hydroxypropyl methylcellulose phthalate, partly methyl esteri(cid:173)
`fied methacrylic acid polymers and the like, if preferred in combination
`with a suitable plasticizer. To this coating various dyes may be added
`in order to distinguish among tablets or granules with different active
`35 compounds or with different amounts of the active compound present.
`
`

`

`00124495
`
`7
`
`Soft gelatine capsules may be prepared with capsules containing a mix(cid:173)
`ture of the active compound or compounds of the invention, vegetable
`oil, fat, or other suitable vehicle for soft gelatine capsules. Soft
`gelatine capsules are preferably enteric coated as described above.
`5 Hard gelatine capsules may contain enteric-coated granules of the
`active compound. Hard gelatine capsules may also contain the active
`compound in combination with a solid powdered carrier e.g.
`lactose,
`saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin,
`cellulose derivatives or gelatine; the hard gelatine capsules are pre-·
`ferably enteric coated as described above.
`
`10
`
`Dosage units for rectal administration may be prepared in the form of
`suppositories which contain the active substance mixed with a neutral
`fat base, or they may be prepared in the form of a gelatine rectal cap-
`15 sule which contains the active substance in a mixture with a vegetable
`oil, paraffin oil or other suitable vehicle for gelatine rectal cap(cid:173)
`sules, or they may be prepared in the form of a ready-made micro enema,
`or they may be prepared in the form of a dry micro enema formulation to
`be reconstituted in a suitable solvent just prior to administration.
`
`20
`
`Liquid preparations for oral administration may be prepared in the
`form of syrups or suspensions, e.g. solutions or suspensions containing
`from 0.2% to 20% by weight of the active ingredient and the remainder
`consisting of sugar or sugar alcohols and a_ mixture of ethanol, water,
`25 glycerol, propylene glycol and polyethylene glycol. If desired, such
`liquid preparations may contain colouring agents, flavouring agents,
`saccharine and carboxymethyl cellulose and thickening agent. Liquid
`preparations for oral administration may also be prepared in the form
`of a dry powder to be reconstituted with a suitable solvent prior to use.
`
`30
`
`Solutions for parenteral administration may be prepared as a solution
`of a compound of the invention in a pharmaceutically acceptable sol(cid:173)
`vent, preferably in a concentration from 0.1% to 10% by weight. These
`solutions may also contain stabilis in~ agents and/or buffering agents
`35 and may be manufactured in unit dose ampoules or vials. Solutions for
`parenteral administration may also be prepared as a dry preparation to
`be reconstituted.with a suitable solvent extemporaneously before use.
`
`

`

`00124495
`
`8
`
`Sodium salts of the invention are preferably used in the preparation
`of parenteral formulations.
`
`5
`
`The typical daily dose of the active substance varies within a wide
`range and will depend on various factors such as for example the in(cid:173)
`dividual requirement of each patient, the manner of administration and
`the disease. In general, oral and parenteral dosages will be in the
`range of 5 to 400 mg per day of active substance.
`
`10 The following examples will further illustrate the invention.
`
`Example 1. Preparation of 5-methoxy-2-[((4-methoxy-3,5-dimethyl-2-
`-pyridinyl)-methyl]sulfinyl]-1~-benzimidazole sodium salt (omeprazole
`sodium salt).
`15 Omeprazole (lOOOg, 2.90 mol} was added to a solution of NaOH (116g, 2.90
`mol) in deionized water (25l). After stirring for 5 min methylene chlor(cid:173)
`ide (5l) was added and stirring was continued for 10 min. The two
`phases were separated. The aqueous phase was washed with methylene
`chloride (5l), filtered clear (Celite} and concentrated by evaporation
`20 under reduced pressure to about 21 total volume. Absolute ethanol {6!)
`was added and the evaporation was continued until dryness. Ethyl acetate
`(7l) was added, the mixture was stirred under reflux for 30 min. After
`cooling and standing over night the resulting slurry was stirred with an
`additional amount (2L} of ethyl acetate and filtered. The filter cake
`25 was washed with diethyl ether and dried under reduced pressure at 40°C
`over night giving omeprazole sodium salt (975g, 92%), mp 208-210°C, NMR:
`cr(o20): 1.85(s,3H), 2.1(s,3H), 3.5(s,3H), 3.85(s,3H), 4.75(s,2H), 6.85
`(dd,lH), 7.2(d,lH), 7.55(d,1H), 8.15(d,lH}.
`
`30 Example 2. Preparation of omeprazole sodium salt.
`Omeprazole (1300g, 3.77 mol) was added under vigorous mechanic stirring
`to a mixture of tetrahydrofuran (13l) and 50% aqueous NaOH (296g, 3.7
`mol} and stirring was then continued for 45 min. Trichloroethylene
`(5.7l) was added and stirring was continued over night at room tempera-
`ture. The mixture was cooled to +5°C and then stirred for 3h. The pre(cid:173)
`cipitate was filtered off and the filter cake was washed with trichloro(cid:173)
`ethylene (5l) and dried under reduced pressure at 50°C giving o~eprazole
`
`35
`
`

`

`00124495
`
`9
`
`sodium salt (1314g, 95%), mp 208-210°C.
`
`Example 3. Preparation of omeprazole potassium salt.
`Omeprazole (lO.Og, 0.0290 mol) was added to a solution of KOH (l.60g.
`5 0.0285 mol) in deionized water and then methylene chloride (50ml) was
`added. The mixture was stirred vigorously for 15 min. The phases were
`separated and the aqueous phase was washed with methylene chloride
`(50ml) and filtered clear (Celite). Evaporation to dryness gave a
`crystalline residue. Recrystallisation from ethyl acetate yielded
`10 omeprazole patassium salt, mp. 148-150°C (soluble in water).
`
`Example 4. Preparation of di-omeprazole calcium salt dihydrate.
`Anhydrous Cacl 2 (17.9g, 0.161 mol) dissolved in deionized water (200 ml)
`was added dropwise under viogorous stirring to a solution of omepra-
`15 zole sodium salt (l25g, 0.340 mol) in deionized water (1250 ml) and
`then stirring was continued for lh at room temperature. The precipitate
`was centrifugated down and washed with deionized water until no Cl
`was detectable (AgN03). After drying in the air and grinding, the cry(cid:173)
`stals were dried in vacuum at 40° for 20h yielding omeprazole calcium
`20 salt dihydrate (104g, 80%), mp 182-184°C, NMR: ~CDC1 3+1 drop of DMSO-d6)
`2.0(s,3H), 2.15(s,3H), 3.6(s,3H), 3.7{s,3H), 4.5{s,2H), 6.7(dd,lH),
`7.1(d,1H), 7.6(d,lH, 8.15(s,lH).
`
`Example 5. Preparation of di-omeprazole ma~nesium salt dihydrate.
`25 Anhydrous MgC1 2 (16.2g, 0.17 mol) dissolved in deionized water (625 ml)
`was added dropwise under vigorous stirring to a solution of omeprazole
`sodium salt {125g, 0.340 mol) in deionized water{l560ml) and then the
`stirring was continued for lh at room temperature~ The precipitate was
`centrifugated down.and then washed with deionized water until no Cl
`30 was detectable (AgN03). Drying in the air, grinding and drying in vacuum
`at 40° for 24h yielded omeprazole magnesium salt dihydrate {lllg, 87%)
`mp 177-178°C.
`
`Example 6. Preparation of di-omeprazole magnesium salt.
`35 Magnesium (0.35g, 0.0145 mol) was reacted with absolute methanol (lOml)
`(in the presence of one drop of CC1 4) to give a solution of Mg{OCH3)2
`in methanol s~ution. More methanol {10~) was added and the solution
`
`

`

`00124495
`
`10
`
`in
`was added dropwise to a solution of omeprazole (10 g. 0.029 m)
`methanol {200 ml) and the mixture was then stirred for 30 min at room
`. temperature. Evaporation gave a crystalline solid of the di-omeprazole
`magnesium salt~ mp. 178-180°.
`
`5
`
`Example 7. Preparation of omeprazole tetrabutylammonium salt.
`Omeprazole sodium salt (3.8g~ 0.010 mol) was added to a mixture of
`tetrabutylammonium hydrogensulphate (3.5g~ 0.010 mol} and NaOH
`(0.42 g,
`0.0105 mol} in deionized water {15m!). Methylene chloride (lOrn!} was
`10 added and the mixture was shaken in a separatory funnel. After sepa(cid:173)
`ration of the phases the organic phase was dried and the solvent evapo(cid:173)
`rated off giving omeprazole tetrabutylammonium salt (3.5g, 60%), NMR:
`oT{CDC1 3): 0.8-1.15(m,l2H), 1.15-l.6{m,16H), 2.25(s,3H), 2.3(s,3H),
`2.75-3.15(m,8H), 3.75(s,3H}, 3.9(s,3H), 4.7(d,1H), 5.05(d,1H}, 6.8
`(dd,lH), 7.3{d,1H), 7.7(d,1H), 8.35(s,1H).
`
`15
`
`Example 8. Preparation of omeprazole guanidinium [C+(NH2}3] salt.
`A solution of guanidine (0.0029 mol)[prepared from guanidinium nitrate
`and KOHl in ethanol (50ml ) was added to a solution of omeprazole
`(l.Og, 0.0029 mol} and the resulting solution was stirred for 15 min.
`The solvent was evaporated giving omeprazole guanidinium salt, mp ll0-
`1120C (soluble in water).
`
`20
`
`Example 9. Preparation of tetra-omeprazole titanium salt.
`25 Titanium tetraisopropylate (1.03g, 0.0036 mol) was added to a solution
`of omeprazole in dry isopropanol (250m!) and the mixture was stirred
`under N2 at room temperature for 4h. (A white precipitate was formed).
`Evaporation of the solvent followed by washing 3 times with light pet(cid:173)
`roleum and drying in vacuum gave a white-crystalline powder of tetra-
`30 omeprazole titanium salt, mp >260°C.
`
`Example 10. Preparation of omeprazole litium salt.
`Omeprazole (3.0 g, 0.0087 mol) was added to a solution of LiOH (0.207 g,
`0.00865 mol} in deionized water and then methylene chloride (25 ml)
`35 was added. The mixture was stirred vigorously for 15 min. The phases
`were separated and the aqueous phase was washed with methylene chloride
`(25 ml) and filtered clear (Celite). Evaporation to dryness gave a cry(cid:173)
`stalline omeprazole litium salt, mp. 198-200°C (soluble in water}.
`
`

`

`ll
`
`00124495
`
`NMR:cf(CDC1 3) 1.65 (s,3H), 1.8 {s,3H), 3.45 (s,3H}, 3.4 (s,3H),
`4.2 {s,2H), 6.6 {dd,lH}, 6.95 (d,lH), 7.45 (d,lH), 7.75 {s,lH).
`
`The NMR data given in the examples are measured at 90 MHz.
`
`Incorporation of the novel omeprazole salts of the present invention
`in pharmaceutical preparations is exemplified in the following examples.
`
`Example 11. Syrup
`
`A syrup containing 1% {weight per volume) of active substance was pre(cid:173)
`pared from the following ingredients:
`
`I
`
`II
`
`Omeprazole sodium salt
`Sugar, powder
`
`l.Og
`30.0 g
`
`0.6 g
`Saccharine
`5.0 g
`Glycerol
`Flavouring agent
`O.OSg
`5.0 g
`Ethanol
`0.5 g
`Sorbic acid
`9.0 g
`Sodium dihydrogen phosphate q.s. to pH=
`Distilled water q.s. to a final volume of 100 ml
`
`I
`
`Powdered omepraiole sodium salt was carefully dry mixed with pow(cid:173)
`dered sugar, dried in a vacuum oven over-night and dispensed into
`bottles each containing 31.0 gram of the powder mixture.
`
`II A solution of saccharine, glycerol, flavouring agent, ethanol,
`sodium dihydrogen phosphate, sorbic acid and water was prepared,
`and dispensed into vials. When mixed with the powder mixture of
`omeprazole sodium salt and sugar the final volume was 100 ml.
`
`Solvent vial II is to be added to powder mixture vial I just prior to
`use. The formed suspension is stable for ten days when stored at re(cid:173)
`frigerator temperature.
`
`The salt given above may be replaced with another salt of the invention.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`

`

`00124495
`
`12
`
`Example 12. Enteric-coated tablets
`
`An enteric-coated tablet containing 20 mg of active compound was pre(cid:173)
`pared from the following ingredients:
`
`5
`
`I
`
`Omeprazole magnesium salt
`Lactose
`Methyl cellulose
`Polyvinylpyrrolidone cross-linked
`Magnesium stearate
`Distilled water
`
`II
`
`Cellulose acetate phthalate
`Cetyl alcohol
`Isopropanol
`Methylene chloride
`
`200 g
`700 g
`6 g
`50 g
`15 g
`q.s.
`
`200 g
`15 g
`2000 g
`2000 g
`
`10
`
`15
`
`25
`
`30
`
`I
`
`20
`
`Omeprazole magnesium salt, powder, was mixed with lactose, and
`granulated with a water solution of methyl cellulose. The wet
`mass was forced through a sieve and the granulate dried in an
`oven. After drying the granulate was mixed with polyvinylpyrroli(cid:173)
`done and magnesium stearate. The dry mixture was_ pressed into tab(cid:173)
`let cores {10 000 tablets), each tablet containing 20 mg of active
`substance, in a tabletting machine using 6 mm diameter punches.
`
`II A solution of cellulose acetate phthalate and cetyl alcohol in
`isopropanol/methylene chloride was sprayed onto the tablets I in
`an Accela Cotae, Manesty coating equipment. A final tablet weight
`of 110 mg was obtained.
`
`Example 13. Solution for intravenous administration
`
`A parenteral formulation for intravenous use, containing 4 mg of active
`35 compound per ml, was prepared from the following ingredients:
`
`

`

`00124495
`
`13
`
`Omeprazole sodium salt
`Sterile water
`
`Polyethylene glycol 400 for injection
`Sodium dihydrogen phosphate
`Steri 1 e water
`to a final volume of
`
`4.26 g
`200 ml
`
`400
`g
`l.Sg
`1000 ml
`
`Omeprazole sodium salt 4.26 g, corresponding to 4.0 g of omepra-
`zole, was dissolved in sterile water to a final volume of 200 ml.
`The solution was filtered through a 0.22~ filter and dispensed
`into sterile vials, each vial containing 2.0 ml. The vials were
`placed in a freeze drier with a shelf temper~ture of -40°C. When
`the solution in the vials had frozen, the solution was freeze
`dried. After drying the vials were stoppered.
`
`I
`
`II
`
`5
`
`I
`
`10
`
`15
`
`20
`
`II A solution of polyethylene glycol and sodium dihydrogen phosphate
`in sterile water was prepared, filtered through a 0.22 ~ filter,
`dispensed into sterile vials and the vials closed with a rubber
`stopper. The vials were sterilised in an autoclave at +120°C for
`twenty minutes. Immediately before use 10.0 ml of solvent II is
`added to vial I. The clear solution contains 4 mg of omeprazole per
`millilitre.
`
`25 Test of the stability of omeprazole salts of the invention
`
`The stability of omeprazole sodium salt, of the invention, obtained
`according to Example 1, was compared with the stability of the neutral
`form of omeprazole. Both test compounds were stored for six months at
`30 + 37°C and at a relative humidity of 80%. Thereafter, the amount of
`degradation products which had formed was measured. The result is given
`in Table 1 below.
`
`

`

`00124495
`
`14
`
`Table 1. Stabi1ity of neutral omeprazole and of omeprazole sodium
`salt after six months storage at + 37°C and 80% relative
`humidity
`
`5 Test compound
`
`Amount of degradation products
`formed (per cent calculated on
`original amount of"omeprazole)
`
`neutral omeprazole
`10 omeprazole sodium salt
`
`6
`0.4
`
`15
`
`As is seen in Table 1 the omeprazole sodium salt of the invention gave
`rise to substantially lower amounts
`of degradation products than
`the neutral form of omeprazol. This shows the improved stability of
`the novel omeprazole salts of the invention.
`
`

`

`00124495
`
`H 724-1
`
`What we claim is:
`
`15
`
`1. A compound of the formula
`
`n
`
`5
`
`10
`
`15
`
`wherein R1 is an alkyl group containing 1-4 carbon atoms.
`
`2. A compound according to claim 1 wherein An+ is Na+, K+, Mg2+ or
`.
`2+
`Ca
`.
`
`20
`
`3. A compound according to claim wherein An+ is Na+.
`
`4. A compound according to claim wherein An+ is Mg2+.
`
`5. A process for the preparation of a compound of the formula
`
`I
`
`n
`
`25
`
`30
`
`35
`
`

`

`00124495
`
`16
`
`wherein R1 is an alkyl group containing 1-4 carbon atoms characterized
`by reacting omeprazole of the formula
`
`5
`
`10
`
`15
`
`20
`
`with a base capable of releasing the cation
`
`{i)
`
`( i i)
`
`to give a salt of the formUla I, which salt is thereafter isolated.
`
`6. A process according to claim 5 wherein the base releasing the cation
`An+ is NaOH, NaNH2, or NaNR2 wherein R is an alkyl group containing
`1-4 carbon atoms.
`
`7. A process according to claim 5 wherein the base releasing the cation
`An+ is Mg{OR) 2 wherein R is an alkyl group containing 1-4 carbon atoms.
`
`8. A pharmaceutical composition containing as active ingredient a com(cid:173)
`pound according to any of claims 1-4.
`
`25
`
`9. A compound as defined in any of claims 1-4, for use in inhib]ting
`gastric acid secretion in mammals and man.
`
`10. A compound as defined in any of claims 1-4, for use as gastrointesti(cid:173)
`nal cytoprotecting agent in mammals and man.
`
`30
`
`11. A compound as defined in any of claims 1-4, for use in the treat(cid:173)
`ment of gastrointestinal inflammatory diseases in mammals and man.
`
`

`

`Europalsches Patentamt
`
`European Patent Office
`
`Office europeen des brevets
`
`® Publication number:
`
`0124 495
`A3
`
`EUROPEAN PATENT APPLICATION
`
`@ Application number: 84850066.6
`
`@ Date offiling: 28.02.84
`
`@)
`
`lnt.cL•:C07D 401/12,A61 K 31/44
`
`@ Priority: 04.03.83 SE8301182
`
`@ Applicant: Aktiebolaget Hassle, Kiirragatan 5,
`S-431 83 Molndal (SE)
`
`@ Date of publication of application: 07.11.84
`Bulletin 84/45
`
`@) Designated Contracting States: AT BE CH DE FR GB IT
`Ll LU NLSE
`
`@
`
`Inventor: Brandstrom, Arne Elof, Anders
`Mattssonsgatan 13B, S-415 06 Goteborg (SE)
`
`@ Date of deferred publication of search
`report: 15.05.85 Bulletin 85/20
`
`® Representative: Hjertrnan, Ivan T. et al, AB Astra Patent
`and Trade Mark Depart, S-151 85 Sodertalje (SE)
`
`® Omeprazole salts.
`@ Novel salts of omeprazole with u+, Na+, K+, Mg2 +,
`Ca2 +, Ti•+, N+(R1 ) 4 or
`
`as cation; processes for their preparation thereof, phar(cid:173)
`maceutical compositions containing such salts and their use
`in medicine.
`
`CW)
`
`c
`10
`
`G) .. 11ft
`
`~ ....
`0
`a. w
`
`ACTORUM AG
`
`

`

`European Patent
`Office
`
`EUROPEAN SEARCH REPORT
`
`DOCUMENTS CONSIDERED TO BE RELEVANT
`CitatiOn of document with indication. where appropnate,
`of relevant passages
`
`Category
`
`Relevant
`to claim
`
`CLASSIFICATION OF THE
`APPLICATION (Int. Cl. 3)
`
`EP 84 85 0066
`
`A
`
`FR-A-1 593 614
`
`(EGYESULT)
`
`C 07 D' 401/12
`A 61 K 31/44
`
`D,A EP-A-0 005 129
`
`(hASSLE)
`
`TECHNICAL FIELDS
`SEARCHED (Int. Cl. >)
`
`C 07 D 401/00
`A 61 K 31/00
`
`Examiner
`DE BUYSER I.
`
`I
`
`The present search report has been drawn up for all claims
`
`Place of search
`THE HAGUE
`
`Date of completion of the search
`08-01-1985
`
`I
`
`CATEGORY OF CITED DOCUMENTS
`
`X : particularly relevant if taken alone
`Y : particularly relevant if combined with another
`document of the same category
`A : technological background
`0 : non-written disclosure
`P : intermediate document
`
`T : theory or principle underlying the invention
`E : earlier patent document. but published on. or
`after the filing date
`D : document cited in the application
`L : document cited for other reasons
`
`& : member of the same patent family. corresponding
`document
`
`

`

`Verweis auf die Berichtigunq von Versehen administrotiver, bzw. drucktechnischer Art
`im Zuge der omtlichen Druckschriftenherstellung.
`In Oruckschrift .Q.}i>.E:i.fsU.i\.) ••••••••••• (Publ,Nr.), veroffentlicht om R~a9.1.~1}f> ••••••• ist/sind
`folgende{r) Mangel/Mangel feststellbor:
`bJUnleserlichkeit
`LJUnvollstandigkeit
`~Fehler in den bibliogrophischen Doten
`LJFolsche Aneinonderreihung (Seiten- od. Textvertouschung1 -verdoppelung u.o.)
`[JUnzutreffende Arntsvermerke
`[]Mitveroffentlichung schriftfrernder Materia
`QSonstiges
`(ggf. erforderl. Erganzung: ••••••••••••••••••••••••••••••••••••••••••••••)
`)
`c
`(
`Titelblatt (54) u. (57) :Formel
`=-Schriftteil ••••••••••••••••••••••••••••••••••••••••••••••• ggf. ode, Fig.
`-------- Stelle(n) i.d. VerOTTentlichung •••••••••••••••••••••••••••••••(S., Sp., Z.)
`
`Betroffene ( r) ....:::
`
`durch
`
`Sie werden ersucht, die angemessene Berichtigung
`~anhand der vorliegenden Druckkorrektur
`r:Jon der Druckschrift selbst und/oder
`0 Beifiigung und/oder
`1:8 Austousch
`Ostreichung oder
`[Jw!e folgt: ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••vorzunehmen.
`(ggf. ErlOuterung zur Vorgongsweise: ••••••••••••••••••••••••••••••••••••••••••••••
`
`Notice for correcting clerical/printing errors in EPO patent documents.
`The following deficiency(ies) appear(s) in document Q •• ~~~--~~7 •• ~! .......... (publication No,),
`published on .m.oJ.. .. aQ •••••••••• :
`Dillegible
`Oincomplete
`~error(s) in the bibliographic data
`Owrong order (page/text transposition/duplication etc.)
`[]inaccurate EPO comment
`bJinclusion of extraneous material
`~other deficiency
`(supplementary remorks1 1~ any: •••••••••••••••••••••••••••••••••••••••••••••••••)
`Section concerned: ••• t+Mt.Mge •••• l!>.4l.MQ. •• (.~7l.;tQ~JlllJ.J.P. •• (code, fig., where applicable)
`Place in the publication concerned : •••••••••••••••••••••••••••••••••••••• (page, column, line)
`
`by
`
`The correction should be made
`0 on the document itself and/or
`~as per attached corrected version
`Osupplementing ond/ or 0 deleting the relevant passage (s) 1 or
`~replacing
`0 as follows:
`(oppropr~ate instructions: •••••••••••••••••••••••••••••••••••••••••••••••••••)
`
`02. 01.86
`~
`)
`t
`bl
`ica ion 1 publi~ le ••••••••••••••••'
`pu
`
`0 166 287 Al ( • de
`,
`,
`,
`Il
`a ete constate que le document ••••••••••••••• n
`presente le (les) defaut(s) suivant(s) :
`(]Document illisible
`0Document incomplet
`~Donnees bibliographiques erronees
`0Assembloge incorrect (interversion OU repetition de pages I de parties de texte 1 etc •)
`LJMentions inexactes apportees par !'Office
`[]Publication de materiel sans rapport avec le document
`QDivers
`(compl&ter le cas &ch&ont : ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••)
`Endroit(s) - partie du document .P!lSI~.P.Ei.SJ.a.:r;~f ••••• <.~1L.Ei!-•• <.~7).=.~fbP1HdG ectJeant, code, figure)
`concern&(s)- emplocement(s) •••••••••••••••••••••••••••••••••••••••••••••••• (page, colonne, ligne)
`
`Nous vous prions de bien vouloir effectuer les rectifications n&cessaires
`en ~a ~- le document, par ecrit et./ou~en utilisant les pages de la version corrigee jointe en
`
`annexa,
`
`0 par suppression ou
`pro..: ~par substitution
`Opor adjonction et/ou
`cia- D de la mani~re suivonte :
`(le cos &ch&ant, indi~er la marche a suivre ••••••••••••••••••••••••••••••••••••••••••• )
`donl
`\
`
`

`

`Europalsches Patentamt
`
`European Patent Office
`
`Office europeen des brevets
`
`® Veri:iffentlichungsnummer:
`
`0166 287
`A1
`
`EUROPAISCHE PATENTANMELDUNG
`
`@ Anmeldenummer: 85107104.3
`
`@ Anmeldetag: 10.06.85
`
`@
`
`lnt.CI.4 :C07D 401/12,C07D 491/04,
`A61 K 31/44
`
`®l Prioritat: 16.06.84 CH 2899/84
`16.06.84 CH 2901/84
`
`® Anmelder: Byk Gulden Lomberg Chemlsche Fabrik
`GmbH, Byk-Gulden-Strasse 2, D-7750 Konstanz (DE)
`
`@ Veroffentlichungstag der Anmeldung: 02.01.86
`Patentblatt 86/1
`
`f8 Benannte Vertragsstaaten: AT BE CH DE FR GB IT Ll LU
`NLSE
`
`@ Erfinder: Kohl, Bernhard, Dr., Helnrlch-v.-Tettlngen
`Strasse 35a, D-7750 Konstanz 19 (DE)
`Erfinder: Sturm, Ernst, Dr., In de Raben 1,
`D-7750 Konstanz 19 (DE)
`Erfinder: Klemm, Kurt, Prof. Dr., lm Weinberg 2,
`D-7753 Allensbach (DE)
`Erfinder: Riedel, Richard, Dr., Salmannswellergasse 36,
`D-7750 Konstanz (DE)
`Erfinder: Flgala, Volker Dr., Am Hochflrst 2,
`D-7753 Allensbach 4 (DE)
`Erfinder: Rainer, Georg, Dr.,
`Josef-Anton-Feuchtmayer-Strasse 7, D-7750 Konstanz
`(DE)
`Erfinder: Schaefer, Hartmann, Dr., Zum Purren 27,
`D-7750 Konstanz 16 (DE)
`Erfinder: Senn-BIIflnger, Jorg, Dr., Santlsstrasse 7,
`D-7750 Konstanz {DE)
`
`® Dlaloxypyridlne, Verfahren zu lhrer Herstellung, lhre Anwendung und sle enthaltende Arznelmlttel.
`
`~ Dialkoxypyridine der allgemeinen Formell
`
`sowie deren Salze sind neue Verbindungen mit interessanten
`pharmakologischen Eigenschaften.
`
`H
`I
`N
`
`R1'
`
`,
`
`R1-0
`
`)::)C)~~-cH, """"
`
`R3
`
`R2XYR4
`
`(O)n
`
`tn.
`
`worin
`R 1 einen ganz oder uberwiegend durch Fluor substituierten
`1-3C-Aikylrest oder einen Chloridfluormethylrest und
`R1' Wasserstoff, Halogen, Trifluormethyl, einen 1-3C-Alkylrest
`oder einen gegebenenfalls ganz oder i.iberwiegend durch
`Fluor substituierten 1-3C-Aikoxyrest oder
`R1 und R1' gemeinsam und unter EinschluB des Sauerstoff(cid:173)
`atoms, an das R1 gebunden ist, einen gegebenenfalls ganz
`oder teilweise durch Fluor substituierten 1-2C-Aikylendioxy(cid:173)
`rest oder einen Chlortrifluorethylendioxyrest darstellen,
`R3 einen 1-3C-Aikoxyrest,
`einer der Reste R2 und R4 einen 1-3C-A!koxyrest und der an(cid:173)
`dere ein Wasserstoffatom oder einen 1-3C-Aikylrest und
`n die Zahlen 0 oder 1 darstellt,
`
`ACTORUM AG
`
`

`

`

`

`Europilsches Patentamt
`
`European Patent Office
`
`Office european des brevets
`
`® Veroffentlichungsnummer:
`
`0166 287
`A1
`
`EUROPAISCHE PATENTANMELDUNG
`
`@ Anmeldenummer: 85107104.3
`
`@ Anmeldetag: 10.06.85
`
`@
`
`tnt.CL': C 07 D 401/12, C 07 D 491/04,
`A 61 K 31/44
`
`@ Prioritat: 16.06.84 CH 2899/84
`16.06.84 CH 2901/84
`
`® Anmelder: Byk Gulden Lomberg Chemlsche Fabrlk
`GmbH, Byk-Gulden-Strasse 2, D-7750 Konstanz (DE)
`
`@ Veroffentlichungstag der Anmeldung: 02.01.86
`Patentblatt 86/1
`
`8 Benannte Vertragsstaaten: AT BE CH DE FR GB IT Ll LU
`NLSE
`
`@ Erfinder: Kohl, Bernhard, Dr., Helnrlch-v.-Tettlngen
`Strasse 35a, D-7750 Konstanz 19 (DE)
`Erfinder: Sturm, Ernst, Dr.,ln de Reben 1,
`D-7750 Konstanz 19 (DE)
`Erfinder: Klemm, Kurt. Prof. Dr.,lm Weinberg 2,
`D-7753 Allensbach (DE)
`Erfinder: Riedel, Richard, Dr., Salmannswellergasse 36,
`D-7750 Konstanz (DE)
`Erfinder: Flgala, Volker Dr., Am Hochflrst 2,
`D-7753 Allensbach 4 (DE}
`Erfinder: Rainer, Georg, Dr.,
`Josef-Anton-Feuchtmayer-Strasse 7, D-7750 Konstanz
`(DE)
`Erfinder: Schaefer, Hartmann, Dr., Zum Purren 27,
`D-7750 Konstanz 16 (DE}
`Erfinder: Senn-BIIflnger, .Jarg, Dr., Sintlsstrasse 7,
`D-7750 Konstanz (DE)
`
`9 Dlalkoxypyrldlne, Verfahren zu lhrer Herstellung,lhre Anwendung und sle enthaltende Arznelmlttel.
`@ Dialkoxypyridine der allgemeinen Forrnell
`
`sowie deren Salze sind neue Verbindungen mit interessanten
`pharmakologischen Eigenschaften.
`
`_:()2 RJ (R4
`
`R1X)' ,
`N
`lOin
`\._ __ II
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`H
`N
`
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`•
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`
`I I I,
`
`R1 einen ganz oder uberwiegend durch Fluor substituierten
`1-3C-Aikylrest oder einen Chloridfluormethylrest und
`•
`2 R1' Wasserstoff, Halogen, Trifluorrnethyl, einen 1-3C-Aikylrest
`•
`oder einen gegebenenfalls ganz oder Oberwiegend durch
`Fluor substituierten 1-3C-Aikoxyrest oder
`) R1 und R1' gemeinsam und unter EinschluB des Sauerstoff(cid:173)
`atoms, an das R1 gebunden ist, einen gegebenenfalls ganz
`)
`•
`oder teilweise durch Fluor substituierten 1-2C-Aikylendioxy(cid:173)
`rest oder einen Chlortrifluorethylendioxyrest darstellen,
`) R3 einen 1-3C-Aikoxyrest,
`einer der Reste R2 und R4 einen 1-3C-Aikoxyrest und der an-
`I. dere ein Wasserstoffatom oder einen 1-3C-Aikylrest und
`,I n die Zahlen 0 oder 1 darstellt,
`
`ACTORUM AG
`
`

`

`287EP
`
`-1-
`
`6853
`
`0166287
`
`Dialkoxypyridine yerfahren zu ihrer Herstellung
`enthaltende Arzneimittel
`
`ihre Anwendung und sie
`
`Anwendungsgebiet der Erfindung
`Die Erfindung betrifft neue Dialkoxypyridine, Verfahren zu ihrer Herstel(cid:173)
`lung, ihre Anwendung und sie enthaltende Arzneimittel. Die erfindungsge(cid:173)
`miBen Verbindungen werden in der pharmazeutischen Industria als Zwischen(cid:173)
`produkte und zur Herstellung von Hedikamenten verwendet.
`
`Stand der Technik
`In der europiischen Patentanmeldung 0 DOS 129 werden substituierte Pyri(cid:173)
`dylsulfinylbenzimidazole beschrieben. die magensiuresekretionshemmende
`Eigenschaften besitzen sollen. -
`In der europiischen Patentanmeldung
`0 074 341 wird die Verwendung einer Reihe von Benzimidazolderivaten zur
`Hagensiuresekretionshemmung beschrieben. In der britischen Patentanmeldung
`GB Z 082 580 werden tricyclische Imidazolderivate beschrieben, die die
`Hagensiuresekretion hemmen und die Entstehung von Ulcera verhindern
`sollen.
`
`Es wurde nun uberraschenderwelse gefunden, daB die unten naher beschriebe(cid:173)
`nen Dialkoxypyridine interessante und unerwartete Eigenschaften aufweisen,
`durch die sie sich in vorteilhafter Weise von den bekannten Verbindungen
`unterscheiden.
`
`Beschreibung der Erfindung
`Gegenstand der Erfindung sind neue Oialkoxypyridine der allgemeinen
`Forme! I
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`

`

`287EP
`
`-2-
`
`6853
`
`0166287
`
`worin
`R1
`einen ganz oder uberwiegend durch Fluor substituierten 1-JC-Alkylrest
`oder einen Chlordifluormethylrest und
`R1' Wasserstoff, Halogen, Trifluormethyl, einen 1-JC-Alkylrest oder einen
`gegebenenfalls ganz oder uberwiegend durch Fluor substituierten
`1-3C-Alkoxyrest, oder
`R1 und R1' gemeinsam und unter Einschlu8 des Sauerstof~atoms, an das R1
`gebunden ist, einen gegebenenfalls ganz oder teilweise durch Fluor
`substituierten 1-2C-Alkylendioxyrest oder einen Chlortrifluorethylen(cid:173)
`dioxyrest darstellen,
`eine~ 1-JC-Alkoxyrest,
`R3
`einer der Reste R2 und R4 einen 1-3C-Alkoxyrest und der andere ein Wasser(cid:173)
`stoffatom oder einen 1-JC-Alkylrest und
`die Zahlen 0 oder 1 darstellt,
`n
`sowie die Salze dieser Verbindungen.
`
`Als ganz oder uberwiegend durch Fluor substituierte 1-JC-Alkylreste seien
`beispielsweise der 1,1,2-Trifluorethylrest, der Perfluorpropylrest, der
`Perfluorethylrest und insbesondere der 1,1,2,2-Tetrafluorethylrest, der
`Trifluormethylrest, der 2,2,2-Trifluorethylrest und der Difluorme