CA1066701A - Method for the preparation of piperazine derivatives - Google Patents
Method for the preparation of piperazine derivativesInfo
- Publication number
- CA1066701A CA1066701A CA191,286A CA191286A CA1066701A CA 1066701 A CA1066701 A CA 1066701A CA 191286 A CA191286 A CA 191286A CA 1066701 A CA1066701 A CA 1066701A
- Authority
- CA
- Canada
- Prior art keywords
- group
- compound
- formula
- ethyl
- piperazinyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- 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
Abstract
ABSTRACT
A process for preparing 8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)pyrido(2,3-d)pyrimidine-6-carboxylic acids (I) and its pharmaceutically acceptable salts, which comprises hydrolyzing 8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)pyrido(2,3-d)pyrimidine-6-carbonitrils(II') oxidizing 6-lower alkanoyl-8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)pyrido(2,3-d)pyrimidines (II"), and if desired, hydrolyzing the product; or subjecting alkyl 4-(N-substituted ethyl-N-ethyl)amino 2-(1-piperazinyl)-pyrimidine-5-carboxylates (IV) to a Dieckmann reaction, dehydrogenating the resulting 8-ethyl-2-(1-piperazinyl)-5-oxo-5,6,7,8-tetrahydropyrido(2,3-d) pyrimidines (III), then oxidizing or hydrolyzing the resulting 5,8-dihydro-8-ethyl-2-(1-piperazinyl)-5-oxo-pyrido (2,3-d)pyrimidines(II) and if desired, converting the resulting 8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)pyrido[2,3-d) pyrimidine-6-carboxylic acids(II) to a pharmaceutically acceptable salt, and a process for proparing 5,8-dihydro-8-ethyl-2-(1-piperazinyl)-5-oxopyrido(2,3-d)pyrimidines(II), which comprises dehydrogenating 8-ethyl-2-(1-piperazinyl)-5-oxo-5,6.7.8-tetrahydropyrido(2,3-d)pyrimidines (III), or subjecting alkyl 4-(N-substituted ethyl-N-ethyl)amino-2-(1-piperazinyl)-pyrimidine-5-carboxylates(IV) to a Dieckmann reaction, and dehydrogenating the resulting 8-ethyl-2-(1-piperazinyl)-5-oxo-5,6,7,8-tetrahydropyrido(2,3-d)pyrimidines (III).
The 8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl) pyrido(2,3-d)pyrimidine-6-carboxylic acids (I) and their pharmaceutically acceptable salts are useful as antibacterial agents, and 5 8-dihydro-8-ethyl-2-(1-piperazinyl)-5-oxopyrido(2,3-c)pyrimidines (II) are used as intermediates for producing the 8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl) pyrido(2,3-d)pyrimidine-6-carboxylic acids (I).
A process for preparing 8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)pyrido(2,3-d)pyrimidine-6-carboxylic acids (I) and its pharmaceutically acceptable salts, which comprises hydrolyzing 8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)pyrido(2,3-d)pyrimidine-6-carbonitrils(II') oxidizing 6-lower alkanoyl-8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)pyrido(2,3-d)pyrimidines (II"), and if desired, hydrolyzing the product; or subjecting alkyl 4-(N-substituted ethyl-N-ethyl)amino 2-(1-piperazinyl)-pyrimidine-5-carboxylates (IV) to a Dieckmann reaction, dehydrogenating the resulting 8-ethyl-2-(1-piperazinyl)-5-oxo-5,6,7,8-tetrahydropyrido(2,3-d) pyrimidines (III), then oxidizing or hydrolyzing the resulting 5,8-dihydro-8-ethyl-2-(1-piperazinyl)-5-oxo-pyrido (2,3-d)pyrimidines(II) and if desired, converting the resulting 8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)pyrido[2,3-d) pyrimidine-6-carboxylic acids(II) to a pharmaceutically acceptable salt, and a process for proparing 5,8-dihydro-8-ethyl-2-(1-piperazinyl)-5-oxopyrido(2,3-d)pyrimidines(II), which comprises dehydrogenating 8-ethyl-2-(1-piperazinyl)-5-oxo-5,6.7.8-tetrahydropyrido(2,3-d)pyrimidines (III), or subjecting alkyl 4-(N-substituted ethyl-N-ethyl)amino-2-(1-piperazinyl)-pyrimidine-5-carboxylates(IV) to a Dieckmann reaction, and dehydrogenating the resulting 8-ethyl-2-(1-piperazinyl)-5-oxo-5,6,7,8-tetrahydropyrido(2,3-d)pyrimidines (III).
The 8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl) pyrido(2,3-d)pyrimidine-6-carboxylic acids (I) and their pharmaceutically acceptable salts are useful as antibacterial agents, and 5 8-dihydro-8-ethyl-2-(1-piperazinyl)-5-oxopyrido(2,3-c)pyrimidines (II) are used as intermediates for producing the 8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl) pyrido(2,3-d)pyrimidine-6-carboxylic acids (I).
Description
~066701 This invention relates to a method for prep&ring new ar.d useful piperazine derivatives and pharmaceutically acceptable salts thereo~ as antibacterial agents, and ~nter~ediates thereof.
The useful piperazine derivatives as antibacterial agents are expressed by the following formula COOH
N3~5~
~ I . .
The useful piperazine derivatives as antibacterial agents are expressed by the following formula COOH
N3~5~
~ I . .
2 5 uherein Rl is a hydrogen atom or lower alkyl group.
The intermediates thereof are expressed by the following formula -R'l - N ~ 1 N~ (II) wherein R'l is a hydrogen atom, lower alkyl group or acyl group and R2 is a cyano group, lower alkoxycarbonyl group, or lower alkanoyl group.
The acyl group as R'l means a group selected from ~ormyl, acetyl, ethoxycarbonyl, benzyloxycarbonyl and benzoyl groups, and the acetyl group is especially preferred.
The louer alkyl group in Rl means an alkyl group having 1 to 4 carbon atoms such as a methyl, ethyl or butyl group. The methyl and ethyl groups are preferred.
The louer alkoxycarbonyl or lower alkanoyl group as R2 respectively -~
means an alkoxycarbonyl or aIkanoyl group having 2 to 5 carbon atoms, such as ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl, acetyl, or propionyl group, The compound of this invention is synthesized as follows:
. , . , . ,: : -First, æ compound of the formula ~ COO alkyl R ' 1--N N N 1 2 2 R2 ( :[V ) wherein R'l and R2 are the same as defined above, and the aIkyl is an alkyl group preferably containing 1 to ~ carbon atoms, is sub~ected to Dieck~ann reaction, and the resulting compound of the formula N ~ J~ 2 R~ \N,J~N 1~ Nl J ~III) wherein R'l and R2 are the same as defined above, is dehydrogenated to Por~ a compound of the following formula ~ ~ 2 (Il) wherein R'l and R2 are the same as defined above, that is an intermediate. ~ -Hydrolysis o`r oxidation of the resulting intermediate (II) accord- .
ing to the nature of radical R2 gives a useful compound as an antibacterial agent. Specifically, the useful compound of the invention is prepared by ~ ~ :
hydrolyzing a compound of the formula 2 (Il where~n R'l i8 the same as defined above, and R'2 is a cyano ~j , group or lower alkoxycarbonyl group, or by oxidizing a compound of the formula (Il ) C H
R'l i8 the same as defined above, and R"2 is a lower alkanoyl group, followed, if desired, by hydrolysis, to form a compound of formula (I) wherein Rl is a hyarogen atom or lower alkyl group.
The above reactions can be schematically shown as follows:
~ COO alkyl cyclization ~ N ~ ~ 2 R 1 ~ N ~ IN CH2,CH2 R2 1 ~ ~ / t (IV) (III) : : .
.'~
de dro- N ~ ~ 2 hydrolysis > ~ ~ ~OOH
R~ - ~ ~ N ~ I or oxidation R~ C H
(II) (I) The reaction route ~ill be specifically described below. .
Pro_ess from comDound (IV)to com~ound (III) : .
(intramolecular cyclization) ~ -Compound (IY) 18 reacted by heating in a ~olYent in the presence
The intermediates thereof are expressed by the following formula -R'l - N ~ 1 N~ (II) wherein R'l is a hydrogen atom, lower alkyl group or acyl group and R2 is a cyano group, lower alkoxycarbonyl group, or lower alkanoyl group.
The acyl group as R'l means a group selected from ~ormyl, acetyl, ethoxycarbonyl, benzyloxycarbonyl and benzoyl groups, and the acetyl group is especially preferred.
The louer alkyl group in Rl means an alkyl group having 1 to 4 carbon atoms such as a methyl, ethyl or butyl group. The methyl and ethyl groups are preferred.
The louer alkoxycarbonyl or lower alkanoyl group as R2 respectively -~
means an alkoxycarbonyl or aIkanoyl group having 2 to 5 carbon atoms, such as ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl, acetyl, or propionyl group, The compound of this invention is synthesized as follows:
. , . , . ,: : -First, æ compound of the formula ~ COO alkyl R ' 1--N N N 1 2 2 R2 ( :[V ) wherein R'l and R2 are the same as defined above, and the aIkyl is an alkyl group preferably containing 1 to ~ carbon atoms, is sub~ected to Dieck~ann reaction, and the resulting compound of the formula N ~ J~ 2 R~ \N,J~N 1~ Nl J ~III) wherein R'l and R2 are the same as defined above, is dehydrogenated to Por~ a compound of the following formula ~ ~ 2 (Il) wherein R'l and R2 are the same as defined above, that is an intermediate. ~ -Hydrolysis o`r oxidation of the resulting intermediate (II) accord- .
ing to the nature of radical R2 gives a useful compound as an antibacterial agent. Specifically, the useful compound of the invention is prepared by ~ ~ :
hydrolyzing a compound of the formula 2 (Il where~n R'l i8 the same as defined above, and R'2 is a cyano ~j , group or lower alkoxycarbonyl group, or by oxidizing a compound of the formula (Il ) C H
R'l i8 the same as defined above, and R"2 is a lower alkanoyl group, followed, if desired, by hydrolysis, to form a compound of formula (I) wherein Rl is a hyarogen atom or lower alkyl group.
The above reactions can be schematically shown as follows:
~ COO alkyl cyclization ~ N ~ ~ 2 R 1 ~ N ~ IN CH2,CH2 R2 1 ~ ~ / t (IV) (III) : : .
.'~
de dro- N ~ ~ 2 hydrolysis > ~ ~ ~OOH
R~ - ~ ~ N ~ I or oxidation R~ C H
(II) (I) The reaction route ~ill be specifically described below. .
Pro_ess from comDound (IV)to com~ound (III) : .
(intramolecular cyclization) ~ -Compound (IY) 18 reacted by heating in a ~olYent in the presence
- 3 ~
,, . "" s of a basic catalyst conventionally used for Dieckmann reaction, for example, metallic sodium or potassium, sodium hydride, or sodium ethoxiae, tbereby intramolecularly cyclizing the compound to form compound (III). This reac-tion can be achieved with better resultg if a catalytic amount of methanol or ethanol or another lower alcohol is added. Aromatic hydrocarbons such as benzene or toluene or ethers such as dioxane, tetrahydrofuran, 1-2-dimethoxyethane or diethylene glycol dimethyl ether are suitable as the solvent for use in this reaction. The heating temperature is not particu-larly restricted, but usually, it is preferred to employ temperatures in the range of 60 to 180C.
Process from compound (III) to comPound (II) Compound (III) and a conventional dehydrogenating aeent, such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), tetrachloro-1,4-benzo-quinone (chloranil), tetracyanoethylene, palladium carbon (Pd-C), N-bromo-succinimide (NBS), manganese dioxide, or selenium dioxide, are heated for a short period of time at a temperature near the boiling point of the solvent used. Or compound (III) is heated in the above solvent without using a dehydrogenating agent. Or the compound (III) is directly heated to a tem-perature above its melting point, thereby to form compound (II). The pre-ferred solvent is an inert solvent, for example, an aromatic hydrocarbon suchas benzene, toluene or xylene, an ether such as dioxane, or an alcohol such as methanol or ethanol. The heating temperature i8 60 to 260C.
Process from comPound (II') to_compound ~I) (hydrolysis) Of the compounds (II), compound (II') in which R2 is a cyano or lower alkoxycarbonyl group is hydrolyzed by a customary method to form com-pound (I). This reaction can be performed by heating the compound (II') with a mineral acid, and pouring the reaction product into water; or by heating (70 to 120C.) or warming this compound in a solvent such as water or a water-containing high-boiling ether such as dioxane or 1,2-dimethoxy-ethane or a water-containing alcohol such as ethanol, propanol or ethylene glycol, in the presence of an organic acid or mineral acid.
Also, this reaction can be performed by heating or warming the ~066701 compound (II') together with water or a water-containing alcohol in the presence of a base.
The compound in ~hich ~2 is a lower alkoxycarbonyl group unaergoes hydrolysis under milder conditions than the compound in which R2 is a cyano group.
Examples of the acid are inorganic acids such as hydrochloric acidj hydrobromic acid, hydroiodic acid, sul~uric acid or phosphoric acid, and organic acids such as acetic acid, oxalic acid or toluenesulfonic acid.
Examples of the base are alkali metal hydroxides such as ~odium hydroxide or barium h~rdroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, snd sodium acetate.
In the compound in which R'l is an acyl group, the acyl group is hydrolyzed in the above reaction and replaced by a hydrogen atom.
Process from compound ~II") to compound (I) (oxidation) Of the compounds of formula (II), compounds (II") in which R2 is a lower alkanoyl group can be oxidized to compounds of formula (I) by a customary method. This reaction can be performed by dissolving or suspend- --ing the compound (II") in a solvent, and causing an oxidizing agent to act on it. ;
Suitable oxidizing agents that can be used in this reaction are, - -for example, permanganates such as potassium permanganate, hypohalogenites such as potassium hypochlorite, sodium hypobromite, or sodium hypoiodite, and nitric acid. In this reaction, there can also be employed an indirect oxidizing method in which a mixture of iodine and pyridine is ~irst caused to act on the compound and then the resulting product is treated with alkali.
~he case of reacting the compound (II~ with bromine or iodine in a sodium hydroxide or potassium hydroxide solution is the same as the oxida-tion with a hypohalogenous acid.
Ihe solvent and the reaction temperatures should be selected according to the properties of the oxidizing agent used. Suitable solvents are water, ethers such as dioxane or 1,2-dimethoxyethane, ketones such as acetone, pyridines such as pyridine or picoline, haloeenoalkanes such as ,. "-i , . . .
. . .. .. ..
chloroform or tetrachloromethane, alcohols such as ethanol or t-butanol, or mixtures of water with the above organic solvents. Generally, the reaction proceeds sufficiently at room temperature or with ice cooling.
Compounds (II') in which R'l is an acyl group may be oxidized and then hyarolyzed, or oxidized under such conditions as to inauce hydrolysis.
In the production of compound (II) or (I) from compound (IV) in the above series Or reactions, the product in each of the steps may be isolated and then sub~ected to the subsequent reaction, but may also be directly sub~ected to the subsequent reaction without isolation and purifica-tion. If the reaction catalyst, temperature, solvent, etc. are properlychosen, compound (II) or (I) can be obtained in one step from the compound (IV) or (III). These reactions are also included within the method of the present invention. However, in the case of a method which covers only the final step Or obtaining compound (I) by hydrolyzing the isolated compound (II'), the case of a compound Or (II') in which R'2 is a lower alkoxy- -carbonyl group is omitted.
The starting material of the formula (IV) is a new compound, and can be readily obtnined by heating compounds (a) and (b) in the presence of a base, as shown below.
~ 00 alkyl ~2 2 -HCl ~ compound (I~
R'l- N 1 ~HC2H5 (a) (b) wherein R'l and R2 are the same as defined above.
The compounds(I) of this invention prepared in the above process can be isolated and purified by usual methods. The compounds (I) can be obtn~ned in the free state, as a hydrate or in the form of salt depending upon the ~election Or the starting materials and the reaction conditions.
Furthermore~ the compounds (I) can be converted to phar~aceutically accept-able amine ~alts or carboxylic acid salts by treatment with acid or alkali, or vice versa. The acid may be a variety Or organic and inorganic acids, ~06670~
examples of which are hydrochloric acid, acetic acid, lactic acid, succinic acid, oxalic acid and methanesulfonic acid.
A clinical dosage of the compound (I) depends on body wieght, age and administration route but it is generally in the range of 100 mg -5 g/day, preferably of 200 mg-3g/day.
The compound (I) may be used as medicines, for example, in the form of pharmaceutical preparations containing the compound in admixture with an organic or inorganic, solid of liquid pharmaceutical ad~uvants suitable for oral, parenteral, enteral or local administration. Pharmaceu-tically acceptable ad~uvants are substances that do not react with the com-pounds for example, water, gelatin, lactose, starch, cellulose, preferably microcrystalline cellulose, carboxymethyl cellulose, methyl cellulose, sorbitol, magnesium stearate, talc, vegetable oils, benzyl alcohol, gums, propylene glycol, polyalkylene glycols, methylparaben and other known medicinal ad~uvant. The pharmaceutical preparations may be, for example, powder, tablets, ointments, suppositories, creams or capsules, or in liquia form as solutions, suspensions or emulsions. They may be sterilized and/or contain assistants such as preserving, stabilizing, wetting or emulsifying agents, salts for regulating the osmetic pressure or buffers. They may ~urther contain other therapeutically valuable substances. The preparations are prepared by conventional methods.
The compounds (I) and their salts have superior antibacterial activities, and are applied in various formulations as medicines and veterinary mediclnes.
The antibacterial activities of the typical compounds of this -invention are shown in Tables I to IV.
In the Tables II to IV, the ED50 and LD50 values were calculated in accordance with the Behrens-Kaerber method [Arch. Exp. Path. Pharm., 162, 480 (1931)].
Compounds Nos. 1 to 4 in the following Tables stand for the ~ollowing.
Compound No. 1: 8-Ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl) - .
106~701 pyrido[2,3-d]pyrimidine-6-carboxylic acid Compound No. 2: ô-Ethyl-2-(4-methyl-1-piperazinyl)-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid Compound No. 3: 8-Ethyl-2-(4-ethyl-1-piperazinyl)-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid Compound No. 4: 8-Ethyl-5,8-dihydro-5-oxo-2-(1-pipera~inyl) pyrido[2,3-d]pyrimidine-6-carboxylic acid hydrochloride 1) In vitro antibacterial activity Table 1 Staphylococcus ¦ Escherichia ¦Shigella ¦ Pseudomonas Compound No. aureus coli flexneri aeru~inosQ
_ M:rC (,ug/ ~) 1 .__ 1 ' - 10 :'-~ 33o 1 13 The minimum inhibitory concentration (MIC) was determined by the well known æerial dilution method.
Experimental conditions: -Medium: nutrient broth, pH 7.0 (5 ml!tube) Inoculum: 1 drop of 1 : 105 dilution of an overnight broth - -culture per tube Incubation temperature and time: 37C i`or 48 hours 2) In vivo efficacy against systemic infection with Pseudomonas aeruginosa in mice Table II
._ .............................................. _ :
Compound Doæe (mg/kg ~_____ ED
No. Route 200 100 5o 25 12.5 6.3 3. (m59kg) _ . ~ ._ __ 1 ip _ _ 8/88/8 4/8 2/8 1/8 10.5 po 8/8 4/8 0/8 _ _ _ _ 100 3 ip _ 4/8 o/8 _ _ _ _ -.100 po 4/8 _ _ _ _ _ _ =.200 ~
,, . "" s of a basic catalyst conventionally used for Dieckmann reaction, for example, metallic sodium or potassium, sodium hydride, or sodium ethoxiae, tbereby intramolecularly cyclizing the compound to form compound (III). This reac-tion can be achieved with better resultg if a catalytic amount of methanol or ethanol or another lower alcohol is added. Aromatic hydrocarbons such as benzene or toluene or ethers such as dioxane, tetrahydrofuran, 1-2-dimethoxyethane or diethylene glycol dimethyl ether are suitable as the solvent for use in this reaction. The heating temperature is not particu-larly restricted, but usually, it is preferred to employ temperatures in the range of 60 to 180C.
Process from compound (III) to comPound (II) Compound (III) and a conventional dehydrogenating aeent, such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), tetrachloro-1,4-benzo-quinone (chloranil), tetracyanoethylene, palladium carbon (Pd-C), N-bromo-succinimide (NBS), manganese dioxide, or selenium dioxide, are heated for a short period of time at a temperature near the boiling point of the solvent used. Or compound (III) is heated in the above solvent without using a dehydrogenating agent. Or the compound (III) is directly heated to a tem-perature above its melting point, thereby to form compound (II). The pre-ferred solvent is an inert solvent, for example, an aromatic hydrocarbon suchas benzene, toluene or xylene, an ether such as dioxane, or an alcohol such as methanol or ethanol. The heating temperature i8 60 to 260C.
Process from comPound (II') to_compound ~I) (hydrolysis) Of the compounds (II), compound (II') in which R2 is a cyano or lower alkoxycarbonyl group is hydrolyzed by a customary method to form com-pound (I). This reaction can be performed by heating the compound (II') with a mineral acid, and pouring the reaction product into water; or by heating (70 to 120C.) or warming this compound in a solvent such as water or a water-containing high-boiling ether such as dioxane or 1,2-dimethoxy-ethane or a water-containing alcohol such as ethanol, propanol or ethylene glycol, in the presence of an organic acid or mineral acid.
Also, this reaction can be performed by heating or warming the ~066701 compound (II') together with water or a water-containing alcohol in the presence of a base.
The compound in ~hich ~2 is a lower alkoxycarbonyl group unaergoes hydrolysis under milder conditions than the compound in which R2 is a cyano group.
Examples of the acid are inorganic acids such as hydrochloric acidj hydrobromic acid, hydroiodic acid, sul~uric acid or phosphoric acid, and organic acids such as acetic acid, oxalic acid or toluenesulfonic acid.
Examples of the base are alkali metal hydroxides such as ~odium hydroxide or barium h~rdroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, snd sodium acetate.
In the compound in which R'l is an acyl group, the acyl group is hydrolyzed in the above reaction and replaced by a hydrogen atom.
Process from compound ~II") to compound (I) (oxidation) Of the compounds of formula (II), compounds (II") in which R2 is a lower alkanoyl group can be oxidized to compounds of formula (I) by a customary method. This reaction can be performed by dissolving or suspend- --ing the compound (II") in a solvent, and causing an oxidizing agent to act on it. ;
Suitable oxidizing agents that can be used in this reaction are, - -for example, permanganates such as potassium permanganate, hypohalogenites such as potassium hypochlorite, sodium hypobromite, or sodium hypoiodite, and nitric acid. In this reaction, there can also be employed an indirect oxidizing method in which a mixture of iodine and pyridine is ~irst caused to act on the compound and then the resulting product is treated with alkali.
~he case of reacting the compound (II~ with bromine or iodine in a sodium hydroxide or potassium hydroxide solution is the same as the oxida-tion with a hypohalogenous acid.
Ihe solvent and the reaction temperatures should be selected according to the properties of the oxidizing agent used. Suitable solvents are water, ethers such as dioxane or 1,2-dimethoxyethane, ketones such as acetone, pyridines such as pyridine or picoline, haloeenoalkanes such as ,. "-i , . . .
. . .. .. ..
chloroform or tetrachloromethane, alcohols such as ethanol or t-butanol, or mixtures of water with the above organic solvents. Generally, the reaction proceeds sufficiently at room temperature or with ice cooling.
Compounds (II') in which R'l is an acyl group may be oxidized and then hyarolyzed, or oxidized under such conditions as to inauce hydrolysis.
In the production of compound (II) or (I) from compound (IV) in the above series Or reactions, the product in each of the steps may be isolated and then sub~ected to the subsequent reaction, but may also be directly sub~ected to the subsequent reaction without isolation and purifica-tion. If the reaction catalyst, temperature, solvent, etc. are properlychosen, compound (II) or (I) can be obtained in one step from the compound (IV) or (III). These reactions are also included within the method of the present invention. However, in the case of a method which covers only the final step Or obtaining compound (I) by hydrolyzing the isolated compound (II'), the case of a compound Or (II') in which R'2 is a lower alkoxy- -carbonyl group is omitted.
The starting material of the formula (IV) is a new compound, and can be readily obtnined by heating compounds (a) and (b) in the presence of a base, as shown below.
~ 00 alkyl ~2 2 -HCl ~ compound (I~
R'l- N 1 ~HC2H5 (a) (b) wherein R'l and R2 are the same as defined above.
The compounds(I) of this invention prepared in the above process can be isolated and purified by usual methods. The compounds (I) can be obtn~ned in the free state, as a hydrate or in the form of salt depending upon the ~election Or the starting materials and the reaction conditions.
Furthermore~ the compounds (I) can be converted to phar~aceutically accept-able amine ~alts or carboxylic acid salts by treatment with acid or alkali, or vice versa. The acid may be a variety Or organic and inorganic acids, ~06670~
examples of which are hydrochloric acid, acetic acid, lactic acid, succinic acid, oxalic acid and methanesulfonic acid.
A clinical dosage of the compound (I) depends on body wieght, age and administration route but it is generally in the range of 100 mg -5 g/day, preferably of 200 mg-3g/day.
The compound (I) may be used as medicines, for example, in the form of pharmaceutical preparations containing the compound in admixture with an organic or inorganic, solid of liquid pharmaceutical ad~uvants suitable for oral, parenteral, enteral or local administration. Pharmaceu-tically acceptable ad~uvants are substances that do not react with the com-pounds for example, water, gelatin, lactose, starch, cellulose, preferably microcrystalline cellulose, carboxymethyl cellulose, methyl cellulose, sorbitol, magnesium stearate, talc, vegetable oils, benzyl alcohol, gums, propylene glycol, polyalkylene glycols, methylparaben and other known medicinal ad~uvant. The pharmaceutical preparations may be, for example, powder, tablets, ointments, suppositories, creams or capsules, or in liquia form as solutions, suspensions or emulsions. They may be sterilized and/or contain assistants such as preserving, stabilizing, wetting or emulsifying agents, salts for regulating the osmetic pressure or buffers. They may ~urther contain other therapeutically valuable substances. The preparations are prepared by conventional methods.
The compounds (I) and their salts have superior antibacterial activities, and are applied in various formulations as medicines and veterinary mediclnes.
The antibacterial activities of the typical compounds of this -invention are shown in Tables I to IV.
In the Tables II to IV, the ED50 and LD50 values were calculated in accordance with the Behrens-Kaerber method [Arch. Exp. Path. Pharm., 162, 480 (1931)].
Compounds Nos. 1 to 4 in the following Tables stand for the ~ollowing.
Compound No. 1: 8-Ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl) - .
106~701 pyrido[2,3-d]pyrimidine-6-carboxylic acid Compound No. 2: ô-Ethyl-2-(4-methyl-1-piperazinyl)-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid Compound No. 3: 8-Ethyl-2-(4-ethyl-1-piperazinyl)-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid Compound No. 4: 8-Ethyl-5,8-dihydro-5-oxo-2-(1-pipera~inyl) pyrido[2,3-d]pyrimidine-6-carboxylic acid hydrochloride 1) In vitro antibacterial activity Table 1 Staphylococcus ¦ Escherichia ¦Shigella ¦ Pseudomonas Compound No. aureus coli flexneri aeru~inosQ
_ M:rC (,ug/ ~) 1 .__ 1 ' - 10 :'-~ 33o 1 13 The minimum inhibitory concentration (MIC) was determined by the well known æerial dilution method.
Experimental conditions: -Medium: nutrient broth, pH 7.0 (5 ml!tube) Inoculum: 1 drop of 1 : 105 dilution of an overnight broth - -culture per tube Incubation temperature and time: 37C i`or 48 hours 2) In vivo efficacy against systemic infection with Pseudomonas aeruginosa in mice Table II
._ .............................................. _ :
Compound Doæe (mg/kg ~_____ ED
No. Route 200 100 5o 25 12.5 6.3 3. (m59kg) _ . ~ ._ __ 1 ip _ _ 8/88/8 4/8 2/8 1/8 10.5 po 8/8 4/8 0/8 _ _ _ _ 100 3 ip _ 4/8 o/8 _ _ _ _ -.100 po 4/8 _ _ _ _ _ _ =.200 ~
4 ip _ _ _ 8/8 _ _ _ ~ 17.7 ~ -po 8/8 7/8 _ _ _ _ _ < 100 _ _ _ - 8 - _ _ _ ,' . ~
.
.
The numerical figures in the table show the number o~ the survival/
the total number. o/8 means that all of 8 mice died. 8/8 means that all 8 mice survived: The survival rate of non-treated control was o/8.
Experimental conditions:
Organism: Pseudomonas aeruginosa No. 12 Mice: male mice (ddY-S) weighing 20 g approximately Infection: intraperitoneal infection with 50 to 100 LD50 (about 5 x 103 cells/mouse) of a bacterial suspension in 4%
gastric mucin Medication: twice, about 5 minutes and 6 hours after infection Drug: an alkaline solution for parenteral administration and a suspension in 0.2% CMC for oral administration Observation: 7 days ip: intraperitoneal administration -po: oral administration 3) In vivo efficacy against systemic infection with Salmonella typh~murium in mice Table III
_ _ Compound Dose (mg/kg) ED
No. Route ~ 100 5o 25 12.56.3 (m~9kg~
.. .~ __ ._ .. __ 1 ip _ _ 8/8 8/8 4/8 6.3 po _ ô/8 8/8 4/8 o/812.5 3 ip _ _ 8/8 _ _< 17.7 po _ _ 8/8 _ _< 17.7 4 .Po _ ~ _ _ _~< 35.4 The numerical figures in the table show the number of the survival/
the total number. o/8 means that all of 8 mice died. 8/8 means that all 8 mice survived. The survival rate of non-treated control was o/8.
Experimental conditions.
Organism: ~almonella typhimurium ~-9 Mice: male mice (ddY-S) weighing 20 g approximately Infection: Intraperitoneal infection with 50 to 100 LD50 -(about 105 cell~/mouse) of a bacterial suspension in nutrient 9 .. ~: .
~066701 Experimental conditions Cont'd.
broth Medication: twice a day for 4 days from the day of infection.
Drug: an alkaline solution for parenteral administration and suspension in 0.2% CMC for oral administration Observation: 14 days ip: intraperitoneal administration po: or~l administration 4) Acute toxicity in mice Table_IV
.. _ ~ _ Compound _ _ DOBe (D 3lkg) _ LD
No. Route4000 2000 1000500 (mg9kg) ._. . . _ . __ . _ .. ._ iY _ _ o/66/6 700 po 6/6 6/6 _ _ > 4000 _ . __ .. ~ :
The numerical figures in the table show the number Or survival/ ~ -the total number. o/6 means that all of 6 mice died and 6/6 means that all of mice survived.
The compound was in alkaline solution for intraveneous administra-tion and suspension containing 0.2% CMC for oral administration, and admin-istered to male mice (ddY~S) weighing 20 g approximately. A~ter 7 days, the lncidence o~ death was recorded and LD50 value was estimated.
iv: intraveneous administration po: oral administration The invention will be further illustrated by the following Examples.
Exam~le A ~ -
.
.
The numerical figures in the table show the number o~ the survival/
the total number. o/8 means that all of 8 mice died. 8/8 means that all 8 mice survived: The survival rate of non-treated control was o/8.
Experimental conditions:
Organism: Pseudomonas aeruginosa No. 12 Mice: male mice (ddY-S) weighing 20 g approximately Infection: intraperitoneal infection with 50 to 100 LD50 (about 5 x 103 cells/mouse) of a bacterial suspension in 4%
gastric mucin Medication: twice, about 5 minutes and 6 hours after infection Drug: an alkaline solution for parenteral administration and a suspension in 0.2% CMC for oral administration Observation: 7 days ip: intraperitoneal administration -po: oral administration 3) In vivo efficacy against systemic infection with Salmonella typh~murium in mice Table III
_ _ Compound Dose (mg/kg) ED
No. Route ~ 100 5o 25 12.56.3 (m~9kg~
.. .~ __ ._ .. __ 1 ip _ _ 8/8 8/8 4/8 6.3 po _ ô/8 8/8 4/8 o/812.5 3 ip _ _ 8/8 _ _< 17.7 po _ _ 8/8 _ _< 17.7 4 .Po _ ~ _ _ _~< 35.4 The numerical figures in the table show the number of the survival/
the total number. o/8 means that all of 8 mice died. 8/8 means that all 8 mice survived. The survival rate of non-treated control was o/8.
Experimental conditions.
Organism: ~almonella typhimurium ~-9 Mice: male mice (ddY-S) weighing 20 g approximately Infection: Intraperitoneal infection with 50 to 100 LD50 -(about 105 cell~/mouse) of a bacterial suspension in nutrient 9 .. ~: .
~066701 Experimental conditions Cont'd.
broth Medication: twice a day for 4 days from the day of infection.
Drug: an alkaline solution for parenteral administration and suspension in 0.2% CMC for oral administration Observation: 14 days ip: intraperitoneal administration po: or~l administration 4) Acute toxicity in mice Table_IV
.. _ ~ _ Compound _ _ DOBe (D 3lkg) _ LD
No. Route4000 2000 1000500 (mg9kg) ._. . . _ . __ . _ .. ._ iY _ _ o/66/6 700 po 6/6 6/6 _ _ > 4000 _ . __ .. ~ :
The numerical figures in the table show the number Or survival/ ~ -the total number. o/6 means that all of 6 mice died and 6/6 means that all of mice survived.
The compound was in alkaline solution for intraveneous administra-tion and suspension containing 0.2% CMC for oral administration, and admin-istered to male mice (ddY~S) weighing 20 g approximately. A~ter 7 days, the lncidence o~ death was recorded and LD50 value was estimated.
iv: intraveneous administration po: oral administration The invention will be further illustrated by the following Examples.
Exam~le A ~ -
5,8-dihydro-ô-ethyl-2-(1-piperazinyl)!5-oxopyrido[2,3-d]pyrimidine-
6-carbo~vlic acid 250 g Starch 54 g Calcium carboxymethyl cellulose 40 g -~icrocrystalline cellulose50 g Magnesium gtearate 6 g -- 10 -- ;' :' "
. . ,: ' ' - , ' : ' ' ' . , .
The above components are blended, granulated and made into tablets in a manner kno~n Per se. Thus, 1000 tablets each weighing 400 mg are formed.
Example B
5,8-dihydro-8-ethyl-2-(1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid 250 g Starch 5 g Lactose 35 g Talc 15 g 10 The above components were blended and ~ranulated and filled into 1,000 capsules in accordance with the conventional methods.
Example C Preparation of Suspension 5,8-dihydro-8-ethyl-2-(1-piperazinyl)-5-oxopyrido[2,3-d]
pyrimidine-6-carboxylic acid hydrochloride 5 g Sorbitol 30 g Sugar 4 g Methylparaben Small amount Sodium carboxymethyl cellulose Small amount Flavour Small amount Water to mske 100 ml Example 1 8-Etlurl-2-(4-met~rl-l-PiperazinYl)-5~8-dih~rdro-5-oxopyrido [2.3-d]Pyrimidine-6-carboxylic acid A mixture containing 3.0 g of 8-ethyl-2-(4-methyl-1-piperazinyl)-5,8-di~rdro-5-oxopyrido[2,3-d]pyrimidine-6-carbonitrile, 270 ml of acetic acid, and 150 ml of concentrated hydrochloric acid was heated at 90C for 25 hours. The mixture was concentrated to dryness in vacuo. The resulting residue was neutralized by addition of a 5% aqueous solution of sodium hydroxide, and extracted with chloroform. ~e extract, after drying, was 30 concentrated to leave a crude solid which was recrystallized from ethanol to give 2,6 g o~ the product, m.p. 232-233 C~
-- 11 -- .
Example 2 8-Ethyl-2-(4-ethyl-1-piperazin~vl~-5~8-dihydro-~ xoP~rido [2~3-d]Pyrimidine-6-carboxylic acid The procedure described in Example 1 was repeated using 8-ethyl-2-(4-ethyl-1-piperazinyl)-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carbonitrile. There was obtained the product, m.p. 228 to 230 C.
Example 3 8-Ethyl-~18-dihydro-5-oxo-2-(l-PiPerazinyl~pyrido ~2,3-d]_~rimidine-6-carboxylic acid ~ydrochloride A mixture containing 5.0 g Or 2-(4-acetyl-1-piperazinyl)-8-ethyl-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carbonitrile, 200 ml of acetic acid, and 200 ml of concentrated hydrochloric acid waæ heated at 90C
for 3 hours. The mixture was concentrated to dryness in vacuo. To the residue was added a small amount of concentrated hydrochloric acid. A
resulting hydrochloride was collected and washed with ethanol to yield 4.7 g of the product, m.p. above 300 C.
ExamPle 4 -- -^o-Ethyl-5.8-dihydro-2-(4-methyl-1-piperazinyl)-5-oxopyrido [2.3 d~p~rimidine-~-carboxylic acid To a solution o~ sodium hypobromite, which was prepared by addi-tion of 3.ô g oP bromine to a mixture containing dioxane (10 ml) and a 15%
aqueous solution (16 ml) of sodium hydroxide with cooling below 10C, was sdded 2.0 g of 6-acetyl-^o-ethyl-5,ô-dihydro-2-(4-methyl-1-piperazinyl)-5-oxopyrido[2,3-d~pyrimidine with stirring. After the mixture was allowed ;~
to stssd at room temperature ~or 2 hours, the br~moPorm Pormed as by-product was removed by extrsction with chloro~orm. The aIkaline, aqueous layer was neutralized with acetic acid to separate the solid, which was collected and recrystallized ~rom diluted ethanol to give the product, m.p.
232-233C.
Exa~ple 5 thYl 8-ethYl-2-(4-methYl-l-PiPerazinyl)-5~l8-dihydro-5-oxo- ~.
imidi~e-6-carboxylate To a solution oP ethyl o^-ethyl-2-(4-methyl-1-piperazinyl)-5-oxo- ~ -- 12 _ ,; , ., l , , ,, , , , , ., ; . , ~06670~
5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carboxylate (3.0 g) in 100 ml of dry benzene was added 2.8 g of chloranil, and the mixture was heated to reflux for 30 minutes. After cooling, the separated solid was collected and recrystalliæed from dimethylformamide to give 2.8 B of the product, m.p. 146-147C.
Example 6 8-Ethyl-2-(4-methyl-1-piperazinyl~-5~8-dihydro-5-oxopyrido ~2,3-d]p~rimidine-6-carbonitrile Two grams of 8-ethyl-2-(4-methyl-1-piperazinyl)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile was heated directly at 220C for 7 minutes and, after cooling, recrystallized from methanol to yield 1.7 g of the product, m.p. 255-258C.
Example 7 Ethyl 8-ethyl-2-(4-methyl-1-pi~erazinyl)-5,8-dih~dro-5-oxo-~yrido~213-d]pyrimidine-6-carboxylate To a solution of ethyl 4-(ethyl-2-ethoxycarbonylethyl)amino-2-(4-methyl-1-piperazinyl)pyrimidine-5-carboxylate (4.0 g) in 10 ml of l,Z-dimethoxyethane was added 0.75 g of 50% sodium hydride and the mixture was heated to reflux for one hour. After removal of the solvent the resulting residue was neutralized with acetic acid and extracted with chloro~orm.
The extract was waæhed with water, dried over anhydrous sodium sulfate, and the solvent removed by distillation to give an intermediate which, if desired, was recrystallized from n-hexane-acetone to yield ethyl 8-ethyl-2-(4-methyl-1-piperazinyl)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine- ~ -6-carboxylate in a pure form, m.p. 97-100C.
The lntermediate tetrahydro-ester thus obtained was dissolved ln benzene and the mixture was heated to reflux for 1.5 hours. The solid separated on cooling was collected and recrystallized from dimethylformamide to give 2.5 g of the product, m.p. 146-147C.
ExamPle 8 8-Eth~1-2-(4-methY1~ razinyl)-5,8-dihydro-5-oxo~yrido [2~3~dJpY-rimi~lne-6-carbonitrlle .
To a mixture containing ethyl 4-(ethyl-2-cyanoethyl)amino-2-(4-methyl-l-piperazinyl)pyrimidine-5-carboxylate (4.3 g) and 10 ml of dioxane was added o.8 g of 50% sodium hydride at roo~ temperature with stirring and the mixture was heated to reflux for 30 minutes. After removal of the solvent, the resulting residue was neutralized with acetic acid and extracted with chloroform. The extract was worked up as in Example 7 and there was obtained an intermediate which, if desired, was recrystallized from n-hexane-acetone to give 8-ethyl-2-(4-methyl-1-piperazinyl)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile in a pure form, m.p. 172-174C.
The tetrahydro-carbonitrile was dissolved in 100 ml of dry benzene and 2.5 g of chloranil was added to it. The mixture was heated to reflux for 30 minutes. The solid separated on cooling was collected and recrystallized from methanol to yield 2.9 g of the product, m.p. 255-258C.
Exam~le 9 2-(4-Acetyl-l-piperazinyl)-8-ethyl-5~8-dihydro-5-oxop~rido[?~3-d]
pyrimidine-6-carbonitrile To a mixture containing 5.0 g of ethyl 2-(4-acetyl-1-piperazinyl)-4-(ethyl-2-cyanoethyl)aminopyrimidine-5-carboxylate and 50 ml of ethylene-glycol dimethyl ether was added 2.0 g of 50~ sodium hydride. Then the mix-ture was heated at 95C for one hour. The mixture was concentrated to dryness in vacuo and the resulting residue was neutralized with acetic acid, and extracted with chloro~orm. The solvent was evaporated from the extract to give an oily intermediate, 2-(4-acetyl-1-piperazinyl)-8-ethyl-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile. The nitrile ~ -without further purification was dissolved in 50 ml of benzene and 2.5 g ~--of chloranil was added to it. The mixture was heated to reflux for 30 minutes. The solid separated on cooling was collected, washed with benzene, and recrystallized from methanol to yield 3.4 g of the product, m.p. 317C.
Example 10 Eth~l 2-(4-acetyl-l-piperazin~l)-8-eth~l-5~8-dihyd-ro-5-oxo- ~;
midine-6-carbo~ylate Following the procedure described in Example 9, using ethyl 2-(4-acetyl-1-piperazinyl)~ ethyl-2-ethoxycarbonylethyl)aminopyrimidine-5-carbo~ylate as a startine material, there was obtained the product, m.p.
208-210C (decomp.) ExaF~ e 11 6-Acetyl-8-ethyl-5,8-dih~dro-?-(4-methyl-l-piperazinyl)-5 rido[2.3-d ~ rimidine Following the procedure described in Example 9, using ethyl 2-(4-methyl-1-piperazinyl)-4-(ethyl-3-oxobutyl)aminopyrimidine-5-carboxylate, there was obtained the product, m.p. 198-200C.
Example 12 8-Ethy1-5.8-dihydro-5-oxo-2-(1-PiPerazinyl)pyrido[2.3-d]
~rimidine-6-carboxylic acid Using 5.0 g of ethyl 4-(ethyl-2-ethoxycarbonylethyl)amino-2-(1-piperazinyl)pyrimidine-5-carboxylate as a starting material, an intermediate ethyl 5,8-dihydro-8-ethyl-5-oxo-2-(1-piperazinyl)pyrido~2,3-d]pyrimidine-6-carboxylate was prepared in the same way as in Example 9. The inter-mediate, if desired, was purified by recrystallization from acetone. m.p. ~ -~
156-158C. The carboxylate was dissolved in 30 ml of a 7% aqueous solution of sodium hydroxid~ by heating at 90C for 20 minutes. After cooling, the resulting solution was neutralized with acetic acid to yield a precipitate which was collected, and recrystallized from dimethylformamide. There was obtained 4.3 g of the product, m.p. 253-255C. -Example 13 8-Ethyl-5~8-dih~dro-7-oxo-2-~ 1-pi~erazinYl)P~rido[2~3-d]
pyrimidine-6-carboxylic acid -Using 10.0 g of ethyl 4-(ethyl-3-oxobutyl)amino-2-(1-piperazinyl)-pyrimidine-5-carboxylate as a starting material, 6-acetyl-8-ethyl-5,8-dlhydro-5-oxo-2-(1-piperazinyl)pyrido[2,3-d]pyrimidine was prepared in the same way as in Example 9. The intermediate (7.3 g), without further puri-fication, was worked up and oxidized in the same way as in Example 4 toyleld ~.2 g of the product, m.p. 253-255C.
: ' ' ' '.' ' . ' ',~ ' ': ' .
Example 14 Ethyl 4-(ethyl-2-ethoxycarbonylethyl)amino-2-(4-methy pi~erazin~rl)pyrimidi~n-e-5-carbox~rlate To a solution of 3.9 g of ethyl 4-chloro-2-(4-methyl-1-piperazinyl) pyrimidine-5-carboxylate in 10 ml of diethyleneglycol dimethyl ether was added 2.4 g of ethyl 3-ethylaminopropionate and 1.3 g of sodium bicarbonate.
The resulting mixture was heated at 140-150C for 2 hours. After removal of the solvent, the residue was taken up in chloroform. The chloroform solution was washed with water, dried, and concentrated to leave the oily product. The oil was chromatographed on silica gel with chloroform as an eluant, giving the product in a pure form. The structure of the product was confirmed by its infra-red absorption (IR) spectrum and nuclear magnetic resonance (NMR) spectrum.
IR 3pectrum (liquid film, cm 1): 1730, 1700, 1678, 1350, and 1230.
NMR spectrum (CDC13, ppm/~): 8.50 (lH, singlet), 4.27 (2H, quartet, J=7 Hz), 3.90-3.83 (4H, multiplet), 2.34 (3H, singlet); 1.33 (3H, triplet, J=7 Hz), 1.25 (3H, triplet, J=7 Hz), and 1.20 (3H, triplet, J=7 Hz).
Exam~le 15 Ethrl 4-(ethyl-2-cyanoethyl)amino-2-(4-methrl-1-pi~erazinyl) ~yrimidine-5-carboxylate Following the procedure described in Example 14 using 1.6 g of 3-ethylaminopropionitrile in place of ethyl 3-ethylaminopropionate, ~
there was obtained the oily product. ~- -IR ~pectrum (liquid film cm 1): 2240, 1698, 1568, and 1578.
NMR spectrum (CDC13, ppm/~): 8.60 (lH, singlet), 3.71 (2H, quartet, J=7 Hz), 3.40 (2H, quartet, J=7 Hz), 1.35 (3H, triplet, J=7 Hz), and 1.24 (3H, triplet, J=7 Hz). ;
~. .... ...
. . ,: ' ' - , ' : ' ' ' . , .
The above components are blended, granulated and made into tablets in a manner kno~n Per se. Thus, 1000 tablets each weighing 400 mg are formed.
Example B
5,8-dihydro-8-ethyl-2-(1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid 250 g Starch 5 g Lactose 35 g Talc 15 g 10 The above components were blended and ~ranulated and filled into 1,000 capsules in accordance with the conventional methods.
Example C Preparation of Suspension 5,8-dihydro-8-ethyl-2-(1-piperazinyl)-5-oxopyrido[2,3-d]
pyrimidine-6-carboxylic acid hydrochloride 5 g Sorbitol 30 g Sugar 4 g Methylparaben Small amount Sodium carboxymethyl cellulose Small amount Flavour Small amount Water to mske 100 ml Example 1 8-Etlurl-2-(4-met~rl-l-PiperazinYl)-5~8-dih~rdro-5-oxopyrido [2.3-d]Pyrimidine-6-carboxylic acid A mixture containing 3.0 g of 8-ethyl-2-(4-methyl-1-piperazinyl)-5,8-di~rdro-5-oxopyrido[2,3-d]pyrimidine-6-carbonitrile, 270 ml of acetic acid, and 150 ml of concentrated hydrochloric acid was heated at 90C for 25 hours. The mixture was concentrated to dryness in vacuo. The resulting residue was neutralized by addition of a 5% aqueous solution of sodium hydroxide, and extracted with chloroform. ~e extract, after drying, was 30 concentrated to leave a crude solid which was recrystallized from ethanol to give 2,6 g o~ the product, m.p. 232-233 C~
-- 11 -- .
Example 2 8-Ethyl-2-(4-ethyl-1-piperazin~vl~-5~8-dihydro-~ xoP~rido [2~3-d]Pyrimidine-6-carboxylic acid The procedure described in Example 1 was repeated using 8-ethyl-2-(4-ethyl-1-piperazinyl)-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carbonitrile. There was obtained the product, m.p. 228 to 230 C.
Example 3 8-Ethyl-~18-dihydro-5-oxo-2-(l-PiPerazinyl~pyrido ~2,3-d]_~rimidine-6-carboxylic acid ~ydrochloride A mixture containing 5.0 g Or 2-(4-acetyl-1-piperazinyl)-8-ethyl-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carbonitrile, 200 ml of acetic acid, and 200 ml of concentrated hydrochloric acid waæ heated at 90C
for 3 hours. The mixture was concentrated to dryness in vacuo. To the residue was added a small amount of concentrated hydrochloric acid. A
resulting hydrochloride was collected and washed with ethanol to yield 4.7 g of the product, m.p. above 300 C.
ExamPle 4 -- -^o-Ethyl-5.8-dihydro-2-(4-methyl-1-piperazinyl)-5-oxopyrido [2.3 d~p~rimidine-~-carboxylic acid To a solution o~ sodium hypobromite, which was prepared by addi-tion of 3.ô g oP bromine to a mixture containing dioxane (10 ml) and a 15%
aqueous solution (16 ml) of sodium hydroxide with cooling below 10C, was sdded 2.0 g of 6-acetyl-^o-ethyl-5,ô-dihydro-2-(4-methyl-1-piperazinyl)-5-oxopyrido[2,3-d~pyrimidine with stirring. After the mixture was allowed ;~
to stssd at room temperature ~or 2 hours, the br~moPorm Pormed as by-product was removed by extrsction with chloro~orm. The aIkaline, aqueous layer was neutralized with acetic acid to separate the solid, which was collected and recrystallized ~rom diluted ethanol to give the product, m.p.
232-233C.
Exa~ple 5 thYl 8-ethYl-2-(4-methYl-l-PiPerazinyl)-5~l8-dihydro-5-oxo- ~.
imidi~e-6-carboxylate To a solution oP ethyl o^-ethyl-2-(4-methyl-1-piperazinyl)-5-oxo- ~ -- 12 _ ,; , ., l , , ,, , , , , ., ; . , ~06670~
5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carboxylate (3.0 g) in 100 ml of dry benzene was added 2.8 g of chloranil, and the mixture was heated to reflux for 30 minutes. After cooling, the separated solid was collected and recrystalliæed from dimethylformamide to give 2.8 B of the product, m.p. 146-147C.
Example 6 8-Ethyl-2-(4-methyl-1-piperazinyl~-5~8-dihydro-5-oxopyrido ~2,3-d]p~rimidine-6-carbonitrile Two grams of 8-ethyl-2-(4-methyl-1-piperazinyl)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile was heated directly at 220C for 7 minutes and, after cooling, recrystallized from methanol to yield 1.7 g of the product, m.p. 255-258C.
Example 7 Ethyl 8-ethyl-2-(4-methyl-1-pi~erazinyl)-5,8-dih~dro-5-oxo-~yrido~213-d]pyrimidine-6-carboxylate To a solution of ethyl 4-(ethyl-2-ethoxycarbonylethyl)amino-2-(4-methyl-1-piperazinyl)pyrimidine-5-carboxylate (4.0 g) in 10 ml of l,Z-dimethoxyethane was added 0.75 g of 50% sodium hydride and the mixture was heated to reflux for one hour. After removal of the solvent the resulting residue was neutralized with acetic acid and extracted with chloro~orm.
The extract was waæhed with water, dried over anhydrous sodium sulfate, and the solvent removed by distillation to give an intermediate which, if desired, was recrystallized from n-hexane-acetone to yield ethyl 8-ethyl-2-(4-methyl-1-piperazinyl)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine- ~ -6-carboxylate in a pure form, m.p. 97-100C.
The lntermediate tetrahydro-ester thus obtained was dissolved ln benzene and the mixture was heated to reflux for 1.5 hours. The solid separated on cooling was collected and recrystallized from dimethylformamide to give 2.5 g of the product, m.p. 146-147C.
ExamPle 8 8-Eth~1-2-(4-methY1~ razinyl)-5,8-dihydro-5-oxo~yrido [2~3~dJpY-rimi~lne-6-carbonitrlle .
To a mixture containing ethyl 4-(ethyl-2-cyanoethyl)amino-2-(4-methyl-l-piperazinyl)pyrimidine-5-carboxylate (4.3 g) and 10 ml of dioxane was added o.8 g of 50% sodium hydride at roo~ temperature with stirring and the mixture was heated to reflux for 30 minutes. After removal of the solvent, the resulting residue was neutralized with acetic acid and extracted with chloroform. The extract was worked up as in Example 7 and there was obtained an intermediate which, if desired, was recrystallized from n-hexane-acetone to give 8-ethyl-2-(4-methyl-1-piperazinyl)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile in a pure form, m.p. 172-174C.
The tetrahydro-carbonitrile was dissolved in 100 ml of dry benzene and 2.5 g of chloranil was added to it. The mixture was heated to reflux for 30 minutes. The solid separated on cooling was collected and recrystallized from methanol to yield 2.9 g of the product, m.p. 255-258C.
Exam~le 9 2-(4-Acetyl-l-piperazinyl)-8-ethyl-5~8-dihydro-5-oxop~rido[?~3-d]
pyrimidine-6-carbonitrile To a mixture containing 5.0 g of ethyl 2-(4-acetyl-1-piperazinyl)-4-(ethyl-2-cyanoethyl)aminopyrimidine-5-carboxylate and 50 ml of ethylene-glycol dimethyl ether was added 2.0 g of 50~ sodium hydride. Then the mix-ture was heated at 95C for one hour. The mixture was concentrated to dryness in vacuo and the resulting residue was neutralized with acetic acid, and extracted with chloro~orm. The solvent was evaporated from the extract to give an oily intermediate, 2-(4-acetyl-1-piperazinyl)-8-ethyl-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile. The nitrile ~ -without further purification was dissolved in 50 ml of benzene and 2.5 g ~--of chloranil was added to it. The mixture was heated to reflux for 30 minutes. The solid separated on cooling was collected, washed with benzene, and recrystallized from methanol to yield 3.4 g of the product, m.p. 317C.
Example 10 Eth~l 2-(4-acetyl-l-piperazin~l)-8-eth~l-5~8-dihyd-ro-5-oxo- ~;
midine-6-carbo~ylate Following the procedure described in Example 9, using ethyl 2-(4-acetyl-1-piperazinyl)~ ethyl-2-ethoxycarbonylethyl)aminopyrimidine-5-carbo~ylate as a startine material, there was obtained the product, m.p.
208-210C (decomp.) ExaF~ e 11 6-Acetyl-8-ethyl-5,8-dih~dro-?-(4-methyl-l-piperazinyl)-5 rido[2.3-d ~ rimidine Following the procedure described in Example 9, using ethyl 2-(4-methyl-1-piperazinyl)-4-(ethyl-3-oxobutyl)aminopyrimidine-5-carboxylate, there was obtained the product, m.p. 198-200C.
Example 12 8-Ethy1-5.8-dihydro-5-oxo-2-(1-PiPerazinyl)pyrido[2.3-d]
~rimidine-6-carboxylic acid Using 5.0 g of ethyl 4-(ethyl-2-ethoxycarbonylethyl)amino-2-(1-piperazinyl)pyrimidine-5-carboxylate as a starting material, an intermediate ethyl 5,8-dihydro-8-ethyl-5-oxo-2-(1-piperazinyl)pyrido~2,3-d]pyrimidine-6-carboxylate was prepared in the same way as in Example 9. The inter-mediate, if desired, was purified by recrystallization from acetone. m.p. ~ -~
156-158C. The carboxylate was dissolved in 30 ml of a 7% aqueous solution of sodium hydroxid~ by heating at 90C for 20 minutes. After cooling, the resulting solution was neutralized with acetic acid to yield a precipitate which was collected, and recrystallized from dimethylformamide. There was obtained 4.3 g of the product, m.p. 253-255C. -Example 13 8-Ethyl-5~8-dih~dro-7-oxo-2-~ 1-pi~erazinYl)P~rido[2~3-d]
pyrimidine-6-carboxylic acid -Using 10.0 g of ethyl 4-(ethyl-3-oxobutyl)amino-2-(1-piperazinyl)-pyrimidine-5-carboxylate as a starting material, 6-acetyl-8-ethyl-5,8-dlhydro-5-oxo-2-(1-piperazinyl)pyrido[2,3-d]pyrimidine was prepared in the same way as in Example 9. The intermediate (7.3 g), without further puri-fication, was worked up and oxidized in the same way as in Example 4 toyleld ~.2 g of the product, m.p. 253-255C.
: ' ' ' '.' ' . ' ',~ ' ': ' .
Example 14 Ethyl 4-(ethyl-2-ethoxycarbonylethyl)amino-2-(4-methy pi~erazin~rl)pyrimidi~n-e-5-carbox~rlate To a solution of 3.9 g of ethyl 4-chloro-2-(4-methyl-1-piperazinyl) pyrimidine-5-carboxylate in 10 ml of diethyleneglycol dimethyl ether was added 2.4 g of ethyl 3-ethylaminopropionate and 1.3 g of sodium bicarbonate.
The resulting mixture was heated at 140-150C for 2 hours. After removal of the solvent, the residue was taken up in chloroform. The chloroform solution was washed with water, dried, and concentrated to leave the oily product. The oil was chromatographed on silica gel with chloroform as an eluant, giving the product in a pure form. The structure of the product was confirmed by its infra-red absorption (IR) spectrum and nuclear magnetic resonance (NMR) spectrum.
IR 3pectrum (liquid film, cm 1): 1730, 1700, 1678, 1350, and 1230.
NMR spectrum (CDC13, ppm/~): 8.50 (lH, singlet), 4.27 (2H, quartet, J=7 Hz), 3.90-3.83 (4H, multiplet), 2.34 (3H, singlet); 1.33 (3H, triplet, J=7 Hz), 1.25 (3H, triplet, J=7 Hz), and 1.20 (3H, triplet, J=7 Hz).
Exam~le 15 Ethrl 4-(ethyl-2-cyanoethyl)amino-2-(4-methrl-1-pi~erazinyl) ~yrimidine-5-carboxylate Following the procedure described in Example 14 using 1.6 g of 3-ethylaminopropionitrile in place of ethyl 3-ethylaminopropionate, ~
there was obtained the oily product. ~- -IR ~pectrum (liquid film cm 1): 2240, 1698, 1568, and 1578.
NMR spectrum (CDC13, ppm/~): 8.60 (lH, singlet), 3.71 (2H, quartet, J=7 Hz), 3.40 (2H, quartet, J=7 Hz), 1.35 (3H, triplet, J=7 Hz), and 1.24 (3H, triplet, J=7 Hz). ;
~. .... ...
Claims (9)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of the formula (IA) wherein R'1 is a hydrogen atom, lower alkyl group or acyl group, and R'2a is a cyano group, lower alkoxycarbonyl group, lower alkanoyl group or carboxyl group, or a pharmaceutically acceptable salt thereof which comprises (a) dehydrogenating a compound of the formula (III) wherein R'1 is as defined above and R2 is a cyano, lower alkoxycarbonyl or lower alkanoyl group, so as to provide a compound of the formula (IA) wherein R'1 is as defined above and R'2a is a cyano group, lower alkoxycarbonyl group or lower alkanoyl group; or (b) subjecting a compound of the formula (IV) wherein R'1 and R2 are as defined above, to a Dieckmann reaction, and dehydro-genating the resulting product of the formula (III) so as to provide a compound of the formula (IA) wherein R'1 is as defined above and R'2 is a cyano group, lower alkoxycarbonyl group or lower alkanoyl group; or (c) hydrolyzing a compound of the formula (II''') wherein R'1 is as defined above, so as to provide a compound of the formula (IA) wherein R'1 is a hydrogen atom or lower alkyl group and R'2a is a carboxyl group; or (d) oxidizing a compound of the formula (II") wherein R'1 is as defined above and R"2 is a lower alkanoyl group, and, when R'l is an acyl group, hydrolyzing the resulting product, so as to provide a compound of the formula (IA) wherein R'1 is a hydrogen atom or lower alkyl group and R'2a is a carboxyl group; or (e) subjecting a compound of the formula (IV') wherein R'1 is as defined above and R'2 is a lower alkoxycarbonyl group or cyano group, to a Dieckmann reaction, dehydrogenating the resulting compound of the formula (III') wherein R'1 and R'2 are as defined above, then, hydrolyzing the resulting com-pound of the formula (II') wherein R'1 and R'2 are as defined above, so as to provide a compound of the formula (IA) wherein R'1 is a hydrogen atom or lower alkyl group and R'2 is a carboxyl group; or (f) subjecting a compound of the formula (IV") wherein R'1 is as defined above and R"2 is a lower alkanoyl group, to a Dieck-mann reaction, dehydrogenating the resulting compound of the formula (III") wherein R'1 and R"2 are as defined above, then, oxidizing the resulting com-pound of the formula (II") wherein R'1 and R"2 are as defined above, and, when R'1 is an acyl group, hydro-lyzing the product, so as to provide a compound of the formula (IA) wherein R'1 is a hydrogen atom or lower alkyl group and R'2 is a carboxyl group; and (g) if desired, converting the resulting compound of the formula (IA) to a pharmaceutically acceptable salt.
2. A process according to claim 1 (a) or (b), in which R'1 is an acetyl group and R'2a is a cyano, lower alkoxycarbonyl or lower alkanoyl group.
3. A process according to claim 1 (a) or (b), in which R'1 is a hydrogen atom and R'2a is a cyano, lower alkoxycarbonyl or lower alkanoyl group.
4. A process according to claim 1 (c), (d), (e) or (f), in which R'1 is a hydrogen atom and K'2a is a carboxyl group.
5. A process according to claim 1 wherein R'1 is a hydrogen atom or an acetyl group, and R'2a is a cyano group, a lower alkoxy carbonyl group, a lower alkanoyl group, or a carboxyl group.
6. A compound of formula wherein R'l is a hydrogen atom or an acetyl group, and R'2a is a cyano group, a lower alkoxy carbonyl group, a lower alkanoyl group, or a carboxyl group, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 5 or by an obvious chemical equivalent thereof.
7. A compound of the formula in which R'2a is a cyano, lower alkoxycarbonyl or lower alkanoyl group, whenever prepared by the process claimed in claim 2, or by an obvious chemical equivalent thereof.
8. A compound of the formula:
in which R'2a is a cyano, lower alkoxycarbonyl or lower alkanoyl group, whenever prepared by the process claimed in claim 3, or by an obvious chemical equivalent thereof.
in which R'2a is a cyano, lower alkoxycarbonyl or lower alkanoyl group, whenever prepared by the process claimed in claim 3, or by an obvious chemical equivalent thereof.
9. A compound of the formula:
whenever prepared by the process claimed in claim 4, or by an obvious chemical equivalent thereof.
whenever prepared by the process claimed in claim 4, or by an obvious chemical equivalent thereof.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3845373A JPS5546400B2 (en) | 1973-04-03 | 1973-04-03 | |
| JP5654473A JPS565753B2 (en) | 1973-05-21 | 1973-05-21 | |
| JP6446473A JPS565755B2 (en) | 1973-06-07 | 1973-06-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1066701A true CA1066701A (en) | 1979-11-20 |
Family
ID=27289838
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA191,286A Expired CA1066701A (en) | 1973-04-03 | 1974-01-30 | Method for the preparation of piperazine derivatives |
Country Status (11)
| Country | Link |
|---|---|
| AR (2) | AR204003A1 (en) |
| AT (1) | AT340931B (en) |
| CA (1) | CA1066701A (en) |
| CH (1) | CH593281A5 (en) |
| ES (1) | ES424851A1 (en) |
| FI (1) | FI56011C (en) |
| IE (1) | IE39102B1 (en) |
| NL (1) | NL186087C (en) |
| NO (1) | NO142221C (en) |
| PH (2) | PH10529A (en) |
| SE (1) | SE416051B (en) |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0031120A1 (en) * | 1979-12-21 | 1981-07-01 | Unibios S.p.A. | A process for the production of 2-substituted 6-alkoxycarbonyl-8-ethyl-5-oxo-5,8-dihydro-pyrido(2,3-d)-pyrimidines and of corresponding free acids |
| US8680108B2 (en) | 2009-12-18 | 2014-03-25 | Incyte Corporation | Substituted fused aryl and heteroaryl derivatives as PI3K inhibitors |
| US8759359B2 (en) | 2009-12-18 | 2014-06-24 | Incyte Corporation | Substituted heteroaryl fused derivatives as PI3K inhibitors |
| US8940752B2 (en) | 2009-06-29 | 2015-01-27 | Incyte Corporation | Pyrimidinones as PI3K inhibitors |
| US9199982B2 (en) | 2011-09-02 | 2015-12-01 | Incyte Holdings Corporation | Heterocyclylamines as PI3K inhibitors |
| US9527848B2 (en) | 2010-12-20 | 2016-12-27 | Incyte Holdings Corporation | N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines as PI3K inhibitors |
| US9732097B2 (en) | 2015-05-11 | 2017-08-15 | Incyte Corporation | Process for the synthesis of a phosphoinositide 3-kinase inhibitor |
| US9944646B2 (en) | 2012-04-02 | 2018-04-17 | Incyte Holdings Corporation | Bicyclic azaheterocyclobenzylamines as PI3K inhibitors |
| US9988401B2 (en) | 2015-05-11 | 2018-06-05 | Incyte Corporation | Crystalline forms of a PI3K inhibitor |
| US10077277B2 (en) | 2014-06-11 | 2018-09-18 | Incyte Corporation | Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors |
| US10336759B2 (en) | 2015-02-27 | 2019-07-02 | Incyte Corporation | Salts and processes of preparing a PI3K inhibitor |
-
1974
- 1974-01-01 AR AR253060A patent/AR204003A1/en active
- 1974-01-30 CA CA191,286A patent/CA1066701A/en not_active Expired
- 1974-02-01 SE SE7401361A patent/SE416051B/en not_active IP Right Cessation
- 1974-02-04 FI FI298/74A patent/FI56011C/en active
- 1974-02-04 NO NO740349A patent/NO142221C/en unknown
- 1974-02-04 NL NLAANVRAGE7401509,A patent/NL186087C/en not_active IP Right Cessation
- 1974-02-14 CH CH205474A patent/CH593281A5/en not_active IP Right Cessation
- 1974-03-25 IE IE00650/74A patent/IE39102B1/en unknown
- 1974-04-02 ES ES424851A patent/ES424851A1/en not_active Expired
- 1974-04-03 AT AT277774A patent/AT340931B/en not_active IP Right Cessation
- 1974-04-03 PH PH15698A patent/PH10529A/en unknown
-
1975
- 1975-01-01 AR AR258571A patent/AR204660A1/en active
- 1975-09-05 PH PH17546A patent/PH10984A/en unknown
Cited By (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0031120A1 (en) * | 1979-12-21 | 1981-07-01 | Unibios S.p.A. | A process for the production of 2-substituted 6-alkoxycarbonyl-8-ethyl-5-oxo-5,8-dihydro-pyrido(2,3-d)-pyrimidines and of corresponding free acids |
| US9975907B2 (en) | 2009-06-29 | 2018-05-22 | Incyte Holdings Corporation | Pyrimidinones as PI3K inhibitors |
| US8940752B2 (en) | 2009-06-29 | 2015-01-27 | Incyte Corporation | Pyrimidinones as PI3K inhibitors |
| US11401280B2 (en) | 2009-06-29 | 2022-08-02 | Incyte Holdings Corporation | Pyrimidinones as PI3K inhibitors |
| US10829502B2 (en) | 2009-06-29 | 2020-11-10 | Incyte Corporation | Pyrimidinones as PI3K inhibitors |
| US10428087B2 (en) | 2009-06-29 | 2019-10-01 | Incyte Corporation | Pyrimidinones as PI3K inhibitors |
| US8680108B2 (en) | 2009-12-18 | 2014-03-25 | Incyte Corporation | Substituted fused aryl and heteroaryl derivatives as PI3K inhibitors |
| US8759359B2 (en) | 2009-12-18 | 2014-06-24 | Incyte Corporation | Substituted heteroaryl fused derivatives as PI3K inhibitors |
| US9527848B2 (en) | 2010-12-20 | 2016-12-27 | Incyte Holdings Corporation | N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines as PI3K inhibitors |
| US9815839B2 (en) | 2010-12-20 | 2017-11-14 | Incyte Corporation | N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines as PI3K inhibitors |
| US10092570B2 (en) | 2011-09-02 | 2018-10-09 | Incyte Holdings Corporation | Heterocyclylamines as PI3K inhibitors |
| US11819505B2 (en) | 2011-09-02 | 2023-11-21 | Incyte Corporation | Heterocyclylamines as PI3K inhibitors |
| US11433071B2 (en) | 2011-09-02 | 2022-09-06 | Incyte Corporation | Heterocyclylamines as PI3K inhibitors |
| US9199982B2 (en) | 2011-09-02 | 2015-12-01 | Incyte Holdings Corporation | Heterocyclylamines as PI3K inhibitors |
| US10376513B2 (en) | 2011-09-02 | 2019-08-13 | Incyte Holdings Corporation | Heterocyclylamines as PI3K inhibitors |
| US9730939B2 (en) | 2011-09-02 | 2017-08-15 | Incyte Holdings Corporation | Heterocyclylamines as PI3K inhibitors |
| US10646492B2 (en) | 2011-09-02 | 2020-05-12 | Incyte Corporation | Heterocyclylamines as PI3K inhibitors |
| US9707233B2 (en) | 2011-09-02 | 2017-07-18 | Incyte Holdings Corporation | Heterocyclylamines as PI3K inhibitors |
| US9944646B2 (en) | 2012-04-02 | 2018-04-17 | Incyte Holdings Corporation | Bicyclic azaheterocyclobenzylamines as PI3K inhibitors |
| US10259818B2 (en) | 2012-04-02 | 2019-04-16 | Incyte Corporation | Bicyclic azaheterocyclobenzylamines as PI3K inhibitors |
| US10077277B2 (en) | 2014-06-11 | 2018-09-18 | Incyte Corporation | Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors |
| US11130767B2 (en) | 2014-06-11 | 2021-09-28 | Incyte Corporation | Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors |
| US10479803B2 (en) | 2014-06-11 | 2019-11-19 | Incyte Corporation | Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors |
| US11084822B2 (en) | 2015-02-27 | 2021-08-10 | Incyte Corporation | Salts and processes of preparing a PI3K inhibitor |
| US10336759B2 (en) | 2015-02-27 | 2019-07-02 | Incyte Corporation | Salts and processes of preparing a PI3K inhibitor |
| US10125150B2 (en) | 2015-05-11 | 2018-11-13 | Incyte Corporation | Crystalline forms of a PI3K inhibitor |
| US9732097B2 (en) | 2015-05-11 | 2017-08-15 | Incyte Corporation | Process for the synthesis of a phosphoinositide 3-kinase inhibitor |
| US9988401B2 (en) | 2015-05-11 | 2018-06-05 | Incyte Corporation | Crystalline forms of a PI3K inhibitor |
Also Published As
| Publication number | Publication date |
|---|---|
| NO142221B (en) | 1980-04-08 |
| IE39102L (en) | 1974-10-03 |
| ATA277774A (en) | 1977-05-15 |
| IE39102B1 (en) | 1978-08-02 |
| FI56011C (en) | 1979-11-12 |
| NO142221C (en) | 1980-07-16 |
| PH10984A (en) | 1977-10-18 |
| NL186087B (en) | 1990-04-17 |
| SE416051B (en) | 1980-11-24 |
| ES424851A1 (en) | 1976-06-01 |
| PH10529A (en) | 1977-05-30 |
| AR204003A1 (en) | 1975-11-12 |
| FI56011B (en) | 1979-07-31 |
| AT340931B (en) | 1978-01-10 |
| NL7401509A (en) | 1974-10-07 |
| AR204660A1 (en) | 1976-02-20 |
| NO740349L (en) | 1974-10-04 |
| CH593281A5 (en) | 1977-11-30 |
| NL186087C (en) | 1990-09-17 |
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