[go: up one dir, main page]

WO2008007835A1 - Dérivés 2,4-quinazoline à activité sur le canal calcique de type t et procédé d'élaboration - Google Patents

Dérivés 2,4-quinazoline à activité sur le canal calcique de type t et procédé d'élaboration Download PDF

Info

Publication number
WO2008007835A1
WO2008007835A1 PCT/KR2006/005275 KR2006005275W WO2008007835A1 WO 2008007835 A1 WO2008007835 A1 WO 2008007835A1 KR 2006005275 W KR2006005275 W KR 2006005275W WO 2008007835 A1 WO2008007835 A1 WO 2008007835A1
Authority
WO
WIPO (PCT)
Prior art keywords
dioxo
carboxylic acid
tetrahydroquinazoline
mmol
amide
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.)
Ceased
Application number
PCT/KR2006/005275
Other languages
English (en)
Inventor
Ae-Nim Pae
Yong-Seo Cho
Joo-Hwan Cha
Hyun-Ah Choo
Hye-Whon Rhim
Hee-Jeong Seo
Mi-Na Jo
Hun-Yeong Koh
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Korea Institute of Science and Technology KIST
Original Assignee
Korea Institute of Science and Technology KIST
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Korea Institute of Science and Technology KIST filed Critical Korea Institute of Science and Technology KIST
Publication of WO2008007835A1 publication Critical patent/WO2008007835A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a 2,4-dioxo-quinazoline compound which is a selective antagonist to a T-type calcium channel and can be developed as a drug for neurogenic pains, epilepsy or hypertension, and to a preparation method thereof.
  • a calcium channel plays a key role in controlling secretion of neurotransmitter at excitation-contraction connection mechanism appearing at muscle cells of a skeletal structure, blood vessels and the heart and at a central and peripheral nervous systems.
  • calcium channels are classified into a high voltage- activated L-type calcium channel and a low voltage-activated T-type calcium channel.
  • the L-type calcium channel plays the biggest role in the transmission of calcium ions passing through the cell walls of blood vessel muscles, skeletal striated muscles, smooth muscles, etc., so as to control the contraction of those muscles, and also involves in the secretion of a neurotransmitter from endocrine glands and nervous tissues.
  • the T-type calcium channel mostly exists in heart cells such as central muscle cells, endocrine gland of an adrenal or a sinus node. It has been known that, in addition to the roles performed by the L-type calcium channel, the T-type calcium channel in the heart cells plays a key role in the creation of heart pulsation and also involves in the introduction of Ca 2+ into myocyte even at a small potential difference.
  • an antagonist of the calcium channel makes it possible to control fibrous cell multiplication, blood pressure, an abnormal neurotransmitter, etc. Therefore, in developing drugs aimed for treating heart diseases, broad range of mental motility disorders, etc., research on the calcium channel antagonist has been actively ongoing.
  • substances having inhibition of L-type Ca + channel were used; however, because of their side effects, an antagonist having selective inhibition of T-type calcium channel is required.
  • Mibefradil which selectively inhibits T-type calcium channel 10 to 30 times, has been recently used as a drug for treating the aforementioned disorders.
  • mibefradil shows pharmacokinetic interactions with a drug such as an antihistamine, there is a need to develop a substance which may replace mibefradil.
  • an object of the present invention is to provide a 2,4-dioxo-quinazoline derivative having selective inhibition of a T-type calcium channel, and a preparation method thereof.
  • a 2,4-dioxo-quinazoline compound represented by Formula 1 below which is a selective antagonist to a T- type calcium channel and can be developed as a drug for neurogenic pains, epilepsy or hypertension, and a preparation method thereof.
  • Formula 1 :
  • Ri is an aryl group having 6 to 10 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from halogen atoms, alkyl having 1 to 15 carbon atoms, alkoxy having 1 to 15 carbon atoms and phenoxy; an alkyl group having 1 to 15 carbon atoms; or a cycloalkyl group having 1 to 15 carbon atoms;
  • R 2 is a saturated or unsaturated 5- to 7-membered heterocyclic ring which contains 1 to 3 hetero atoms selected from N, O and S, and which may be unsubstituted or substituted with at least one substituent selected from alkyl having 1 to 15 carbon atoms, amino, alkylamino having 1 to 15 carbon atoms and halogen atoms.
  • the halogen atoms are selected from fluorine, chlorine, bromine and iodine atoms; example of the alkyl may be methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc.; and the cycloalkyl may be cyclopentyl and cyclohexyl.
  • the aryl group may be a monocycle or a bicycle wherein two rings are fused together, containing 6 to 10 carbon atoms, and examples of which include phenyl, naphthyl, etc.
  • the aryl group may be substituted with at least one substituent such as alkyl having 1 to 15 carbon atoms, halogen atoms selected from fluorine, chlorine, bromine and iodine atoms, alkoxy having 1 to 15 carbon atoms, phenoxy, etc.
  • the heterocycle may be pyridine, pyrazine, pyrimidine, pyridazine, triazine, imidazole, triazole, quinoline, isoquinoline, quinazoline, quinoxaline, phthalazine, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, oxadiazole, pyrole, furan, thiopene, and hydrogenated derivatives thereof, which may be, in particular, piperidine, pyrrolidine, azetidine and tetrohydrofuran, wherein the heterocycle may have at least one N-oxide structure when it contains at least one nitrogen atoms.
  • the compound of Formula 1 may be prepared by a reductive acylation of an amine compound represented by Formula 2 below and a carboxylic acid compound represented by Formula 3 below.
  • Reaction Schemes 1 to 4 below are the specific embodiments of the present invention for preparing the compound of Formula 1.
  • n, Ri and R 2 are the same as those defined in Formula 1.
  • m is 0 or 1 ;
  • R 3 is an alkyl having 1 to 15 carbon atoms, amino, an alkylamino having 1 to 15 carbon atoms, or a halogen atom selected from fluorine, chlorine, bromine and iodine.
  • a combinatorial synthesis is a technique of making a library comprising a large number of compounds at a time, and finding out lead substances of new drugs with higher activities by a quick screening.
  • This method has been used in various other fields of science such as a material science, catalysts, biosynthesis, and the like, as well as for the development of new drugs.
  • the conventional method which results in lead compounds for the development of new drugs is a classical synthesis, which is an ineffective process because it requires a long period of time and it is difficult to obtain a large number of compounds.
  • a preparation process using a solid-phase or liquid-phase combinatorial synthesis which makes it possible to synthesize a large amount of compounds is preferred.
  • the solid-phase combinatorial synthesis is advantageous in that separation and manipulation of products, and automation are easy, while it is disadvantageous in that there are restrictions in reaction scales, and a large amount of solvents and reagents are required.
  • the liquid-phase combinatorial synthesis is advantageous in that there is no restriction in reaction scales, the progress of reaction can be easily checked and structural diversities can be achieved by expansion and wide ranges of chemical reactions, although it is disadvantageous in that automation of the reaction process and separation of desired products are uneasy.
  • a solution-phase combinatorial chemistry in which a reaction is performed without attachment to or separation from a solid support was developed, by which enables to prepare a large number of compounds of Formula 1 at a time. The processes for preparing the compound of Formula 1 according to the present invention will now be described in more detail.
  • a carboxylic acid represented by Formula 3 may be activated to an acid chloride, which is then reacted with a secondary amine compound represented by Formula 2.
  • the reaction is performed at a temperature range of 0°C to 40°C, preferably at room temperature. Multiple reactions may be simultaneously performed using a multi-functional reactor. Thionyl chloride, oxalyl chloride, phosphorus oxychloride or the like may be used for activating the carboxylic acid of Formula 3 into an acid chloride.
  • a reaction solvent dimethyl formamide, tetrahydrofuran, 1 ,2-dichloroethane, acetonitrile or dichloromethane may be used.
  • the reaction time may be about 30 minutes to 2 hours, and the progress of the reaction can be checked by a thin-layer chromatography (TLC).
  • TLC thin-layer chromatography
  • a saturated aq. NaHCO 3 solution may be added to the reaction solution, and a product may be extracted with a suitable organic solvent.
  • an extraction solvent dichloromethane or ethyl acetate may be used, and the most suitable one is dichloromethane.
  • the solvent may be distilled off under a reduced pressure, and the residue may be dried and concentrated, and separation and purification may be performed by a column chromatography, to obtain the desired compound.
  • Table 1a and 1b show % inhibition of T-type calcium channels of the compounds of Formula 1 according to the present invention.
  • Compound 108 exhibits the best activity to T-type calcium channel.
  • Table 2 shows activities (IC 50 ) to T-type calcium channel of the selected compounds.
  • Example 16 Syhtnesis of 3-(2-fluorophenyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-7-carboxylic acid (3-moipolin-4-yl-propyl)-amide
  • 3-(3-Fluorophenyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-7-carboxylic acid (79.2 mg, 0.252 mmol) was dissolved in thionyl chloride (4 ml). The resultant was refluxed with stirring for 2 hours at 85 0 C, and then, production of acyl chloride was checked by TLC. The produced acyl chloride was concentrated under a reduced pressure, and the residue was maintained under vacuum for about 8 hours.
  • Example 28 Synthesis of 3-cyclohexyl-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-7-carboxylic acid (3-molpolin-4-yl-propyl)-amide
  • 3-(2-Methoxyphenyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-7-carboxylic acid (90 mg, 0.288 mmol) was dissolved in purified dichloromethane (3 ml), oxalyl chloride (1 ml) and a catalytic amount of dimethyl formamide. The resultant was then stirred for two hours at room temperature, and then, production of acyl chloride was checked by TLC. The produced acyl chloride was concentrated under a reduced pressure, and the residue was maintained under vacuum for about 8 hours.
  • Example 36 Synthesis of 3-(4-methoxyphenyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-7-carboxylic acid (2-pyrrolidin-4-yl-ethyl)-amide
  • the resulting material was dissolved in purified dichloromethane (4 ml), to which 2-pyrrolidin-1-yl-ethylamine (58 ml, 0.466 mmol) was slowly added dropwise at 0 0 C for a reaction, and the resultant was then stirred for two hours at room temperature. After the reaction was completed, the resulting material was filtered5 with dichloromethane to obtain 49 mg of the desired compound (38%).
  • Example 38 Synthesis of 3-(3-fluorobenzyl)-2,4-dioxo-1 , 2,3,4-0 tetrahydroquinazoline-7-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide
  • Example 48 Synthesis of 3-(4-fluorophenyl)-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-7-carboxylic acid (3-pyrrolidin-1 -yl-propyl)-amide
  • 3-(2-Methoxyphenyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-7-carboxylic acid (90 mg, 0.288 mmol) was dissolved in purified dichloromethane (3 ml), oxalyl chloride (1 ml) and a catalytic amount of dimethyl formamide. The resultant was then stirred for two hours at room temperature, and then, production of acyl chloride was checked by TLC. The produced acyl chloride was concentrated under a reduced pressure, and the residue was maintained under vacuum for about 8 hours.
  • Example 50 Synthesis of 3-(3-methoxyphenyl)-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-7-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide
  • 3-(3-Methoxyphenyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-7-carboxylic acid (90 mg, 0.288 mmol) was dissolved in purified dichloromethane (3 ml), oxalyl chloride (1 ml) and a catalytic amount of dimethyl formamide. The resultant was then stirred for two hours at room temperature, and then, production of acyl chloride was checked by TLC. The produced acyl chloride was concentrated under a reduced pressure, and the residue was maintained under vacuum for about 8 hours.
  • Example 51 Synthesis of 3-(4-methoxyphenyl)-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-7-carboxylic acid (3-pyrrolidin-1 -yl-propyl)-amide
  • Example 54 Synthesis of 3-(4-fluorobenzyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-7-carboxylic acid (3-pyrrolidin-1 -yl-propyl)-amide (Compound 54) 3-(4-Fluorobenzyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-7-carboxylic acid (90 mg, 0.286 mmol) and 3-pyrrolidin-1-yl-propylamine (44 ⁇ l, 0.343 mmol) were used in the same manner as described in Example 52 to obtain 76 mg of the desired compound (63%).
  • Example 58 Synthesis of 3-cyclohexyl-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-7-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide
  • Example 60 Synthesis of 3-methyl-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-7-carboxylic acid (3-pyrrolidin-1 -yl-propyl)-amide
  • Example 62 Synthesis of 3-(3-fluorophenyl)-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-7-carboxylic acid [3-(4-methyl-piperazin-1 -yl)-propyl]-amide
  • Compound 62 3-(3-Fluorophenyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-7-carboxylic acid (99 mg, 0.329 mmol) and 3-(4-methyl-piperazin-1-yl)-propylamine (84 ml, 0.494 mmol) were used in the same manner as described in Example 61 to obtain 50 mg of the desired compound (35%).
  • 1H NMR 300 MHz, DMSO-d 6 ) ⁇ 11.79 (s, 1 H), 8.94 (bs, 1 H), 8.01 (d, J
  • Example 63 Synthesis of 3-(4-fluorophenyl)-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-7-carboxylic acid [3-(4-methyl-piperazin-1 -yl)-propyl]-amide (Compound 63)
  • 3-(2-Methoxyphenyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-7-carboxylic acid (90 mg, 0.288 mmol) was dissolved in purified dichloromethane (3 ml), oxalyl chloride (1 ml) and a catalytic amount of dimethyl formamide. The resultant was then stirred for two hours at room temperature, and then, production of acyl chloride was checked by TLC. The produced acyl chloride was concentrated under a reduced pressure, and the residue was maintained under vacuum for about 8 hours.
  • Example 65 Synthesis of 3-(3-methoxyphenyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-7-carboxylic acid [3-(4-methyl-piperazin-1 -yl)-propyl]-amide
  • Example 66 Synthesis of 3-(4-methoxyphenyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-7-carboxylic acid [3-(4-methyl-piperazin-1 -yl)-propyl]-amide
  • Example 73 Synthesis of 3-cyclohexyl-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-7-carboxylic acid [3-(4-methyl-piperazin-1 -yl)-propyl]-amide (Compound 73) 3-Cyclohexyl-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-7-carboxylic acid (90 mg, 0.312 mmol) was dissolved in thionyl chloride (4 ml). The resultant was refluxed with stirring for 2 hours at 85 0 C, and then, production of acyl chloride was checked by TLC.
  • the produced acyl chloride was concentrated under a reduced pressure, and the residue was maintained under vacuum for about 8 hours.
  • Example 77 Synthesis of 3-(3-fluorophenyl)-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-7-carboxylic acid (2-piperidin-1-yl-ethyl)-amide (Compound 77)
  • Example 78 Synthesis of 3-(4-fluorophenyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-7-carboxylic acid (2-piperidin-1-yl-ethyl)-amide
  • Compound 78 3-(4-Fluorophenyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-7-carboxylic acid (99 mg, 0.329 mmol) and 2-piperidin-1-yl-ethylamine (70 ⁇ l, 0.495 mmol) were used in the same manner as described in Example 73 to obtain 45 mg of the desired compound (34%).
  • 3-(2-Methoxyphenyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-7-carboxylic acid (90 mg, 0.288 mmol) was dissolved in purified dichloromethane (3 ml), oxalyl chloride (1 ml) and a catalytic amount of dimethyl formamide. The resultant was then stirred for two hours at room temperature, and then, production of acyl chloride was checked by TLC. The produced acyl chloride was concentrated under a reduced pressure, and the residue was maintained under vacuum for about 8 hours.
  • Example 83 Synthesis of 3-(3-fluorobenzyl)-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-7-carboxylic acid (2-piperidin-1-yl-ethyl)-amide (Compound 83) 3-(3-Fluorobenzyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-7-carboxylic acid (99 mg, 0.315 mmol) and 2- ⁇ iperidin-1-yl-ethylamine (67 ml, 0.472 mmol) were used in the same manner as described in Example 82 to obtain 36 mg of the desired compound (26%).
  • Example 84 Synthesis of 3-(4-fluorobenzyl)-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-7-carboxylic acid (2-piperidin-1-yl-ethyl)-amide
  • Compound 84 3-(4-Fluorobenzyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-7-carboxylic acid (99 mg, 0.315 mmol) and 2-piperidin-1-yl-ethylamine (67 ml, 0.472 mmol) were used in the same manner as described in Example 82 to obtain 60 mg of the desired compound (45%).
  • Example 91 Synthesis of 3-(2-fluorophenyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-7-carboxylic acid [3-(2-methyl-piperidin-1 -yl)-propyl]-amide
  • Compound 91 3-(2-Fluorophenyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-7-carboxylic acid (99 mg, 0.329 mmol) was dissolved in thionyl chloride (4 ml). The resultant was refluxed with stirring for 2 hours at 85°C, and then, production of acyl chloride was checked by TLC.
  • the produced acyl chloride was concentrated under a reduced pressure, and the residue was maintained under vacuum for about 8 hours.
  • 3-(2-Methoxyphenyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-7-carboxylic acid (90 mg, 0.288 mmol) was dissolved in purified dichloromethane (3 ml), oxalyl chloride (1 ml) and a catalytic amount of dimethyl formamide. The resultant was then stirred for two hours at room temperature, and then, production of acyl chloride was checked by TLC. The produced acyl chloride was concentrated under a reduced pressure, and the residue was maintained under vacuum for about 8 hours.
  • Example 98 Synthesis of 3-(3-fluorobenzyl)-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-7-carboxylic acid [3-(2-methyl-piperidin-1 -yl)-propyl]-amide
  • Compound 98 3-(3-Fluorobenzyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-7-carboxylic acid (99.2 mg, 0.316 mmol) and 3-(2-methyl-piperidin-1-yl)-propylamine (82 ⁇ l, 0.474 mmol) were used in the same manner as described in Example 97 to obtain 51 mg of the desired compound (36%).
  • Example 100 Synthesis of 3-(2-methoxybenzyl)-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-7-carboxylic acid [3-(2-methyl-piperidin-1-yl)-propyl]-amide (Compound 100)
  • Example 102 Synthesis of 3-(4-methoxybenzyl)-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-7-carboxylic acid [3-(2-methyl-piperidin-1 -yl)-propyl]-amide (Compound 102) 3-(4-Methoxybenzyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-7-carboxylic acid (90 mg, 0.276 mmol) and 3-(2-methyl-piperidin-1-yl-propylamine (96 ⁇ l, 0.552 mmol) were used in the same manner as described in Example 100 to obtain 105 mg of the desired compound (82%).
  • Example 103 Synthesis of 3-cyclohexyl-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-7-carboxylic acid [3-(2-methyl-piperidin-1 -yl)-propyl]-amide (Compound 103)
  • Example 106 Synthesis of 3-(2-fluorobenzyl)-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-7-carboxylic acid [3-(2-ethyl-piperidin-1 -yl)-propyl]-amide (Compound 106) 3-(2-Fluorobenzyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-7-carboxylic acid (90 mg, 0.286 mmol) and 3-(2-ethyl-piperidin-1-yl)-propylamine (121 mg, 0.715 mmol) were used in the same manner as described in Example 103 to obtain 42 mg of the desired compound (32%).
  • Example 110 Synthesis of 3-(3-methoxybenzyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-7-carboxylic acid [3-(2-ethyl-piperidin-1 -yl)-propyl]-amide (Compound 110)
  • Example 111 Synthesis of 3-(4-methoxybenzyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-7-carboxylic acid [3-(2-ethyl-piperidin-1 -yl)-propyl]-amide (Compound 111)
  • Example 112 Synthesis of 3-cyclohexyl-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-7-carboxylic acid [3-(2-ethyl-piperidin-1 -yl)-propyl]-amide (Compound 112)
  • Example 114 Synthesis of 3-(3-fluorobenzyl)-2,4-dioxo-1 ,2,3,4-5 tetrahydroquinazoline-7-carboxylic acid [2-(2-ethyl-piperidin-1-yl)-ethyl]-amide (Compound 114)
  • Example 117 Synthesis of 3-(3-methoxybenzyl)-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-7-carboxylic acid [2-(2-ethyl-piperidin-1 -yl)-ethyl]-amide (Compound 117) 3-(3-Methoxybenzyi)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-7-carboxylic acid (90 mg, 0.275 mmol) and 2-(2-ethyl-piperidin-1-yl)-ethylamine (86 mg, 0.550 mmol) were used in the same manner as described in Example 103 to obtain 20 mg of the desired compound (16%).
  • Example 119 Synthesis of 3-cyclohexyl-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-7-carboxylic acid [2-(2-ethyl-piperidin-1 -yl)-ethyl]-amide (Compound 119) 3-Cyclohexyl-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-7-carboxylic acid (90 mg, 0.312 mmol) and 2-(2-ethyl-piperidin-1-yl)-ethylamine (107 mg, 0.605 mmol) were used in the same manner as described in Example 103 to obtain 20 mg of the desired compound (15%).
  • Example 120 Synthesis of 3-(2-fluorobenzyl)-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-7-carboxylic acid 3-(piperidin-1 -yl)-propyl-amide
  • Example 122 Synthesis of 3-(4-fluorobenzyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-7-carboxylic acid 3-(piperidin-1-yl)-propyl-amide (Compound 122)
  • Example 124 Synthesis of 3-(3-methoxybenzyl)-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-7-carboxylic acid 3-(piperidin-1 -yl)-propyl-amide
  • Example 126 Synthesis of 3-cyclohexyl-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-7-carboxylic acid [3-(piperidin-1 -yl)-propyl]-amide (Compound 126)
  • Example 127 Synthesis of 3-(2-fluorobenzyl)-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-7-carboxylic acid [2-(2-methyl-piperidin-1 -yl)-ethyl]-amide (Compound 127) 3-(2-Fluorobenzyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-7-carboxylic acid (90 mg, 0.286 mmol) and 2-(2-methyl-piperidin-1-yl)-ethylamine (81 mg, 0.572 mmol) were used in the same manner as described in Example 103 to obtain 50 mg of the desired compound (47%).
  • Example 128 Synthesis of 3-(3-fluorobenzyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-7-carboxylic acid [2-(2-methyl-piperidin-1 -yl)-ethyl]-amide (Compound 128)
  • Example 129 Synthesis of 3-(4-fluorobenzyl)-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-7-carboxylic acid [2-(2-methyl-piperidin-1-yl)-ethyl]-amide (Compound 129)
  • Example 133 Synthesis of 3-cyclohexyl-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-7-carboxylic acid [2-(2-methyl-piperidin-1 -yl-ethyl]-amide (Compound 133)
  • Example 134 Synthesis of 3-(4-chloro-benzyl)-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-7-carboxylic acid (2-molpolin-4-yl-ethyl]-amide (Compound 134) S ⁇ -Chloro-benzyl ⁇ -dioxo-I ⁇ .S ⁇ -tetrahydroquinazoline-Z-carboxylic acid (90 mg, 0.272 mmol) and 2-molpolin-4-yl-ethylamine (78 ml, 0.598 mmol) were used in the same manner as described in Example 103 to obtain 61 mg of the desired compound (50%).
  • Example 135 Synthesis of 3-(4-chloro-benzyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-7-carboxylic acid (3-molpolin-4-yl-ethyl]-amide (Compound 135) S- ⁇ -Chloro-benzyO ⁇ -dioxo-I ⁇ .S ⁇ -tetrahydroquinazoline ⁇ -carboxylic acid (90 mg, 0.272 mmol) and 3-molpolin-4-yl-ethylamine (87 ml, 0.598 mmol) were used in the same manner as described in Example 103 to obtain 30 mg of the desired compound (25%).
  • Example 136 Synthesis of 3-(4-chloro-benzyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-7-carboxylic acid (2-pyrrolidin-1-yl-ethyl]-amide (Compound 136) 3-(4-Chloro-benzyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-7-carboxylic acid (90 mg, 0.272 mmol) and 2-pyrrolidin-1-yl-ethylamine (76 ml, 0.598 mmol) were used in the same manner as described in Example 103 to obtain 69 mg of the desired compound (59%).
  • Example 137 Synthesis of 3-(4-chloro-benzyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-7-carboxylic acid (3-pyrrolidin-1 -yl-propyl]-amide (Compound 137) 3-(4-Chloro-benzyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-7-carboxylic acid (71 mg, 0.214 mmol) and 3-pyrrolidin-1-yl-propylamine (40 ml, 0.321 mmol) were used in the same manner as described in Example 103 to obtain 23 mg of the desired compound (25%).
  • Example 138 Synthesis of 3-(4-chioro-benzyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-7-carboxylic acid [3-(4-methyl-piperazin-1 -yl)-propyl]-amide
  • Compound 138 3-(4-Chloro-benzyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-7-carboxylic acid (90 mg, 0.272 mmol) and 3-(4-methyl-piperazin-1-yl)-propylamine (101 ml, 0.598 mmol) were used in the same manner as described in Example 103 to obtain 42 mg of the desired compound (33%).
  • Example 139 Synthesis of 3-(4-chloro-benzyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-7-carboxylic acid (2-piperidin-1-yl-ethyl)-amide (Compound 139)
  • Example 148 Synthesis of 3-(2-chloro-benzyl)-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-7-carboxylic acid [3-pyrrolidin-1-yl-propyl]-amide
  • Example 152 Synthesis of 3-(2-chloro-benzyl)-2,4-dioxo-1 , 2,3,4- tetrahydroquinazoline-7-carboxylic acid [3-(2-ethyl-piperidin-1 -yl-propy)]-amide
  • Example 154 Synthesis of 3-(2-chloro-benzyl)-2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-7-carboxylic acid [2-(2-ethyl-piperidin-1-yl)-ethyl]-amide (Compound 154)
  • the present invention provides a novel 2,4-dioxo- quinazoline derivative which is a selective antagonist to T-type calcium channel and can be developed as a drug for neurogenic pains, epilepsy or hypertension, and a preparation method thereof. Because the 2,4-di
  • the present invention relating to a method for preparing the 2,4-dioxo-quinazoline derivative using solution phase combinatorial synthesis makes it possible to obtain chemical substances with activity as antagonists of T- type calcium channel quickly and effectively.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Composés de dérivés 2,4-quinazoline de formule I tenant lieu d'antagonistes sélectifs vis-à-vis d'un canal calcique de type T et susceptibles d'être développés comme médicaments pour les douleurs neurogéniques, l'épilepsie ou l'hypertension, et procédé d'élaboration.
PCT/KR2006/005275 2006-07-13 2006-12-07 Dérivés 2,4-quinazoline à activité sur le canal calcique de type t et procédé d'élaboration Ceased WO2008007835A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2006-0065975 2006-07-13
KR1020060065975A KR100749843B1 (ko) 2006-07-13 2006-07-13 Ｔ-타입 칼슘 채널에 억제 활성을 지닌 신규2,4-디옥소-퀴나졸린 유도체 및 이의 제조방법

Publications (1)

Publication Number Publication Date
WO2008007835A1 true WO2008007835A1 (fr) 2008-01-17

Family

ID=38614674

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2006/005275 Ceased WO2008007835A1 (fr) 2006-07-13 2006-12-07 Dérivés 2,4-quinazoline à activité sur le canal calcique de type t et procédé d'élaboration

Country Status (2)

Country Link
KR (1) KR100749843B1 (fr)
WO (1) WO2008007835A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008138126A1 (fr) * 2007-05-09 2008-11-20 Neuromed Pharmaceuticals Ltd. Dérivés bicycliques de pyrimidine en tant que bloqueurs des canaux calciques
WO2017070680A1 (fr) 2015-10-22 2017-04-27 Cavion Llc Procédés pour traiter le syndrome d'angelman et des troubles associés
US11130750B2 (en) 2017-02-15 2021-09-28 Cavion, Inc. Calcium channel inhibitors
US11311522B1 (en) 2018-10-03 2022-04-26 Cavion, Inc. Treating essential tremor using (R)-2-(4-Isopropylphenyl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide
US11324733B2 (en) 2017-04-26 2022-05-10 Cavion, Inc. Methods for improving memory and cognition and for treating memory and cognitive disorders
US11427540B2 (en) 2019-07-11 2022-08-30 Praxis Precision Medicines, Inc. Formulations of T-type calcium channel modulators and methods of use thereof

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100879636B1 (ko) 2007-08-22 2009-01-21 한국과학기술연구원 세로토닌 ５―ｈｔ₃ａ 길항적 효과를 갖는 퀴나졸린유도체 함유 약제 조성물
CN114907323B (zh) * 2022-05-31 2023-08-15 内蒙古民族大学 喹喔啉酮类化合物及其制备方法和应用
CN114957222B (zh) * 2022-05-31 2023-08-15 内蒙古民族大学 化合物及其制备方法和用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004087172A1 (fr) * 2003-03-28 2004-10-14 Nissan Chemical Industries Ltd. Agents bloquant les canaux calciques de type t
EP1568695A1 (fr) * 2004-02-24 2005-08-31 Korea Institute of Science and Technology Dérivés de 3,4-dihydroquinazoline comme agents de blocage des canaux calciques de type T et procédés pour leur préparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004087172A1 (fr) * 2003-03-28 2004-10-14 Nissan Chemical Industries Ltd. Agents bloquant les canaux calciques de type t
EP1568695A1 (fr) * 2004-02-24 2005-08-31 Korea Institute of Science and Technology Dérivés de 3,4-dihydroquinazoline comme agents de blocage des canaux calciques de type T et procédés pour leur préparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DODDAREDDY M.R. ET AL.: "First Pharmacophoric Hypothesis for T-type Calcium Channel Blockers", BIOORGANIC AND MEDICINAL CHEMISTRY, vol. 12, 2004, pages 1605 - 1611 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008138126A1 (fr) * 2007-05-09 2008-11-20 Neuromed Pharmaceuticals Ltd. Dérivés bicycliques de pyrimidine en tant que bloqueurs des canaux calciques
US8133998B2 (en) 2007-05-09 2012-03-13 Zalicus Pharmaceuticals, Ltd. Bicyclic pyrimidine derivatives as calcium channel blockers
WO2017070680A1 (fr) 2015-10-22 2017-04-27 Cavion Llc Procédés pour traiter le syndrome d'angelman et des troubles associés
US11273218B2 (en) 2015-10-22 2022-03-15 Cavion, Inc. Methods for treating Angelman syndrome and related disorders
US11130750B2 (en) 2017-02-15 2021-09-28 Cavion, Inc. Calcium channel inhibitors
US11324733B2 (en) 2017-04-26 2022-05-10 Cavion, Inc. Methods for improving memory and cognition and for treating memory and cognitive disorders
US11311522B1 (en) 2018-10-03 2022-04-26 Cavion, Inc. Treating essential tremor using (R)-2-(4-Isopropylphenyl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide
US12383539B2 (en) 2018-10-03 2025-08-12 Cavion, Inc. Treating essential tremor using (R)-2-(4-Isopropylphenyl)-N-(1-(5-(2,2,2-Trifluoroethoxy)pyridin-2-yl)ethyl)acetamide
US11427540B2 (en) 2019-07-11 2022-08-30 Praxis Precision Medicines, Inc. Formulations of T-type calcium channel modulators and methods of use thereof
US11649207B2 (en) 2019-07-11 2023-05-16 Praxis Precision Medicines, Inc. Formulations of T-type calcium channel modulators and methods of use thereof
US12077502B2 (en) 2019-07-11 2024-09-03 Praxis Precision Medicines, Inc. Formulations of T-type calcium channel modulators and methods of use thereof

Also Published As

Publication number Publication date
KR100749843B1 (ko) 2007-08-21

Similar Documents

Publication Publication Date Title
EP1948663B1 (fr) Pyrazolopyrimidines en tant que modulateurs de caseine kinase ii (ck2)
WO2009055917A1 (fr) Inhibiteurs de l'histone déacétylase
DK3077375T3 (en) PROCEDURE FOR LARGE SCALE PREPARATION OF 1 - [(2-BROMPHENYL) SULPHONYL] -5-METHOXY-3 - [(4-METHYL-1-PIPERAZINYL) METHYL] -1H-INDOL-DIMESYLATE-MONOHYDRATE
HUP0203477A2 (hu) Alkil-amino-helyettesített biciklikus nitrogén-heterociklusok mint P38 protein-kináz-inhibitorok, ezeket tartalmazó gyógyszerkészítmények és előállítási eljárásaik
HU198916B (en) Process for producing new thiazol derivatives active for the colinerg systhem and pharmaceutical compositions containing them
CA1244016A (fr) Diazepinones condenses, procede de preparation et composes pharmaceutiques les contenant
CA1336431C (fr) Composes de thiazolo(5,4-b)azepine
US8921550B2 (en) Process for the preparation of benzoimidazol-2-yl pyrimidine derivatives
CA2781661A1 (fr) Modulateurs de ship1 et methodes associees
WO2008007835A1 (fr) Dérivés 2,4-quinazoline à activité sur le canal calcique de type t et procédé d'élaboration
JPH0249775A (ja) ６員環又は７員環を有する複素環化合物及びその製造方法
HK134994A (en) Hydrogenated 1-benzooxacycloalkyl-pyridine carboxylic-acid compounds
Thompson et al. Versatile assembly of 5-aminothiazoles based on the Ugi four-component coupling
DE69527786T2 (de) Diaminomethyliden-derivate
GB2120670A (en) Piperazine derivatives
Rajappa et al. Nitroenamines—III: Synthesis of 3, 3-diamino-2-nitroacrylonitriles from 1, 1-diamino-2-nitroethylenes
Heine et al. The isomerization of some aziridine derivatives. III. A new synthesis of 2-imidazolines
Farrokh et al. A Parham cyclization approach to diaryl-fused seven-membered ring heterocyclic ketones
CA2100366A1 (fr) Utilisation de derives de thiazolo-[2,3-a]-iso-indole comme medicaments antiviraux et nouveaux derives de thiazolo-[2,3-a]-iso-indole
US20250263367A1 (en) A facile and odor-free approach to convert sulfonyl urea derivatives to chalcogenide sulfonyl urea derivatives
CA1314885C (fr) Derives tricycliques agonistes de recepteurs cholinergiques, et medicaments en comportant
JP3629052B2 (ja) 置換キナゾリン− ２，４− ジオンの製造方法
Lei et al. Synthesis of trisubstituted isoxazoles from nitroenamines and aromatic aldehydes
Bátori et al. Novel synthesis of pyrido [2, 1‐f]‐as‐triazinium system and its zwitterionic derivatives. Different reactivities of 1‐and 3‐olates with electrophiles
Molteni et al. A one-step synthesis of enantiopure 2-substituted 4, 5-dihydro-1, 4-benzodiazepine-3-ones via intramolecular azide cycloaddition

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 06823982

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: RU

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC; EPO FORM 1205A DATED 02.06.2009

122 Ep: pct application non-entry in european phase

Ref document number: 06823982

Country of ref document: EP

Kind code of ref document: A1