Prodrugs of the pyridyl methyl sulfinyl benzimidazole type proton pump inhibitor drugs have a hydrolyzable arylsulfonyl or heteroarylsulfonyl group attached to the benzimidazole nitrogen. The prodrugs of the invention hydrolyze under physiological conditions to provide the proton pump inhibitors with a half life measurable in hours, and are capable of providing sustained plasma concentrations of the proton pump inhibitor drugs for longer time than presently used drugs. The generation of the proton pump inhibitor drugs from the prodrugs of the invention under physiological conditions allows for more effective treatment of several diseases and conditions caused by gastric acid secretion.

Field of the Invention
The present invention is directed to prodrugs of proton pump inhibitors which are useful as anti-ulcer agents. More particularly, the present invention is directed to prodrugs that slowly hydrolyze to provide benzimidazole-type proton pump inhibitors which inhibit exogenously or endogenously gastric acid secretion and thus can be used in the prevention and treatment of gastrointestinal inflammatory diseases in mammals, including humans.
Brief Description of the Prior Art
Benzimidazole derivatives intended for inhibiting gastric acid secretion are disclosed in the U.S. Pat. Nos. 4,045,563; 4,255,431; 4,628,098; 4,686,230; 4,758,579; 4,965,269; 5,021,433; 5,430,042 and 5,708,017. Generally speaking, the benzimidazole-type inhibitors of gastric acid secretion work by undergoing a rearrangement to form a thiophilic species which then covalently binds to gastric H,K-ATPase, the enzyme involved in the final step of proton production in the parietal cells, and thereby inhibits the enzyme. Compounds which inhibit the gastric H,K-ATPase enzyme are generally known in the field as xe2x80x9cproton pump inhibitorsxe2x80x9d (PPI).
Some of the benzimidazole compounds capable of inhibiting the gastric H,K-ATPase enzyme have found substantial use as drugs in human medicine and are known under such names as LANSOPRAZOLE (U.S. Pat. No. 4,628,098), OMEPRAZOLE (U.S. Pat. Nos. 4,255,431 and 5,693,818), PANTOPRAZOLE (U.S. Pat. No. 4,758,579), and RABEPRAZOLE (U.S. Pat. No.5,045,552). The diseases treated by proton pump inhibitors and specifically by the four above-mentioned drugs include peptic ulcer, heart burn, reflux esophagitis errosive esophagitis, non-ulcer dispepsia, infection by Helicobacter pylori, alrynitis and asthma among others.
Whereas the proton pump inhibitor type drugs represent substantial advance in the field of human and veterinary medicine, they are not totally without shortcomings or disadvantages. The shortcomings of the presently used proton pump inhibitor (PPI) type drugs can be best explained by a more detailed description of the mode of their action, the diseases or condition against which they are employed and the circumstances of their application. Thus, acid related diseases include but are not limited to erosive esophagitis, esophageal reflux, gastric and duodenal ulcer, non-ulcer dyspepsia and infection by Helicobacter pylori. Current therapy of all but the infection by H. pylori bacteria involves treatment with drugs designed to suppress acid secretion, one type of which are the above-mentioned proton pump inhibitors.
The presently used proton pump inhibitors are pyridyl methyl sulfinyl benzimidazoles (or compounds of closely related structure) with a pKa of 4.0 to 5.0. Their mechanism of action requires accumulation in the acidic space of the parietal cell (secretory canaliculus, pH ca. 1.0) and subsequently hydrogen ion catalyzed conversion to the reactive thiophilic species that is capable of inhibiting the gastric ATPase, enzyme resulting in effective inhibition of gastric secretion. Because of this mechanism the presently used PPI type drugs require specialized gastro protection to remain active for duodenal absorption. For this reason, and due to sensitivity to degradation in the acid milieu of the stomach, oral formulations of the PPI drugs are usually enteric coated. The need for enteric coating is a shortcoming because enteric coating is expensive and moisture sensitive.
Because of the requirement for accumulation in the acid space of the parietal cell, acid secretion is necessary for the efficacy of the PPI type drugs. It was found that the plasma half life of these drugs is between 60 to 90 minutes. All acid pumps are not active at any one time, rather only about 75% are active on the average during the time the drug is present in the blood following oral administration. It was also found in medical experience that on a currently used once-a-day oral administration therapy the maximal inhibition of stimulated acid output is approximately 66%. This is due to a combination of the short plasma half life of the drug, to the limited number of acid pumps active during presentation of the drug and to the turn-over of acid pumps. In present practice it is not possible to control night time acid secretion by evening therapy of oral administration because the drug is dissipated from the plasma by the time acid secretion is established after midnight. The ideal target for healing in acid related diseases and for treatment of H. pylori infection (in conjunction with antibiotics), as well as for relief of symptoms of non-ulcer dyspepsia would be full inhibition of acid secretion. With the currently used PPI type drugs this is achieved only by intravenous infusion; in case of the drug OMEPRAZOLE this requires intravenous infusion of 8 mg per hour. Clearly, there is a need in the art for a drug or drugs acting through the mechanism of PPI-type drugs which can attain or approach full inhibition of acid secretion through oral therapy.
Because of the less than full inhibition of acid secretion and less than 24 hour inhibition through oral administration that is attained by the current dosage forms of currently used PPI-type drugs, therapy for healing of gastric and duodenal ulcerations is 4 to 8 weeks. This is in spite of the fact that the generation time of surface cells of the esophagus, stomach and duodenum is approximately 72 hours. Undoubtedly the presently observed prolonged healing times with these drugs is due to inadequate acid suppression and acid related damage. The foregoing underscores the need in the art for a drug or drugs acting through the mechanism of PPI-type drugs which can attain or approach full inhibition of acid secretion through oral therapy.
As further pertinent background to the present invention, applicants note the concept of prodrugs which is well known in the art. Generally speaking, prodrugs are derivatives of per se drugs, which after administration undergo conversion to the physiologically active species. The conversion may be spontaneous, such as hydrolysis in the physiological environment, or may be enzyme catalyzed. From among the voluminous scientific literature devoted to prodrugs in general, the foregoing examples are cited: Design of Prodrugs (Bundgaard H. ed.) 1985 Elsevier Science Publishers B. V. (Biomedical Division), Chapter 1; Design of Prodrugs: Bioreversible derivatives for various functional groups and chemical entities (Hans Bundgaard); Bundgaard et al. Int. J. of Pharmaceutics 22 (1984) 45-56 (Elsevier); Bundgaard et al. Int. J. of Pharmaceutics 29 (1986) 19-28 (Elsevier); Bundgaard et al. J. Med. Chem. 32 (1989) 2503-2507 Chem. Abstracts 93, 137935y (Bundgaard et al.); Chem. Abstracts 95, 138493f (Bundgaard et al.); Chem. Abstracts 95, 138592n (Bundgaard et al.); Chem. Abstracts 110, 57664p (Alminger et al.); Chem. Abstracts 115, 64029s (Buur et al.); Chem. Abstracts 115, 189582y (Hansen et al.); Chem. Abstracts 117, 14347q (Bundgaard et al.); Chem. Abstracts 117, 55790x (Jensen et al.); and Chem. Abstracts 123, 17593b (Thomsen et al.).
As far as the present inventors are aware, there are no prodrugs of the proton pump inhibitors presently in use. However, several U.S. patents describe compounds which can act as prodrugs of certain proton pump inhibitors. Specifically, U.S. Pat. No. 4,686,230 (Rainer et al.) describes derivatives of pyridyl methyl sulfinyl benzimidazoles which include a group designated xe2x80x9cR5xe2x80x9d on one of the benzimidazole nitrogens. The xe2x80x9cR5xe2x80x9d group is expected to cleave under physiological condition, or under the influence of an enzyme to provide the corresponding compound with a free N-H bond (see column 3 of U.S. Pat. No. 4,686,230). U.S. Pat. Nos. 5,021,433 (Alminger et al.), 4,045,563 (Berntsson et al.), 4,965,269 and (Brxc3xa4ndstrxc3x6m et al.) also describe pyridyl methyl sulfinyl benzimidazoles where one of the nitrogens of the benzimidazole moiety bears a substituent that cleaves under physiological or enzymatic conditions. U.S. Pat. No. 4,045,563 (Berntsson et al.)describes N-alkoxycarbonyl benzimidazole derivates.
A publication by Sih., et al. Journal of Medicinal Chemistry, 1991, vol. 34, pp 1049-1062, describes N-acyloxyalkyl, N-alkoxycarbonyl, N-(aminoethyl), and N-alkoxyalkyl derivatives of benzimidazole sulfoxide as prodrugs of proton-pump inhibitors. According to this article these prodrugs exhibited improved chemical stability in the solid state and in aqueous solutions, but had similar activity or less activity than the corresponding parent compounds having a free imidazole N-H group. This publication does not provide data regarding the duration of the inhibitory activity of these prodrugs.
The present invention represents further advance in the art in that it provides prodrugs of improved structure of the proton pump inhibitor type drugs and provides proof of the suitability of the prodrugs of the invention for use as prodrug of proton pump inhibitors, with improved efficacy in therapy of acid related diseases due to prolongation of the presence of the proton pump inhibitors in the body.
The present invention relates to compounds of Formula 1
Het1xe2x80x94Xxe2x80x94S(O)xe2x80x94Het2
wherein
Het1 is selected from the formulas shown below
X is selected from the formulas
and Het2 is selected from the formulas
where N in the benzimidazole moiety means that one of the ring carbons may be exchanged for an unsubstituted N atom;
R1, R2 and R3 are independently selected from hydrogen, alkyl of 1 to 10 carbons, fluoro substituted alkyl of 1 to 10 carbons, alkoxy of 1 to 10 carbons, fluoro substituted alkoxy of 1 to 10 carbons, alkylthio of 1 to 10 carbons, fluoro substituted alkylthio of 1 to 10 carbons, alkoxyalkoxy of 2 to 10 carbons, amino, alkylamino and dialkylamino each of the alkyl groups in said alkylamino and dialkyl amino groups having 1 to 10 carbons, halogen, phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, phenylalkoxy, each of the alkyl groups in said alkyl substituted phenyl, alkoxy substituted phenyl and phenylalkoxy having 1 to 10 carbons, piperidino, morpholino or two of the R1, R2 and R3 groups jointly forming a 5 or 6 membered ring having 0 or 1 heteroatom selected from N, S and O;
R4 and R5 are independently selected from hydrogen, alkyl of 1 to 10 carbons, fluoro substituted alkyl of 1 to 10 carbons, phenylalkyl, naphthylalkyl and heteroarylalkyl, alkyl in said phenylalkyl, naphthylalkyl and heteroarylalkyl groups having 1 to 10 carbons;
R6 is hydrogen, halogen, alkyl of 1 to 10 carbons, fluoro substituted alkyl of 1 to 10 carbons, alkoxy having 1 to 10 carbons or fluoro substituted alkoxy having 1 to 10 carbons;
R6 through R9 are independently selected from hydrogen, halogen, alkyl of 1 to 10 carbons, halogen substituted alkyl of 1 to 10 carbons, alkoxy of 1 to 10 carbons, halogen substituted alkoxy of 1 to 10 carbons, alkylcarbonyl, alkoxycarbonyl the alkyl group in said alkylcarbonyl and alkoxycarbonyl having 1 to 10 carbons, oxazolyl, imidazolyl, thiazolyl, morpholinyl, piperazinyl, pyrazinyl, pyrazolyl, or any two adjacent ones of the R6 through R9 groups may form a ring that may optionally include a heteroatom selected from N, O and S and said ring may be further substituted;
R10 is hydrogen, alkyl of 1 to 10 carbons, or R10 may form an alkylene chain together with R3,
R11 and R12 are independently selected from hydrogen, halogen, alkyl of 1 to 10 carbons and halogen substituted alkyl of 1 to 10 carbons;
R15 has the formula below
where
R17 is alkyl of 1 to 10 carbons, halogen substituted alkyl of 1 to 10 carbons, alkoxy having 1 to 10 carbons, halogen substituted alkoxy of 1 to 10 carbons, alkylthio having 1 to 10 carbons, halogen substituted alkylthio of 1 to 10 carbons, alkoxy carbonyl having 1 to 10 carbons, halogen substituted alkoxy carbonyl having 1 to 10 carbons, F, Cl, Br, I, NO2 , CN, OCOalkyl, NH2, alkylamino and dialkylamino where in said OCOalkyl, alkylamino and dialkylamino groups each of said alkyl group has 1 to 10 carbons, further R17 is carbamoyl, N- lower alkyl carbamoyl having 1 to 6 carbons, alkylcarbonyl having 1 to 10 carbons, (alkoxycarbonyl)alkoxy groups of each of said alkoxy group has 1 to 10 carbons, (alkoxycarbonyl)alkyl groups of each of said alkoxy or alkyl group has 1 to 10 carbons, (carbamoyl)alkoxy having 1 to 10 carbons, (N-alkylcarbamoyl)alkoxy where each of said alkoxy or alkyl groups has 1 to 6 carbons, (N,N-dialkylcarbamoyl)alkoxy where each of said alkoxy or alkyl groups has 1 to 6 carbons, (N-alkyl substituted or unsubstituted carbamoyl)poly(alkoxy)n where each of said alkoxy or alkyl groups has 1 to 6 carbons and where n represents an integer selected from 2 to 5, (N-alkyl substituted or unsubstituted carbamoyl)alkyl where each of said alkyl groups has 1 to 5 carbons, (carbamoyl)alkenyl having 2 to 5 carbons, (dialkylcarbamoyl)alkenyl where each of said alkyl groups has 1 to 5 carbons and where the alkenyl group has 2 to 5 carbons, [N-(heteroaryl)carbamoyl]alkyl having 1 to 10 carbons wherein heteroaryl has 1 to 3 heteroatoms independently selected from N, O, and S, [N-(heteroaryl)carbamoyl]alkoxy having 1 to 10 carbons wherein heteroaryl has 1 to 3 heteroatoms independently selected from N, O, and S, poly(alkoxy)n where each of said alkoxy groups has 2 to 10 carbons and wherein n represents an integer selected from 2 to 5, 2-[(2-oxy-ethoxy)-ethoxyl-(ethoxy)n-ethanoxy wherein n represents an integer selected from 1 to 3, guanidinyl group, ureido group, (dialkylamino)alkyl where each of said alkyl groups has 1 to 5 carbons, (dialkylamino)alkoxy where each of said alkyl or alkoxy groups has 1 to 5 carbons, dialkylamino-poly(alkoxy)n where each of said alkyl or alkoxy groups has 1 to 5 carbons and wherein n represents an integer selected from 2 to 5, [N-(carbamoylalkyl)carbamoyl]alkoxy where each of said alkoxy or alkyl groups has 1 to 5 carbons, (N-peptidyl carbamoyl)alkoxy where the alkoxy group has 1 to 5 carbons and wherein said peptidyl consists of two or three amino acids, N-peptidyl amido wherein said peptidyl consists of two or three amino acids, [N-(carbamoylalkyl)carbamoyl]alkyl where each of said alkyl groups has 1 to 5 carbons, [N-[(dicarbamoyl)alkyl]carbamoyl]alkoxy where each of said alkoxy or alkyl groups has 1 to 5 carbons, [N-(di(alkoxycarbonyl)alkyl]carbamoyl]alkoxy where each of said alkoxy or alkyl groups has 1 to 5 carbons, [N-[(dicarbamoyl)alkyl]amido where alkyl groups has 1 to 5 carbons, [N-[di(alkoxycarbonyl)alkyl]amido where each of said alkoxy or alkyl groups has 1 to 5 carbons, [N-[(carbamoyl)alkyl]amido where alkyl groups has 1 to 5 carbons, [N-[(alkoxycarbonyl)alkyl]amido where each of said alkoxy or alkyl groups has 1 to 5 carbons, [N-[[N-(heteroaryl) carbamoyl]alkyl]carbamoyl]alkoxy where each of said alkoxy or alkyl groups has 1 to 5 carbons and wherein said heteroaryl has 1 to 3 heteroatoms independently selected from N, O, and S, [(tri-alkyl)ammonium]-alkoxy where each of said alkoxy or alkyl groups has 1 to 5 carbons, SO3xe2x88x92, aminosulfonyl, (sulfonato)alkyl having 2 to 5 carbons, (sulfonato)alkoxy having 2 to 5 carbons, N-[(sulfonato)alkyl]amido having 2 to 5 carbons, maleimido- and succinimido, and
R21 is (aryl)alkyl, (heteroaryl)alkyl where alkyl has 1 to 10 carbons, phenyl, naphthyl or heteroaryl having 1 to 3 heteroatoms independently selected from N, O and S, said phenyl, naphthyl or heteroaryl groups being unsubstituted or substituted with 1 to 5 R17 groups,
or to a pharmaceutically acceptable salt of said compounds.
The compounds of the invention are sulfoxides and have an asymmetric center in the sulfur atom. Both the pure enatiomers, racemic mixtures and unequal mixtures of the two are within the scope of the present invention. Some of the compounds of the invention may have one or more asymmetric carbon atoms (for example in a branch-chained alkyl group). All optical isomers, racemates, diastereomers and their mixtures are within the scope of the invention.
The compounds of the invention act as prodrugs of proton pump inhibitor type drugs which are useful for inhibiting gastric acid secretion. The compounds of the invention have excellent stability in tablet or capsule form, are acid stable, have excellent bioavailability and plasma half life which is significantly longer than the plasma half life of the presently used proton pump inhibitors.
The chemical structure of the compounds of the invention is shown and described in broad terms in the Summary of the Invention in connection with Formula 1. As it can be seen in the formula, the compounds of the invention are pyridyl methyl sulfinyl benzimidazoles, or compounds of closely related structure, wherein one of the benzimidazole nitrogens is substituted with a group (designated R15 in Formula 1) that gradually cleaves under physiological conditions and thereby provides the pyridyl methyl sulfinyl benzimidazole compound (or compound of closely related structure) which has a free N-H function in the benzimidazole (or related) moiety. The compound thus obtained by cleavage of the R15 group then undergoes the acid catalyzed rearrangement and provides the thiophilic species which inhibits the H,K-ATPase enzyme involved in gastric acid production. Thus, the novel compounds of the present invention bearing the R15 group are prodrugs of the proton pump inhibitor compounds which could also be depicted by Formula 1, where, however the R15 group would be designated hydrogen.
Generally speaking, among the prodrugs compounds of the present invention those are preferred wherein the structure of the pyridyl methyl sulfinyl benzimidazole or structurally related moiety is also preferred in the prior art. In other words, preferably prodrugs are provided in accordance with the present invention for those proton pump inhibitor drugs which are themselves preferred.
Referring now to the specific designation of symbols in connection with Formula 1, compounds are preferred in accordance with the present invention wherein the moiety designated Het1 is pyridyl substituted with alkyl, O-alkyl, O-alkoxyalkyl and/or O-fluoroalkyl groups. Most preferred substituents for the pyridine moiety, designated R1, R2 and R3 in Formula 1, are CH3Oxe2x80x94, CH3xe2x80x94, CF3CH2Oxe2x80x94, and CH3O(CH2)3Oxe2x80x94.
The moiety designated X in Formula 1 is preferably a methylene (xe2x80x94CH2xe2x80x94) group, or a xe2x80x94CHR10 group and the methylene or xe2x80x94CHR10 group is preferably attached in xcex1 position to the nitrogen in the pyridine moiety. Compounds where the X is ortho phenylene or substituted ortho phenylene are also preferred; in the most preferred compounds X is methylene.
Referring now to the group designated Het2 in Formula 1, this moiety is preferably a substituted benzimidazole. The R6 through R9 groups preferably are selected from hydrogen, chlorine and fluoro-substituted alkoxy groups, with hydrogen, chlorine, CF2HOxe2x80x94 and CH3Oxe2x80x94 being even more preferred.
Referring now to the group designated R15 in connection with Formula 1 it will be apparent to those skilled in the art that this group represents the principal novel structural feature of the present invention. Among the R15 groups shown in connection with Formula 1 the phenylsulfonyl and heteroarylsulfonyl groups (designated R21(R17)SO2xe2x80x94) are preferred. Even more preferably the aryl portion (R21) is phenyl or pyridyl unsubstituted or substituted with 1 to 3 R17 groups. When the R21 group is substituted, then the substituent (R17) is preferably selected from Cl, Br, F, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, di-(alkyl)amino, alkoxycarbonyl, (alkoxycarbonyl)alkoxy, ureido, guanidinyl, carbamoyl, N-alkyl carbamoyl, carbamoylalkyl, (N-alkyl carbamoyl)alkyl, (carbamoyl)alkenyl, (dialkylcarbamoyl)alkenyl, di-(alkylamino)alkoxy, morpholinyl, (morpholin-4-yl)alkoxy, (morpholin-4-yl)poly(alkoxy)n where n is an integer having the value of 2 to 5, di-(alkylamino)alkyl, poly(alkoxy)n alkoxy where n is an integer having the value of 1 to 5, 2-[(2-oxy-ethoxy)-ethoxy]-(ethoxy)n-ethanoxy wherein n represents an integer selected from 1 to 3, (carbamoyl)alkoxy, [(N-(alkyl)carbamoyl]alkoxy, [N,N-(dialkyl)carbamoyl)alkoxy, (N,N-dialkylcarbamoyl)alkyl, [N-(heteroaryl)carbamoyl]alkyl, [N-(heteroaryl)carbamoyl]alkoxy, [N-(aryl)carbamoyl]alkoxy, [N-[(dicarbamoyl)alkyl]carbamoyl]alkoxy, [N-[(carbamoyl)alkyl]carbamoyl]alkoxy, [N-[(N-alkyl carbamoyl)alkyl]carbamoyl]alkoxy, [N-[di(alkoxycarbonyl)alkyl]carbamoyl]alkoxy, [N-[(dicarbamoyl)alkyl]amido, [N-[di(alkoxycarbonyl)alkyl]amido, [N-[(carbamoyl)alkyl]amido, [N-[(alkoxycarbonyl)alkyl]amido, SO3xe2x88x92, aminosulfonyl, (sulfonato)alkyl, (sulfonato)alkoxy, N-[(sulfonato)alkyl]amido, maleimido-, succinimido and [(tri-alkyl)ammonium]-alkoxy groups, wherein the terms alkyl and alkoxy, define groups having 1 to 6 carbons, and alkenyl defines groups having 2 to 5 carbons, and heteroaryl has 1 to 3 heteroatoms independently selected from N, O, and S.
Even more preferably the R21 group is unsubstituted (R17 is H) or the substituent of the R21 group is selected from Cl, Br, F, methyl, methoxy, trifluoromethyl, trifluoromethoxy, dimethylamino, ethoxycarbonyl, (methoxycarbonyl) methoxy, carbamoyl, guanidinyl, ureido, 2-carbamoyl vinyl, 2-(N,N-dimethylcarbamoyl)vinyl, (carbamoyl)methoxy, [N-(pyridyl)carbamoyl]methoxy, morpholinyl, (morpholin-4-yl)alkoxy, [(morpholin-4-yl)alkoxy]alkoxy, 2-(dimethylamino)ethoxy, [N-[(carbamoyl)methyl]carbamoyl]methoxy, (N-(1,3-dicarbamoyl-propyl)carbamoyl)methoxy, (dimethylamino)methyl, SO3xe2x88x92, aminosulfonyl, sodium(sufonato)alkoxy having 2 to 4 carbons, (trimethylammonium) alkoxy having 2 to 4 carbons, poly(alkoxy),, wherein the alkoxy groups have 1 to 3 carbons and n is an integer having the values of 2 to 5, and xe2x80x94(OCH2CH2)nxe2x80x2xe2x80x94Oxe2x80x94 where nxe2x80x2 is 4 or 5. Still more preferably there are one or two R17 substituents (other than hydrogen) in the phenyl (R21) moiety, and preferably the R17 substituent is in a position para (1,4) and/or meta (1,3) to the sulfonyl (SO2) group.
The most preferred compounds of the invention are those wherein the proton pump inhibitor portion is the same as in the widely used proton pump inhibitor drugs known under the names LANSOPRAZOLE, OMEPRAZOLE, PANTOPRAZOLE and RABEPRAZOLE and wherein the R15 group is a benzenesulfonyl group or pyridyl group substituted in the 4 (para) and/or in the 3 (meta) position with a Cl, Br, F, CH3, CH3O, CF3, CF3Oxe2x80x94, (CH3)2N, NH2CO, NH2CONH, NH2C(xe2x95x90NH)NH, 4-morpholino, 2-(4-morpholinyl)ethoxy, 2-[2-(4-morpholinyl)ethoxy]ethoxy, 3-(4-morpholinyl)propoxy, poly(alkoxy)n-alkoxy where n is an integer having the value of 1 to 3, xe2x88x92O3Sxe2x80x94, Na+xe2x88x92O3Sxe2x80x94CH2CH2CH2xe2x80x94O, Xxe2x88x92 (CH3)3NCH2CH2Oxe2x80x94 (X is an anion, such as a halogen ion), NH2COCH2O, (pyridyl)NHCOCH2O, NH2COCH2NH2COCH2O, (CH3)2NCH2 or EtOCO group. These compounds are shown by Formulas 2, 3, 4 and 5, respectively, where R17* represents said Cl, Br, F, CH3, CH3O, CF3, CF3Oxe2x80x94, (CH3)2N, NH2CO, NH2CONH, NH2C(xe2x95x90NH)NH, 4-morpholino, 2-(4-morpholinyl)ethoxy, 2-[2-(4-morpholinyl)ethoxy]ethoxy, 3-(4-morpholinyl)propoxy, poly(alkoxy)n-alkoxy where n is an integer having the value of 1 to 3, xe2x88x92O3Sxe2x80x94, NH2COCH2O, (pyridyl)NHCOCH2O, NH2COCH2NHCOCH2O, (CH3)2NCH2, Na+ xe2x88x92O3Sxe2x80x94 CH2CH2CH2xe2x80x94O, (CH3)3N+CH2CH2Oxe2x80x94, MeOCOCH2CH(COOMe)NHCO or EtOCO groups in the 4 (para) or in the 3 (meta) position of the phenyl ring, or in the 3 and 4 positions of the phenyl ring and where the numbering of the benzimidazole ring is shown in the formulas. In Formula 3 the CH3Oxe2x80x94 group can occupy the 5 or the 6 position of the benzimidazole moiety, and in Formula 4 the CF2HOxe2x80x94 group can occupy the 5 or the 6 position of the benzimidazole moiety.
The compounds of the invention include
2-[[(3-chloro-4-morpholino-2-pyridyl)methyl]sulfinyl]-5-methoxy-(1H)-benzimidazole,
2-[[[4-(2,2,3,3,4,4,4-heptafluorobutyl)oxy]-2-pyridyl]methyl]sulfinyl]-1H-thieno[3,4-d]imidazole,
2-[[(4-ethythio-3-methyl-2-pyridyl)methyl]sulfinyl]-1h-benzimidazole
2-[(3-methoxyphenyl)methylsulfinyl]-1H-benzimidazole,
2-[(3-methoxyphenyl)methylsulfinyl]imidazolo[5,4-c]pyridine,
2-[(3-methoxyphenyl)methylsulfinyl]imidazolo[4,5-c]pyridine,
and 2-[(3-methoxyphenyl)methylsulfinyl]-5-nitro-benzimidazole, of which 1-position have R15 group. R15 group of these compounds is a benzenesulfonyl group mono-substituted either in the 4 (para) or in the 3 (meta) position with a Cl, Br, F, CH3, CH3O, CF3, CF3O, (CH3)2N, NH2CO, NH2CONH, NH2C(xe2x95x90NH)NH, 4-morpholino, 2-(4-morpholinyl)ethoxy, 2-[2-(4-morpholinyl)ethoxy]ethoxy, 3-(4-morpholinyl)propoxy, NH2COCH2O, (pyridyl)NHCOCH2O, NH2COCH2NH2COCH2O, (CH3)2NCH2, Na+ xe2x88x92O3Sxe2x80x94CH2CH2CH2xe2x80x94O, (CH3)3N+CH2CH2Oxe2x80x94, or EtOCO group.
Examples of the presently most preferred compounds of the invention are as follows:
1-benzenesulfonyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-benzenesulfonyl-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-benzenesulfonyl-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-benzenesulfonyl-6-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-benzenesulfonyl-2-[(3-methyl-4-(2xe2x80x2,2xe2x80x2,2xe2x80x2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-chlorobenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-chlorobenzenesulfonyl)-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-chlorobenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-chlorobenzenesulfonyl)-6-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-chlorobenzenesulfonyl)-2-[(3-methyl-4-(2xe2x80x2,2xe2x80x2,2xe2x80x2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-bromobenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-bromobenzenesulfonyl)-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-bromobenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-bromobenzenesulfonyl)-6-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-bromobenzenesulfonyl)-2-[(3-methyl-4-(2xe2x80x2,2xe2x80x2,2xe2x80x2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-fluorobenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-fluorobenzenesulfonyl)-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-fluorobenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-fluorobenzenesulfonyl)-6-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-fluorobenzenesulfonyl)-2-[(3-methyl-4-(2xe2x80x2,2xe2x80x2,2xe2x80x2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-methylbenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-methylbenzenesulfonyl)-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-methylbenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-methylbenzenesulfonyl)-6-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-methylbenzenesulfonyl)-2-[(3-methyl-4-(2xe2x80x2,2xe2x80x2,2xe2x80x2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-methoxybenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-methoxybenzenesulfonyl)-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-methoxybenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-methoxybenzenesulfonyl)-6-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-methoxybenzenesulfonyl)-2-[(3-methyl-4-(2xe2x80x2,2xe2x80x2,2xe2x80x2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(3-trifluoromethylbenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(3-trifluoromethylbenzenesulfonyl)-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(3-trifluoromethylbenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(3-trifluoromethylbenzenesulfonyl)-6-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(3 -trifluoromethylbenzenesulfonyl)-2-[(3-methyl-4-(2xe2x80x2,2xe2x80x2,2xe2x80x2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-trifluoromethoxybenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-trifluoromethoxybenzenesulfonyl)-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-trifluoromethoxybenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-trifluoromethoxybenzenesulfonyl)-6-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-trifluoromethoxybenzenesulfonyl)-2-[(3-methyl-4-(2xe2x80x2,2xe2x80x2,2xe2x80x2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-dimethylaminobenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-dimethylaminobenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-dimethylaminobenzenesulfonyl)-2-[(3-methyl-4-(2xe2x80x2,2xe2x80x2,2xe2x80x2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-ethoxycarbonylbenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-ethoxycarbonylbenzenesulfonyl)-2-[(3-methyl-4-(2xe2x80x2,2xe2x80x2,2xe2x80x2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(pyridine-3-sulfonyl)-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-(pyridine-3-sulfonyl)-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-(pyridine-3-sulfonyl)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole,
1-(pyridine-3-sulfonyl)-5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-(pyridine-3-sulfonyl)-6-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[4-[(morpholin-4-yl)phenyl]sulfonyl]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[4-[(morpholin-4-yl)phenyl]sulfonyl]-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
N-[4-[[5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]benzimidazol-1-yl]sulfonyl]phenyl]urea,
N-[4-[[6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]benzimidazol-1-yl]sulfonyl]phenyl]urea,
N-(4-{[2-({[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl}sulfinyl)benzimidazol-1-yl]sulfonyl}phenyl)urea,
N-(4-{[2-({[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl}sulfinyl)benzimidazol-1-yl]sulfonyl}phenyl)urea,
N-(4-{[2-{[(3,4-di(methoxy)-2-pyridyl)methyl]sulfinyl}-5-(difluoromethoxy)-benzimidazol-1-yl]sulfonyl}phenyl)urea,
N-(4-{[2-{[(3,4-di(methoxy)-2-pyridyl)methyl]sulfinyl}-6-(difluoromethoxy)-benzimidazol-1-yl]sulfonyl}phenyl)urea,
2-[4-(3-Methoxy-propoxy)-3-methyl-pyridin-2-ylmethanesulfinyl]-1-(6,7,9,10,12,13,15,16-octahydro-5,8,11,14,17-pentaoxa-benzocyclopentadecene-2-sulfonyl)-1H-benzimidazole,
2-[3-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-1-(6,7,9,10,12,13,15,16-octahydro-5,8,11,14,17-pentaoxa-benzocyclopentadecene-2-sulfonyl)-1H-benzimidazole,
5-Methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethanesulfinyl)-1-(6,7,9,10,12,13,15,16-octahydro-5,8,11,14,17-pentaoxa-benzocyclopentadecene-2-sulfonyl)-1H-benzimidazole,
6-Methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethanesulfinyl)-1-(6,7,9,10,12,13,15,16-octahydro-5,8,11,14,17-pentaoxa-benzocyclopentadecene-2-sulfonyl)-1H-benzimidazole,
5-Difluoromethoxy-2-(3,4-dimethoxy-pyridin-2-ylmethanesulfinyl)-1-(6,7,9,10,12,13,15,16-octahydro-5,8,11,14,17-pentaoxa-benzocyclopentadecene-2-sulfonyl)-1H-benzimidazole,
6-Difluoromethoxy-2-(3,4-dimethoxy-pyridin-2-ylmethanesulfinyl)-1-(6,7,9,10,12,13,15,16-octahydro-5,8,11,14,17-pentaoxa-benzocyclopentadecene-2-sulfonyl)-1H-benzimidazole,
2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}acetamide,
2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide,
N-(carbamoylmethyl)-2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}acetamide,
2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}acetamide,
2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide,
N-(carbamoylmethyl)-2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}acetamide,
2-(4-{[2-({[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl}sulfinyl)benzimidazol-1-yl]sulfonyl}phenoxy)acetamide,
2-(4-{[2-({[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl}sulfinyl)benzimidazol-1-yl]sulfonyl}phenoxy)-N-(2-pyridyl)acetamide,
N-(carbamoylmethyl)-2-(4-{[2-({[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl}sulfinyl)benzimidazol-1-yl]sulfonyl}phenoxy)acetamide,
2-{4-[(5-(difluoromethoxy)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}acetamide,
2-{4-[(5-(difluoromethoxy)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide,
6N-(carbamoylmethyl)-2-{4-[(5-(difluoromethoxy)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}acetamide,
2-{4-[(6-(difluoromethoxy)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}acetamide,
2-{4-[(6-(difluoromethoxy)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide,
N-(carbamoylmethyl)-2-{4-[(6-(difluoromethoxy)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}acetamide,
2-(4-{[2-({[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl}sulfinyl)benzimidazol-1-yl]sulfonyl}phenoxy)acetamide,
2-(4-{[2-({[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl}sulfinyl)benzimidazol-1-yl]sulfonyl}phenoxy)-N-(2-pyridyl)acetamide,
N-(carbamoylmethyl)-2-(4-{[2-({[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl}sulfinyl)benzimidazol-1-yl]sulfonyl}phenoxy)acetamide,
1-[[4-{3-(morpholin-4-yl)propoxy}phenyl)sulfonyl]-5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[[4-{3-(morpholin-4-yl)propoxy}phenyl]sulfonyl]-6-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[[4-{3-(morpholin-4-yl) propoxy}phenyl]sulfonyl]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[[4-{3-(morpholin-4-yl) propoxy}phenyl]sulfonyl]-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[[4-{3-(morpholin-4-yl)propoxy}phenyl]sulfonyl]-2-[(3-methyl-4-methoxypropoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-[[4-{3-(morpholin-4-yl) propoxy}phenyl]sulfonyl]-2-[(3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-[4-[2-(morpholin-4-yl)ethoxy]phenylsulfonyl]-2-[[[(4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole,
1-[4-[2-(morpholin-4-yl)ethoxy]phenylsulfonyl]-5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[4-[2-(morpholin-4-yl)ethoxy]phenylsulfonyl]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]]-1H-benzimidazole,
1-[4-[2-(morpholin-4-yl)ethoxy]phenylsulfonyl]-6-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[4-[2-(morpholin-4-yl)ethoxy]phenylsulfonyl]-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]]-1H-benzimidazole,
1-[4-[2-(morpholin-4-yl)ethoxy]phenylsulfonyl]-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole,
1-[{(N,N-dimethylamino)methyl}benzene-4-sulfonyl]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[2-acetamido-4-methyl-5-thiazolylsulfonyl]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-(thiophene-2-sulfonyl)-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[{(N,N-dimethylamino)methyl}benzene-4-sulfonyl]-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[2-acetamido-4-methyl-5-thiazolylsulfonyl]-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-(thiophene-2-sulfonyl)-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-(thiophene-2-sulfonyl)-2-[[[(4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole,
1-(thiophene-2-sulfonyl)-5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-(thiophene-2-sulfonyl)-6-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-(thiophene-2-sulfonyl)-]-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole,
1-(phenylmethylsulfonyl)-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[(N,N-dimethylamino)benzene-4-sulfonyl]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-(phenylmethylsulfonyl)-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[(N,N-dimethylamino)benzene-4-sulfonyl]-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-(pyridine-3-sulfonyl)-2-[[(3-methyl-4-methoxypropoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[4-(morpholin-4-yl)phenylsulfonyl]-2-[[[(4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole,
1-benzenesulfonyl-2-[[(3-chloro-4-morpholino-2-pyridyl)methyl]sulfinyl]-5-methoxy-(1H)-benzimidazole,
1-benzenesulfonyl-2-[[[(4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole,
1-benzenesulfonyl-2-[(3-methoxyphenyl)methylsulfinyl]-1H-benzimidazole,
1-benzenesulfonyl-2-[(3-methoxyphenyl)methylsulfinyl]imidazolo[5,4-c]pyridine,
1-benzenesulfonyl-2-[(3-methoxyphenyl)methylsulfinyl]imidazolo[4,5-c]pyridine,
1-benzenesulfonyl-2-[(3-methoxyphenyl)methylsulfinyl]-5-nitro-benzimidazole,
1-benzenesulfonyl-2-[{2-(dimethylamino)phenyl}methylsulfinyl]-1H-benzimidazole,
1-benzenesulfonyl-2-[[[4-(2,2,3,3,4,4,4-heptafluorobutyl)oxy]-2-pyridyl]methyl]sulfinyl]-1H-thieno[3,4-d]imidazole,
1-[4-[2-(morpholin-4-yl)ethoxy]phenylsulfonyl]-2-[(3-methoxyphenyl)methylsulfinyl]imidazolo{5,4-c]pyridine,
1-[4-[2-(morpholin-4-yl)ethoxy]phenylsulfonyl]-2-[{2-(dimethylamino)phenyl}methylsulfinyl]-1H-benzimidazole,
1-[[2-{2-(morpholin-4-yl)ethoxy}ethoxy]phenyl-4-sulfonyl]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[[2-{2-(morpholin-4-yl)ethoxy}ethoxy]phenyl-4-sulfonyl]-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[[2-{2-(morpholin-4-yl)ethoxy}ethoxy]phenyl-4-sulfonyl]-2-[[[(4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole,
1-[[2-{2-(morpholin-4-yl)ethoxy}ethoxy]phenyl-4-sulfonyl]-5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[[2-{2-(morpholin-4-yl)ethoxy}ethoxy]phenyl-4-sulfonyl]-6-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[[2-{2-(morpholin-4-yl)ethoxy}ethoxy]phenyl-4-sulfonyl]-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole,
1-(4-acetaminobenzenesulfonyl)-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-(4-acetaminobenzenesulfonyl)-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[(2-dimethylcarbamoyl-vinyl)benzene-4-sulfonyl]-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
-[(2-dimethylcarbamoyl-vinyl)benzene-4-sulfonyl]-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-[(2-carbamoyl-vinyl)benzene-4-sulfonyl]-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-[(2-carbamoyl-vinyl)benzene-4-sulfonyl]-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
sodium 2-[5-methoxy-2-(4-methoxy-3,5-dimethyl pyridin-2-yl
methanesulfinyl)benzimidazole-1-sulfonyl]benzene sulfonate,
sodium 2-[6-methoxy-2-(4-methoxy-3,5-dimethyl pyridin-2-yl
methanesulfinyl)benzimidazole-1-sulfonyl]benzene sulfonate,
{4-[5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridinyl)methanesulfinyl benzimidazole-1-sulfonyl]phenoxy}acetic acid methyl ester,
{4-[6-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridinyl)methanesulfinyl benzimidazole-1-sulfonyl]phenoxy}acetic acid methyl ester,
1-[(4-(2-dimethylaminoethoxy))benzenesulfonyl]-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-[(4-(2-dimethylamino ethoxy))benzenesulfonyl]-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
N-(2-{4-[5-methoxy-2-(4-methoxy-3,5-dimethyl pyridin-2-yl methanesulfinyl)benzimidazole-1-sulfonyl]-phenoxy}ethyl)-N,N,N-trimethyl ammonium trifluoromethanesulfonate,
N-(2-{4-[6-methoxy-2-(4-methoxy-3,5-dimethyl pyridin-2-yl methanesulfinyl)benzimidazole-1-sulfonyl]-phenoxy}ethyl)-N,N,N-trimethyl ammonium trifluoromethanesulfonate,.
2-{2-carbamoylmethoxy-4-[5-methoxy-2-((4-methoxy-3,5-dimethyl pyridin-2yl)methanesulfinyl)benzimidazole-1-sulfonyl]phenoxy}acetamide,
2-{2-carbamoylmethoxy-4-[6-methoxy-2-((4-methoxy-3,5-dimethyl pyridin-2-yl)methanesulfinyl)benzimidazole-1-sulfonyl]phenoxy}acetamide,
1,3-bis[5-methoxy-2-[((4-methoxy-3,5-dimethyl) pyridin-2-yl) methanesulfinyl]benzimidazole-1-sulfonyl]-benzene,
1,3-bis[6-methoxy-2-[((4-methoxy-3,5-dimethyl) pyridin-2-yl) methanesulfinyl]benzimidazole-1-sulfonyl]-benzene,
1-[5- methoxy-2-[((4-methoxy-3,5-dimethyl) pyridin-2-yl) methanesulfinyl]benzimidazole-1-sulfonyl]-3-[6-methoxy-2-[((4-methoxy-3,5-dimethyl) pyridin-2-yl) methanesulfinyl]benzimidazole-1-sulfonyl]-benzene,
1-[6-methoxy-2-[((4-methoxy-3,5-dimethyl) pyridin-2-yl) methanesulfinyl]benzimidazole-1-sulfonyl]-3-[5-methoxy-2-[((4-methoxy-3,5-dimethyl) pyridin-2-yl) methanesulfinyl]benzimidazole-1-sulfonyl]-benzene, sodium 2-[2-[[(4-methoxypropoxy-3-methyl) pyridin-2-yl]methanesulfinyl]benzimidazole-1-sulfonyl]benzenesulfonate,
2-(2-carbamoylmethoxy-4-{2-[4-(3-methoxypropoxy)-3-methyl pyridin-2-yl methylsulfinyl]benzimidazole-1-sulfonyl}phenoxy)acetamide,
2-{2-carbamoylmethoxy-4-[6-difluoromethoxy-2-(3,4-dimethoxy-pyridin-2-ylmethanesulfinyl)-benzimidazole-1-sulfonyl]-phenoxy}-acetamide,
2-{2-carbamoylmethoxy-4-[5-difluoromethoxy-2-(3,4-dimethoxy-pyridin-2-ylmethanesulfinyl)-benzimidazole-1-sulfonyl]-phenoxy}-acetamide,
2-(2-carbamoylmethoxy-4-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl)-benzimidazole-1-sulfonyl}-phenoxy)-acetamide, and
2-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-benzoimidazole-1-sulfonyl}-benzenesulfonic acid sodium salt.
The compounds of the invention can be prepared by the reacting the 2-pyridylmethylsulfinyl-1H-benzimidazole derivatives (or structurally related compounds) having a free NH group within the imidazole moiety, with an arylsulfonyl chloride. In the broad sense the benzimidazole or structurally related compound which is the starting material having the free NH group, can be described by Formula 1 wherein the R15 group would be H. Similarly, in the broad sense the arylsulfonyl chloride reagent is described by the formula R21(R17)SO2Cl where the R21 and R17 groups are defined as in connection with Formula 1. Reaction Scheme 1 discloses a process for preparing examplary preferred compounds of the invention by reacting the 2-pyridylmethylsulfinyl-1H-benzimidazole derivative of Formula 6 with a benzenesulfonyl chloride derivative of Formula 7 in the presence of a suitable base. The reaction is typically conducted in an inert organic solvent, such as dichloromethane in the presence of an organic base, such as triethylamine. For compounds of Formula 6 and Formula 7 the R1-R3, R6-R9 and R17 groups are defined as in connection with Formula 1. As it can be seen in Reaction Scheme 1, the benzenesulphonylation reaction may give rise to two isomeric or tautomeric products depending on the nature and positions of the R6-R9 substituents on the benzimidazole ring. The two isomeric products (which may be merely tautomers) are shown in Formulas 8 and 9.
The benzenesulfonyl chloride derivatives of Formula 7 can be obtained in accordance with procedures well known in the art.
Those skilled in the art will recognize the 2-pyridylmethylsulfinyl-1H-benzimidazole derivatives of Formula 6 as the proton pump inhibitors generally known in the art and described for example in U.S. Pat. No. 4,686,230 (Rainer et. al.) and in published international application WO 97/48380 (Astra Aktiobiolag). Starting materials within the scope of Formula 13 include the known drugs LANSOPRAZOLE (U.S. Pat. No. 4,628,098), OMEPRAZOLE (U.S. Pat. Nos. 4,255,431 and 4,255,431), PANTOPRAZOLE (U.S. Pat. No. 4,758,579) and RABEPRAZOLE (U.S. Pat. No.5,045,552) Thus, the starting-compounds of Formula 6 can be prepared in accordance with the state-of-the-art, for example as described in U.S. Pat. Nos. 4,686,230, 4,628,098, 4,255,431, 4,758,579, 5,045,552, international application WO 97/48380, Journal of Medicinal Chemistry, 32, 1970-1977 (1989), Chem. Pharm. Bull. 38, 2853-2858 (1990), J. Med. Chem., 34, 1049-1062 (1991), Journal of Medicinal Chemistry, 35, 1049-1057 (1992), and Journal of Medicinal Chemistry, 35, 438-450 (1992), all of which are specifically incorporated herein by reference.
Instead of using the free benzimidazole compounds of Formula 6, their suitable salts such as the sodium, potassium, magnesium (and other) salts can be reacted with the benzenesulfonyl chloride derivative of Formula 7, to also provide the exemplary compounds of the invention in accordance with Formulas 8 and 9.
Reaction Scheme 2 discloses an alternative method for preparing the exemplary compounds of the invention, shown in Formulas 8 and 9. This reaction involves the oxidation of the corresponding 1-(N)-benzenesulfonyl-benzimidazolyl, 2-pyridylmethyl sulfide compounds of Formulas 10 and 11 to the corresponding sulfoxides. Those skilled in the art will recognize that Formulas 10 and 11 represent isomeric compounds which may be different or identical (tautomeric) with one another depending on the nature and position of the R6-R9 substituents. The oxidation reaction can be performed with oxidizing agents known in the art for forming sulfoxides, for example hydrogen peroxide, m-chloroperoxybenzoic acid and iodosobenzene may serve for this purpose. The oxidation reaction is normally conducted in an aprotic neutral solvent, such as dichloromethane. The sulfide compounds of Formulas 10 and 11 can be obtained by performing a benzenesulphonylation reaction (in analogy to the reaction of Scheme 1) on the sulfide compounds having a free benzimidazole NH group, or their suitable salt. The latter sulfides having the free benzimidazole NH group can be obtained in accordance with the state-of-the-art.
A significant advantage of the compounds of the present invention is that they can release the active forms of the proton pump inhibitors spontaneously by hydrolysis in the mammalian (including human) body. Hydrolysis can occur chemically or enzymatically. Because the compounds of this invention spontaneously release the active form of the proton pump inhibitor drugs by in vivo hydrolysis, they can attain longer duration of effective drug concentration in the body. Thus, the compounds of the present invention are prodrugs which are converted to active drugs by hydrolysis in the body, providing long duration of effective concentration. The long duration of inhibitory activity by spontaneous hydrolysis of the compounds of this invention allows more effective inhibition of gastric acid secretion, which enables better therapy of acid related disease as defined on pages 1 and 2. Compounds of this invention can be administered for inhibiting gastric acid secretion orally. The typical daily dose of the compounds will depend on various factors such as the individual requirement of each patient. In general, oral and parenteral dosages will be in the range of 5 to 100 mg per day.
Those skilled in the art will readily understand that for oral administration the compounds of the invention are admixed with pharmaceutically acceptable excipients which per se are well known in the art. Specifically, a drug to be administered systemically, it may be confected as a powder, pill, tablet or the like or as a syrup or elixir suitable for oral administration. Description of the subtances normally used to prepare tablets, powders, pills, syrups and elixirs can be found in several books and treatise well known in the art, for example in Remington""s Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pa.
Compounds of the present invention can be combined with certain amounts of known proton pump inhibitors, e. g. LANSOPRAZOLE, OMEPRAZOLE, PANTOPRAZOLE, or RABEPRAZOLE, to provide a drug-prodrug combination, and the combination administered for inhibition of gastric acid secretion. Thus, initially the proton pump inhibitor (drug) inhibits gastric acid secretion of the patient. The aforesaid known and widely used proton pump inhibitors have 60-90 minutes of plasma half-life. As the effective concentration of the proton pump inhibitor (drug) is decreased by metabolism, the compound of the present invention (prodrug) continuosly undergoes hydrolysis and provides and maintains new active inhibitor concentration in the mammalian, including human body.
A disadvantage of the presently used proton pump inhibitors is that for therapy by injection in a liquid form they must be reconstituted from a lyophilized powder in a medium having the high pH of approximately 9.5. The prodrugs of the present invention overcome the disadvantage of requiring a reconstituting medium having such high pH, because the compounds of the present invention can be reconstituted to form an injectable liquid in a medium of approximately pH 6.0 to 8.5. It will be readily appreciated by those skilled in the art that for administration in liquid form by injection the liquid that reconstitutes the drug is a pharmaceutically acceptable aqueous solution that per se is known in the art. Such pharmaceutically acceptable solutions utilized for administration of drugs in injectable form are described for example in the treatise PHARMACEUTICAL DOSAGE FORMS (Parenteral Medications, Volume 1, Edited by K. E. Avis, H. A. Lieberman and L. Lachman (1992).
For example, an exemplary compound of the invention, such as 2-(2-carbamoylmethoxy-4-{2-[4-(3-methoxypropoxy)-3-methyl pyridin-2-yl methylsulfinyl]benzimidazole-1-sulfonyl}phenoxy)acetamide is dissolved in aqueous 40% 2-hydroxypropyl-beta-cyclodextrin solution buffered at pH 7.4, to provide a concentration of 8 mg per ml of the compound of the invention, The latter formulation is injectable intravenously at pH 7.4 and 2-hydroxypropyl-beta-cyclodextrin is known to be safe and non-toxic excreted unchanged in urine within 12 hours. If necessary to dissolve a compound of the invention 20% sulfobutyl ether-beta-cyclodextrin and 20% hydroxypropyl-beta-cyclodextrin can be used for increasing solubility, as suggested (for other drugs) by the publications (J. Clin. Pharm., 1998, 38 (7) 593-602, J. Pharm. Sci., 1997, 86(3) 335-339, J. Pharm. Sci., 1992, 81, 524-548, J. Pharm. Sci., 1999, 88, 1016-1020, and J. Pharm. Sci., 1999, 88, 1107-1111.).
Among the benefits of the pre-proton pump inhibitor (P-PPI) type of drugs of the present invention is their ability to provide more effective treatment of erosive esophagitis and of less severe reflux diseases as well. This is because effective treatment of erosive esophagitis (and to a lesser extent of lesser reflux diseases) requires prevention of the reflux of gastric contents at pH 3.0 or still lower pH. The current PPI drugs allow several acidic excursions to pH  less than 2.0 per day, resulting in a moderate to weak amelioration of symptoms. However, healing would require elevation to pH  greater than 4.0 for about 16 hours per day or longer. When, as in current usual treatment by PPIs, the other 8 hours contain episodic acidity to pH 3.0 or less, the patients tend to continue to complain of pain. The more effective and more continues acid suppression by the drugs of the present invention is likely to result in substantially better treatment of this disease, as well as faster healing of all acid related erosions or ulcers.
The pre-proton pump inhibitor (P-PPI) type of drugs of the present invention provide improved dual therapy for H. pylori eradication. This is because the PPI""s synergize with cell division dependent antibiotics such as amoxicillin (cell wall biosynthesis) and clarithromycin (protein synthesis) by elevating gastric surface pH to enable a larger fraction of the bacterial population to be in dividing phase during presentation of the antibiotic to the gastric lumen. However, their effect on intragastric pH is limited by their dwell time in the plasma. The pre-proton pump inhibitor (P-PPI) type of drugs of the present invention can continuously elevate intra gastric pH close to neutrality on current once a day therapy. Therefore, 100% eradication of the bacteria is expected in dual therapy with the prodrugs of the invention (for example a pro-drug of OMEPRAZOLE in accordance with the invention) plus an effective antibiotic, such as amoxicillin.
Even monotherapy for H. pylori eradication is likely to be successful with the pre-proton pump inhibitor (P-PPI) type of drugs of the present invention. This is because in the absence of acid, the enzyme H. pylori urease elevates environmental pH to  greater than 8.3, which is toxic to the organism. PPI""s in current formulation inhibit growth or present of the organism in the antrum, due to elevation of antral pH to close to neutrality. Elevation of 24 hour pH to neutrality, as it can be accomplished with the drugs of the present invention, is likely to result in xe2x80x9cself eradicationxe2x80x9d of the bacteria.
Approximately 30% of patients with gastrointestinal distress appear with symptoms without quantitative underlying disease (non-ulcer dyspepsia). The most likely cause for these symptoms is upper gastrointestinal afferent nerve sensitivity to gastric acid. Only acid ablation ameliorates these symptoms and this can be attained with the drugs of the present invention.
By way of concrete examples, the following tests and results are described. Certain compounds of the invention have been tested in one or more standard laboratory tests that demonstrate gastric antisecretory activity. The compounds of the invention did not directly inhibit the K+-dependent ATP hydrolysis of gastric H,K-ATPase. However, after hydrolysis the compounds of this invention showed strong inhibition of gastric H,K-ATPase activity. This is consistent with the knowledge that the compounds obtained by hydrolysis e. g. LANSOPRAZOLE, OMEPRAZOLE, PANTOPRAZOLE and RABEPRAZOLE are well known H,K-ATPase inhibitors. For example, 1-benzenesulfonyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole was tested for inhibitory activity of gastric H,K-ATPase. Initially this compound did not inhibit gastric H,K-ATPase. However, gastric H,K-ATPase activity was spontaneously inhibited as hydrolysis of this compound in aqueous solution at pH 7.4 proceeded. After 5.75 hr -hydrolysis at pH 7.4, this compound inhibited 91% of gastric H,K-ATPase activity, same as 5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole (OMEPRAZOLE) which was the product of the hydrolysis. It was determined that 1-benzenesulfonyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-H-benzimidazole was hydrolyzed to 5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole (OMEPRAZOLE) with a half-life (txc2xd) 3xc2x10.5 hr at 37xc2x0 C. at pH 7.4 in the presence of the plasma proteins. Another good example is 2-(2-carbamoylmethoxy-4-{2-[4-(3-methoxypropoxy)-3-methyl pyridin-2-yl methylsulfinyl]benzimidazole-1-sulfonyl}phenoxy)acetamide. The half life of this compound dependes on pH. At pH 2 the half-life of this compound is about 1.8 hr (which mimics in vivo gastric juice pH), at pH 7.4 in the presence of bovine serum albumin it is about 3.7 hr (which mimics blood plasma serum), at pH 8 it is about 10.7 hr (which mimics similar pH of duodenum), and at pH 7.4 without bovine serum albumin it is about 22.2 hr. This data show that this pro-drug compound of the invention is reasonably stable in the stomach compared to the parent RABEPRAZOLE, which has a half-life of a few minutes at pH 2. Based on these measured characteristics the compound 2-(2-carbamoylmethoxy-4-{2-[4-(3-methoxypropoxy)-3-methyl pyridin-2-yl methylsulfinyl]benzimidazole-1-sulfonyl}phenoxy)acetamide is expected to be well absorbed, and slowly release the parent RABEPRAZOLE in the blood, resulting in long-lasting in vivo activity. This compound can also be administered intravenously in an aqueous solution at pH 7.4 which solution may include 2-hydroxypropyl-xcex2-cyclodextrin.
When a mixture of 2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide and 2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide was orally administrated to male rat, 5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (OMEPRAZOLE) was continuously released to the plasma for more than 4 hours as a result of the hydrolysis of 2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl }benzimidazol-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide and 2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide. As a control experiment, when OMEPRAZOLE was administrated to male rat, OMEPRAZOLE has completely disappeared from the plasma within 1.5 hr. Bioavailability of2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]benzimidazol-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide was much higher than that of OMEPRAZOLE after oral administration.
Additional experiments, described below, with further compounds of the invention showed good inhibition of gastric acid secretion. For example, when a mixture of 2-{2-carbamoylmethoxy-4-[5-methoxy-2-((4-methoxy-3,5-dimethyl pyridin-2-yl)methanesulfinyl)benzimidazole-1-sulfonyl]phenoxy}acetamide and 2-{2-carbamoylmethoxy-4-[6-methoxy-2-((4-methoxy-3,5-dimethyl pyridin-2-yl)methanesulfinyl)benzimidazole-1-sulfonyl]phenoxy}acetamide (1:1 mixture of isomers) was administrated to male rat, gastric acid secretion was observed to be significantly and continuously inhibited. Using pylorus-ligated male rats, when acid-output stimulated by histamine was measured, intraduodenal administration of 10 xcexcmole of 2-{2-carbamoylmethoxy-4-[5-methoxy-2-((4-methoxy-3,5-dimethyl pyridin-2-yl)methanesulfinyl)benzimidazole-1-sulfonyl]phenoxy}acetamide and 2-{2-carbamoylmethoxy-4-[6-methoxy-2-((4-methoxy-3,5-dimethyl pyridin-2-yl)methanesulfinyl)benzimidazole-1-sulfonyl]phenoxy}acetamide (1:1 mixture of isomers) provided 64.2% inhibition, while OMEPRAZOLE provided only 54.6% under identical condition. Also, when acid-output stimulated by histamine and carbachol was measured after 5.5 hr of oral administration, the latter mixture of isomers provided 49.7% inhibition, while OMEPRAZOLE provided only 19.6% inhibition. Under similar condition, (pyridine-3-sulfonyl)OMEPRAZOLE (the compound of Example 25) inhibited 61% and a mixture of 2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl } benzimidazol-1-yl)sulfonyl]phenoxy} acetamide and 2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl} benzimidazol-1-yl)sulfonyl]phenoxy}acetamide inhibited 65%, while OMEPRAZOLE showed relatively rapid decline of inhibition (about 20%) with fast elimination of drug in the plasma level. Similarly, 2-(2-carbamoylmethoxy-4-{2-[4-(3-methoxypropoxy)-3-methyl pyridin-2-yl methylsulfinyl]benzimidazole-1-sulfonyl}phenoxy)acetamide provided 56% inhibition after 5 hr of oral administration, while the parent RABEPRAZOLE showed 32% of inhibition under the same condition. 2-(4-{[2-({[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl}sulfinyl) benzimidazol-1-yl]sulfonyl}phenoxy)acetamide provided 46.9% inhibition and 2-(2-carbamoylmethoxy-4-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl methanesulfinyl]-benzimidazole-1-sulfonyl}-phenoxy)-acetamide gave 36.8% inhibition, while the parent LANSOPRAZOLE showed only 29% inhibition after 4 hour of oral administration.
It is well known that oral potency of OMEPRAZOLE without enteric-coating is significantly lower than that found after i.v. or i.d. administration in both rat and dog (Larsson et al., Scand. J. Gastroenterology, vol. 20 (suppl. 108), 23-35, 1985). The compounds of this invention do not need enteric-coating for protection from acid-catalyzed decomposition. Furthermore, the compounds of this invention provide continuous inhibition of gastric acid secretion, as described above.

The United States of America as represented by the Department of Veteran Affairs


A thermal barrier fabricated from pumice, or pumice-like material, and a suitable binder is provided. It may be formed as a self-supporting or load-bearing structural member, or as a thick coating for IR signature reduction. A first embodiment may be used to build a structure, e.g., a room onboard a ship that serves as an effective thermal barrier. Should a fire start in the room, the thermal barrier prevents rapid spreading of the fire and provides crews additional time to fight the fire. A second embodiment, as a thick coating, reduces the IR signature of a radiating body, such as an exhaust stack, by a factor of four. This thick coating helps shield an object from IR surveillance devices or seekers, resulting in much shorter acquisition and tracking times for these IR devices and seekers. In addition to benefits as a thermal barrier, structural members using concepts disclosed for this invention may provide inherent blast and shock resistance.

The present invention pertains to a robust thermal barrier suitable for use as a structural member or as a coating. In particular, a first configuration may be a self-supporting or load-bearing wall of a structure, e.g., a room in a ship. A second configuration may be a surface coating for energy conservation or reducing the infrared (IR) signature of an object.
Today""s navies are operating with reduced crews that are being asked to respond to emergencies with the same efficiency as the larger crews of the past. This impacts the ability to protect resources, especially given that some of the crew has been replaced with additional high explosive ordnance, increasing the volume susceptible to hostile action or catastrophic accidents. Additionally, new and retrofit shipbuilding is being scrutinized for implementation of cost saving initiatives, to include impact on life cycle costs. A solution that reduces operational risk as well as capital investment and maintenance expense is needed. In the recent past, pumice has been used as part of a technological solution to enhance the U.S. Navy""s mission readiness by providing an effective barrier against sympathetic detonation of weapons stored in magazines and transport containers. The natural characteristics of a pumice-based barrier include both shock absorption and thermal insulation as discussed in more detail below. Of course, other materials, natural or man-made, with properties similar to pumice may be substituted.
Pumice used for construction often is mixed with Portland cement, water, and other additives to provide desirable attributes of weatherproofing, appearance, and water and wear resistance. See U.S. Pat. No. 5,759,260, Method for Using Lightweight Concrete for Producing a Combination Therefrom and a Combination Produced Thereby, issued to Groh, Jun. 2, 1998. A common use of lightweight materials, such as pumice, is for production of pre-formed panels or other structures. See U.S. Pat. No. 5,440,846 (panel with insulated core), Construction for Building Panels and Other Building Components, issued to Record, Aug. 15, 1995; U.S. Pat. No. 4,567,705 (panel for fire protection), Fire Protection Arrangement and Method for Positioning Same, issued to Carlson, Feb. 4, 1986; and U.S. Pat. No. 4,259,824 (panel with some inherent insulative property), Precast Concrete Modular Building Panel, issued to Lopez, Apr. 7, 1981. Another use of lightweight materials is for smaller building components such as construction blocks. See U.S. Pat. No. 4,641,470, Construction Element, issued to Baumberger, Feb. 10, 1987 in which a block of lightweight materials, having cavities cast therein, has the cavities filled, in a second step, with insulating materials.
Applying commonly used construction materials in formulation of the material""s mixture and the resultant structure assures local availability and an inherent confidence in the product since the builder is familiar with the performance of known materials. See U.S. Pat. No. 5,860,268, Light-Weight Concrete Door, issued to McWilliams, Jan. 19, 1999 in which a metal frame, wire mesh, hinges, and wooden molds, all common construction material, are combined with a concrete mix and a novel air entrainment admixture. . See U.S. Pat. No. 5,875,607, Low-Cost Exterior Insulation Process and Structure, issued to Vohra, Mar. 2, 1999, in which bags of insulating material that may contain pumice as part of the mix, are placed against existing exterior walls, connected to the wall, covered with stucco wire, and stuccoed for a finished surface.
Should one wish to particularly exploit a particular characteristic of material having the properties of pumice as used in a building material, one needs to carefully select a binder, and method of application of the binder, in order to optimize that characteristic. One such desirable characteristic of a pumice-like material is its resistance to conducting heat, in particular, high heat.
When exploiting a number of desirable characteristics of pumice, however, no one characteristic is likely to be optimized. See U.S. Pat. No. 4,231,884, Water Retardant Insulation Composition Comprising Treated Low Density Granular Mineral Material and Finely Divided Limestone or Similar Carbonate or Silicate Mineral Particles and Method for Using Same, issued to Dorius, Nov. 4, 1980. The ""884 patent provides an insulative composition that is also a water retardant, a corrosion preventative, and capable of use in building a load-bearing wall. To accomplish all of these objectives, certain additional coatings are provided for the lightweight inorganic material. As well, the physical composition of the mixture is adjusted to accommodate each objective. No one objective is being optimized in the mixture.
Pumice has been used for the fabrication of refractory materials. See U.S. Pat. No. 5,228,914), Pumice Containing Composition, issued to Miceli, Jul. 20, 1993 (a mixture of crushed pumice, calcium aluminate, glass fibers and water for use in ovens, heaters, and other high-temperature applications). For this application, the precise makeup of the mixture must be followed to attain the refractory material, an important ingredient being calcium aluminate.
Pumice, in combination with a binder of cement, such as PORTLAND cement, and water, and other optional ingredients such as volcanic ash, scoria, vermiculite, mineral wool and even kerosene, was used to create an insulative thermal barrier. See U.S. Pat. No. 4,803,107, Light Weight Thermal Insulation Material Product and Process, issued to Knowles, Feb. 7, 1989. Again, the product resultant from the above process was intended to address a number of objectives such as water retardation, the xe2x80x9cR-factorxe2x80x9d of the product for use in residences, and structural strength. Further, pumice comprised less than twenty percent of the mixture so that objectives other that fire retardation could be addressed by the product.
Aggregates of inorganics have also been an ingredient in coatings that may be applied by spraying, brushing, rolling, troweling, or using generally accepted stuccoing methods. See U.S. Pat. No. 5,556,578, Aggregate Containing Hydration Water in Spray Applied Fireproofing, issued to Bemeburg et al, Sep. 17, 1996 and U.S. Pat. No. 5,034,160, Sprayable Fireproofing Composition, issued to Kindt et al, Jul. 23, 1991. The ""578 patent describes a slurry for spraying on structural components, such as steel beams, to provide a flame-retardant surface. The slurry comprises a cementitious binder, such as PORTLAND cement and water, and a hard aggregate having hydration water, such as bauxite, together with optional additives, such as shredded polystyrene aggregate and starches, to aid application. The ""160 patent describes a multi-element composition suitable for use as a sprayed-on coating. The composition includes a cementitious binder such as PORTLAND cement and water, a porous aggregate that could include pumice, a fibrous material, an air-entraining agent, and a rheopectic (a fluid mixture that, when subjected to a shear force, increases in viscosity) agent. Both the ""578 patent and the ""160 patent are directed to a solution of the problem of pumping the mixture over large distances, e.g., the upper floors of high-rise buildings and, as such, are addressing a number of competing objectives.
Optimizing the use of pumice-like material for construction may key on the attributes of strength, cost, appearance, and ease of application with little or no attention paid to thermal conduction. A carefully crafted mixture, optimized for performance as a thermal barrier, may not meet one or more of the above requirements for general construction. In fact, this xe2x80x9ccarefully craftedxe2x80x9d mixture may have been considered and subsequently rejected because it did not meet the builder""s more immediate objectives.
As noted above, pumice has been used as an ingredient in construction materials where a lightweight substitute for concrete or adobe has been called out in specifications. It has also been used for packing around explosives to preclude sympathetic detonation of a neighboring explosive should one of a package be detonated. See U.S. Pat. No. 5,158,173, Weapons Storage Container to Prevent Sympathetic Detonation of Adjacent Weapons, issued to Halsey et al, Oct. 27, 1992, incorporated herein by reference in particular to the shock and blast resistance of pumice barriers, and U.S. Pat. No. 5,160,468, Method for Preparing a Storage Container for Explosive Rounds, issued to Halsey et al, Nov. 3, 1992, incorporated herein by reference in particular to the shock and blast resistance of pumice barriers. Further, there exist any number of methods to provide a separate insulation barrier, examples of which are the ""607 patent and the ""884 patent.
Combining pumice-like material with a suitable binder for pouring into forms for making, in a single process, a thermal barrier with structural integrity has not been perfected prior to this invention.
A preferred embodiment of the present invention comprises a mixture of pumice or pumice-like particles and a binder, whereupon said mixture is either poured into a form, with optional reinforcement, for fabricating a structure or applied as a coating. The binder can be any of a number of suitable admixtures, including, but not limited to, a Portland cement; a plaster; an epoxy; a resin, including a polyester or epoxy resin; and a polymer binder, or a combination of the above.
In one preferred embodiment, the pumice or pumice-like particles are of a size between xc2xcxe2x80x3 (0.63 cm) and xe2x85x9cxe2x80x3 (0.94 cm) and the epoxy is a commercially available two-part epoxy. This mixture is poured into forms much like concrete forms but not requiring the same strength since the material is much lighter than concrete. It can be poured into forms positioned horizontally, vertically, or any angle in between. It can also be poured into forms enclosing non-traditional shapes, such as ogives, truncated pyramids, cylinders, and irregular shapes to enclose odd-shaped devices such as gun turrets or boilers with accompanying ductwork and piping. Because of the relatively low density of the material, lightweight removable partitions or panels can be formed from it, facilitating modification or maintenance work.
In a second preferred embodiment, a mixture of pumice or pumice-like particles and binder is used to coat heat emitting devices in order to conserve heat or reduce the infrared signature of the device, or both. This coating may serve as a replacement for asbestos barriers now subject to strict environmental regulations.
Although the same size particles may be used in the coating mixture as for forming a structural member, ease of application may call for the use of smaller particles on the order of xe2x85x9xe2x80x3 or smaller. However, it is beneficial to maintain a minimum particle size. The insulation value of this thermal barrier depends on formation of air spaces, or voids, between the particles. Since the particles do not pack tightly, one surface mating exactly with another, these voids are an inherent consequence of forming such a coating. This coating may be applied to any surface, including those of irregular conformation and texture. Optionally, a first adhesive layer may be needed to insure proper adhesion of the mixture to the surface. Material to coat such an adhesive layer is selected based on the materials content and conformation of the surface to be coated.
Advantages of preferred embodiments of the present invention, include:
dual use fabrication as a structural member and a thermal barrier;
high weight percent of naturally heat resistant material;
lightweight, high strength substitute for concrete;
able to be formed into any shape;
increased fire resistance, lowering operating costs and risks;
reduced fire insurance rates;
simplified design of alternate configurations;
inexpensive fabrication;
reduced system complexity requiring a single member to serve multiple functions;
environmentally friendly, using natural materials and suitable for use with
the most environmentally compliant binders;
able to be sprayed, brushed, rolled, troweled, or applied as a stucco to any surface;
impervious to sporadic water damage;
reduced system capital costs;
increased operational readiness;
low maintenance costs;
increased flexibility;
high reliability;
particularly suitable for renovations and modifications; and
readily applied as a coating to existing structures and objects.
Embodiments of the present invention can be applied to land, sea, or airborne vehicles or fixed facilities. Incorporating the invention into a design saves capital as well as operations and maintenance costs. Further, a preferred embodiment of the present invention may be used anywhere in the world that common building practices are followed.
Preferred embodiments are fully disclosed below, albeit without placing limitations thereon.

The United States of America as represented by the Secretary of the Navy


A still video camera includes an image pickup device with a non-volatile memory incorporated in the camera, wherein an image taken by the image pickup device can be recorded or an image recorded in the non-volatile memory can be erased. An external memory, which is detachably attached by a connector portion to the camera, may also be used to store images taken by the image pickup device. The still video camera includes a connection detecting device which detects the connection between the connector portion and the external memory. A recording device records image signals representative of the image taken by the image pickup device in the non-volatile memory or the external memory. The recording device records the image signals in the external memory when the connection between the connector portion and the external memory is detected by the connection detecting device.

1. Field of the Invention
The present invention relates to a still video camera having an internal flash memory and an external card-type memory which can be detachably attached to the still video camera.
2. Description of Related Art
A still video camera is known having a flash memory (non-volatile memory) in which data can be erased and rewritten, incorporated therein, in which picked-up image data is recorded (stored) in the flash memory.
The flash memory has a large storage capacity and is inexpensive. Also, with a flash memory, no backup battery is necessary to retain up the stored data. However, the number of times data to be retained can be rewritten is limited. Hence, repetitive writing and erasing of the image data causes a reduction in the reliability of the stored data, thus resulting in a deterioration in the S/N (signal-to-noise) ratio of the reproduced image.

Still video camera including detachably attachable external memory


In one embodiment, a first dielectric film (24), and a second dielectric film (32) are formed over a substrate (10). The substrate is cured to at least partially change a property of the second dielectric film thereby forming an intermediate etch stop (46). A third dielectric film (42) is formed over the substrate (10). The substrate (10) is then etched to remove portions of the first dielectric film (24) and portions of the third dielectric film (42) using the intermediate etch stop (46) to form a portion of an interconnect opening (103). In an alternative embodiment, a resist layer (92), and portions of an interlevel dielectric layer (50) are etched. Upon completion of the step of etching, the photoresist layer (92) and portions of the interlevel dielectric layer (50) are completely removed.

The present invention relates to semiconductor devices, and in particular, to forming low dielectric constant interlevel dielectric layers for those devices.
Semiconductor devices are continuing to being scaled to smaller dimensions. Copper interconnects and low dielectric constant (low-k) materials are two areas of technology that are being developed by semiconductor device manufacturers in an effort to reduce device dimensions. A film""s dielectric constant is a measure of its electrical insulating value. Air has a dielectric constant, or k value equal to one. Commonly used silicon dioxide (SiO2), by comparison, has a dielectric constant of approximately 4.0. For the purposes of this specification, a low-k material is any material having a dielectric constant less than approximately 3.5.
In one particular interconnect scheme, a dual inlaid structure is formed. After forming a first interconnect level, an interlevel dielectric (ILD) layer having a dual inlaid opening is formed. One prior art technique uses three relatively high dielectric constant hardmask films with low-k dielectric films layered between them. The dual inlaid structure is formed by opening a via and a trench in the dielectric films using a xe2x80x9cvia first, trench lastxe2x80x9d or xe2x80x9ctrench first, via lastxe2x80x9d processing sequence. Following these steps, an interconnect structure is formed within the trench and the via opening.
One problem with the prior art includes its use of chemically vapor deposited silicon nitride materials including plasma enhanced silicon nitride or silicon oxynitride compounds to form the hardmask. These materials have a relatively high dielectric constant (i.e., greater than five) that increases the total dielectric constant of the ILD layer and raises the total capacitance within the structure. Another problem with the prior art is that the top hardmask film is susceptible to erosion when forming the trench and the via openings. If the hardmask is eroded to a point where the underlying low-k dielectric is exposed during the trench or via etch, the low-k dielectric film will begin to etch laterally resulting in wider than specified feature sizes.

Method for forming an opening in a semiconductor device substrate


A balancer apparatus of an engine includes a crank case, a crankshaft supported by the crank case and including a crank web having a pin connecting portion connected with a crank pin and a counter weight portion, a balancer shaft arranged in parallel with the crankshaft and rotated in cooperation with the crankshaft and a balance weight provided on the balancer shaft and rotated integrally with the balancer shaft. The balancer shaft is installed at a position of overlapping the crank web when viewed from an axial direction of the crankshaft.

1. Field of the Invention
The present invention relates to a balancer apparatus of an engine having a balance weight rotated in cooperation with a crankshaft for canceling an inertia force accompanied by reciprocal movement of a piston.
2. Description of Related Art
There is known an engine for a motorcycle, for example, containing a balancer apparatus for canceling an inertia force of a reciprocal movement portion of a piston, a connecting rod or the like inside of a crank case.
A balancer apparatus of this kind includes a balance weight rotated at a speed the same as that of the crankshaft and in a direction inverse thereto. There is a mode of the balance weight installed on the crankshaft coaxially therewith and another mode thereof installed on a shaft separate from the crankshaft, and in either of the cases, the balance weight is driven by transmitting power from the crankshaft.
A conventional balancer apparatus includes a pair of balance weights and the balance weights are respectively supported rotatably on journal portions disposed at both ends of the crankshaft. The balance weights need to rotate in a direction inverse to that of the crankshaft and therefore, a middle shaft is arranged in parallel with the crankshaft. The middle shaft includes a pair of sprockets rotating at a speed the same as that of the crankshaft and in a direction inverse thereto at both ends thereof and chains are hung between the sprockets and the balance weights.
Therefore, an output outputted to the crankshaft is temporarily transmitted to the sprockets on the intermediate shaft and thereafter transmitted to the balance weights via the chains.
When the balance weights are coaxially installed on the crankshaft, there is needed the exclusive middle shaft for driving the balance weights in the direction inverse to that of the crankshaft. Therefore, there is a drawback that the number of shafts is increased and the crank case supporting shafts becomes large-sized.
Further, since the balance weights are disposed at the journal portions at both ends of the crankshaft, when, for example, an output is outputted from a shaft end of the crankshaft by utilizing a gear, the gear cannot be disposed proximate to a center portion of the crankshaft along an axial direction due to a hindrance by the balance weights or the chains.
As a result, the gear for outputting the output is considerably extended to an outer side in the axial direction of the crankshaft to cause to bring about a large-size formation of the crank case. Along therewith, in outputting the output from the shaft end of the crankshaft, there poses a problem that a path of outputting the output becomes complicated, or the output is difficult to be outputted.
On the other hand, according to another conventional balancer apparatus, a balance weight is disposed on a main shaft of a transmission or a balancer shaft. The main shaft or the balancer shaft is disposed in parallel with the crankshaft and disposed on an outer side of a rotational locus drawn by an outer peripheral face of a crank web to avoid interference of the crankshaft with the crank web.
However, according to the constitution, spaces for bringing in the crank web need to be ensured between the crankshaft and the main shaft as well as between the crankshaft and the balancer shaft, and it is unavoidable that a distance between the shafts is increased. As a result, the crank case becomes large-sized and the balance weight cannot compactly be integrated to the crank case.
It is an advantage of the invention to provide a balancer apparatus of an engine capable of compactly integrating a balance weight to a crank case and capable of preventing a large-size formation of the crank case.


An airborne mobile platform may have a wing having a length and a chord wise dimension, and a plurality of elongated structural components extending span-wise along the length of the wing. The elongated structural components may each have a localized hinge area. A device may be used for manipulating the elongated structural component to position the localized hinge area to selectively change a hinge line of the wing in response to an airflow over the wing.

Aircraft designers are tasked with developing efficient technologies for controlling an aircraft flight path. In the earliest years of aviation, the Wright brothers used mechanical wires to twist the wing for aircraft roll control. Traditionally, aircraft have used moveable flap-like control surfaces (ailerons) to roll the aircraft or adjust the aircraft attitude. Recently, aircraft designers have started to devise ways of controlling and using aircraft aero-elastic wing twisting for roll control. This has involved using such components as a torque tube disposed in each wing, and running substantially the full span-wise length of the wings, to assist in twisting the wings to help provide flight control maneuvering for the aircraft. Such systems, however, have often required large, heavy and expensive motors to provide the necessary twisting force to the torque tube.
Accordingly, it would be highly advantageous to provide some means for controllably twisting a wing to assist in controlling flight of an aircraft, but without the large, heavy and expensive wing twisting structures that have previously been attempted.

Apparatus and method for controlling twist of a wing of an airborne mobile platform


A selective call receiver (130) receives radio transmitted messages and stores the received messages such that the messages may be simultaneously accessed from that memory by another device. The selective call receiver comprises an antenna (202) for receiving the transmitted messages, the antenna (202) being coupled to a receiver module (204) for recovering the messages. A decoder (206) is coupled for receiving the messages from the receiver module (204). A controller (212) is coupled for determining whether the recovered message is addressed to the selective call receiver (130). A dual port RAM (208) is coupled to the controller (212) via a first address and data bus for storing the messages addressed to the selective call receiver (130), and the dual port RAM (208) has a second address and data bus for providing simultaneous access to another device.

Communication systems, such as paging systems, typically communicate messages from an originating device to one or more destination devices. These messages can include numeric and alphanumeric information for a user of the destination device. The destination device, for example, a selective call receiver or pager, typically presents the information received to the user by displaying the information on the pager's display.
Contemporary paging systems, necessarily using pagers having small form factors, offer limited message displays for communicating information. For example, an alphanumeric message is typically limited to 80 characters or less in length. These typical message lengths have provided users reasonably reliable delivery of messages while meeting a market need to communicate limited information in a wireless environment and with little delay.
Users, on the other hand, desire to receive information comprising much longer character lengths, such as from ten to one hundred times longer character lengths or more than historically available with selective call receivers. Examples of such desired information includes, for example, E-mail (Electronic mail) which can communicate overnight news and weather, sports coverage, stock quotes, etc.
The need for receiving longer length messages in a wireless environment has been met by integrating a selective call receiver or pager with a notebook, laptop or palmtop personal computer. The pager receives the message and is able to store that message in an internal memory. The personal computer next reads the contents of the pager's memory into the memory of the personal computer for output on the personal computers larger display. One of the major benefits of such wireless communication is the timeliness of receiving, and hence displaying the message. The longer messages, however, due to sheer size alone, necessarily increase the time for display as the message is transferred from pager memory to personal computer memory. If a pager has a memory and must transfer a message stored therein using a bus protocol, and the personal computer must re-transfer the stored message back to its own memory, then resources and time are wasted. This is because personal computers work best with memory type accesses, instead of communication protocols across a shared bus.
Thus, what is needed is a Radio Frequency (RF) device and a Personal Computer (PC) having a dual port memory as a communication means for memory type accesses therebetween.

Dual port memory communication for a radio frequency device and a personal computer