Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
  • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
  • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
  • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
  • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/08—Bridged systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/08—Bridged systems

Definitions

• This invention relates to novel 4-oxo-naphthyridine- and 4-oxo-quinoline-3-carboxylic acids derivatives having anti-bacterial activity, to compositions containing the same, and to novel amines and intermediates used in the preparation of the same.
• quinoline derivatives More particularly, derivatives of 1,4-dihydro-4-oxo-3-quinoline- carboxylic acids having the following structural formula:
• Such quinolones unsubstituted in the benzene nucleus, B, wherein R is H, are described as having only slight antibacterial activity.
• quinoline derivatives having the above structural formula wherein the pyridone nucleus, A, possesses various substitutents in the 1-position selected from unsubstituted lower alkyl groups or lower alkyl substituted with, for example, halogen and hydroxy-groups, lower alkenyl, alkynyl, and unsubstituted and substituted phenyl.
• substitutents in the 1-position selected from unsubstituted lower alkyl groups or lower alkyl substituted with, for example, halogen and hydroxy-groups, lower alkenyl, alkynyl, and unsubstituted and substituted phenyl.
• naphthyridine derivatives i.e 1,8-naphthyridine ⁇ r more particularly 1,4-dihydro-4-oxo- 1,8-naphthyridine-3-carboxylic acid derivatives, having the following structural formula:
• 1,8-naphthyridine derivatives having the above structural formula there are disclosed derivatives having piperazinyl and pyrrolidinyl groups in the 7-position and ethyl in the 1-position. See pages 51-56.
• substituents in the 1-position it is disclosed that among those same 1-position substituents described above in the quinoline derivatives, maximum activity is achieved with ethyl or propyl groups whereas all smaller or larger alkyl groups or those with additional double bonds or functional groups decrease activity. See page 60, lines 8-19.
• norfloxacin (1-ethyl-6-fluoro-1,4-dihydro-7- (1-piperazinyl)-4-oxo-quinoline-3-carboxylic acid) and ciprofloxacin (1-cyclopropyl-6-fluoro-1,4-dihydro-7- (1-piperazinyl)-4-oxo-quinoline-3-carboxylic acid).
• U.S. Patent 3,590,036 discloses numerous 1-substituted- 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids and derivatives thereof having the following formula, including nalidixic acid mentioned above, wherein the substituent on the 1-position can be aliphatic hydrocarbon radicals having one to ten carbon atoms inclusive such as, for example, alkyl, alkenyl and alkynyl radicals.
• Illustrative of these radicals are methyl, ethyl, n-propyl, i-propyl, 2-butyl, isoamyl, and the like, when alkyl; and 2-propenyl (allyl), 2-methyl-2-propenyl, 3-butenyl, and the like when alkenyl.
• the substituents on the pyridine nucleus that is at the 5-, 6-, and 7-positions of the naphthyridine ring system, can be lower-alkyl, halo, and lower-cycloalkylamino.
• R 1a denotes an alkyl, cycloalkyl, aralkyl, aryl or an amino group
• R 2a denotes a hydrogen atom or an alkyl, aralkyl or an aryl group
• R 3a denotes a derivative of a carboxyl group such as a nitrile or ester group
• up to three of the symbols A, B, D and E denote a nitrogen atom and the remaining of the symbols A, B, D, and
• R 1a are ethyl and tert-butyl
• R 1a a single example illustrating tertiary-butyl as the R 1a radical, namely,
• X is a halogen atom, especially a fluorine atom
• R 1 is an ethyl or vinyl group
• R 2 is a hydrogen atom or a lower alkyl group, and non-toxic salts thereof.
• U. S. Patent 4,146,719 discloses the compound, 1-ethyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxoquino- line-3-carboxylic acid (norfloxacin) and the hydrates and addition salts thereof. German Offen .
• DE 3142854 discloses 1-cyclopropyl-6- fluoro-1,4-dihydro-4-oxo-7-piperazinyl-quinoline-3-carboxylic acids including the specific compound wherein the substituent in the 7-position is unsubstituted piperazinyl (ciprofloxacin) as well as 4-substituted piperazinyl wherein the substituent is methyl,ethyl, or beta-hydroxyethyl.
• EP 0,153,163 discloses antibacterial compounds having the following structural' formula:
• X is CH, C-Cl, C-F, C-OH, C-O-alkyl having from one to three carbon atoms, C-NH-alkyl having from one to three carbon atoms or N;
• Y is H, F, Cl or Br;
• Z is representative of heterocylic substituents having the formula
• R 3 is hydrogen, methyl, ethyl, 1- or 2-propyl
• R 1 is hydrogen, alkyl having one to six carbon atoms or a cation
• R 2 is alkyl having one to four carbon atoms, vinyl, haloalkyl, or hydroxyalkyl having two to four carbon atoms, or cycloalkyl having three to six carbon atoms.
• R 2 is a tertiary alkyl group, namely, 1-methylcyclopropyl (See Examples 61 and 68).
• Z is an amine substituent selected from
• R is hydrogen, alkyl of one to three carbon atoms, hydroxyalkyl of two to three carbon atoms, benzyl or p-aminobenzyl;
• R' is hydrogen or alkanoyl of one to three carbon atoms;
• X is CH, CF, or N;
• Y is hydrogen, fluoro, or amino;
• R 1 is hydrogen, alkyl having from one to six carbon atoms or a cation; and
• R 2 is alkyl having one to four carbon atoms, vinyl, haloalkyl, or hydroxyalkyl having two to four carbon atoms, or ⁇ ycloalkyl having three to six carbon atoms, and the pharmaceutically acceptable acid addition or base salts thereof.
• R 1 and R 2 are identical or different and represent a
• C 1 -C 4 alkyl radical which is optionally substituted by a hydroxyl, amino, methylamino or dimethylammo group, and R 1 and R 2 together with the nitrogen atom to which they are bonded, furthermore form a 5- or 6-membered heterocyclic ring which can additionally have, as a ring member, the atoms or groups -O-, -S-, -SO-, -SO 2 - or >NR 3 .
• the patented compounds are said to couple low toxicity with a broad antibacterial spectrum against Gram-positive and
• Gram-negative bacteria in particular against
• Enterobacteriaceae especially against those which are resistant to various antibiotics such as penicillins, cephalosporins, aminoglycosides, sulfonamides and the like.
• A is a substituted ammo group, R 1 R 2 N-; X is H or F; and R 2 is C 1 -C 3 alkyl or C 1 -C 6 cycloalkyl.
• EP O 166 939 discloses antibacterial 1-cyclopropyl-6- fluoro-1,4-dihydro-4-oxo-7-(3-oxo-1-piperazinyl)-3-quinolinecarboxylic acids having the structural formula
• EP O 167 763 discloses antibacterial compounds having the structural formula
• X 1 and X 2 are the same or different and represent Cl or F provided that they are not both F at the same time and R 1 and R 2 , together with the nitrogen atom to which they are bound, form a 5- or 6-membered ring which can further include -O-, -S-, -SO-, -SO 2 -, >N-R 3 or -CONR 3 .
• Spanish Patent 8504767 discloses a process to produce compounds having the structural formula
• R 1 is hydrogen or lower alkyl, for example, methyl, ethyl, or isopropyl
• R 2 is methyl or ethyl
• U. S. Patent 4,563,448 discloses a method of combatinn plant-pathogenic bacteria using a cyclopropyl-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid derivative of the formula
• R 1 is H or alkyl
• EP O 132 845 discloses antibacterial 1,8-naphthyridine derivatives of the formula
• EP 0 134 165 discloses antibacterial 7-(pyrrol-1-yl) derivatives of 1-ethyl-1,4-dihydro-4-oxo-quinoline-3- carboxylic acid and 1-ethyl-1,4-dihydro-4-oxo- -(1,8-naphthyridine)-3-carboxylic acid of the formula
• X is a carbon atom or nitrogen atom and R is hydrogen or fluoro.
• U. S. Patent 4,341,784 discloses antibacterial 7- (3-amino-1-pyrrolidinyl)-1-ethyl-6-fluoro-1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acids of the formula
• This invention in a first aspect is a generic chemical compound representing one of the group of compounds consisting of naphthyridine- and quinoline-carboxylic acids and having the formula
• R 1 is a unsubstituted or substituted tertiary-alkyl group wherein the t-alkyl group may contain 1-3 halo, e.g. fluoro, groups, X is a halogen or trihalomethyl group, Y is a C or a N atom which provides a quinoline or a naphthyridine ring system, respectively, and Z is a N-heterocyclic ring selected from the group of piperazinyl, piperidinyl, 3-amino-1-pyrrolidinyl, 3-aminoalkyl-1-pyrrolidinyl, 2-aminoalkyl-morpholin-4-yl, 2-aminoalkyl-thiomorpholin-4-yl, and diazabicycloakyl groups containing 7-9 atoms in the diazobicycloalkyl ring system.
• X is a halogen or trihalomethyl group
• Y is a C or a N
• this invention is an intermediate for the preparation of compounds of Formula I having the generic formula
• this invention is an amine compound, Z-H, useful in preparing compounds of Formula I .
• this invention is a compound having the formula
• R 1 is a unsubstituted or substituted tertiary alkyl group selected from
• R is H or CH 3 and wherein the t-alkyl group may contain 1-3 halo, e.g. fluoro groups;
• X is a member of the group of halogen groups selected from F, Cl and Br and trihaloalkyl groups selected from CF 3 and CCl 3 ;
• Y is selected from CH, CF, CCl, CBr, and N; and Z is selected from
• W is NR 2 , S or O ,
• R 2 is independently selected from H, unsubstituted and substituted alkyl having 1 to 6 carbon atoms wherein the substituent is independently selected from 1-3 hydroxy, fluoro, chloro, amino, alkylamino, trifluoroacetylamino, and phenyl groups; cycloalkyl having 3 to 6 carbon atoms; and cycloalkenyl having 3 to 6 carbon atoms; and wherein A, B, C, and D are independently selected from H; unsubstituted and substituted lower alkyl having 1 to 4 carbon atoms wherein the substituent is independently selected from 1-3 hydroxy, fluoro, chloro, amino, alkylaraino, trifluoroacetylamino, and phenyl groups; amino; hydroxy; fluoro; chloro; and phenyl groups; and wherein n, when present, is selected from the integers 0, 1, 2, and 3; provided that when R 1 is then Z is not R 2 ⁇ N(CH 2 )
• R 2 is independently selected from CH 3 and C 2 H 5 .
• this invention is a pharmaceutical composition comprising an antibacterially effective amount of a compound of Formula I above.
• this invention is a method of combatting bacterial infection in warm-blooded animals comprising administering to said animals an antibacterially effective amount of a compound of Formula I or of a pharmaceutical composition thereof.
• this invention is a compound having the formula M (Formula II) wherein: R 1 is a tertiary alkyl group selected from
• R is H or CH 3 ;
• X is a member of the group of halogen groups selected from F, Cl, and Br and trihaloalkyl groups selected from CF 3 and CCl 3 ;
• X' may be the same as X or an alkyl-, aryl- or aralkylsulfonyl
• Y is selected from CH, CF, CCl, CBr and N;
• M is selected from H, C 1 -C 4 alkyl and alkali and alkaline earth metal ions, and ammonium ions.
• this invention is a compound represented by the formula
• ZH is selected from (1R, 4R), H and the free amine hydrolysis product thereof, and Preferred compounds of Formula I above according to
• R 1 is unsubstituted or substituted -C(CH 3 ) 3 ,
• X is F
• Y is selected from CH, CF and N;
• R 2 is independently selected from H, CH 3 , -C 2 H 5 and
• A, B, C , and D are independently selected from H, CH 3 and C 2 H 5 ; and n is
• R 1 is -C(CH 3 ) 3 , -C(CH 2 F) (CH 3 ) 2 , -C(CH 2 F) 2 CH 3 , or
• Y is selected from CH and N;
• X is F
• Y is CH
• R 1 is -C(CH 3 ) 3 ;
• X is F
• Y is N
• R 2 H or CH 3
• R 1 is -C(CH 3 ) 3
• X is F
• Y is N
• Z is selected from
• cis-isomer and trans-isomer are on the same side of the plane of the pyrrolidine ring system or are on opposite sides of the plane of the pyrrolidine ring system, respectively. It will be apparent to those skilled in the art that here there are present 2 asymetric carbon atoms and, thus, there are two isomers when the methyl and amino groups are cis and two isomers when they are trans.
• the compounds having formulas I, II, and III may contain an asymmetric carbon atom.
• the formulas I, II and III herein representing the various compounds of the invention are intended to embrace all optical isomers, as well as racemic mixtures thereof, of the compounds within the scope of the given formula.
• the compounds of this invention may be readily prepared by reacting a compound having the formula
• X' in Formula II above may be selected from the same substituents, namely, F, Cl and Br and CF 3 and CCl 3 , which define "X", X' also may be an organic leaving group other than CF 3 and CCl 3 . More preferably, X' may be selected from F and Cl and an organic leaving group such as alkylsulfonyl (for example methanesulfonyl), arylsulfonyl (for example phenylsulfonyl), and aralkylsulfonyl (for example p-toluenesulfonyl).
• alkylsulfonyl for example methanesulfonyl
• arylsulfonyl for example phenylsulfonyl
• aralkylsulfonyl for example p-toluenesulfonyl
• reaction sequence illustrates a typical preparation of the compounds of formulas I and also II.
• R Et or PhCH 2
• Y CH, CF or N.
• polyhalogenated aromatic acid (1) is converted with sulfuryl chloride to acid chloride (2) which acylates malonate diester in the presence of magnesium ethylate to give the aroylmalonate (3).
• Compound (10) may be obtained from (7) by two ways: (a) Ester (7) is first hydrolyzed under basic condition to lead to carboxylic acid (8) which reacts with the appropriate amine to give (10); and (b) Ester (7) can be converted to (9) with the appropriate amine and the ester (9) hydrolyzed under basic condition to (10).
• Preferred species of the compounds of this invention include the following:
• the compounds of Formula I according to this invention may be provided as pharmaceutically acceptable acid addition and base salts wherein the anion or cation, respectively, does not contribute significantly to the toxicity of the salt and which salts are compatible with the standard and conventional pharmaceutically acceptable carriers and other conventional adjuvants and excipients customarily employed in producing pharmaceutical compositions adapted for oral or parenteral administration.
• Pharmaceutically acceptable base salts are formed by conventional techniques involving reaction of the compounds of Formula I with alkali (Na,K) and alkaline earth (Ca, Ba, Zn, Mn) metal bases, more preferably with alkali metal bases such as, for example, dilute solutions of sodium hydroxide, and potassium carbonate.
• pharmaceutically acceptable base salts are formed by conventional techniques involving reaction with amines such as, for example, triethylamine, dibenzylamine, triethanolamine, ethanolamine, N,N'-dibenzylethylenediamine, procaine and equivalent amines.
• Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, low melting wax, cocoa butter, and the like.
• Liquid form compositions include solutions, suspensions and emulsions.
• solutions of the compounds of this invention dissolved in water and water-propylene glycol and water-polyethylene glycol systems, optionally containing suitable conventional coloring agents, flavoring agents, stabilizers and thickening agents.
• the pharmaceutical composition is provided employing conventional techniques in unit dosage form containing appropriate amounts of the active component, that is, the compound of Formula I according to this invention.
• compositions for parenteral administration will generally contain a pharmaceutically acceptable amount of the compound according to formula I as a soluble salt (acid addition salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection and a buffer to provide a suitably buffered isotonic solution, for example, having a pH of about 3.5-6.
• a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection and a buffer to provide a suitably buffered isotonic solution, for example, having a pH of about 3.5-6.
• Suitable buffering agents include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine to name but a few representative buffering agents.
• the compound according to formula I generally will be dissolved in the carrier in an amount sufficient to provide a pharmaceutically acceptable injectable concentration in the range of about 1 mg/ml to about 400 mg/ml of solution.
• the resulting liquid pharmaceutical composition will be administered so as to obtain the above-mentioned antibacterially effective amount of dosage in the range of about 0.1 to about 15, more preferably about 1.5 to about 10, still more preferably about 3 to about 7 mg/kg of body weight/day.
• Examples 1 to 44 describe different methods used to prepare representative compounds according to the invention.
• Examples A to H describe preparations of sofar unknown amines.
• the crude product was suspended in 823 mL 95% aqueous isopropanol. The suspension was heated to reflux and 3.20 mL (49.3 mmoles) of methanesulfonic acid was added. The mixture was kept at room temperature overnight, filtered and dried to yield 8.12 g of titled compound, mp > 270oC.
• NAPHTHYRIDINE-3-CARBOXYLIC ACID METHANESULFONATE SALT.
• This ester (370 mg - 0.78 mmole) was suspended in 3.1 mL 1N aqueous sodium hydroxide and refluxed one hour. The solution was cooled and adjusted to pH 7.8 with IN HCl. The precipitate v/as filtered and washed with water to give 250 mg of titled compound. MP 260°C dec.
• This compound was prepared by following substantially the procedure of example 33 except the reaction lasted one hour.
• This compound was prepared by following substantially the procedure of example 32.
• Trifluoroacetatic acid anhydride (4.6 mL) was added to ice-cooled 3-benzyl-3,8-diazabicyclo(3.2.1) octane (1.4 g, 6.9 mmoles). The resulting mixture was heated under reflux for 15 minutes, cooled, diluted with ethanol (20 mL) and treated with 2 mL of 5N hydrochloric acid in ethanol, evaporated to dryness. The so-obtained solid was taken-up with ether, collected by filtration, and dried in vacuo to afford 1.6 g of titled compound. MP 176°C.
• 3-chlorocyclopentene (306 mmoles, 36.9 g) was added dropwise to a solution of anhydrous piperazine (496 mmoles, 36.9 g) in dry methanol (350 mL) at -13°C. The final solution was stirred at -13°C for 15 minutes and at room temperature for one hour. The solvent was evaporated to dryness, and the residue was first taken up with chloroform and then filtered to eliminate the precipitate. After elimination of chloroform by evaporation the filtrate give 10 g of 1-(cyclopenten-3-yl) piperazine (yellow oil).
• Acetone (90mL) was added to a mixture of 1.96 g (6 mmoles) of 6-fluoro-7-chloro-1-(1,1-dimethylethyl)-1,4-dihydro-4- oxo-1,8 naphthyridine-3-carboxylic acid ethyl ester and 2.5 g (18 mmoles) of anhydrous potassium carbonate.
• To this suspension was added 1.33 mL (18 mmoles) of ethanethiol. After heating to reflux for 2.5 hours, the solvent was eliminated in vacuo. The residue was taken up with ethylacetate and water. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. The resulting solid was treated with ether to give 1.67 g of titled compound. MP 159-60°C.
• EXAMPLE XI 6-fluoro-7-chloro-1-(1,1-dimethylethyl)-1,4-dihydro
• Table 1 illustrates the quinoline- and naphthyridine-carboxylic acid antibacterial compounds described above in Examples 1-44 which are represented by the structural formula at the top of the table.
• the compounds of this invention display antibacterial activity when tested by the microtitration dilution method reported by Heifetz et al., Antimicr. Agents & Cheraoth., 6. 124 (1974).
• Minimum inhibitory concentrations (MICs, in ⁇ g/ml) for but a few representative compounds according to this invention were determined by the above-mentioned method. The results are set forth in the following Table 2.
• Naphthyridine analogs of Example 1 are also specifically contemplated and are expected to show improvement in antibacterial activity over their quinoline analogs comparable to the improvement illustrated by Example 20 relative to Example 1.
• 1,8-naphthyridine-3-carboxylic acid, ethyl ester in 15 ml acetonitrile was added 1.40 g (9.26 mmol) of 1,8-diazabi- cyclo[5.4.0]undec-7-ene.
• the solution was heated one hour at +65oC.
• the reaction mixture was cooled in an ice-bath.
• This amino-acid was suspended in 60 ral methanol and heated under reflux. To this hot suspension was added 1.28 ml

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• 1987
  • 1987-10-05 ZA ZA877471A patent/ZA877471B/xx unknown
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• 1988
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