FR2724383A1 - 2-Amino-pyrimidine-4-carboxamide derivs. are alpha 1 adrenergic receptor antagonists for urinary system - Google Patents
2-Amino-pyrimidine-4-carboxamide derivs. are alpha 1 adrenergic receptor antagonists for urinary system Download PDFInfo
- Publication number
- FR2724383A1 FR2724383A1 FR9410884A FR9410884A FR2724383A1 FR 2724383 A1 FR2724383 A1 FR 2724383A1 FR 9410884 A FR9410884 A FR 9410884A FR 9410884 A FR9410884 A FR 9410884A FR 2724383 A1 FR2724383 A1 FR 2724383A1
- Authority
- FR
- France
- Prior art keywords
- general formula
- amino
- carboxamide
- pyrimidine
- alpha
- 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.)
- Granted
Links
- ASFQWXQESJPZFG-UHFFFAOYSA-N 2-aminopyrimidine-4-carboxamide Chemical compound NC(=O)C1=CC=NC(N)=N1 ASFQWXQESJPZFG-UHFFFAOYSA-N 0.000 title abstract description 3
- 239000000674 adrenergic antagonist Substances 0.000 title 1
- 102000030619 alpha-1 Adrenergic Receptor Human genes 0.000 title 1
- 108020004102 alpha-1 Adrenergic Receptor Proteins 0.000 title 1
- 230000002485 urinary effect Effects 0.000 title 1
- 239000002253 acid Substances 0.000 claims abstract description 3
- 230000003287 optical effect Effects 0.000 claims abstract description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 5
- UXXQEVFRPLIOHJ-UHFFFAOYSA-N 2-chloropyrimidine-4-carboxamide Chemical compound NC(=O)C1=CC=NC(Cl)=N1 UXXQEVFRPLIOHJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000005544 phthalimido group Chemical group 0.000 claims description 4
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 150000003973 alkyl amines Chemical group 0.000 claims description 3
- 150000004985 diamines Chemical class 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000006242 amine protecting group Chemical group 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 239000012458 free base Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 5
- -1 triethylamine Chemical class 0.000 description 5
- 206010020852 Hypertonia Diseases 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 210000003708 urethra Anatomy 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 210000005036 nerve Anatomy 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 210000001635 urinary tract Anatomy 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QIPSWJFYYUTYHX-UHFFFAOYSA-N 2,3-dihydro-1,4-benzodioxin-3-ylmethylazanium;chloride Chemical compound [Cl-].C1=CC=C2OC(C[NH3+])COC2=C1 QIPSWJFYYUTYHX-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- ZEWXXXGRRPMXPY-UHFFFAOYSA-N n'-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)ethane-1,2-diamine Chemical compound C1=CC=C2OC(CNCCN)COC2=C1 ZEWXXXGRRPMXPY-UHFFFAOYSA-N 0.000 description 2
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 2
- 229960001802 phenylephrine Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- HKSQZEGSMBFHGC-UHFFFAOYSA-N pyrimidine-4-carboxamide Chemical compound NC(=O)C1=CC=NC=N1 HKSQZEGSMBFHGC-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- JHNURUNMNRSGRO-UHFFFAOYSA-N 2,3-dihydro-1,4-benzodioxin-3-ylmethanamine Chemical compound C1=CC=C2OC(CN)COC2=C1 JHNURUNMNRSGRO-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- MFSIEROJJKUHBQ-UHFFFAOYSA-N O.[Cl] Chemical compound O.[Cl] MFSIEROJJKUHBQ-UHFFFAOYSA-N 0.000 description 1
- 206010036018 Pollakiuria Diseases 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 210000004079 adrenergic fiber Anatomy 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 230000009989 contractile response Effects 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 206010013990 dysuria Diseases 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 208000013403 hyperactivity Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000007383 nerve stimulation Effects 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
La présente invention a pour objet des dérivés de 2-aminopyrimidine-4-carboxamide, leur préparation et leur application en thérapeutique.The present invention relates to 2-aminopyrimidine-4-carboxamide derivatives, their preparation and their therapeutic use.
Les composés de l'invention répondent à la formule générale (I)
dans laquelle n représente le nombre 1 ou 2, et Rt représente un atome d'hydrogène.The compounds of the invention correspond to the general formula (I)
in which n represents the number 1 or 2, and Rt represents a hydrogen atom.
Les composés de l'invention peuvent se présenter à l'état de bases libres ou de sels d'addition à des acides, et également sous forme d'isomères optiques purs ou de mélanges de tels isomères, notamment de mélanges racémiques.The compounds of the invention may be in the form of free bases or of addition salts with acids, and also in the form of pure optical isomers or of mixtures of such isomers, in particular of racemic mixtures.
Conformément à l'invention on peut préparer les composés de formule générale (I) selon un procédé illustré par le schéma qui suit.In accordance with the invention, the compounds of general formula (I) can be prepared according to a process illustrated by the scheme which follows.
On fait réagir l'amine de formule (II), éventuellement sous forme de chlorhydrate, avec un réactif halogéné de formule générale (III), dans laquelle Y représente un atome d'halogène, n est tel que défini ci-dessus et, soit Rl est tel que défini ci-dessus et R représente un groupe protecteur de l'amine, par exemple un groupe triphénylméthyle, soit Rl et R forment ensemble, et avec l'atome d'azote, un groupe tel que le groupe phtalimido, comme décrit dans J. Med. Chem. (1989) 32(8) 1921-1926 et Chem. Pharm. Bull. (1989) 34(1) 100-105.The amine of formula (II), optionally in the form of the hydrochloride, is reacted with a halogenated reagent of general formula (III), in which Y represents a halogen atom, n is as defined above and either Rl is as defined above and R represents a protective group for the amine, for example a triphenylmethyl group, that is to say Rl and R form together, and with the nitrogen atom, a group such as the phthalimido group, as described in J. Med. Chem. (1989) 32 (8) 1921-1926 and Chem. Pharm. Bull. (1989) 34 (1) 100-105.
La réaction s'effectue dans un solvant aprotique tel que l'acétonitrile, en présence d'une base organique telle que la triéthylamine, ou minérale telle que le carbonate de potassium, à une température de 40 à 1000C. The reaction is carried out in an aprotic solvent such as acetonitrile, in the presence of an organic base such as triethylamine, or an inorganic base such as potassium carbonate, at a temperature of 40 to 1000C.
Schéma
On obtient une diamine de formule générale (IV), dont on déprotège l'alkylamine terminale : dans le cas où R est un groupe triphénylméthyle, on effectue un traitement à l'acide chlorhydrique gazeux dans un alcool aliphatique, par exemple le méthanol, à une température de 0 à 600C ; dans le cas où
R et Rt font partie d'un groupe phtalimido, on effectue un traitement analogue à celui décrit dans la littérature citée ci-dessus, par exemple avec de l'hydrazine.A diamine of general formula (IV) is obtained, from which the terminal alkylamine is deprotected: in the case where R is a triphenylmethyl group, treatment is carried out with gaseous hydrochloric acid in an aliphatic alcohol, for example methanol, with a temperature from 0 to 600C; in the case where
R and Rt are part of a phthalimido group, a treatment similar to that described in the literature cited above is carried out, for example with hydrazine.
On obtient une amine de formule générale (V), que l'on fait finalement réagir avec le 2-chloropyrimidine-4-carboxamide, de formule (VI), dans un solvant tel que le propan-2-ol, en présence d'une base, par exemple le carbonate de potassium, à une température de 20 à 800C. An amine of general formula (V) is obtained, which is finally reacted with 2-chloropyrimidine-4-carboxamide, of formula (VI), in a solvent such as propan-2-ol, in the presence of a base, for example potassium carbonate, at a temperature of 20 to 800C.
La 2, 3-dihydro-l, 4-benzodioxine-2-méthanamine de formule (II) peut être préparé par un méthode analogue à celle décrite dans J. Med. Chem (1969) 12 326. Les w-halogéno-
N-(triphénylméthyl)alkylamines de formule générale (III) et le 2-chloropyrimidine-4-carboxamide sont décrits dans le brevet US-5164397.2,3-dihydro-1,4-benzodioxin-2-methanamine of formula (II) can be prepared by a method analogous to that described in J. Med. Chem (1969) 12 326. The w-halogeno-
N- (triphenylmethyl) alkylamines of general formula (III) and 2-chloropyrimidine-4-carboxamide are described in patent US-5164397.
Les exemples suivants illustrent en détail la préparation de quelques composés selon l'invention. Les microanalyses élémentaires et les spectres IR et RMN confirment les structures des composés obtenus.The following examples illustrate in detail the preparation of some compounds according to the invention. Elementary microanalyses and IR and NMR spectra confirm the structures of the compounds obtained.
ExemPle 1 2-[[2-tE(2,3-Dihydro-1,4-benzodioxin-2-yl)méthyl]amino]- éthyl]amino]pyrimidine-4-carboxamide, chlorhydrate.Example 1 2 - [[2-tE (2,3-Dihydro-1,4-benzodioxin-2-yl) methyl] amino] - ethyl] amino] pyrimidine-4-carboxamide, hydrochloride.
1.1 2-[2-[(2,3-Dihydro-1,4-benzodioxin-2-yl)méthyl]ami- no)éthyl]-lH-isoindol-l,3 (2H) -dione. 1.1 2- [2 - [(2,3-Dihydro-1,4-benzodioxin-2-yl) methyl] amino) ethyl] -1H-isoindol-1,3 (2H) -dione.
On fait réagir 15,4 g (76,36 mmoles) de chlorhydrate de 2,3-dihydro-1,4-benzodioxine-2-méthanamine, 19,4 g (76,36 mmoles) de 2-bromoéthyl-N-phtalamide et 31,66 g (219 mmoles) de carbonate de potassium dans 300 ml d'acétonitrile pendant 10h à la température du reflux.15.4 g (76.36 mmol) of 2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride are reacted, 19.4 g (76.36 mmol) of 2-bromoethyl-N-phthalamide and 31.66 g (219 mmol) of potassium carbonate in 300 ml of acetonitrile for 10 h at reflux temperature.
On évapore le solvant sous pression réduite, on ajoute 200 ml d'eau au résidu et on l'extrait au dichlorométhane.The solvent is evaporated off under reduced pressure, 200 ml of water are added to the residue and it is extracted with dichloromethane.
On sèche la phase organique sur sulfate de sodium, on la filtre, on évapore le solvant sous pression réduite et on purifie le résidu par chromatographie sur colonne de gel de silice en éluant avec un mélange de dichlorométhane et d'acétate d'éthyle de 100/0 à 0/100, puis avec un mélange d'acétate d'éthyle et de méthanol 90/10.The organic phase is dried over sodium sulfate, filtered, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and ethyl acetate of 100 / 0 to 0/100, then with a mixture of ethyl acetate and methanol 90/10.
On isole 12,48 g (36,88 mmoles) de produit huileux qu'on utilise tel quel dans l'étape suivante.12.48 g (36.88 mmol) of oily product are isolated and used as such in the next step.
1.2 N-[ (2,3-Dihydro-l,4-benzodioxin-2-yl)méthyl]éthane-
1,2-diamine.1.2 N- [(2,3-Dihydro-1,4-benzodioxin-2-yl) methyl] ethane-
1,2-diamine.
On fait réagir 12,48 g (36,88 mmoles) de 2-[2-[(2,3-dihydro 1,4-benzodioxin-2-yl)méthyl]amino]éthyl]-lH-isoindol- 1,3(2H)-dione dans 300 ml d'éthanol avec 3,42 ml (73,77 mmoles) d'hydrazine à la température du reflux pendant 6h.12.48 g (36.88 mmol) of 2- [2 - [(2,3-dihydro 1,4-benzodioxin-2-yl) methyl] amino] ethyl] -1H-isoindol-1,3 are reacted (2H) -dione in 300 ml of ethanol with 3.42 ml (73.77 mmol) of hydrazine at reflux temperature for 6 h.
On évapore le solvant sous pression réduite, on ajoute de l'eau au résidu, puis de l'acide chlorhydrique pour amener le pH à 1, on chauffe le mélange au reflux pendant 30 min et on le laisse revenir à température ambiante.The solvent is evaporated off under reduced pressure, water is added to the residue, then hydrochloric acid to bring the pH to 1, the mixture is heated to reflux for 30 min and allowed to return to room temperature.
On filtre le mélange, on ajoute au filtrat de l'acétate d'éthyle puis de la soude aqueuse à 30%, on sépare la phase organique et on extrait la phase aqueuse de nouveau à l'acétate d'éthyle. On réunit les deux phases organiques, on les sèche sur sulfate de sodium, on les filtre et on évapore le solvant sous pression réduite.The mixture is filtered, ethyl acetate and then 30% aqueous sodium hydroxide are added to the filtrate, the organic phase is separated and the aqueous phase is extracted again with ethyl acetate. The two organic phases are combined, dried over sodium sulfate, filtered and the solvent is evaporated off under reduced pressure.
On obtient 6,7 g (32,17 mmoles) de diamine qu'on utilise telle quelle dans l'étape suivante.6.7 g (32.17 mmol) of diamine are obtained which is used as it is in the next step.
1.3 2-[2-[[(2,3-Dihydro-l,4-benzodioxin-2-yl)méthyl]-
amino] éthyl] amino]pyrimidine-4-carboxamide, chlor
hydrate.1.3 2- [2 - [[(2,3-Dihydro-1,4-benzodioxin-2-yl) methyl] -
amino] ethyl] amino] pyrimidine-4-carboxamide, chlor
hydrate.
On fait réagir les 6,7 g (32,17 mmoles) de N-[(2,3-dihydro 1,4-benzodioxin-2-yl)méthyl]éthane-1,2-diamine avec 5,07 g (32,17 mmoles) de 2-chloropyrimidine-4-carboxamide et 5 g (36,17 mmoles) de carbonate de potassium dans 250 ml de propan-2-ol à la température du reflux pendant 10h.The 6.7 g (32.17 mmol) of N - [(2,3-dihydro 1,4-benzodioxin-2-yl) methyl] ethane-1,2-diamine are reacted with 5.07 g (32 , 17 mmol) of 2-chloropyrimidine-4-carboxamide and 5 g (36.17 mmol) of potassium carbonate in 250 ml of propan-2-ol at reflux temperature for 10 h.
On refroidit le mélange à température ambiante, on évapore le solvant sous pression réduite, on ajoute de l'eau au résidu et on l'extrait au dichlorométhane. On sèche la phase organique sur sulfate de sodium, on la filtre, on évapore le solvant sous pression réduite et on purifie le résidu par chromatographie sur colonne de gel de silice en éluant avec un mélange de dichlorométhane et de méthanol de 95/5 à 80/20.The mixture is cooled to room temperature, the solvent is evaporated off under reduced pressure, water is added to the residue and it is extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol from 95/5 to 80 / 20.
On recristallise le produit obtenu dans l'acétonitrile et on obtient 1,2 g (3,6 mmoles) de base.The product obtained is recrystallized from acetonitrile and 1.2 g (3.6 mmol) of base are obtained.
On la dissout dans un mélange de dichlorométhane et de méthanol, on ajoute 36 ml d'une solution 0,1 N d'acide chlorhydrique dans le propan-2-ol, on concentre le mélange sous pression réduite et on recristallise le solide dans le méthanol.It is dissolved in a mixture of dichloromethane and methanol, 36 ml of a 0.1 N solution of hydrochloric acid in propan-2-ol are added, the mixture is concentrated under reduced pressure and the solid is recrystallized from methanol.
On obtient finalement 1,18 g (3,22 mmoles) de chlorhydrate.1.18 g (3.22 mmol) of hydrochloride are finally obtained.
Point de fusion : 197-2000C. Melting point: 197-2000C.
Exemple 2 2-[[3-[[(2,3-Dihydro-1,4-benzodioxin-2-yl)méthyl]amino]- propyl]amino]pyrimidine-4-carboxamide, fumarate hémihydraté.Example 2 2 - [[3 - [[(2,3-Dihydro-1,4-benzodioxin-2-yl) methyl] amino] - propyl] amino] pyrimidine-4-carboxamide, fumarate hemihydrate.
On opère comme décrit dans l'exemple 1, en partant de chlorhydrate de 2, 3-dihydro-1, 4-benzodioxine-2-méthanamine et de 3-bromopropyl-N-phtalamide.The procedure is as described in Example 1, starting with 2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride and 3-bromopropyl-N-phthalamide.
Point de fusion : 185-187,5"C. Melting point: 185-187.5 "C.
Les composés de l'invention ont été soumis à des essais pharmacologiques qui ont mis en évidence leur intérêt comme substances à activités thérapeutiques.The compounds of the invention have been subjected to pharmacological tests which have demonstrated their advantage as substances with therapeutic activities.
Ainsi ils ont fait l'objet d'études quant à leur activité antagoniste des récepteurs adrénergiques du type a1 au niveau du bas appareil urinaire.Thus, they have been the subject of studies as to their antagonistic activity of the adrenergic receptors of the a1 type at the level of the lower urinary tract.
Leur activité in vitro a été étudiée sur l'urètre isolé de lapin.Their in vitro activity was studied on the isolated rabbit urethra.
On prépare des anneaux d'urètre de lapin adulte selon la méthode de Ueda et al., Eur. J. Pharmacol., (1984), 103, 249-254, puis, après sensibilisation à la noradrénaline, on détermine la courbe concentration-réponse à la phényléphrine, en absence puis en présence du composé à étudier.Adult rabbit urethra rings are prepared according to the method of Ueda et al., Eur. J. Pharmacol., (1984), 103, 249-254, then, after sensitization to noradrenaline, the concentration-response curve to phenylephrine is determined, in the absence and then in the presence of the compound to be studied.
On évalue la puissance de l'antagonisme a1-adrénergique de chaque composé par calcul du pA2, antilogarithme de la concentration molaire d'antagoniste en présence de laquelle la concentration d'agoniste doit être doublée pour engendrer le même effet qu'en son absence.The potency of the a1-adrenergic antagonism of each compound is evaluated by calculating pA2, an antilogarithm of the antagonist molar concentration in the presence of which the agonist concentration must be doubled to generate the same effect as in its absence.
Les pA2 des composés sont de l'ordre de 6 à 7,6.The pA2 of the compounds are of the order of 6 to 7.6.
L'activité in vivo des composés de l'invention a été étudiée quant à leur effet sur l'hypertonie urétrale engendrée par la stimulation du nerf hypogastrique chez le chat anesthé sié. The in vivo activity of the compounds of the invention has been studied as to their effect on urethral hypertonia caused by stimulation of the hypogastric nerve in anesthetized cats.
On anesthésie des chats mâles adultes au pentobarbital sodique, et on les prépare selon la méthode de Theobald, J.Adult male cats are anesthetized with sodium pentobarbital and prepared according to the method of Theobald, J.
Auton. Pharmac., (1983), 3, 235-239, afin d'obtenir une hypertonie urétrale par stimulation des fibres sympathiques du nerf hypogastrique. On note les réponses contractiles de l'urètre à la stimulation électrique du nerf hypogastrique avant et après administration intraveineuse des composés à étudier, à doses cumulatives de 1 à 1000 pg/kg. Auton. Pharmac., (1983), 3, 235-239, in order to obtain urethral hypertonia by stimulation of the sympathetic fibers of the hypogastric nerve. The contractile responses of the urethra to electrical stimulation of the hypogastric nerve are noted before and after intravenous administration of the compounds to be studied, at cumulative doses of 1 to 1000 pg / kg.
On évalue la puissance de l'antagonisme a,-adrénergique de chaque composé par calcul de la Dol501 dose qui inhibe de 50% l'hypertonie urétrale.The potency of the α, -adrenergic antagonism of each compound is evaluated by calculating the Dol501 dose which inhibits urethral hypertonia by 50%.
Les DI50 des composés de l'invention sont de l'ordre de 0,015 à 0,3 mg/kg.The ID 50 of the compounds of the invention are of the order of 0.015 to 0.3 mg / kg.
Les résultats des essais montrent que les composés de l'invention possèdent une activité antagoniste des récepteurs a,-adrénergiques des muscles lisses du bas appareil urinaire (urètre) stimulés par un agoniste a,-adrénergique (phényléphrine).The results of the tests show that the compounds of the invention have an antagonist activity of the α, -adrenergic receptors of the smooth muscles of the lower urinary tract (urethra) stimulated by an α, -adrenergic agonist (phenylephrine).
In vivo, ils inhibent l'hypertonie urétrale engendrée par la stimulation nerveuse sympathique.In vivo, they inhibit urethral hypertonia caused by sympathetic nerve stimulation.
Les composés de l'invention peuvent donc être utilisés pour le traitement symptomatique des maladies et affections impliquant une hyperactivité du système a-adrénergique au niveau du bas appareil urinaire, et notamment pour le traitement de l'hypertrophie bénigne de la prostate, de la dysurie, de la pollakiurie.The compounds of the invention can therefore be used for the symptomatic treatment of diseases and conditions involving hyperactivity of the a-adrenergic system in the lower urinary tract, and in particular for the treatment of benign prostatic hyperplasia, of dysuria , pollakiuria.
A cet effet ils peuvent être présentés sous toutes formes appropriées à l'administration entérale ou parentérale, associés à des excipients pharmaceutiques, par exemple sous forme de comprimés, dragées, gélules, capsules, solutions ou suspensions buvables ou injectables, suppositoires, étant dosés pour permettre une dose journalière de 0,5 à 100 mg de substance active. For this purpose they can be presented in all forms suitable for enteral or parenteral administration, associated with pharmaceutical excipients, for example in the form of tablets, dragees, capsules, capsules, solutions or suspensions, drinkable or injectable, suppositories, being dosed for allow a daily dose of 0.5 to 100 mg of active substance.
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9410884A FR2724383B1 (en) | 1994-09-13 | 1994-09-13 | 2-AMINOPYRIMIDINE-4-CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9410884A FR2724383B1 (en) | 1994-09-13 | 1994-09-13 | 2-AMINOPYRIMIDINE-4-CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| FR2724383A1 true FR2724383A1 (en) | 1996-03-15 |
| FR2724383B1 FR2724383B1 (en) | 1996-10-18 |
Family
ID=9466875
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FR9410884A Expired - Lifetime FR2724383B1 (en) | 1994-09-13 | 1994-09-13 | 2-AMINOPYRIMIDINE-4-CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
Country Status (1)
| Country | Link |
|---|---|
| FR (1) | FR2724383B1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997003071A1 (en) * | 1995-07-13 | 1997-01-30 | Knoll Aktiengesellschaft | Heterocyclylcarboxamide derivatives and their use as therapeutic agents |
| US7829545B2 (en) | 1998-05-06 | 2010-11-09 | Duke University | Method of treating bladder and lower urinary tract syndromes |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0084993A2 (en) * | 1982-01-21 | 1983-08-03 | Adir | Benzodioxine derivatives, processes for their preparation and pharmaceutical compositions containing them |
| US4405622A (en) * | 1980-10-16 | 1983-09-20 | Syntex (U.S.A.) Inc. | [1-(1,4-Benzodioxan-2-yl)-4-(4-aminopyrimidin-2-yl]piperazines useful as anti-depressants |
| GB2171997A (en) * | 1985-03-09 | 1986-09-10 | Pfizer Ltd | 4-Amino-6,7-dimethoxy-2-Piperazin-1-ylquinazoline derivatives |
| EP0435749A1 (en) * | 1989-12-28 | 1991-07-03 | Synthelabo | Derivatives of 2-aminopyrimidine-4-carboxamide, their preparation and therapeutic use |
| EP0480794A1 (en) * | 1990-10-02 | 1992-04-15 | Synthelabo | 2-Aminopyrimidine-4-carboxamide derivatives, their preparation and therapeutic use |
| EP0511072A1 (en) * | 1991-04-24 | 1992-10-28 | Synthelabo | 2-Aminopyrimidin-4-carboxamid derivatives, their preparation and their therapeutical use |
| WO1993017017A1 (en) * | 1992-02-27 | 1993-09-02 | Janssen Pharmaceutica N.V. | [(benzodioxan, benzofuran or benzopyran)-alkylamino] alkyl substituted guanidines as selective vascoconstrictors |
-
1994
- 1994-09-13 FR FR9410884A patent/FR2724383B1/en not_active Expired - Lifetime
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4405622A (en) * | 1980-10-16 | 1983-09-20 | Syntex (U.S.A.) Inc. | [1-(1,4-Benzodioxan-2-yl)-4-(4-aminopyrimidin-2-yl]piperazines useful as anti-depressants |
| EP0084993A2 (en) * | 1982-01-21 | 1983-08-03 | Adir | Benzodioxine derivatives, processes for their preparation and pharmaceutical compositions containing them |
| GB2171997A (en) * | 1985-03-09 | 1986-09-10 | Pfizer Ltd | 4-Amino-6,7-dimethoxy-2-Piperazin-1-ylquinazoline derivatives |
| EP0435749A1 (en) * | 1989-12-28 | 1991-07-03 | Synthelabo | Derivatives of 2-aminopyrimidine-4-carboxamide, their preparation and therapeutic use |
| US5164397A (en) * | 1989-12-28 | 1992-11-17 | Synthelabo | 2-aminopyrimidine-4-carboxamide derivatives, their preparation and their application in urinary therapeutics |
| EP0480794A1 (en) * | 1990-10-02 | 1992-04-15 | Synthelabo | 2-Aminopyrimidine-4-carboxamide derivatives, their preparation and therapeutic use |
| EP0511072A1 (en) * | 1991-04-24 | 1992-10-28 | Synthelabo | 2-Aminopyrimidin-4-carboxamid derivatives, their preparation and their therapeutical use |
| WO1993017017A1 (en) * | 1992-02-27 | 1993-09-02 | Janssen Pharmaceutica N.V. | [(benzodioxan, benzofuran or benzopyran)-alkylamino] alkyl substituted guanidines as selective vascoconstrictors |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997003071A1 (en) * | 1995-07-13 | 1997-01-30 | Knoll Aktiengesellschaft | Heterocyclylcarboxamide derivatives and their use as therapeutic agents |
| US5935973A (en) * | 1995-07-13 | 1999-08-10 | Knoll Aktiengesellschaft | Heterocyclcarboxamide derivatives and their use as therapeutic agents |
| US7829545B2 (en) | 1998-05-06 | 2010-11-09 | Duke University | Method of treating bladder and lower urinary tract syndromes |
| US7858312B2 (en) | 1998-05-06 | 2010-12-28 | Duke University | Method of treating bladder and lower urinary tract syndromes |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2724383B1 (en) | 1996-10-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0522915B1 (en) | Pyrimidine-4-carboxamide derivatives, their preparation and their use in therapeutics | |
| EP0435749B1 (en) | Derivatives of 2-aminopyrimidine-4-carboxamide, their preparation and therapeutic use | |
| EP0480794A1 (en) | 2-Aminopyrimidine-4-carboxamide derivatives, their preparation and therapeutic use | |
| EP0520883B1 (en) | 2-Aminopyrimidin-4-carboxamide derivatives, their preparation and their use in therapy | |
| EP0447292A1 (en) | 4-Aminomethyl-piperidine derivatives, their preparation and therapeutic application | |
| EP0527081B1 (en) | Substituted 3-piperazinylalkyl-2,3-dihydro-4H-1,3-benzoxazine-4-ones, their preparation and their therapeutical use | |
| EP0610140B1 (en) | 2-[4-(4-Azolylbutyl)-1-piperazinyl]-5-hydroxypyrimidin derivatives, their preparation and their use as medicines | |
| FR2675799A1 (en) | 2-AMINOPYRIMIDINE-4-CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THERAPEUTIC USE THEREOF | |
| EP0301936B1 (en) | Piperidine derivatives, their preparation and their therapeutical use | |
| FR2696177A1 (en) | Piperidine derivatives, their preparation and their therapeutic application. | |
| BG62349B2 (en) | N-substituted derivatives of 3-azabicyclo [3.2.0] heptane as neuroleptics | |
| FR2724383A1 (en) | 2-Amino-pyrimidine-4-carboxamide derivs. are alpha 1 adrenergic receptor antagonists for urinary system | |
| EP0119107B1 (en) | Derivatives of bicyclo(4.2.0)octatriene-1,3,5, their preparation and their therapeutical application | |
| EP0577470B1 (en) | 2-Amino-N-[[[4-(aminocarbonyl)pyrimidin-2-yl]amino]alkyl]-pyrimidine-4-carboxamide derivates, their preparation and their use in therapeutics | |
| EP0101380A2 (en) | N-substituted nicotinamide-1-oxide, its salts, process for their preparation and pharmaceutical compositions containing them | |
| EP0520882B1 (en) | 2-Aminopyrimidin-4-carboxamide derivatives, their preparation and their application in therapy | |
| EP0522914A1 (en) | 2-Piperidinylpyrimidin-4-carboxamide derivatives, their preparation and their application in therapy | |
| EP0067094A1 (en) | Heterocyclic derivatives of amidoximes, their preparation and therapeutic uses | |
| EP0347305B1 (en) | [(Aryl-4-piperazinyl-1)-2-ethoxy]-3 p cymene, the ortho-, meta-, para-monosubstituted or disubstituted phenyl ring derivatives, process for their preparation and medicaments containing the same as the active principle | |
| EP0625514B1 (en) | 2-Amino-pyrazin-5-carboxamid derivatives, their preparation and their use in therapy | |
| EP0594484A1 (en) | 2-Aminopyrimidin-4-carboxamide derivatives, their preparation and their use in therapy | |
| FR2724382A1 (en) | Piperidinyl pyrimidine carboxamide(s) | |
| EP0101379A1 (en) | Benzamides, their salts, process for their preparation and pharmaceutical compositions containing them | |
| FR2691148A1 (en) | New 2-amino:pyrimidine-4-carboxamide derivs. | |
| FR2703355A1 (en) | 2-Aminopyrimidine-4-carboxamide derivatives, their preparation and their application in therapeutics |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| TP | Transmission of property | ||
| CD | Change of name or company name |