The Chalcogen And The Nitrogen Are In The 1,5-positions Of The Bicyclo Ring System (e.g., 1,5-benzothiazepinone, Etc.) Patents (Class 540/491)
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Patent number: 5411954Abstract: Compounds characterized generally as benzo-fused oxazopinyl-terminated alkylamino ethynyl alanine amino diol derivatives are useful as renin inhibitors for the treatment of hypertension. Compounds of particular interest are those of Formula I ##STR1## wherein A is selected from CO and SO.sub.2 ; wherein X is selected from oxygen atom and methylene; wherein B is a benzo-fused oxazopinyl group; wherein R.sub.1 is selected from hydrido, methyl, ethyl, isopropyl and n-propyl; wherein R.sub.2 is phenylmethyl; wherein each of R.sub.3 and R.sub.5 is hydrido; wherein R.sub.4 is selected from--(CH.sub.2).sbsb.q--C.ident.C-Vwherein V is selected from hydrido and methyl; wherein R.sub.6 is cyclohexylmethyl; wherein R.sub.7 is selected from isobutyl, cyclopropyl and cyclopropylmethyl; wherein q is a number selected from zero through three, inclusive; and wherein n is a number selected from zero through three, inclusive; or a pharmaceutically-acceptable salt thereof.Type: GrantFiled: February 22, 1994Date of Patent: May 2, 1995Assignee: G. D. Searle & Co.Inventors: Gunnar J. Hanson, Robert E. Manning
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Patent number: 5382663Abstract: (+)-Cis-3-(acetoxy)-5-[2-(dimethylamino)-ethyl]-2,3-dihydro-2-(4-methoxyphe nyl)-1,5-benzothiazepin-4(5H)-one hydrochloride is prepared by N-alkylation of (+)-cis-3-hydroxy-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H) -one with dimethylaminoethyl chloride and K.sub.2 CO.sub.3 in toluene/water, addition of a solubilizing agent and in the presence of a phase-transfer catalyst, the toluene phase being directly subjected to the final O-- acetylation.Type: GrantFiled: June 23, 1993Date of Patent: January 17, 1995Assignee: Lusochimica S.p.A.Inventors: Elso Manghisi, Bruno Perego
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Patent number: 5378698Abstract: A compound of the formula: ##STR1## wherein X is .dbd.N--A--R.sup.1 or .dbd.C(R.sup.1)R.sup.2 ; A is a single bond, polymethylene or --CO--; R.sup.1 and R.sup.2 are each hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, unsubstituted or substituted phenyl, optionally substituted benzhydryl, or optionally substituted 5 to 6 membered heterocyclic group; Y is hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.1 -C.sub.6 alkoxy, optionally substituted phenoxy, optionally substituted benzyloxy, or optionally substituted benzyl; Z is hydrogen or acyl; n is an integer of from 2 to 6, and pharmaceutically acceptable salt thereof. A pharmaceutical composition containing the compound, which is useful for treating hypertension and cardiac diseases, is also provided.Type: GrantFiled: October 14, 1992Date of Patent: January 3, 1995Assignee: Shionogi & Co., Ltd.Inventors: Teruo Yamamori, Hiroshi Harada, Katsunori Sakai, Kazumi Iwaki, Kazuki Matsunaga
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Patent number: 5374721Abstract: There are disclosed certain novel compounds identified as benzo-fused lactams which promote the release of growth hormone in humans and animals. This property can be utilized to promote the growth of food animals to render the production of edible meat products more efficient, and in humans, to increase the stature of those afflicted with a lack of a normal secretion of natural growth hormone. Growth promoting compositions containing such benzo-fused lactams as the active ingredient thereof are also disclosed.Type: GrantFiled: October 14, 1992Date of Patent: December 20, 1994Assignee: Merck & Co., Inc.Inventors: William R. Schoen, Matthew J. Wyvratt
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Patent number: 5317017Abstract: There are disclosed certain compounds identified as N-biphenyl-3-amido substituted benzolactams which promote the release of growth hormone in humans and animals. This property can be utilized to promote the growth of food animals to render the production of edible meat products more efficient, and in humans, to increase the stature of those afflicted with a lack of a normal secretion of natural growth hormone. Growth promoting compositions containing such benzolactams as the active ingredient thereof are also disclosed.Type: GrantFiled: September 30, 1992Date of Patent: May 31, 1994Assignee: Merck & Co., Inc.Inventors: Hyun O. Ok, William R. Schoen, Matthew Wyvratt
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Patent number: 5315005Abstract: A purification method of intermediates for the preparation of Diltiazem which consists of the crystallization of a mixture enantiomerically enriched in (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H) -one is described.Type: GrantFiled: January 25, 1993Date of Patent: May 24, 1994Assignee: Zambon Group S.p.A.Inventors: Claudio Giordano, Dario Tentorio, Laura Russo
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Patent number: 5310737Abstract: There are disclosed certain novel compounds identified as benzo-fused lactams which promote the release of growth hormone in humans and animals. This property can be utilized to promote the growth of food animals to render the production of edible meat products more efficient, and in humans, to increase the stature of those afflicted with a lack of a normal secretion of natural growth hormone. Growth promoting compositions containing such benzo-fused lactams as the active ingredient thereof are also disclosed.Type: GrantFiled: February 2, 1993Date of Patent: May 10, 1994Assignee: Merck & Co., Inc.Inventors: Michael H. Fisher, William R. Schoen, Matthew J. Wyvratt, Robert J. DeVita
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Patent number: 5310904Abstract: Process for preparing optically active cis-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one compounds [I] of the formula: ##STR1## wherein Ring A and Ring B are substituted or unsubstituted benzene, R.sup.1 is hydrogen or di-lower alkylaminoalkyl, which comprises subjecting 1,5-benzothiazepin-4(5H)-one (II) of the formula [II]: ##STR2## wherein R.sup.4 is hydrogen or lower alkanoyl, and the other symbols are the same as defined above, to asymmetric reduction with a reaction product of optically active .alpha.-amino acid and metal hydride, in high optically yield, and said compounds [I] are very important as intermediate for preparing various medicines.Type: GrantFiled: January 8, 1993Date of Patent: May 10, 1994Assignee: Tanabe Seiyaku Co., Ltd.Inventors: Yasuhiko Ozaki, Shinichi Yamada, Hiroyasu Seko
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Patent number: 5300235Abstract: Amine derivatives which are compounds of the formula (I): ##STR1## in which R is a C.sub.6-20 hydrocarbon; Y is --CO--NH-- and n is an integer of 1 to 6; or ##STR2## in which X is an alkylene group of 2 to 6 carbon atoms and n is an integer of 0 to 6;each R.sub.1 is independently H, --(CH.sub.2).sub.1-4 COOH, a C.sub.6-20 hydrocarbon or C.sub.6-20 hydrocarbon-carbonyl;R.sub.2 is H, (CH.sub.2).sub.1-4 COOH or C.sub.6-20 hydrocarboncarbonyl;the compound containing at least one (CH.sub.2).sub.1-4 COOH group; or a salt thereof are useful in inhibiting corrosion of metals in oil- and gas-field applications, and also show low toxicity to marine organisms.Type: GrantFiled: May 14, 1992Date of Patent: April 5, 1994Assignee: Exxon Chemical Patents Inc.Inventors: Paul J. Clewlow, John A. Haselgrave, Niall Carruthers, Terence M. O'Brien
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Patent number: 5294706Abstract: There is disclosed a process for preparing 1,5-benzothiazepine derivatives of the formula: ##STR1## wherein R.sup.1 is a lower alkyl group, or a salt thereof which comprises subjecting a propionate derivatives of the formula: ##STR2## wherein R.sup.2 is an ester residue and R.sup.1 is the same as defined above, to intramolecular cyclization in the presence of a sulfonic acid compound of the formula:R.sup.3 SO.sub.3 H (III)wherein R.sup.3 is a lower alkyl group or a substituted or unsubstituted phenyl group, in a non-halogenated organic solvent and, if desired, converting the product to a salt thereof.Type: GrantFiled: November 19, 1992Date of Patent: March 15, 1994Assignee: Tanabe Seiyaku Co., Ltd.Inventors: Tadayuki Koumoto, Hironori Hayashi, Toshiya Kadowaki, Masahiko Seto, Toyonari Oine
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Patent number: 5284841Abstract: There are disclosed certain novel compounds identified as benzo-fused lactams ##STR1## which promote the release of growth hormone in humans and animals. This property can be utilized to promote the growth of food animals to render the production of edible meat products more efficient, and in humans, to increase the stature of those afflicted with a lack of a normal secretion of natural growth hormone. The compounds are prepared by substitution of an amino-lactam with a substituted amide function. Growth promoting compositions containing such benzo-fused lactams as the active ingredient thereof are also disclosed.Type: GrantFiled: February 4, 1993Date of Patent: February 8, 1994Assignee: Merck & Co., Inc.Inventors: Lin Chu, Michael H. Fisher, Helmut Mrozik, William R. Schoen
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Patent number: 5283241Abstract: There are disclosed certain novel compounds identified as benzo-fused lactams which promote the release of growth hormone in humans and animals. This property can be utilized to promote the growth of food animals to render the production of edible meat products more efficient, and in humans, to increase the stature of those afflicted with a lack of a normal secretion of natural growth hormone. The compounds are prepared by substitution of an amino-lactam with a substituted amide function. Growth promoting compositions containing such benzo-fused lactams as the active ingredient thereof are also disclosed.Type: GrantFiled: August 28, 1992Date of Patent: February 1, 1994Assignee: Merck & Co., Inc.Inventors: Richard J. Bochis, Matthew J. Wyvratt, William R. Schoen
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Patent number: 5250680Abstract: An amino-acid ester compound can be cyclized into a cyclic amido-carbonyl compound by contacting the amino-acid ester compound in a liquid medium with a heterogeneous acidic ion-exchange substance. For example, 2-hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)propionic acid, methyl ester, threo form, can be cyclized in an aqueous mixture into cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one by employing a sulfonated polystyrene-divinylbenzene ion-exchange resin in its acid form, e.g., Dowex.RTM. 50X4-400. at yields exceeding 85 percent of theory, and the product can be used to make diltiazem hydrochloride.Type: GrantFiled: September 2, 1992Date of Patent: October 5, 1993Assignee: Merrell Dow Pharmaceuticals Inc.Inventor: Daniel E. Martin
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Patent number: 5244803Abstract: There is disclosed a process for preparing optically active 3-phenylglycidic acid ester compound, which comprises permitting a culture broth, cells or treated cells of a microorganism having an ability of stereoselectively hydrolyzing a (2R, 3S)-3-phenylglycidic acid ester compound to act on a racemic 3-phenylglycidic acid ester compound which may also have a substituent on the phenyl group, thereby hydrolyzing the (2R, 3S) optically active isomer and separating and collecting the (2S, 3R) antipode from the reaction mixture.Type: GrantFiled: September 7, 1990Date of Patent: September 14, 1993Assignee: Tanabe Seiyaku Co., Ltd.Inventors: Takao Mori, Toshiyuki Furutani, Akio Nakao, Atsuhiko Tsujimura, Takeji Shibatani
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Patent number: 5223612Abstract: Process for the preparation of (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H) -one of formula ##STR1## by direct cyclization of the compound of the formula ##STR2## with a catalytic amount of phosphonic acid.Type: GrantFiled: May 13, 1992Date of Patent: June 29, 1993Assignee: Zambon Group S.p.A.Inventors: Claudio Giordano, Maurizio Paiocchi
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Patent number: 5206235Abstract: There are disclosed certain novel compounds identified as benzo-fused lactams which promote the release of growth hormone in humans and animals. This property can be utilized to promote the growth of food animals to render the production of edible meat products more efficient, and in humans, to increase the stature of those afflicted with a lack of a normal secretion of natural growth hormone. Growth promoting compositions containing such benzo-fused lactams as the active ingredient thereof are also disclosed.Type: GrantFiled: February 28, 1992Date of Patent: April 27, 1993Assignee: Merck & Co., Inc.Inventors: Michael H. Fisher, William R. Schoen, Matthew J. Wyvratt, Robert J. DeVita
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Patent number: 5169946Abstract: A process for preparing hydrochloride of 3-acetoxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-b enzothiazepin-4(5H)-one which comprises reacting 3-hydroxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-b enzothiazepin-4(5H)-one which acetyl chloride in acetic acid or a mixed solvent of acetic acid and acetic anhydride. According to the process, hydrochloride of 3-acetoxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-b enzothiazepin-4(5H)-one is readily obtained in one step.Type: GrantFiled: November 27, 1991Date of Patent: December 8, 1992Assignee: Tanabe Seiyaku Co., Ltd.Inventors: Masanori Yoshioka, Mitsuyoshi Wagatsuma, Akiyoshi Yoda, Yoshihisa Yamada, Gunji Yoshimura
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Patent number: 5144025Abstract: A process for the resolution of amminoesters of the formula ##STR1## wherein R.sub.1 and R.sub.3 have the meanings reported in the specification, by tartaric acid and analogs thereof, is described. The compounds of formula IV-A are intermediates useful in the preparation of optically active (2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)ones.Type: GrantFiled: April 5, 1990Date of Patent: September 1, 1992Assignee: Zambon Group S.p.A.Inventor: Dario Tentorio
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Patent number: 5134139Abstract: Novel 1,5-benzothiazepine derivatives of the formula: ##STR1## wherein X is hydrogen atom, a halogen atom or a lower alkyl group; R.sup.1 is a lower alkyl group or a lower alkoxy group; R.sup.2 is hydrogen atom, a lower alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenyl-lower alkyl grup or a diphenyl-lower alkyl group; R.sup.3 is a lower alkyl group or a substituted or unsubstituted phenyl-lower alkyl group, Q is single bond, or an alkylene or lower alkenylene group which may optionally be substituted by a lower alkoxy group or oxo group; R.sup.Type: GrantFiled: August 21, 1990Date of Patent: July 28, 1992Assignee: Tanabe Seiyaku Co., Ltd.Inventors: Akiyoshi Kawai, Hirozumi Inoue, Hiroshi Narita, Taku Nagao
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Patent number: 5128469Abstract: This disclosure describes a process for the preparation of 1,5-benzothiazepinone derivatives. The process involves the use of sulfonic acids as catalysts to effect ring closure to form the 1,5-benzothiazepinone ring. The resulting compounds have well known pharmaceutical properties.Type: GrantFiled: June 26, 1991Date of Patent: July 7, 1992Assignee: Tanabe Seiyaku Co., Ltd.Inventors: Shigeru Nishimoto, Akio Nakao, Yasuji Ikeda, Hiroyuki Nate, Hironori Hayashi, Tamotsu Okuno, Masashi Kitano, Sadao Maeda
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Patent number: 5128468Abstract: The present invention relates to a novel process for synthetizing 2-aryl-3-hydroxy-cis-2,3-dihydro-1,5-benzothiazepin-4(5H)-ones and their derivatives, an optically pure compounds or as their racemic mixtures, having the following general formula (I): ##STR1## by using, as synthesis precursors, methyl esters of 2-hydroxy-3-arylthio-3-arylpropionic acids in their threo form, as their hydrochlorides, or as free bases, of generally formula (II): ##STR2## and treating such precursors with an excess of sodium methoxide, at low temperature, in diethyleneglycol, dimethylether, diemthylformamide and ethyl acetate.Type: GrantFiled: November 19, 1990Date of Patent: July 7, 1992Assignee: FIS--Fabbrica Italiana Sintetici S.p.A.Inventors: Amleto Rizzi, Gaetano Marchioro
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Patent number: 5120730Abstract: A class of benzothiazepine esters having structures related to that of diltiazem are provided which possess vasodilating activity while being virtually free of cardiodepressive effects. The esters are useful in the treatment of arterial hypertension and disturbances of the cerebral circulation.The compounds have the general formula I ##STR1## wherein R represents hydrogen or an electronegative group (preferably a halogen atom, or a nitro, trifluoromethyl or methoxy group); andX is a hydrocarbyl group containing from 1 to 15 carbon atoms.Type: GrantFiled: June 12, 1991Date of Patent: June 9, 1992Assignee: IdB Holding SpAInventors: Giorgio Pifferi, Rita Nizzola, Salvatore Malandrino
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Patent number: 5112969Abstract: A cyano glycidic acid ester compound can be prepared by reaction of an alkyl haloester and a cyano-aldehyde in the presence of an alkali metal alkoxide; an amino-acid ester cyano compound can be prepared by reaction of the cyano glycidic acid ester compound and an attachable amino compound, and a cyclic amido-carbonyl cyano compound can be prepared by contact of the amino-acid ester cyano compound in a liquid medium with a heterogeneous acidic ion-exchange substance.Type: GrantFiled: May 30, 1991Date of Patent: May 12, 1992Assignee: Merrell Dow Pharmaceuticals Inc.Inventor: Daniel E. Martin
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Patent number: 5102998Abstract: 2-Aminothiophenol is reacted with methyl (-)-(2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate, and the intermediate methyl (2S,3S)-3-[(2-aminophenyl)thio]-2-hydroxy-3-(4-methoxyphenyl)propionate is cyclized in the presence of methanesulfonic acid, in the same vessel and without isolating said intermediate product, using e.g. chlorobenzene as a solvent.Type: GrantFiled: October 24, 1989Date of Patent: April 7, 1992Assignee: SynthelaboInventors: Guy Rossey, Isaac Chekroun, Antonio Ugolini, Alexander Wick, Andre Bourbon, Jean-Baptiste Graux
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Patent number: 5102999Abstract: A process for the preparation of intermediates useful for the synthesis of Diltiazem consisting in the racemization of (--)-cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H )-one is described.Type: GrantFiled: November 15, 1990Date of Patent: April 7, 1992Assignee: Zambon Group S.p.A.Inventors: Claudio Giordano, Roberto Casagrande
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Patent number: 5097059Abstract: A process of spontaneous resolution of compounds of formula ##STR1## wherein R has the meanings reported in the description, is described. The compounds of formula III are intermediates useful for the preparation of Diltiazem.Type: GrantFiled: July 26, 1990Date of Patent: March 17, 1992Assignee: Zambon Group S.p.A.Inventors: Claudio Giordano, Dario Tentorio, Roberto Casagrande, Placido Bertin, Valeriano Merli, Giorgio Sagramora
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Patent number: 5081240Abstract: The object of the invention is a process for the preparation of the trans(-) (2R,3S) diastereoisomer of the glycidic esters of general formula: ##STR1## wherein a chlorohydrin of general formula: ##STR2## is reacted with a strong organic base in a suitable solvent and at a temperature between -10.degree. C. and room temperature.Another object of the invention is intermediate compounds cis(+) (2S,3S) 1,5-benzothiazepin-4-one.Type: GrantFiled: July 12, 1990Date of Patent: January 14, 1992Assignee: SanofiInventors: Andre Bousquet, Jean-Robert Dormoy, Alain Heymes
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Patent number: 5063225Abstract: A compound selected from the group consisting of all possible isomeric forms, racemic or optically active of a compound of the formula ##STR1## wherein the substituents are defined in the specification, and their non-toxic, pharmaceutically acceptable acid addition salts having antiarhythmic activity.Type: GrantFiled: April 11, 1990Date of Patent: November 5, 1991Assignee: Roussel UclafInventors: Francois Clemence, Daniel Frechet, Gilles Hamon, Simone Jouquey
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Patent number: 5057513Abstract: The invention relates to thiazepine derivatives, which are antagonists of platelet activating factor, of the formula: ##STR1## wherein R.sup.1 is ar(lower)alkyl which may have suitable substituent(s),R.sup.2 is hydrogen, lower alkyl which may have suitable substituent(s), or a group of the formula: ##STR2## in which A is lower alkylene and X is halogen, n is 0, 1 or 2 and Y is --CH.sub.2 --CH.sub.2 -- or ##STR3## or a pharmaceutically acceptable salt thereof.Type: GrantFiled: May 4, 1990Date of Patent: October 15, 1991Assignee: Fujisawa Pharmaceutical Co., Ltd.Inventors: Keiji Hemmi, Ichiro Shima, Naoki Fukami, Masashi Hashimoto
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Patent number: 5055575Abstract: There is disclosed a process for preparing 1,5-benzothiazepine derivatives represented by the formula: ##STR1## wherein one of R.sup.1 and R.sup.2 is a lower alkyl group or halogen atom, and the other is hydrogen atom, R.sup.3 is a lower alkyl group or a lower alkoxy group, which comprises subjecting a propionic acid compound represented by the formula (II): ##STR2## wherein R.sup.1, R.sup.2 and R.sup.3 have the same meanings as defined above, and R.sup.4 represents hydrogen atom or an ester residue, to intramolecular ring closing reaction in the presence of a sulfonic acid compound represented by the formula (III):R.sup.5 SO.sub.3 H (III)wherein R.sup.5 represents a lower alkyl group or a substituted or unsubstituted phenyl group.Type: GrantFiled: April 30, 1990Date of Patent: October 8, 1991Assignee: Tanabe Seiyaku Co., Ltd.Inventors: Shigeru Nishimoto, Akio Nakao, Yasuji Ikeda, Hiroyuki Nate
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Patent number: 5055464Abstract: Benzolactam compounds of the general formula ##STR1## or isomers thereof as well as salts thereof inclusive of hydrates and/or solvates forms thereof, and benzolactam compounds of the general formula ##STR2## wherein each of the symbols is as defined in the specification. The compound (I) exhibit antiamnesic activity, and are useful as brain function-improving drugs. The compounds (a) and (b) are useful as an intermediate for said compounds (I). Futher, the compound (a) show diuretic or antiulcer activity, and are useful as a diuretic or antiulcer agent.Type: GrantFiled: January 25, 1990Date of Patent: October 8, 1991Assignee: Yoshitomi Pharmaceutical Industries Ltd.Inventors: Shu Murakami, Tsuguo Ikebe, Ichiro Hakamada, Koretake Anami
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Patent number: 5028704Abstract: The present invention relates to compounds of the formula ##STR1## wherein R.sub.c is carboxy, esterified carboxy or amidated carboxy;R.sub.2 is hydrogen or lower alkyl or joins with R.sub.a and R.sub.b and the atoms therebetween to form a fused ring ##STR2## and either R.sub.a is methyl and R.sub.b is ##STR3## or R.sub.2 and R.sub.b and the atoms therebetween form a group wherein R.sub.3 and R.sub.4 are either both hydrogen, or together are propylene, butylene, or with the two atoms to which they are attached form a benzene ring. Methods of manufacture and use thereof in the production of angiotensin converting enzyme inhibitors are disclosed.Type: GrantFiled: February 8, 1990Date of Patent: July 2, 1991Assignee: Ciba-Geigy CorporationInventor: Stephen K. Boyer
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Patent number: 5015638Abstract: This invention relates to substituted pyridooxazinone and naphtheridone pyridones which are useful as cardiotonic agents for the treatment of congestive heart failure, to methods for increasing cardiac contractility using said compounds, and pharmaceutical compositions including the same.Type: GrantFiled: November 3, 1989Date of Patent: May 14, 1991Assignee: Rhone-Poulenc Rorer Pharmaceuticals Inc.Inventors: Alfred P. Spada, William L. Studt, Henry F. Campbell, Donald E. Kuhla, Thomas Tucker
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Patent number: 5013834Abstract: A process for the optical resolution of 2-hydroxy-3-(4-methoxyphenyl)-3-(2-acetylaminophenylthio)-propionic acid sodium salt by seeding of a supersaturated solution of said salt with one of the enantiomers.Type: GrantFiled: May 21, 1990Date of Patent: May 7, 1991Assignee: Industria Chimica Profarmaco S. p. A.Inventor: Fulvio L. Piselli
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Patent number: 5013835Abstract: 2-Aminothiophenol is reacted with (-)-(2R,3S)-2,3-epoxy-3-(4-methoxyphenyl) methylpropionate, and the intermediate (2S,3S)-3-[(2-aminophenyl)thio]-2-hydroxy-3-(4-methoxyphenyl) methylpropionate is then cyclized in the presence of methane sulfonic acid, in the same container and without isolating said intermediate product, using chlorobenzene as a solvent.Type: GrantFiled: September 14, 1989Date of Patent: May 7, 1991Assignee: SynthelaboInventors: Guy Rossey, Isaac Chekroun, Antonio Ugolini, Alexander Wick, Bernard Gerin, Andre Bourbon, Jean-Baptiste Graux
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Patent number: 5008433Abstract: The titled ester, especially having the (2S,3S)-configuration, which is an intermediate for the production of diltiazem, is provided. Very high yields are obtainable.Type: GrantFiled: April 6, 1990Date of Patent: April 16, 1991Assignee: Marion Laboratories, Inc.Inventor: James T. Palmer
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Patent number: 5008411Abstract: A process for the preparing a compound of the formula ##STR1## wherein R.sub.1 and R.sub.2 are each independently hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, trifluoromethyl or nitro; or R.sub.1 and R.sub.2 taken together with the benzene ring to which they are attached are naphthalene, and Ar is p-lower alkoxy phenyl.which comprises reacting ##STR2## wherein R.sub.1 and R.sub.2 are as described above with the compound of the formula ##STR3## wherein Ar is as described above, in an aromatic organic compound. The intermediates formed by the process of the invention are useful in the production of thiazepin-4(5H)-ones which have activity as calcium channel blockers and accordingly are useful as agents for lowering blood pressure and agents for treating ischemia.Type: GrantFiled: October 2, 1989Date of Patent: April 16, 1991Assignee: Hoffmann-La Roche Inc.Inventors: David L. Coffen, Pradeep B. Madan, Alan Schwartz
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Patent number: 5002942Abstract: Compounds of formula (I): ##STR1## in which: R.sup.1 is aryl or aromatic heterocyclic; R.sup.2 and R.sup.3 are hydrogen, alkyl, alkoxy, halogen, phenyl, phenoxy, C.sub.1 -C.sub.6 alkylthio, phenylthio, C.sub.1 -C.sub.6 haloalkyl, cyano or nitro, or together are alkylene optionally containing oxygen; R.sup.4 is hydrogen, aliphatic acyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aromatic acyl, alkoxycarbonyl or benzyloxycarbonyl; R.sup.5 and R.sup.6 are alkyl; and X is oxygen, sulfur or methylene, have calcium channel blocking activity and can serve for the treatment or prophylaxis of cardiovascular diseases and disorders. They may be prepared by reacting a corresponding compound where R.sup.4 is hydrogen and the aminoethyl group is replaced by hydrogen with a compound providing the aminoethyl group and the, if required, acylating the product.Type: GrantFiled: July 21, 1989Date of Patent: March 26, 1991Assignee: Sankyo Company, LimitedInventors: Hiroaki Yanagisawa, Koichi Fujimoto, Yasuo Shimoji, Takuro Kanazaki, Hiroyuki Koike, Hiroshi Nishino
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Patent number: 4983733Abstract: 2-Aromatic-3-HALobenzothizepines are prepared by reaction of a 2,3-dihydro-2-aromatic-3-hydroxybenzothiazepine with a thionyl HALide. For example, dl-cis-2-(4-methoxyphenyl)-2,3-dihydro-3-hydroxy-1, 5-benzothiazzepin-4(5H)-one relfuxed with thionyl chloride can prepare E-2-(4-methoxyphenyl)-3-chloro-1,5-benzothiazepin-4(5H)-one in 66 percent yield.Type: GrantFiled: November 20, 1989Date of Patent: January 8, 1991Assignee: Marion Laboratories, Inc.Inventor: David R. Borcherding
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Patent number: 4963671Abstract: This process enables preparation of the preferred (+)-threo enantiomer by resolution of its racemic mixture of a compound of the formula ##STR1## wherein Y.sup.1 and Y.sup.2 are each independently lower alkyl and R.sup.1 is hydrogen or lower alkyl. The compound is treated with a chiral acid (tartaric aicd preferred) in an organic solvent (ethanol preferred) to yield the (+)-threo enantiomer, which is then recovered from the reaction mixture. This enantiomer may then be used to produce the preferred (+)-cis enantiomer of certain benzothiazepine cardiovascular agents.Type: GrantFiled: November 20, 1989Date of Patent: October 16, 1990Assignee: E. R. Squibb & Sons, Inc.Inventor: John Krapcho
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Patent number: 4952692Abstract: Novel compounds of the formula ##STR1## exhibit calcium channel blocking activity and are useful as cardiovascular agents.Type: GrantFiled: April 4, 1989Date of Patent: August 28, 1990Assignee: E. R. Squibb & Sons, Inc.Inventors: John Krapcho, Joel C. Barrish, Spencer D. Kimball
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Patent number: 4948886Abstract: Benzothiazepinone derivatives can be prepared by alkaline hydrolysis of benzothiazoles to give o-amino-thiophenols, isolation thereof by acidification and further reaction with acrylic acids. In this connection, the acidification is carried out using a mineral acid, after which the o-amino-thiophenol is extracted using a water-insoluble solvent and is reacted in this extract with an acrylic acid.Type: GrantFiled: January 4, 1989Date of Patent: August 14, 1990Assignee: Bayer AktiengesellschaftInventors: Franz-Josef Mais, Helmut Fiege
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Patent number: 4946840Abstract: Vasodilating activity is exhibited by compounds having the formula ##STR1## and the pharmaceutically acceptable salts thereof, wherein X is --CH.sub.2 -- or --S--;R.sub.1 is ##STR2## or --O--Y.sub.3 ; R.sub.2 is heterocyclo or heteroaryl;R.sub.3 and R.sub.4 are each independently hydrogen, halogen, alkyl, alkoxy, aryloxy, arylalkoxy, arylalkyl, cyano, hydroxy, alkanoyloxy, ##STR3## fluoro-substituted alkoxy, fluoro-substituted alkyl, (cycloalkyl)alkoxy, --NO.sub.2, --NY.sub.10 Y.sub.11, --S(O).sub.k alkyl, --S(O).sub.k aryl ##STR4## n is 0, 1, 2 or 3; m is 0, 1, 2 or 3;k is 0, 1 or 2;Y.sub.1 and Y.sub.2 are each independently hydrogen or alkyl; or Y.sub.1 is hydrogen and Y.sub.2 is alkenyl, alkynyl, aryl, heteroaryl, or cycloalkyl; or Y.sub.1 and Y.sub.2, together with the carbon atom to which they are attached, are cycloalkyl;Y.sub.3 is hydrogen, alkyl, alkanoyl, alkenyl, arylcarbonyl, heteroarylcarbonyl, or ##STR5## Y.sub.8 and Y.sub.9 are each independently hydrogen, alkyl, aryl, or heteroaryl; or Y.sub.Type: GrantFiled: April 6, 1989Date of Patent: August 7, 1990Assignee: E. R. Squibb & Sons, Inc.Inventors: Joel C. Barrish, Spencer D. Kimball, John Krapcho
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Patent number: 4939251Abstract: Novel 1-azaspiro[4.4] lactams are produced by reaction of at least one hydroxy-containing primary amino compound with a 4-ketodiacid compound or a 1,6-dioxaspiro[4.4]lactone. Molar excesses of amion compound result in production of spirodilactams, while limited molar quantities of amino compound results in production of a spirolactam-lactone which reacts further with hydroxy-containing primary amino compound or with hydroxy-free primary amino compound to produce a spirodilactam. Certain of the spirolactams are useful as precursors for glycidyloxy derivatives which react with epoxy curing agents to form insoluble thermoset resins while others are useful as curing agents and yet others are converted to glycidyloxy derivatives useful as reactive diluents in epoxy resin applications.Type: GrantFiled: September 16, 1988Date of Patent: July 3, 1990Assignee: Shell Oil CompanyInventor: Pen C. Wang
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Patent number: 4937334Abstract: A process for the preparation of the compound (2S,3S)(+)-3-hydroxy-2,3-dihydro-2-(4-methoxyphenyl)-5-(2-dimethylaminoeth yl)-1, 5-benzothiazepin-4(5H)-one is described. Said compound is an intermediate useful in the synthesis of Diltiazem.Type: GrantFiled: July 25, 1989Date of Patent: June 26, 1990Assignee: Zambon Group S.p.A.Inventors: Silvia Cavicchioli, Maurizio Paiocchi, Claudio Giordano
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Patent number: 4931587Abstract: A process for the optical resolution of 2-hydroxy-3-(4-methoxyphenyl)-3-(2-acetylaminophenylthio)-propionic acid sodium salt by seeding of a supersaturated solution of said salt with one of the enantiomers.Type: GrantFiled: January 17, 1989Date of Patent: June 5, 1990Assignee: Industria Chimica Profarmaco S.p.A.Inventor: Fulvio L. Piselli
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Patent number: 4929269Abstract: Compounds of the formula ##STR1## and salts thereof, W and W, being independently O and S, A being a nitrogen-containing heterocyclic ring system, E being O, S(O)m or NR.sub.3 where m is 0-2, R.sub.1, R.sub.2 and R.sub.3 is hydrogen, C.sub.1 -C.sub.4 alkyl or C.sub.2 -C.sub.4 alkenyl or alkynyl and E.sub.1 being hydrogen, halogen or one of a variety of organic substituents.The compounds are effective herbicides.Type: GrantFiled: October 19, 1988Date of Patent: May 29, 1990Assignee: ICI Australia Operations Proprietary LimitedInventors: Keith G. Watson, Peter Drygala, Stephen Bell
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Patent number: 4918187Abstract: The present invention relates to compounds of the formula ##STR1## wherein R.sub.c is carboxy, esterified carboxy or amidated carboxy; R.sub.2 is hydrogen or lower alkyl or joins with R.sub.a and R.sub.b and the atoms therebetween to form a fused ring ##STR2## and either R.sub.a is methyl and R.sub.b is ##STR3## or R.sub.2 and R.sub.b and the atoms therebetween form a group ##STR4## wherein R.sub.3 and R.sub.4 are either both hydrogen, or together are propylene, butylene, or with the two atoms to which they are attached form a benzene ring. Methods of manufacture and use thereof in the production of angiotensin converting enzyme inhibitors are disclosed.Type: GrantFiled: September 27, 1988Date of Patent: April 17, 1990Assignee: Ciba-Geigy CorporationInventor: Stephen K. Boyer
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Patent number: 4914092Abstract: A compound, in the form of a pure diastereoisomer or mixture thereof, which is a benzothiazepin-4-one derivative of formula (I): ##STR1## in which: R1 is hydrogen or a C.sub.2 -C.sub.4 alkanoyl group;R2 and R3 independently each is hydrogen, a linear or branched C.sub.1 -C.sub.4 alkyl group, a C.sub.3 -C.sub.5 cycloalkyl group, a phenyl group, a benzyl group or a phenethyl group, or R2 and R3 together form, with the nitrogen atom to which they are attached, a pyrrolidinyl, 2,2-dimethylpyrrolidinyl, piperidyl, 4-phenylpiperidyl, 4-(3-methoxyphenyl)piperidyl, 4-(4-fluorobenzoyl)piperidyl, 1,2,3,6-tetrahydropyridyl, perhydroazepinyl, perhydroazocinyl, 1,3-thiazolidinyl, thiomorpholinyl, morpholinyl, 2,3-dihydroindolyl, 1,2,3,4-tetrahydroisoquinolyl, 6-methoxy-1,2,3,4-tetrahydroisoquinolyl, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolyl or 2,3,4,5-tetrahydro-1H-benz[b]azepinyl group; andX is hydrogen or chlorine;or a pharmacologically acceptable acid addition salt thereof.Type: GrantFiled: April 18, 1989Date of Patent: April 3, 1990Assignee: SynthelaboInventors: Alistair Lochead, Jean C. Muller, Colombe Denys, Andre Dumas
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Patent number: 4908469Abstract: In general, the present invention provides, in one aspect, a process comprising contacting a 2-Aminothiophenol with an optically active 3-(4-alkyloxyphenyl)glycidic acid acyclic alkyl ester by step(s) under conditions such that an optically active 2-hydroxy-3-(4-alkyloxyphenyl)-3-(2-Aminophenylthio)propionic acid acyclic alkyl ester is prepared. Another aspect comprises the optically active 2-hydroxy-3-(4-alkyloxyphenyl)-3-(2-Aminophenylthio)propionic acid acyclic alkyl ester. A preferred aspect is a process comprising contacting 2-aminothiophenol per se with a 3-(4-methoxyphenyl)glycidic acid methyl ester by step(s) under conditions such that a 2-hydroxy-3-(4-methoxyphenyl)-3-(2-aminophenylthio)propionic acid methyl ester is prepared.Type: GrantFiled: May 18, 1988Date of Patent: March 13, 1990Assignee: Marion Laboratories, Inc.Inventor: Daniel E. Martin