Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• This invention relates to a method of treating 5-lipoxygenase and cyclooxygenase pathway mediated diseases. BACKGROUND OF THE INVENTION
• the metabolism of arachidonic acid occurs by many pathways.
• One route of metabolism is via the cyclooxygenase (CO) mediated pathway which produces PGH2 which is in turn metabolized to the prostanoids (PGE2, TxA2, and prostacyclin). These products are produced by various cells including polymoiphonuclear leukocytes, mast cells and monocytes.
• Another route is by the lipoxygenase mediated pathway which oxidizes arachidonic acid initially to 5-hydroperoxy-eicosatetraenoic acid (5-HPETE) which is further metabolized to LTA4, the precursor to the peptidoleukotrienes (LTC4, LTD4, and LTE4) and LTB4. Additionally 5-HPETE is converted to 5-hydroxyeicosatetraenoic acid
• Lipoxygenases are classified according to the position in the arachidonic acid which is oxygenated. Platelets metabolize arachidonic acid to 12-HETE, while polymoiphonuclear leukocytes (PMNs) contain 5 and 15 lipoxygenases. It is known that 12-HETE and 5,12-diHETE are chemotactic for human neutrophils and eosinophils, and may augment the inflammation process. 5-HPETE is known to be a precursor to the peptidylleukotrienes, formerly known as slow reacting substance of anaphylaxis (SRS-A) and LTB4. The SRS family of molecules, such as leukotrienes C4 and D4 have been shown to be potent bronchoconstrictors.
• SRS-A slow reacting substance of anaphylaxis
• LTB4 has been shown to be a potent chemotatic for PMNs.
• the products of the 5-lipoxygenase pathway are believed to play an important role in initiating and maintaining the inflammatory response of asthma, allergy, arthritis, psoriasis, and inflammatory bowel disease. It is believed that blockage of this enzyme will interrupt the various pathways involved in these disease states and as such inhibitors should be useful in treating a variety of inflammatory diseases, such as those inumerated above.
• the absence of selective inhibitors of lipoxygenase, as opposed to cyclooxygenase, which are active in vivo has prevented adequate investigation of the role of leukotrienes in inflammation.
• the arachidonic acid oxygenated products have been identified as mediators of various inflammatory conditions.
• the various inflam-matory disease states caused by these mediators and many other conditions, as discussed herein, are all conditions in which an oxygenated polyunsaturated fatty acid metabolite inhibitor, such as a 5-lipoxygense (5-LO) inhibitor, would be indicated.
• an oxygenated polyunsaturated fatty acid metabolite inhibitor such as a 5-lipoxygense (5-LO) inhibitor
• Such inflammatory conditions are rheumatoid arthritis, bronchial inflammation, inflammatory bowel disease, asthma, cardiovasular disorders, glaucoma, emphysema, acute respiratory distress syndrome, lupus, gout, psoriasis, pyresis, pain and other allergic oriented disorders such as allergic rhinits, food allergies, and uticaria.
• OPUFA oxygenated polyunsaturated fatty acids
• 5-LO 5-lipoxygenase
• CO cyclooxgenase
• substituents are the same and are selected from halo, C1.3 alkc y, C1.3 alkylamino, C1.3 dialkylamino, N- pyrrolidino, N-piperidino, 2, 2-trihaloethoxy, prop-2-ene-l-oxy, hydroxy, C1.3 alkylthio, C . alkylsulfinyl, Cj.3 alkyl-sulfonyl, C2-5 1- alkenyl-1-thio, C2-5 -1-alker.
• R4 and Re are independently elected from hydrogen, C1-.9 alkyl, aryl or heteroaryl;
• Zi is Cj_9 alkyl, aryl or hete >aryl; or a pharmaceutically acceptable salt thereof
• Another aspect of this inventior elates to a method of treating a cyclooxygenase pathway mediated disease i a subject in need thereof which comprises administering to such subject an effective, n i-toxic cyclooxygenase pathway inhibiting amount of a compound of Formula (I).
• Another aspect of this invention relates to the novel compounds of Formula (II) and a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of Formula (II).
• Another aspect of this invention relates to a method of treating an OPUFA mediated disease in a subject in need thereof which comprises administering to such subject an effective, OPUFA inhibiting amount of a compound of Formula (II).
• the compounds of Formula (II) are also effective cyclooxygenase inhibitors and therefor useful in the treatment of CO mediated disease states as well.
• Another aspect of this invention relates to a method of treating an OPUFA mediated disease in a subject in need thereof which comprises administering to such subject an effective, OPUFA inhibiting amount of a compound of Formula (HI).
• the compounds of Formula (HI) are also effective cyclooxygenase inhibitors and therefor useful in the treatment of CO mediated disease states as well.
• This invention relates to a method of using the compounds of Formula (I), as described above, for OPUFA mediated diseases comprising administration of an effective amount of a compound of Formula (I) to a mammal, including humans, in need thereof.
• the invention further relates to a method of treating a cyclooxygenase pathway mediated disease, which process comprises administration of an effective amount of a compound of Formula (I) to a mammal, including humans, in need thereof.
• This invention also relates to the novel compounds of Formula (II), described below and pharmaceutical compositions comprising a compound of Formula (II) and a pharmaceutically acceptable carrier or diluent.
• This invention also relates to a method of using the compounds of Formula (II) for treating OPUFA mediated disease, preferably by inhibition of the 5-lipoxygenase enzyme in a mammal, including humans, in need thereof.
• This invention also relates to a method of treating a cyclooxygenase pathway mediated disease comprising administration of an effective amount of cyclooxygenase pathway inhibiting amount of a compound of Formula (II) to a mammal, including humans, in need of such inhibition.
• the compounds of Formula (II) are encompassed within the genus of the compounds of Formula (I) and are represented by the structure:
• R2, R3, R5, and R7 are, independently, -H or C ⁇ _2 alkyl;
• one of Ti and To is 4-pyridyl or Cl-4 alkyl-4-pyridyl, provided that when T ⁇ is C ⁇ _4 alkyl-4-pyridyl the alkyl substituent is located at the 2-position of the pyridine ring, and the other of Ti and To is
• t is 0 or 1
• R4 and R $ are independently selected from hydrogen, C1.9 alkyl, aryl or heteroaryl;
• Z is -S-(CR4R6) t -S-Z ⁇
• Zi is C ⁇ _9 alkyl, aryl or heteroaryl; or a pharmaceutically acceptable salt thereof.
• One aspect of this invention is use in medicine of the compounds of Formula (IE), which are also encompassed within the genus of the compounds of Formula (I).
• the compounds of Formula (UI) are useful as OPUFA inhibitors and in the treatment of CO mediated diseases, preferably by inhibition of the 5-LO and CO enzymes respectively.
• the compounds of Formula (III) are represented by the structure:
• R2 5 R3, R5, and R7 are, independently, -H or C ⁇ _2 alkyl; and one of Si is 4-pyridyl or Cl-4 alkyl-4-pyridyl, provided that when Si or So is C .4 alkyl-4-pyridyl the alkyl substituent is located at the 2-position of the pyridine ring, and the other of Si and So is
• Another aspect of the present invention is a pharmaceutical composition
• a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of Formula (III) for use in treating an OPUFA or CO pathway mediated disease state.
• Another aspect of the present invention is a method of treating an OPUFA mediated disease state, in a mammal, including humans, in need of such treatment by administering an effective amount of a compound or pharmaceutically acceptable salt thereof selected from
• Another aspect of the present invention is a method of treating a CO pathway mediated disease state, in a mammal, including humans, in need of such treatment, which process comprises administering, an effective amount of a compound or pharmaceutically acceptable salt thereof, selected from 2-(4-Methoxyphenyl)-3-(4-pyridyl)-7-oxo-5,6-dihydro-[7H]-pyrrolo-[l,2-a]- imidazole;
• Yet another aspect of the present invention is a pharmaceutical composition
• a pharmaceutically acceptable carrier or diluent and a compound or pharmaceutically acceptable salt thereof, selected from 2-(4-Methoxyphenyl)-3-(4-pyridyl)- 7-oxo-5,6-dihydro-[7H]-pyrrolo-[l,2-a]-imidazole; 5,6-dihydro-2-(4-Methoxyphenyl)-3- (4-pyridyl)-[7H]-pyrrolo-[l ,2-a]-imidazole-7-ol; or 5,6-dihydro-7,7-difluoro-2-(4- Methoxyphenyl)-3-(4-pyridyl)-[7H]-pyrrolo-[l,2-a]-imidazole, for use in treating a CO or OPUFA pathway mediated disease.
• Preferred OPUFA mediated disease states inhibited in the processes of the present invention include, but are not limited to, arthritis, rheumatoid arthritis, osteoarthritis, allergic rhinitis, psoriasis, dermatitis, ischemic induced myocardial injury, reperfusion injury, gout, asthma, adult respiratory distress syndrome, atherosclerosis, inflammatory bowel disease, stroke, spinal cord injury and traumatic brain injury.
• Cyclooxygenase mediated disease states inhibited in the processes of the present invention include, but are not limited to, pyresis, pain, osteoarthritis, rheumatoid arthritis, thrombosis, inflammation, uticaria or edema.
• R2 and R3 are hydrogen, one of Rj and Ro is 4-pyridyl or C ⁇ _2 alkyl-4-pyridyl, provided that when Rj is C _2 alkyl-4-pyridyl the alkyl substituent is located at the 2-position of the pyridine ring, and the other of Ri and RQ is
• R2 and R3 are hydrogen, one of Ri and Ro is 4-pyridyl or C ⁇ _2 alkyl-4-pyridyl, provided that when Ri is C ⁇ _2 alkyl-4-pyridyl the alkyl substituent is located at the 2- position of the pyridine ring, and the other of R and Ro is
• the most preferred compound of Formula (I) is 2-(4-Methoxyphenyl)-3-(4- pyridyl)-imidazo[l,2-a]-pyridine.
• R2 and R3 are hydrogen, one of Ri and Ro is 4-pyridyl or C ⁇ _2 alkyl-4-pyridyl, provided that when Ri is C ⁇ _2 alkyl-4-pyridyl the alkyl substituent is located at the 2-position of the pyridine ring, and the other of Ri and Ro is (a) monosubstituted phenyl wherein said substituent is C 1 - 3 alkylamino,
• More preferred compounds of Formula (II) are those where
• Ri or R ⁇ may be a C ⁇ _3 alkylsulfinyl, C2-5 1-alkenyl-l-sulfinyl, C2-5 -2-alkenyl-l-sulfinyl, alkoxyalkylsulfinyl, and phenylsulfinyl moiety, are prodrugs which are reductively converted in vivo to the corresponding alkylthio or alkenylthio form.
• halo as used herein is meant all halogens, i.e., chloro, fluoro, bromo and iodo, preferably fluorine.
• aryl as used herein is meant phenyl, or naphthyl, which are both optionally substituted with halogen, C ⁇ .3 alkoxy, C ⁇ .3 alkylthio or C ⁇ _4 alkyl.
• heteroaryl as used herein is meant a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S; such as, but not limited, to quinoline, isoquinoline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole; all of which may be optionally substituted by one or more of halogen, C ⁇ -3 alkoxy, C ⁇ -3 alkylthio or C ⁇ _4 alkyl moieties.
• OPUA mediated disease or disease state any disease state which is mediated (or modulated) by oxidation of polyunsaturated fatty acids, specifically the arachidonic acid metabolic pathway.
• the oxidation of arachidonic acid by such enzymes as the lipoxygenase enzymes or cyclooxgenase enzyme is specifically targeted by the present invention.
• Such enzymes include, but are not limited to, 5-LO, 12- LO, 15-LO, and CO; which produce the following mediators, including but not limited to, PGE2, LTB4, LTC4, LTD4, prostaglandins, thromboxane, and prostocyclin.
• OPUA interfering amount an effective amount of a compound of Formula (I) which shows a reduction of the in vivo levels of an oxgyenated arachidonic acid metabolite.
• a and A 1 are hydrogen or alkyl; and D and D 1 are hydrogen, C 1 -9 alkyl, or phenyl; B is C ⁇ -9 alkyl or aryl; and Zx is aryl, heteroaryl or C 1 -9 alkyl.
• the hydrogen atoms in the CH2 groups described in Table 1 are, independently, optionally substituted by a C ⁇ _4 alkyl moiety.
• Another aspect of the present invention is the novel oxidation of an aryl sulfide, in particular alkyl thio aryl function, such as a methylthiophenyl group, to the corresponding sulfoxide wherein the aryl sulfide is substituted on a heteroaromatic nitrogen containing ring system, such as imidazole, triazole, pyrimidine, pyridine, 6,7-dihydro- [5H]-pyrrolo[2,l-a]imidazole, 2,3-dihydroimidazo[2,l-b] -thiazole, imidazo[2,l- bjthiazole, imidazo[2,l-b]oxazole, imidazo[l,2-a]pyridine, 5,6,7,8-tetrahydroimidazo[l,2- a]pyridine, or a imidazo[l,2-a]pyrimidine ring system.
• a heteroaromatic nitrogen containing ring system such as
• the process occurs in high yield with minimal formation of the sulfone byproducts. This process oxidizes the sulfide in higher yields than do alternative methods, such as m-chloroperbenzoic acid. This process also utilizes the inexpensive and readily available reagents, potassium or sodium persulfate.
• This process also does not utilize toxic metal, thus providing advantages in purification of the reaction product and disposal of wastes.
• Sodium and potassium persulfate are salts of peroxysulfuric acid.
• Other more commonly used peroxyacids such as m-chloroperbenzoic acid, are well-known to oxidize amines and pyridines to their N-oxides. It would be the expectation, that persulfuric acid or its salts would exhibit similiar reactivity and hence make them useless for the oxidation of compounds such as those disclosed herein, as they contain several nitrogen atoms.
• sodium and potassium persulfate have been known for some time to oxidize aniline derivatives to aniline-o-sulfates (the Boyland-Sims oxidation, disclosed in Boyland et al., J. Chem. Soc.
• persulfate reagents not only work on the compounds of Formula (I), (II) and (III) disclosed herein, but will also work well on their intermediates and other ring systems which contain a heterocyclic nitrogen atom, such as pyridine, imidazole, or other tertiary amine moieties.
• Prefered aryl sulfides are the phenylsulfide derivatives. Further preferred are the alkyl substituted alkyl sulfide derivatives, such as methyl or ethyl thio.
• Hetero-aromatic and non-aromatic nitrogen containing ring system on which the aryl sulfide moiety is found includes but is not limited to pyrrole, pyrazole, imidazole, imidazolididine, pyrazolidine, pyrazoline, morpholine, pyridine, pyrazine, indolizine, indoline, purine, quinoline, isoquinoline, napthyridine, triazole, pyrimidine, piperidine, isoindole, 3H- indole, cinnoline, carbazole, phenanthradine, phenazine, isothiazole, imidazo[l,2- b][l,2,4]triazine
• the nitrogen heterocyclic ring system is imidazole, pyrole, 2,3- dihydroimidazo[2,l-b]-thiazole, imidazo[2,l-b]thiazole-l -oxide or 1,1 -dioxide, imidazo[l,2-a]pyridine, 6,7-dihydro-[5H]-pyrrolo[2,l-a]imidazole or imidazole.
• the particulars of the oxidation are further described herein in the synthetic chemistry section.
• Formula (I) or Formula (II) which are useful in the present invention include, but are not limited to, maleate, fumarate, lactate, oxalate, methanesulfonate, ethane-sulfonate, benzenesulfonate, tartrate, citrate, hydrochloride, hydrobromide, sulfate and phosphate salts.
• Preferred pharmaceutically acceptable salts of the compounds of Formula (I) or Formula (II) include hydrochloride and hydrobromide salts, and such salts can be prepared by known techniques such as the method of Bender et al.. U.S. Patent 4,175,127, issued November 20, 1979.
• the compounds of the present invention may contain 1 or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are contemplated to be within the scope of the present invention.
• R2, R3, R5 and R7 are, independently H or C1-2 alkyl;
• X is a) 4-pyridyl or mono-C ⁇ .4alkyl-substituted pyridyl; or b) monosubstituted phenyl wherein said substituent is selected from halo, Q_3 alkoxy, hydroxy, Q_3 alkylthio, Q-4 alkyl, alkenylthio, phenylthio, alkoxyalkylthio, alkylthioalkylthio, _3 alkylamino, alkylcarbonylalkylthio, carbalkoxyalkylthio, C1.3 dialkylamino, CF3, N- (Ci-3 alkyl)-N-(C ⁇ _3 alkanamido), N-pyrrolidino, N-piperidino, prop-2- ene-1-oxy or 2,2,2-trihaloethoxy;
• R2, R3, R5 and R7 are, independently, -H or C ⁇ _2 alkyl;
• Y is 4-(l,4-dihydro)pyridyl substituted with N-(C ⁇ _g alkanoyl), N-(C ⁇ _8 alkoxycarbonyl), N-benzoyl, N-phenoxycarbonyl, N-phenylacetyl, or N-benzyloxy- carbonyl;
• Y ⁇ is (a) monosubstituted phenyl wherein said substituent is C .3 alkylthio, C .3 alkoxy, halo, C ⁇ _4 alkyl, hydroxy, alkenylthio, phenythio, alkoxyalkylthio, alkylthioalkylthio, alkylcarbonylalkylthio, carbalkoxy ⁇ alkylthio, C1-.3 dialkylamino, CF3, N-(C ⁇ _3 alkyl)-N-
• R2, R3, R5 and R7 are, independently, -H or C ⁇ -2 alkyl;
• one of Zi and ZQ is 4-(l,2-dihydro-2-alkyl)pyridyl substituted with N-(Cl-8 alkanoyl), N-(Cl-8 alkoxycarbonyl), N-benzoyl, N-phenoxycarbonyl, N-phenylacetyl, or N-benzyloxycarbonyl; and the other of Zi and ZQ is
• substitutents are the same and are selected from halo, _3 alkoxy, Q-3 dialkylamino, C ⁇ _3alkylthio, N- pyrrolidino, N-piperidino, 2,2,2-trihaloethoxy,or prop-2-ene-l-oxy, alkenylthio, phenylthio, alkoxyalkylthio, or alkylthioalkylthio; or wherein the substitutents together form a methylene dioxy group;
• R2, R3, R5 and R7 are, independently, -H or C ⁇ _2 alkyl
• RlO is C ⁇ _4 alkyl
• X2 is 4-pyridyl or mono-C ⁇ .4alkyl-substituted pyridyl;or (a) monosubstituted phenyl wherein said substituent is selected from fluoro, chloro, C1.3 alkoxy, C1.4 alkyl, C1.3 alkylthio, alkenythio, phenylthio, alkoxyalkylthio, alkylthioalkylthio, C1-.3 dialkylamino, CF3, C1.3 alkylamino, N-pyrrolidino, N-piperidino, prop-2-ene-l-oxy or 2,2,2- trihaloethoxy; (b) disubstituted phenyl wherein said substituents are the same and are selected from fluoro, chloro, C ⁇ _3 alkoxy, C ⁇ _3 dialkylamino, N- pyrrolidino, N-piperidino, 2,2,2-trihaloethoxy, prop-2-ene
• R2, R3, R5 and R7 are, independently, -H or C ⁇ _2 alkyl;
• one of Vi or Vo is 4-pyridyl or C ⁇ _4alkyl-4-pyridyl, provided that when Vi is C ⁇ _4a]kyl-4-pyridyl the alkyl substitutent is located at the 2-position of the pyridine ring, and the other of Vi and VQ is selected from:
• R2, R3, R5 and R7 are, independently, -H or C ⁇ _2 alkyl;
• X- is selected from
• CF3 C1.3 alkylamino, N-pyrrolidino, N-piperidino, prop-2-ene-l- oxy, 2,2,2-trihaloethoxy, C1-3 alkylthio, alkenylthio, phenylthio, alkoxyalkylthio, or alkylthioalkylthio;
• C ⁇ _3 alkoxy, 2,2,2-trihaloethoxy or prop-2-ene-l-oxy and the other substituent is independently selected from fluoro, chloro, C1.3 alkylamino, C1.3 dialkylamino, N-pyrrolidino, or N-piperidino;
• Additional intermediate compounds which are also useful in the process of this invention to make the compounds of Formula (II) are compounds of Formulas ( ⁇ a) and
• X is chosen from a group consisting of mono or disubstituted phenyl as defined in Formula (C), 4-pyridyl and mono-Ci gall l-substituted-4-pyridyl;
• X is a halogen such as Cl or Br.
• R2, R3, R5 and R7 are, independently, -H or C _2 alkyl.
• R2, R3, R5, and R7 are, independently, -H or C ⁇ _2 alkyl; and one of Rl and Ro is 4-pyridyl or Cl-4 alkyl-4-pyridyl, and the other of Rl and Ro is
• R3, R5, R7 and R9 are, independently, H or C ⁇ _2 alkyl
• Ri or RQ is 4-pyridyl and the other is selected from: (a) phenyl or monosubstituted phenyl wherein said substituent is selected from C1.3 alkylthio, C1.3 alkoxy, halo, C1.4 alkyl, alkenylthio, phenylthio, alkoxyalkylthio, alkylthioalkylthio, N-(Ci-3 alkyl)-N-(C ⁇ _3 alkanamido),C ⁇ _3 dialkylamino, CF3, N-pyrrolidino, N-piperidino, prop-2- ene-1-oxy, 2,2,2-trihaloethoxy, alkylcarbonylalkylthio, carbalkoxyalkylthio, phenylthio, alkoxyalkylthio, or alkylthioalkylthio; or
• the compounds of Formula (II) can be prepared according to the following
• the mono and disubstituted l-phenyl-2-chloro-ethanone Formula (A) compounds can be prepared by Friedel Crafts acylation of the corresponding mono or disubstituted benzenes with 2- chloroacetyl chloride and aluminum chloride by the method of Joshi et al.. J. Heterocyclic
• Formula (A) compounds are prepared wherein X is 4-pyridyl, mono-C ⁇ _4alkyl-substituted pyridyl, monosubstituted phenyl (as defined in Formula (C); or disubstituted phenyl (as defined in Formula (C)).
• Compounds of Formula (C) as defined above are prepared from the following classes of Formula (B) compounds wherein R2, R3, R5, or R7 are hydrogen or are one or more C ⁇ _2 alkyl groups; i.e.,:
• Formula (B) compound is reacted with a l-aryl-2-halo-ethanone Formula (A) compound to afford the Formula (C) compound by alkylation followed by cyclodehydration.
• Formula (C) compounds are prepared:
• the reaction to form the Formula (C) compounds is performed in a nonpolar solvent such as chloroform or toluene, or in a polar nonprotic solvent such as dimethylformamide or acetonitrille.
• Alkylation is facilitated by the presence of one to four equivalents of a base such as powdered sodium carbonate or triethylamine, and cyclodehydration is facilitated by heating (between ambient temperature and reflux) or removing the solvent and refluxing the residue in water or dilute aqueous acid.
• Compounds of Formula (C) may be treated with an alkyllithium compound to yield the corresponding lithium reagent by metallation.
• the lithium intermediate may then be treated with an excess of magnesium halide or zinc halide etherate to yield the corresponding organometallic reagent by transmetallation.
• a 4-bromo, 4-iodopyridine or the triflate ester of a 4-hydroxy pyridine (a 4-trifluoromethyl- sulfonyloxypyridine) is added in the presence of a palladium (O) catalyst, such as tetrakis(triphenyl-phosphine)-palladium, with hexamethyl-phosphoramide; or with a palladium (II) catalyst, such as PdCl2(1.4-bis(diphenylphosphino)-butane) catalyst , optionally, in the presence of lithium chloride and a base.such as triethylamine, to yield the corresponding Formula (II) compounds.
• a palladium (O) catalyst such as tetrakis(triphenyl-phosphine)-palladium
• Compounds of Formula (F) as defined above are intermediates to the corresponding Formula (II) compounds and are prepared by metallation of the appropriate Formula (C) compounds, where X is 4-pyridyl or monoalkyl-substituted 4-pyridyl, with a lithiating agent (such as s-butyllithium or n-butyllithium) in an ethereal solvent (such as tetrahydrofiiran), followed by treatment with a trialkyltin halide.
• a lithiating agent such as s-butyllithium or n-butyllithium
• ethereal solvent such as tetrahydrofiiran
• Formula (F) compounds are employed to prepare the Formula (II) compounds where Ro is 4-pyridyl or monoalkyl-substituted 4-pyridyl, i.e., one mole equivalent of the Formula (F) compound is added to an excess of a solution of a mono- or di-substituted phenyl bromide, triflate, or preferably the iodide, in an inert solvent (such as tetrahydrofuran) preferably containing
• HMPA hexamethyl-phosphoramide
• a palladium (0) catalyst such as tetrakis(triphenylphosphine)-palladium
• a palladium (II) catalyst in the presence of lithium chloride and an added base such as triethylamine
• Triflate precursors are prepared from the corresponding substituted phenols by treatment with trifluorosulfonic anhydride in the presence of a base such as pyridine or triethylamine.
• (II) may be prepared by the analogous reaction of an aryl or heteroaryl trialkyltin compound with a mixture of a Formula (H) compound and tetrakis-(triphenylphosphine)-palladium under similar conditions.
• the reaction conditions for Formula (F), and (H) compounds require that the substituent amino and sulfur substituted compounds, for example, be non- oxidized, or protected, i.e. N-(C ⁇ _3 alkyl)-N-(C _3alkanamido), etc., hence the final products of these reactions are all optionally subject to additional oxidation/acylation, etc. procedures.
• a compound of Formula (C) contains X as a phenyl (mono- or di- substiuted)
• the phenyl must be substituted with other than hydroxy, bromine, or iodine to yield a compound of Formula (H).
• the compounds of Formula (C) may also be treated with an excess of bromine to yield a bromo derivative, (a compound of Formula (H)) wherein the substituent group on the phenyl of a Formula (C) compound is substituted with other than an iodine, bromine, hydrogen, hydroxy or nitro substituent group, and is added to a pyridine boronic acid [B(OH)2 -4-pyridyl ] with a palladium catalyst such as Pd(Ph2P(CH2)4- PPh2)Cl2 or Pd(PPh3)4 in the presence of about three equivalents of sodium bicarbonate for about 12 hours under reflux conditions with a DME (dimethyl ethane)/H2 in a 3:1 ratio.
• a pyridine boronic acid [B(OH)2 -4-pyridyl ]
• a palladium catalyst such as Pd(Ph2P(CH2)4- PPh2)Cl2 or Pd(PPh3)4
• the pyridine-4-boronic acid is prepared from 4-bromopyridine by reation with n-butyllithium, trapping of the anion with riethyl borate and acid hydrolysis of the boronate ester.
• the method is similiar to that of Fischer and Haviniga, Rec. Trav. Chim. pays Bas. 84. 439 (1965).
• Additional references for coupling of bromopyridines with boronic acids are Snieckus,V., Tetrahedron Lett.. 29, 2135 (1988) and Terashimia, M., Chem. Pharm. Bull., U, 4755 (1985).
• the brominated Formula (C) compound can also, following halogen-metal exchange with n-BuLi and transmetallation with MgBr2, be coupled to a substituted halobenzene, preferably an iodide in the presence of bidentate palladium (II) catalyst or a Ni( ⁇ )Cl2 (l,2-bi-diphenyl-phosphino)ethane) catalyst to yield the desired regioisomer of the compounds of Formula (II).
• a substituted halobenzene preferably an iodide in the presence of bidentate palladium (II) catalyst or a Ni( ⁇ )Cl2 (l,2-bi-diphenyl-phosphino)ethane
• the magnesium or zinc derivative of a Formula (C) compound, however derived, when X is other than a 4-mono Ci-4 alkylpyridyl or 4-pyridyl may also be coupled to a substituted 4-halopyridine in the presence of the noted palladium (II) or Ni (II) catalyst to yield the final desired compounds of Formula (II).
• Formula (D) co ⁇ ounds are prepared by treatment of the corresponding Formula (C) compounds of classes 1, 2,3,and 4 described above, with a substituted carbonyl pyridinium salt by the method of Bender et al.. U.S. Patent 4,803,279, issued February 9, 1989; Adams et al.. U.S. Patent 4,719,218, issued 01/12/88 and in Adams et al.. U.S. Patent Number 5,002,942, issued March 26, 1991.
• the pyridinium salt may be either preformed or preferably prepared in situ by addition of the substituted carbonyl halide (such as an acyl halide, an aroyl halide, an arylalkyl haloformate ester, or preferably an alkyl haloformate ester, such as acetyl bromide, benzoylchloride, benzyl chloroformate, or preferably ethyl chloroformate) to a solution of the Formula (C) compound in pyridine or in an inert solvent such as methylene chloride to which pyridine has been added.
• the substituted carbonyl halide such as an acyl halide, an aroyl halide, an arylalkyl haloformate ester, or preferably an alkyl haloformate ester, such as acetyl bromide, benzoylchloride, benzyl chloroformate, or preferably ethy
• Compounds of Formula (E), as defined above, serve as intermediates in the preparation of Formula (II) compounds where one of RQ or Ri in the product Formula (II) compound is mono-alkyl substituted pyridyl.
• Compounds of Formula (E) are N- (substituted carbonyl)-4-(l,2-dihydro-2-alkyl)pyridines and are prepared by the method of Comins et al.. J. Org. Chem..
• Compounds of Formula (D) and Formula (E) serve as intermediates in the preparation of the compounds of Formula (II) and are converted into compounds of Formula (II) by deacylation and oxidation with a mild oxidizing agent by the methods described in Bender et al.. U.S. Patent No. 4,803,279; Adams et al.. U.S. Patent 4,719,218, issued 01/12/88 and in Adams et al.. U.S. Patent Number 5,002,942, issued March 26, 1991.
• Exemplary oxidation systems are sulfur in a refluxing inert solvent, or solvent mixture (such as decalin, decalin and diglyme, p-cymene, xylene, mesitylene), or preferably with potassium tert.-butoxide in tert-butanol with O2 gas at reflux for 15 minutes to the afford the corres-ponding compound of Formula (II).
• the compounds of Formula (II) may now be optionally reduced, hydrolyzed, oxidized, demethylated, or acylated to produce other desired Formula (II) compounds produced by this synthetic route.
• the metallated pyridine or substituted benzene may be coupled to the Formula (H) compounds employing the catalysts as described above.
• Compounds of Formula (G) possessing one or more mercapto functionalities are prepared via Pummerer Rearrangement on the corresponding alkylsulfinyl-substituted compounds of Formula (Ha).
• Pummerer Rearrangement of the corresponding compounds of Formula ( ⁇ a) is accomplished by the method described in Adams et al.. U.S. Patent Number 5,002,942, issued March 26, 1991 by refluxing with an alkanoic acid anhydride.
• the compounds of Formula (C) may also be used to make the analagous compounds of Formula (G) containing a hydrogen in the Vi position.
• Formula (C) compounds wherein the alkylthio group is oxidized to an alkylsulfinyl function and then reacted in the similiar manner as the Formula (Ha) compounds described herein to yield the corresponding mercapto substituted Formula (C) compounds, which may in turn be used to prepare the various other Formula (C) compounds, such as alkoxyalkylthio, alkenylthio, alkylthioalkylthio, alkylcarbonylalkylthio, or carbalkoxyalkylthio functions.
• the Formula (G) compounds where one of Vi or VQ is a mono or di ⁇ substituted phenyl having at least one mercapto substituent are obtained by hydrolysis of the Formula (II) acyloxyalkylthio products or preferably by treatment of a Formula (Ha) compound with trifluoroacetic anhydride followed by basic solvolysis with a base such as sodium methoxide in methanol, similar to the method of R. N. Young et al.. Tetrahedron
• Formula (G) co ⁇ ounds serve as intermediates for the synthesis of Formula (H) compounds where one of Ri or Ro of the Formula (II) compound is mono or disubstituted phenyl having at least one 2-alkenyl-l-thio function.
• a solution of the Formula (G) intermediate in a polar solvent such as dimethylformamide is treated with a base, preferably a metal hydride such as sodium hydride, and the sodium mercaptide salt formed is treated with a l-halo-2-alkene such as allyl bromide and heated from 25 to 80°C to give the Formula (II) compounds where one of Ri or RQ is a disubstituted phenyl having at least one 2-alkenyl-l-thio substituent.
• Formula (G) compounds described above also serve as intermediates for the synthesis of Formula (II) comr ⁇ mnds in which one of R or RQ is a di-substituted phenyl having at least one 1-alkenyl-l-thio function.
• Formula (G) compound Treatment of the Formula (G) compound in a nonprotic solvent such as tetrahydrofuran with a strong base such as lithium diethylamide at low temperature (-78 to -20°C) generates the lithium mercaptide salt
• This salt is alkylated at 0°C with a trimethylsilyl-methylating agent (such as trimethylsilylmethyl halide, triflate, or acetate) to form the trimethylsilylmethylthio substituent
• a trimethylsilyl-methylating agent such as trimethylsilylmethyl halide, triflate, or acetate
• the latter is deprotonated with addition of another molar equivalent of lithium diethylamide and treated with an aldehyde or ketone to give the Formula (LT) compound where VQ or V is a di ⁇ substituted phenyl having at least one 1-alkenyl-l-thio substituent.
• Compounds of Formula (II) where one of R or RQ is mono or disubstituted phenyl possessing a 4-halogen substituent (preferably fluoride) can be converted to the 4-alkylthio Formula (LT) compound by displacement of the halide ion with a metal alkyl-mercaptide salt (such as sodium thioethoxide) in a polar nonprotic solvent (such as dimethylformamide) heated to between 70 and 150°C.
• a metal alkyl-mercaptide salt such as sodium thioethoxide
• a polar nonprotic solvent such as dimethylformamide
• the Formula (G) compounds may be obtained by treatment of a Formula (II) or (HI) compounds containing a halophenyl function, preferably a fluoro or bromophenyl, having at least one halo substituent on the phenyl ring, in dimethyl sulfoxide (DMSO) with NaSH(sodium bisulfide).
• a Formula (II) or (HI) compounds containing a halophenyl function preferably a fluoro or bromophenyl, having at least one halo substituent on the phenyl ring
• DMSO dimethyl sulfoxide
• An alternative reaction to yield a Formula (C) compound containing a substituted phenyl wherein one of the substituents is a mercapto function, or a Formula (G) compound is to treat a halophenyl derivative of Formula (LT), or (C) with the sodium salt of an alkylmercaptan with catalytic amount of a palladium (O) compound, such as tetrakis(triphenylphosphine)-palladium in a solvent, such as DMSO.
• a palladium (O) compound such as tetrakis(triphenylphosphine)-palladium in a solvent, such as DMSO.
• R or R- is a mono- or di ⁇ substituted phenyl having at least one Q-3alkylsulfinyl, Ci-3alkylsulfonyl, or C ⁇ _3 alkenylsulfinyl, or compounds of Formula (II) wherein R or R- is a di-substituted phenyl having at least one C ⁇ _3alkylsulfinyl, Ci-3alkylsulfonyl, or C ⁇ _3alkenylsulfinyl; or R or R- is a mono- or di-substituted phenyl having at least one alkoxyalkylsulfinyl or phenyl- sulfinyl substituent are prepared by treatment of one or more equivalents of the corresponding compound of Formula's (I), (II) or (UI) wherein R or R- are C .3 • alkylthiophenyl,
• the oxidizing agent may be an organic peracid (such as 3-chloroperoxybenzoic) added dropwise to a solution of the Formula (II) co ⁇ ound in a halocarbon (such as methylene chloride) at ice bath temperature, or an inorganic agent (such as sodium ⁇ >eriodate, sodium persulfate, potassium persulfate, or hydrogen peroxide) in aqeuous acetic acid, or acetic acid, added dropwise to a solution of the Formula (II) compound in water containing 2 equivalents of an inorganic acid (such as hydrochloric acid).
• a halocarbon such as methylene chloride
• an inorganic agent such as sodium ⁇ >eriodate, sodium persulfate, potassium persulfate, or hydrogen peroxide
• Applicant's have found as one aspect of this invention the use of the oxidizing agents, sodium persulfate and potassium persulfate for producing aryl sulfoxides from arylsulfides on nitrogen containing heterocyclic ring systems.
• This is a process which comprises treating said aryl sulfide with sodium or potassium persulfate in aqeuous acetic acid yielding the corresponding arylsulfoxide.
• Srinivasan et al. Indian J. Chem..268. p.
• the reaction te ⁇ eratures may be quite varied and ranger from about 0° C to about 100° C. Preferably the temperature range is from about 0° C to about 60° C.
• the reaction time may be from minutes to days, and an additional co-solvent may also be used.
• co-solvents include, but are not limited to, THF (tetrahydrofiiran) and acetone.
• the method of mixing need not be in a dropwise fashion as indicated above for other oxiziding agents.
• Prefered aryl sulfides are the phenylsulfice derivatives. Further preferred are the alkyl substituted alkyl sulfide derivatives, such as methyl or ethyl thio.
• Hetero-aromatic and non-aromatic nitrogen containing ring system on which the aryl sulfide moiety is found includes but is not limited to, imidazole, triazole, pyrrole, pyrimidine, pyridine, 6,7-dihydro-[5H]-pyrrolo[2,l-a]imidazole, pyrrolo[2,l-a]imidazole; 2,3- dihydroimidazo[2,l-b] -thiazole, imidazo[2,l-b]thiazole ⁇ oxide or 1,1-dioxide; 2,3,4,5, tetrahydro-imidazo[2,l-b]thiazole-l-oxide or 1,1-dioxide, imidazo[2,l
• the aryl sulfide in the case of multiple ring systems may be attached to either ring.
• the nitrogen heterocyclic ring system is 2,3- dihydroimidazo[2,l-b]-thiazole, imidazo[2,l-b]thiazole-l -oxide or 1,1-dioxide, imidazo[l,2-a]pyridine, 6,7-dihydro-[5H]-pyrrolo[2,l-a]imidazole or imidazole.
• Acetophenones substituted with a mono- or di-substituted phenyl having at least one N-(C ⁇ _3alkanamido)or N-(C ⁇ _3 alkyl)-N-(C ⁇ _3 alkanamido), and in some cases the Formula (C), and Formula (LT) compounds, are prepared by acylation of the corresrjonding amino and N-(C ⁇ _3 alkylamino) compounds with the alkanoic acid anhydride or chloride in pyridine.
• N-(C ⁇ _3 alkyl)-N- (C ⁇ _3 alkanamido) phenyl substituted Formula (C) and Formula (LT) compounds is the alkylation of the corresponding N-(C ⁇ _3 alkanamido) substituted compounds with sodium hydride and a C1.3 alkyl bromide or iodide in dimethylformamide.
• Formula (C) and Formula (II) compounds containing a mono- or di ⁇ substituted phenyl having at least one amino substituent are prepared either by hydrolysis of the co ⁇ es]x>nding N-(C ⁇ _3 alkanamido) compounds in refluxing 6 N mineral acid or by catalytic reduction of the corresponding nitro compounds.
• Formula (C) and Formula (LT) compounds containing a mono- or di- substituted phenyl having at least one N-(C ⁇ _3 alkylamino) substituent are preferably prepared by acid catalyzed hydrolysis of the corres ⁇ x)nding N-(C ⁇ _3 alkyl)-N-(C ⁇ _3 alkanamido) compounds of Formula (C) and Formula (LT), respectively, prepared as described above for the aminophenyl substituted compounds, or alternatively, either by (a) reduction of the corresponding N-(C ⁇ _3 alkanamido) compounds with borane or borane dimethylsulfide complex in THF by the method of Brown, "Organic Synthesis via
• Formula (C) and Formula (II) compounds containing a mono- or di ⁇ substituted phenyl having at least one N,N-(di C ⁇ .- ⁇ alkylamino) substituent are alternatively prepared either by reduction of the corresponding N-(C ⁇ _3 alkyl)-N-(C _3 alkanamido) compounds of Formula (C) and Formula (LT) with borane as described above for the N-(C ⁇ _3 alkylamino) substituted compounds, or by displacement of the bromide by a N,N-dialkylamine in the corresponding 4-bromo-3-nitrophenyl Formula (C) and Formula (H) compounds by heating at 140°C with the N,N-dialkylamine and potassium carbonate in an inert solvent.
• Formula (C) and Formula (II) compounds containing a mono- or di ⁇ substituted phenyl having at least one N-pyrrolidino and N-piperidino substituent are alternatively prepared by cyclodialkylation of the corres]X>nding aminophenyl compounds with dibromobutane or dibromopentane and anhydrous potassium carbonate in an inert solvent such as dimethylformamide.
• Appropriately substituted mono and dihydroxy phenyl compounds or disubstitued phenyl compounds wherein one substituent is hydroxy of Formula (C) and Formula (II) are obtained by treatment of their respective correspondingly substituted methoxy derivatives with HBr in acetic acid, or preferably with BBr3 in CH2CI2 by the method described by Bender et al., J. Med. Chem.. 28. 1169 (1985), for the preparation of compound No. 14 described therein.
• acyloxyalkylthio compounds yields compounds of Formula (G) wherein one of R or R is phenyl substituted with a sulfhydryl function.
• the sulfhydryl substituted compounds can be treated with an alkanoic acid anhydride or an alkylthiono acid chloride in pyridine or a hindered amine, such as di(C ⁇ _3alkyl)amine under appropriate conditions, to prepare compounds of Formula (G) wherein one of R- or R is phenyl substituted with one or more acylthio or dithioacyl groups.
• Compounds of Formula (II) wherein one of R or R is phenyl substituted with at least one thiocarbamyl or dithiocarbamyl group are prepared by treating the sulfhydiyl-containing Formula (G) compound, prepared as above,with a carbamyl halide or thiocarbamyl halide in the presence of a base such as pyridine to yield the desired compounds.
• the two hydrogen atoms on the respective nitrogen atom in the carbamyl halides or thiocarbamyl halide derivatives may be replaced independently by alkyl, alkenyl, alkynyl, aryl or heteroaryl derivative, which may in turn be optionally substituted.
• Compounds of Formula (LT) wherein R* or R is phenyl disubstituted with an alkenylthio group wherein one saturated carbon atom separates the sulfur from the carbon bearing the double bond can be prepared by alkylating a compound of Formula (G) (or Formula (C) wherein one of Rl or Ro may be a phenyl substituted with at least one sulfhydryl group),with an appropriately substituted alkenylhalide, such as allylbromide.
• the metal mercaptide salt is treated with trialkylsilylmethylchloride in an aprotic solvent such as tetrahydrofuran is treated at reduced temperature with a lithiating reagent such as lithium diethylamide followed by treatment with an appropriate aliphatic aldehyde or ketone to prepare the compounds of Formula (II) and Formula (C),wherein R , Ri or X, is phenyl substituted with one or more alkenylthio groups.
• an aprotic solvent such as tetrahydrofuran
• a lithiating reagent such as lithium diethylamide
• Compounds of Formula (II) wherein R or Rl is phenyl substituted with an alkoxycarbonylthio are prepared by reacting a metal mercaptide salt prepared as described above, with an appropriate alkyl or aryl chloroformate.
• the metal mercaptide salt is formed from a compound of Formula (G) wherein one of R or R is phenyl substituted with a sulfhydryl function prepared as previously described.
• Compounds of Formula (II) wherein R or R is phenyl substituted with one or more alkoxythionothio groups are prepared by reacting the metal mercaptide with the appropriate alkyl or aryl halothionoformate.
• Comr ⁇ nmds of Formula (II) wherein R or Rl is alkoxyalkylthio are prepared by reacting the metal mercaptide salt of Formula (G) or Formula (C), prepared as described above, with an appropriate halomethyl ether. Oxidation of the resulting alkoxyalkylthio compounds by reacting with a suitable oxidizing agent such as chloroperbenzoic acid yields the compounds of Formula (LT) wherein R or R- is phenyl substituted with an alkoxyalkylsulfinyl.
• the nonsymmetrical disulfide (Z) wherein Z is -S-S-Zi and Zi is phenyl or C 1 - 9 alkyl the compound may be prepared by reaction of the sulfhydryl compound with the appropriate sulfenyl halide in an ethereal solvent to afford compounds of Formula (II) wherein one of R or Rl is phenyl substituted with one or more alkyl-dithio or aryl-dithio groups The method of Mukaiyama et al..
• Tetrahedron Letters.56:5907-08 (1968) allows for use of the desired aryl-SH or alkyl-SH reagent treated with diethylazodicarboxylate in 1:1 equivalence at room tempertaure in a solvent, yielding an adduct which is then treated with 1:1 ratio of the desired mercaptan of Formula (G).
• This process will also yield the disulfide dimer of the compounds of Formula (II).
• the disulfide linkage is on the Ro position of the compounds of Formulas (I) and (LT).
• Compounds of Formula (LT) and Formula (C), wherein R, Ri or X, is phenyl substituted with an alkylthioalkylthio group are prepared by reacting the analogous sulfhydryl compound, prepared as described above, with the appropriate carbonyl component, such as formaldehyde, acetone, or acetaldehyde, using either mineral or Lewis acid catalysis conditions to yield the symmetrical dithioketal.
• the intermediate hydroxylalkylthio derivative reacts with another sulhydryl containing compound under the acid catalysis conditions to yield what is essentially a "bis" type compound, differing only by the alkyl chain insertion, i.e.
• the metal salt reacts with an independent and varying alkyl chain length halomethyl-[CRRl]-thioalkyl[aryl/heteroaryl] compound to yield the "non-bis" type compounds, [Formula (I)-S-CRRl-S-R2], wherein R and R- are as defined above for the "bis" compounds, and R***- is a Cj-9 alkyl, aryl or heteroaryl group which may be optionally substituted.
• a mixture of Ro and Ri linkages is contemplated, as part of the present invention, hoever, preferably the linkage is on both Ro positions of the compounds of Formula (I) or (II).
• An alternate method of preparation of the nonsymmetrical disulfide compound wherein only one component is a compound of Formula (II), and the other half of the disulfide link is an alkyl, aryl or heteroaryl derivative, may be prepared by reaction of a sulfhydryl compound of Formula (II), with the appropriate sulfenyl halide, in an ethereal solvent to afford compounds of Formula (II) wherein one of R or Rl is phenyl substituted with one or more [alkyl]- dithio groups, i.e. [Formula ( ⁇ )-S-S-R-*--], wherein R-R2 are as defined in the above paragraph.
• the contemplated sulfenyl halide derivatives of alkyl, aryl, or heteroaryl groups may be optionally substituted.
• the disulfide compound(s) may also be ⁇ )repared from the corresponding alkyl sulfoxide compounds, such as methylsulfinyl, propylsulfinyl, iso-propylsulfinyl, wherein the alkyl can be a straight chain or branched derivative having from 1 to 9 carbon atoms, in a solvent, preferably a chlorinated one such as chloroethylene, methylene chloride or chloroform, to which is added a carboxcylic acid anhydride, such as trifluToacetic anhydride, or acetic anhydride.
• the Pummerer rearrangement reaction may require some heating prior to addition of an alkali metal hydroxide, such as sodium hydroxide. If acetic anhydride is used than heating is also likely to be needed during the hydroxide treatment, before addition of iodine solid (I2), which then affords the symmetrical disulfide compound as is noted above Mixtures of the sulfoxide compounds may be present in the solution to yield "symmetrical" compounds but with varying substituent groups on the di-heteroaiyl-imidazole ring system of the present invention.
• an alkali metal hydroxide such as sodium hydroxide.
• This invention also relates to the use of a pharmaceutical composition comprising an effective, non-toxic amount of a compound of Formula (IA) and a pharmaceutically acceptable carrier or diluent in the methods disclosed herein.
• Pharmaceutically acceptable salts and their preparation are well known to those skilled in pharmaceuticals.
• Pharmaceutically acceptable salts of the compounds of Formula (I) which are useful in the present invention include, but are not limited to, maleate, fumarate, lactate, oxalate, methanesulfonate, ethane-sulfonate, benzenesulfonate, tartrate, citrate, hydrochloride, hydrobromide, sulfate and phosphate salts.
• Preferred pharmaceutically acceptable salts of the compounds of Formula (I) include hydrochloride and hydro-bromide salts, and such salts can be prepared by known techniques such as the method of Bender et al.. U.S. Patent 4,175, 127, the disclosure of which is hereby incorporated by reference.
• the compounds of Formula (I) are useful for treating disease states mediated by the 5-li ⁇ joxygenase pathway of arachidonic acid metabolism in an animal, including mammals, in need thereof.
• the discovery that the compounds of Formula (I) are inhibitors of the 5-lipoxy genase pathway is based on the effects of the compounds of Formula (I) on the production of 5-lipoxygenase products in blood ex vivo and on the 5-lipoxygenase in vitro assays, some of which are described hereinafter.
• the 5-lipoxygenase pathway inhibitory action of the compounds of Formula (I) was confirmed by showing that they impaired the production of 5-lipoxygenase products such as leukotriene B4 production by RBL-1 cell supernants.
• Lipoxygenase products have been identified in exudate fluids from gouty patients. This disorder is characterized by massive neutrophil infiltration during the acute inflammatory phases of the disease. Since a major 5-lipoxygenase product, LTB4, is produced by neutrophils, it follows that inhibition of the synthesis of LTB4 may block an amplification mechanism in gout
• Another area of utility for inhibitors of the 5-lipoxy genase pathway is in the treatment of asthma. [See, e.g., Ford-Hutchinson, J. Allergy Clin. Immunol.. 74. 437- 440 (1984)]. Additionally another utility for inhibitors of the 5-lipoxygense pathway is in the treatment of Adult Respitory Distress Syndrome. [See, e.g., Pacitti et. al., Circ. Shock , 21 ⁇ 155-168 (1987)]. Yet another utility for inhibitors of the 5-lipoxygenase pathway is in the treament of allergic rhinitis.
• vasculitis Mechanism of Vessel Damage
• Inflammation Basic Principles and Clinical Correlates. 703-718, Ed. Gallin et al., Raven Press, N.Y., N.Y. (1988).
• An additional area of utility for inhibitors of the 5-lipoxygenase pathway is in the optical area, in particular general inflammation of the corneal anterior and posterior segments due to disease or surgery such as in post surgical inflammation, uveitis, and allergic conjuntivitis.
• optical area in particular general inflammation of the corneal anterior and posterior segments due to disease or surgery such as in post surgical inflammation, uveitis, and allergic conjuntivitis.
• OPUFA mediated can have utility is that generally refered as degenerative neurological disorders, such as Parkinson's disease.
• Another area is that of traumatic or ischemic injuries, such as stroke, brain or spinal cord injuries and inflammatory disease of the brain and spinal column.
• More specicially preferred disease states are the mycardial induced ischemic injuries and/or reperfusion injuries.
• the compounds of Formula (I) are useful for treating disease states mediated by the cyclooxygenase pathway of arachodonic acid in an animal, including mammals, in need thereof.
• the discovery that the compound of Formula (I) are inhibitors of cyclooxygenase products is based upon the effects of the compounds of Formula (I) on the production of the PGE2 products, and the human monocyte data, the assays of which are described herein.
• This invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising an effective, non-toxic amount of a Formula (I), Formula (II) or (III) compound or salt thereof, and a pharmaceutically acceptable carrier or diluent for use in the methods described herein.
• the compounds of Formula (I), Formula (H or (El) are administered in conventional dosage forms prepared by combining a compound of Formula (I), Formula (II) or (ITT) in an amount sufficient to produce an OPUFA inhibiting, 5-LO inhibiting or CO inhibiting activity with standard pharmaceutical carriers according to conventional procedures.
• the compounds of Formula (I), Formula (II), or Formulas (HI) may also be administed in conventional dosages in combination with a known, second therapeutically active compound, such as an antihistamine, anti-bacterial or anti-fungal agent These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
• a known, second therapeutically active compound such as an antihistamine, anti-bacterial or anti-fungal agent
• This invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising an effective amount of a compoundor a pharmaceutically acceptable salt thereof of 2-(4- MethoxyphenyI)-3-(4-pyridyl)-7-oxo-5,6-dihydro-[7H]-pyrrolo[l,2-a]imidazole; 5,6-
• the pharmaceutical carrier employed may be, for example, either a solid or liquid.
• solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
• liquid carriers are syrup, peanut oil, olive oil, water and the like.
• the carrier or diluent may include time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
• the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
• the amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 g.
• the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
• Formula (LT) compound a pharmaceutically acceptable salt of the Formula (I) or Formula (II) compound is dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3 M solution of succinic acid or, preferably, citric acid.
• each parenteral dosage unit will contain the active ingredient [i.e., the compound of Formula (I) or (II)] in an amount of from about 50 mg. to about 500 mg.
• each oral dosage will contain the active ingredient in an amount of from about 100 mg to about 1000 mg.
• the compounds of Formula (I) or (T) may also be administered topically.
• the compounds of Formula (I) or Formula (LT) may be administered topically in the treatment or prophylaxis of inflammation in an animal, including man and other mammals,and may be used in the relief or prophylaxis of 5-lipoxygenase pathway mediated diseases such as rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and other arthritic conditions, inflamed joints, eczema, psoriasis or other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis; pyresis, pain and other conditions associated with inflammation.
• 5-lipoxygenase pathway mediated diseases such as rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and other arthritic conditions, inflamed joints, eczema, psoriasis or other inflammatory skin conditions such as sun
• a suitable anti-inflammatory dose of an active ingredient is 1.5 mg to 500 mg of base for topical administration, the most preferred dosage being 1 mg to 1000 mg, for example 5 to 250 mg administered two or three times daily.
• topical administration is meant non-systemic administration and includes the application of a compound of Formula (I) or (LT) externally to the epidermis, to the buccal cavity and instillation of such a compound into the ear, eye and nose, and where the compound does not significantly enter the blood stream.
• systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration. While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation.
• the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, e.g. from 1% to 2% by weight of the formulation although it may comprise as much as 10% w/w but preferably not in excess of 5% w/w and more preferably from 0.1% to 1% w/w of the formulation.
• topical formulations of the present invention comprise an active ingredient together with one or more acceptable carrier(s) therefor and optionally any other therapeutic ingredient(s).
• the carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
• Drops according to the pjresent invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent
• the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100C. for half an hour.
• the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
• bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01 %).
• Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
• Lotions according to the pjresent invention include those suitable for application to the skin or eye.
• An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
• Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
• Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application.
• the basis may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, com, arachis, castor or olive oil; wool fat or its derivatives, or a fatty acid such as steric or oleic acid together with an alcohol such as prolylene glycol or macrogols.
• hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap
• a mucilage an oil of natural origin such as almond, com, arachis, castor or olive oil
• wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as prolylene glycol or macrogols.
• the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic sulfactant such as sorbitan esters or polyoxyethylene derivatives thereof.
• suitable surface active agent such as an anionic, cationic or non-ionic sulfactant such as sorbitan esters or polyoxyethylene derivatives thereof.
• Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
• the compounds of Formula (I) or (H) may also be administered by inhalation.
• inhalation is meant intranasal and oral inhalation administration.
• Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
• the daily dosage amount of a compound of Formula (I) or (II) administered by inhalation is from about .lmg to about 100 mg/kg preferably about 1 mg to about 10 mg kg pier day.
• a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof can be administered to such human in a conventional dosage form prepared by combining a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, with a conventional pharmaceutically acceptable carrier or diluent according to known techniques, such as those described above as well as those described in Adams et al.. U.S. Patent Number 5,002,942, issued March 26, 1991. It will be recognized by one of skill in the art that the form and character of the pharmaceutically acceptable ca ⁇ ier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables.
• the route of administration may be oral, pulmonary, parenteral, buccal, intra- articular ,nasal or topical.
• parenteral as used herein includes intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred.
• the daily oral dosage regimen will preferably be from about 5 to about 100 mg/kilogram of total body weight
• the daily parenteral dosage regimen will preferably be from about 2 to about 80 mg per kilogram (kg) of total body weight, most preferably from about 3 to about 60 mg kg.
• the daily topical dosage regimen will preferably be from about 2 mg to about 10 mg per site of administration.
• the optimal quantity and spacing of individual dosages of the Formula (I) or (II) compound will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular animal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of Formula (I) or (LT) or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
• the route of administration for the compounds an their pharmaceutically acceptable salts of 2-(4-Methoxyphenyl)-3-(4-pyridyl)-7-oxo-5,6-dihydro-[7H]- pyrrolo[l,2-a]imidazole; 5,6-Dihydro-2-(4-Methoxyphenyl)-3-(4-pyridyl)-[7H]- pyrrolo[l ,2-a]imidazole-7-ol; or 5,6-Dihydro-7,7-difluoro-2-(4-Methoxyphenyl)-3-(4- pyridyl)-[7H]-pyrrolo[l,2-a]-imidazole may be by oral, pulmonary, parenteral, buccal, intra-articular ,nasal or topical means as defined herein.
• the subcutaneous and intramuscular forms of parenteral administration are generally preferred.
• the daily oral dosage regimen will preferably be from about 1 to about 100 mg kilogram of total body weight dependent upon the route of administration, preferably from about 2mg to about 80mg/kg per day. It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of one of these three compounds or pharmaceutically acceptable salts thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques.
• a pharmaceutical composition of this invention in the form of a capsule is prepared by filling a standard two-piece hard gelatin capsule with 50 mg. of a compound of
• EXAMPLE B - INJECTABLE PARENTERAL COMPOSITION A pharmaceutical composition of this invention in a form suitable for administration by injection is prepared by stirring 1.5% by weight of a compound of Formula (I) in 10% by volume propylene glycol and water. The solution is sterilized by filtration.
• the compound of Formula (I) is dispersed in a small volume of the vehicle and this dispersion is gradually incorporated into the bulk to produce a smooth, homogeneous product which is filled into collapsible metal tubes.
• the carbowax, beeswax and lanolin are heated together at 60°C and added to a solution of methyl hydroxybenzoate. Homogenization is achieved using high speed stirring and the temperature is allowed to fall to 50°C.
• the compound of Formula (I) is added and dispersed throughout, and the composition is allowed to cool with slow speed stirring.
• the methyl hydroxybenzoate and glycerin are dissolved in 70 ml of the water at 75°C.
• the sorbitan monolaurate, polysorbate 20 and cetostearyl alcohol are melted together at 75°C and added to the aqueous solution.
• the resulting emulsion is homogenized, allowed to cool with continuous stirring and the compound of Formula (I) is added as a suspension in the remaining water. The whole suspension is stirred until homogenized.
• Span 85 or oleic acid and disperse such in a propellant (ca.), such as freon, preferably a combintion of freon 144 and freon 12, and put into an appropriate aerosol container adapted for either intranasal or oral inhalation administration.
• a propellant ca.
• freon preferably a combintion of freon 144 and freon 12
• mice Male Balb/c mice (20-28 g), were used. All mice were obtained from Charles River Breeding Laboratories, Springfield, N.Y. Within a single experiment, mice were age matched. Reagents were employed as follows:
• Compounds of Formula (I) were used as the free base. The compounds were dissolved in acid saline. Compounds were administered by lavage at the indicated dose in a final volume of 10 ml/kg.
• Arachidonic Acid-Induced Mouse Ear Inflammation Arachidonic Acid-Induced Mouse Ear Inflammation Arachidonic acid in acetone (2 mg/20 ml) was applied to the inner surface of the left ear. The thickness of both ears was then measured with a dial micrometer one hour after treatment, and the data were expressed as the change in thickness (IO-**- * cm) between treated and untreated ears.
• Test compounds were given orally in acid/saline at the times indicated in the text prior to the topical application of arachidonic acid.
• the 5-lipjoxygenase (5-LO) was isolated from extracts of RBL- 1 cells.
• the inhibition of 5-lipoxygenase activity was measured by one of two assays, the radiotracer extent assay either measured after 90 seconds at 20°C or measured according to the method of G. K. Hogaboom et al., Molecular Pharmacol. __ ⁇ , 510-519 (1986) or the continuous O2 consumption assay. The results from either assay are comparable if not identical. All compounds were dissolved in ethanol with the final concentration of ethanol being 1 % in the assay.
• the radiotracer extent assay examined the 5-lipoxygenase products [transLTB4 (DI-HETE), 5HETE and 5HPETE] produced after a 90 second incubation at
• the second assay for assessing inhibition of the 5-lipoxygenase activity was a continuous assay which monitored the consumption of O2 as the reaction progressed.
• the 5-lipjoxygenase enzyme (200mL) was preincubated with the inhibitor or its vehicle in 25mM BisTris buffer (pH 7.0) that contained ImM EDTA, ImM ATP, 5mM NaCl and 5% ethylene glycol for 2 minutes at 20°C (total volume 2.99 ml).
• Arachidonic acid (lOmM) and CaCl2 (2mM) were added to start the reaction, and the decrease in O2 concentration followed with time using a Clark-type electrode and the Yellow Spring O2 monitor (type 53)(Yellow Springs, OH).
• the optimum velocity was calculated from the progress curves.
• the compound mediated inhibition of 5-lipoxygenase activity is described as the concentration of compound causing a 50% inhibition of optimum velocity for the vehicle- treated sample.
• the assay buffer consisted of RPMI 1640 buffer, [Moore, G. E. et al., JAMA. 199. 519 (1967) herein incorporated by reference] 1% human AB serum, 2mM glutamine, 100 U/ml Penicillin/Streptomycin, 25 mMHEPES [4-(2-hydroxyethyl)-l-piperazine-ethanesulfonic acid], and ImM CaCl2.
• D compound no. 1 is 2-(4-methoxyphenyl)-3-(4-pyridyl)-imidazo-[l,2-a]-pyridine.
• compound no. 2 is 5,6-Pihydro-7,7-difluoro-2-(4-Methoxyphenyl)-3-(4-pyridyl)-[7H]- pyrrolo[l,2-a]-imidazole.
• d compound no. 3 is 2-(4-Methoxyphenyl)-3-(4-pyridyl)-7-oxo-5,6-dihydro-[7H]- pyrrolo[l ,2-a]imidazole.
• e compound no. 4 is 5,6-Pihydro-2-(4-Methoxyphenyl)-3-(4-pyridyl)-[7H]-pyrrolo[l,2- a]imidazole-7-ol.
• the compounds of Formula (I) show inhibition of both 5-LO and CO activity and the 7-substituted difluroro, 7-oxo and 7- hydroxy derivatives of a pyrrolo[2,l-a]imidazole, and therefore are expected to be useful in the treatment of OPUFA , spjecifically mediated by inhibition of the 5-LO and CO mediated enzymes.
• the title compound is prepared by treating 2-(4-methylsulfinylphenyl)-3-(4- pyridyl)imidazo[l,2-a]-pyridine, prepared as described in Example 15, of Bender et al.. U.S. Aplication Serial Number 07/365,349, filed June 13, 1989.
• Ethanesulfenyl chloride (0.33 g) is added dropwise to an ice-bath cooled solution containing 1.03 g (3.4 mmole) of 2-(4-mercaptophenyl)-3-(4-pyridyl)- imidazo[l,2-a]pyridine prepared as in Example 1 above, in tetrahydrofuran. The mixture is allowed to warm to room temperature. Workup yields the crude disulfide which is purified by chromatography on silica.
• Phenyl isocyanate (0.38ml, 3.5mmole) is added dropwise to a stirring ice- bath cooled solution containing 1.03 g (3.4 mmole) of 2-(4-mercaptophenyl)-3-(4-pyridyl)- imidazo[l,2-a]pyridine prepared as in Example 1 above, in tetrahydrofuran. The mixture is allowed to warm to room temperature. Workup yields the crude titled compound which is purified by chromatography on silica.
• EXAMPLE 10 2-(4-N-Phenyldithiocarbamoylphenyl)-3-(4-pyridyl)--imidazori.2-alpyridine
• Phenyl isothiocyanate (0.42 ml, 3.5 mmole) is added dropwise to a stirring ice-bath cooled solution containing 1.03 g (3.4 mmole) of 2-(4-mercaptophenyl)-3-(4- pyridyl)-imidazo[l,2-a]pyridine pjrepared as in Examplel in tetrahydrofuran. The mixture is allowed to warm to room temperature and stirred for several hours. Workup yields the crude titled comp ⁇ mnd which is purified by chromatography on silica.
• Thiocarbamoyl chloride (336 mg, 3.5mmole) is added dropwise to a stirring ice-bath cooled solution containing 1.03 g (3.4 mmole) of 2-(4-mercaptophenyl)-3-(4- pyridyl)-imidazo[l,2-a]pyridine prepared as in Example 1 above, in tetrahydrofuran. The mixture is allowed to warm to room temperature and stirred for several hours. Workup yields the crude titled compound which is purified by chromatography on silica.
• N,N-Dimethylcarbamoyl chloride (375 mg, 3.5 mmole) is added dropwise to a stirring -20°C solution containing 1.03g (3.4 mmole) of 2-(4-mercaptophenyl)-3-(4- pyridyl)-imidazo[l,2-a]pyridine prepared as in Example 1 above, in tetrahydrofuran. The mixture is allowed to warm to room temperature. Workup yields the crude thiocarbamate which is purified by chromatography on silica.
• the title compound is prepared by treating 6-(4-methylthiophenyl)-5-(4- pyridyl)imidazo[2,l-b]thiazole, as described in Example 20 of Bender et al.. U.S. Application Serial Number 07/365,349, filed June 13, 1989.
• EXAMPLE 15 6-(4-Methylsulfinylphenyl)-5-(4-pyridyl)imidazor2.1 -bloxazole.
• Formula (D Compound The title compound is prepared by treating 6-(4-methylthiophenyl)-5-(4- pyridyl)-imidazo[2,l-b]oxazole,as described in Example 23, Bender et al.. U.S. Application Serial Number 07/365,349, filed June 13, 1989.
• the title compound is prepared by treating 2-(4-methylthiophenyl)-3-(4- pyridyl)-imidazo[l,2-a]-pyrimidine, as described in Example 26, Bender __ a_., U.S. Application Serial Number 07/365,349, filed June 13, 1989.
• EXAMPLE 17 2-(4-Methoxyphenyl)-3-(4-pyridyl imidazo ⁇ .2-alpyridine.
• Formula (D Compound a) 2-(4-Methoxyphenyl)imidazori.2-alpyridine A chloroform solution of 7.3 g (32 mmoles) of l-(4-methoxyphenyl)-2- bromo-ethan-1-one and 3.0 g (32 mmoles) of 2-aminopyridine was stirred for 5 hours and a precipitate was obtained on chilling.
• the reaction mixture was stirred for 28 h. A 50 mL portion of water added, the pH was adjusted to 8-9 by the addition of solid potassium carbonate, and then the mixture was extracted three times with 20 mL of methylene chloride. The combined extracts were washed successively with 25 mL water, 25 mL of saturated aqueous sodium chloride solution, then dried over magnesium sulfate. The drying agent was removed by filtration, and the filtrate was evaporated in vacuo. After drying for 18 h at 56°C/35 mm of Hg, the solid weighed 153.6 mg for a chemical yield of 95%. The chemical purity was determined by HPLC to be 92%. No sulfone derivative was detected by HPLC.

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• 1991
  • 1991-06-07 JP JP91512077A patent/JPH05508153A/ja active Pending
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