BRPI0903803B1 - COMPOUND, PREPARATION PROCESS, PHARMACEUTICAL COMPOSITION AND USE OF COMPOUNDS - Google Patents
COMPOUND, PREPARATION PROCESS, PHARMACEUTICAL COMPOSITION AND USE OF COMPOUNDS Download PDFInfo
- Publication number
- BRPI0903803B1 BRPI0903803B1 BRPI0903803-5A BRPI0903803A BRPI0903803B1 BR PI0903803 B1 BRPI0903803 B1 BR PI0903803B1 BR PI0903803 A BRPI0903803 A BR PI0903803A BR PI0903803 B1 BRPI0903803 B1 BR PI0903803B1
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- BR
- Brazil
- Prior art keywords
- alkyl
- compound
- compounds
- formula
- methyl
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 72
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 12
- -1 (2- (benzo [d] [1,3] dioxol-5-carbonyl) -1h-indol-3-yl) methyl Chemical group 0.000 claims abstract description 40
- 239000000203 mixture Substances 0.000 claims abstract description 38
- SXWTYPIIBMLMNG-MRXNPFEDSA-N (3r)-3-[[2-(1,3-benzodioxole-5-carbonyl)-1h-indol-3-yl]methyl]-1-methylpiperazine-2,5-dione Chemical compound O=C1N(C)CC(=O)N[C@@H]1CC1=C(C(=O)C=2C=C3OCOC3=CC=2)NC2=CC=CC=C12 SXWTYPIIBMLMNG-MRXNPFEDSA-N 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 238000011282 treatment Methods 0.000 claims abstract description 14
- 238000011321 prophylaxis Methods 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 6
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- 125000000217 alkyl group Chemical group 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 102000011016 Type 5 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 claims description 11
- 108010037581 Type 5 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 claims description 11
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- 230000002040 relaxant effect Effects 0.000 claims description 11
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 8
- 238000009109 curative therapy Methods 0.000 claims description 7
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 6
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- 201000001881 impotence Diseases 0.000 claims description 6
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
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- 102400001282 Atrial natriuretic peptide Human genes 0.000 claims description 4
- 101800001890 Atrial natriuretic peptide Proteins 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 4
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 4
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 claims description 4
- 229960004373 acetylcholine Drugs 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
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- NSQLIUXCMFBZME-MPVJKSABSA-N carperitide Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)=O)[C@@H](C)CC)C1=CC=CC=C1 NSQLIUXCMFBZME-MPVJKSABSA-N 0.000 claims description 4
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- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 claims description 2
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- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 claims description 2
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- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 claims 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 3
- 229910018162 SeO2 Inorganic materials 0.000 claims 2
- 239000002131 composite material Substances 0.000 claims 2
- SXWTYPIIBMLMNG-INIZCTEOSA-N (3s)-3-[[2-(1,3-benzodioxole-5-carbonyl)-1h-indol-3-yl]methyl]-1-methylpiperazine-2,5-dione Chemical group O=C1N(C)CC(=O)N[C@H]1CC1=C(C(=O)C=2C=C3OCOC3=CC=2)NC2=CC=CC=C12 SXWTYPIIBMLMNG-INIZCTEOSA-N 0.000 claims 1
- SXWTYPIIBMLMNG-UHFFFAOYSA-N 3-[[2-(1,3-benzodioxole-5-carbonyl)-1h-indol-3-yl]methyl]-1-methylpiperazine-2,5-dione Chemical group O=C1N(C)CC(=O)NC1CC1=C(C(=O)C=2C=C3OCOC3=CC=2)NC2=CC=CC=C12 SXWTYPIIBMLMNG-UHFFFAOYSA-N 0.000 claims 1
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 38
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
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Landscapes
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Abstract
composto, isômero do composto, processo de sua preparação, composto intermediário, composição farmacêutica; medicamento, uso dos compostos e métodos de tratamento. a presente invenção se refere a uma série de derivados de 2 - (3 - metilenodioxi) - benzoil indol, suas misturas, seus sais farmaceuticamente aceitáveis, seus enantiômeros, as composições farmacêuticas que os contêm, aos processos de preparação, ao uso no tratamento profilático e/ou curativo para disfunção sexual. mais especificamente, a invenção trata dos derivados (r) - 3 - ( (2 - (benzo[d] [1,3] dioxol - 5 - carbonil) - 1h - indol - 3 - il) metil) - 1 - metilpiperazina - 2,5 - diona, (s) - 3 - ( (2 - (benzo [d] [1,3] dioxol - 5 - carbonil) - 1h - indol - 3 - il) metil) - 1 - metilpiperazina - 2,5 - diona.compound, isomer of compound, process of its preparation, intermediate compound, pharmaceutical composition; medicine, use of compounds and methods of treatment. The present invention relates to a series of 2- (3-methylenedioxy) benzoyl indole derivatives, mixtures thereof, pharmaceutically acceptable salts thereof, enantiomers, pharmaceutical compositions containing them, preparation processes, use in prophylactic treatment and / or dressing for sexual dysfunction. more specifically, the invention deals with the derivatives (r) - 3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1h-indol-3-yl) methyl) -1-methylpiperazine 2,5 - dione, (s) - 3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1h-indol-3-yl) methyl) -1-methylpiperazine-2, 5 - diona.
Description
COMPOSTO, PROCESSO DE PREPARAÇÃO, COMPOSIÇÃO FARMACÊUTICA ECOMPOUND, PREPARATION PROCESS, PHARMACEUTICAL COMPOSITION AND
USO DOS COMPOSTOSUSE OF COMPOUNDS
Campo da InvençãoField of the Invention
A presente invenção se refere a uma série de derivados de 2-(3-metilenodioxi)-benzoil indol, suas misturas em quaisquer proporções, seus sais farmaceuticamente aceitáveis, seus enantiômeros, composições farmacêuticas que os contêm, aos processos para suas de preparações e intermediários, assim como aos seus usos no tratamento profilático e/ou curativo para disfunção sexual. Mais especificamente, a presente invenção se refere a derivados (R)-3-((2-(benzo[d][1,3]dioxol5-carbonil)-lH-indol-3-il)metil)-l-metilpiperazina-2,5-diona e (Sj-3-((2-(benzo[d][1,3]dioxol-5-carbonil)-1H-indol-3il)metil)-l-metilpiperazina-2,5-diona.The present invention relates to a series of 2- (3-methylenedioxy) benzoyl indole derivatives, their mixtures in any proportions, their pharmaceutically acceptable salts, their enantiomers, pharmaceutical compositions containing them, the processes for their preparation and intermediates , as well as its uses in prophylactic and / or curative treatment for sexual dysfunction. More specifically, the present invention relates to (R) -3 - ((2- (benzo [d] [1,3] dioxol5-carbonyl) -1H-indol-3-yl) methyl) -1-methylpiperazine derivatives 2,5-dione and (Sj-3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3yl) methyl) -1-methylpiperazine-2,5-dione .
A presente invenção também contempla um método de tratamento profilático e/ou curativo para disfunção erétil utilizando derivados de 2-(3-metilenodioxi)-benzoil indol e, mais particularmente, os derivados (R}-3-((2(benzo[d][1,3]dioxol-5-carbonil)-1H-indol-3-il)metil)-1metilpiperazina-2,5-diona, e seu enantiômero (S)-3-((2(benzo[d][1,3]dioxol-5-carbonil)-lH-indol-3-il)metil)-1metilpiperazina-2,5-diona.The present invention also contemplates a prophylactic and / or curative treatment method for erectile dysfunction using 2- (3-methylenedioxy) -benzoyl indole derivatives and, more particularly, the (R} -3 - ((2 (benzo [d ] [1,3] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1methylpiperazine-2,5-dione, and its (S) -3 - ((2 (benzo [d] [ 1.3] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1methylpiperazine-2,5-dione.
A presente invenção abrange esses compostos e suas misturas em quaisquer proporções, seus sais farmaceuticamente aceitáveis, as composições farmacêuticas que os contêm, assimThe present invention covers these compounds and their mixtures in any proportions, their pharmaceutically acceptable salts, the pharmaceutical compositions containing them, as well as
2/29 como seus usos como estimuladores de expressão de NO em tecidos e como inibidor seletivo da enzima fosfodiesterase, em particular da fosfodiesterase do tipo 5 (PDE-5).2/29 as its uses as stimulators of NO expression in tissues and as a selective inhibitor of the enzyme phosphodiesterase, in particular phosphodiesterase type 5 (PDE-5).
Fundamentos da InvençãoFundamentals of the Invention
Até a época do aparecimento do primeiro tratamento por via oral, a impotência sexual masculina era tratada por meio de injeções intracavernosas e outros meios, devido, particularmente, as inúmeras dúvidas decorrentes das reações adversas que a administração via oral poderia acarretar no ser humano. Papaverina e pentoxifilina, por exemplo, eram utilizadas no tratamento da disfunção erétil, justamente por injeções intracavernosas. Outros meios de tratamento, menos eficazes, eram, por exemplo, as terapias psicológicas e os implantes cirúrgicos.Until the time when the first oral treatment appeared, male sexual impotence was treated through intracavernous injections and other means, due, in particular, to the innumerable doubts arising from the adverse reactions that oral administration could cause in humans. Papaverine and pentoxifylline, for example, were used to treat erectile dysfunction, precisely by intracavernous injections. Other less effective means of treatment were, for example, psychological therapies and surgical implants.
tratamento por via oral é o mais aceitável pelo homem e surgiu a partir de pesquisas clínicas com certos inibidores de cGMP PDE, mais especificamente, a PDE-5. O precursor desses compostos foi o 5-[2-etoxi-5-(4metilpiperazinilsulfonil)fenil]-l-metil-3-n-propil-l,6-diidro7H-pirazolo[4,3-d]pirimidin-7-ona, ou sildenafila, com propriedades vasodilatadora e potencializadora dos efeitos do fator relaxante derivado do endotélio (EDRF) e nitrovasodilatadores. A sildenafila é o princípio ativo do medicamento Viagra®.oral treatment is the most acceptable for man and arose from clinical research with certain cGMP PDE inhibitors, more specifically, PDE-5. The precursor to these compounds was 5- [2-ethoxy-5- (4methylpiperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro7H-pyrazolo [4,3-d] pyrimidin-7-one , or sildenafil, with vasodilating and potentiating properties of the effects of the endothelium-derived relaxing factor (EDRF) and nitrovasodilators. Sildenafil is the active ingredient in Viagra®.
Posteriormente, outros compostos inibidores da PDE-5 foram desenvolvidos e estão citados em várias publicações daLater, other PDE-5 inhibitor compounds were developed and are cited in several publications of the
3/29 literatura especializada, assim como em publicações de patentes. Os mais conhecidos são a vardenafila, princípio ativo do medicamento Levitra®, e a tadalafila, princípio ativo do medicamento Cialis®.3/29 specialized literature, as well as patent publications. The best known are vardenafil, the active ingredient in Levitra®, and tadalafil, the active ingredient in Cialis®.
Uma outra classe de compostos inibidores específicos deAnother class of specific inhibitor compounds of
PDE-5 é citada na publicação WO 03/000691. Nesta, encontra-se revelada uma série de compostos derivados de β-carbolina, os quais são preparados a partir dos compostos de fórmula (A) e 10 (B) abaixo, revelados, respectivamente, nas patentes americanas US 6,117,881 e US 5,859,006.PDE-5 is cited in publication WO 03/000691. In this, a series of compounds derived from β-carboline is disclosed, which are prepared from the compounds of formula (A) and 10 (B) below, disclosed, respectively, in US patents US 6,117,881 and US 5,859,006.
Os compostos da presente invenção, derivados de 2—(3 — metilenodioxi)-benzoil indol, podem ser utilizados no 25 tratamento de disfunção sexual e, em uma concretização, podem ser utilizados como estimuladores de expressão de NO em tecidos e, em outra concretização, podem ser utilizados como inibidores seletivos da enzima fosfodiesterase, em particular da fosfodiesterase do tipo 5 (PDE-5).The compounds of the present invention, derived from 2— (3 - methylenedioxy) benzoyl indole, can be used in the treatment of sexual dysfunction and, in one embodiment, can be used as stimulators of NO expression in tissues and, in another embodiment , can be used as selective inhibitors of the phosphodiesterase enzyme, in particular phosphodiesterase type 5 (PDE-5).
Descrição da Invenção indol, suas misturas, sais farmaceuticamente aceitáveis, seusDescription of the indole invention, its mixtures, pharmaceutically acceptable salts, its
4/29 isômeros e composições farmacêuticas que os contêm, eficazes no tratamento profilático e/ou curativo da e/ou erétil. Em uma concretização, os compostos possuem propriedades vasodilatadora e relaxante muscular, em outra concretização, os composto estimulam a expressão de4/29 isomers and pharmaceutical compositions containing them, effective in the prophylactic and / or curative treatment of and / or erectile. In one embodiment, the compounds have vasodilating and muscle relaxing properties, in another embodiment, the compounds stimulate the expression of
NO em tecidos e em outra concretização os compostos inibem seletivamente fosfodiesterase, particularmente fosfodiesterase do tipo 5 (PDE-5). Preferencialmente, os novos compostos derivados de 2-(3-metilenodioxi)-benzoil indol são derivados (R)-3-((2-(benzo[d][1,3]dioxol-5-carbonil)-lH-indol3-((2-(benzo[d][1,3]dioxol-5-carbonil)-lH-indol-3-il)metil)-1metilpiperazina-2,5-diona e as suas misturas em quaisquerNO in tissues and in another embodiment the compounds selectively inhibit phosphodiesterase, particularly phosphodiesterase type 5 (PDE-5). Preferably, the new compounds derived from 2- (3-methylenedioxy) -benzoyl indole are derived (R) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol3- ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1methylpiperazine-2,5-dione and mixtures thereof in any
É também objetivo da presente invenção prover processos de preparação dos derivados de 2-(3-metilenodioxi)-benzoil indol e suas misturas, mais especificamente, derivados (2?)-3-((2(benzo[d][1,3]dioxol-5-carbonil)-lH-indol-3-il)metil)-1metilpiperazina-2,5-diona, seu enantiômero (S)-3-((2(benzo[d] [1,3]dioxol-5-carbonil)-lH-indol-3-il)metil)-1metilpiperazina-2,5-diona e as suas misturas em quaisquer proporções.It is also an objective of the present invention to provide processes for the preparation of 2- (3-methylenedioxy) -benzoyl indole derivatives and mixtures thereof, more specifically, (2?) - 3 - ((2 (benzo [d] [1,3 ] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1methylpiperazine-2,5-dione, its (S) -3 - ((2 (benzo [d] [1,3] dioxol- enantiomer) 5-carbonyl) -1H-indol-3-yl) methyl) -1methylpiperazine-2,5-dione and mixtures thereof in any proportions.
Em alguns aspectos, a presente invenção provê composiçõesIn some respects, the present invention provides compositions
5/29 farmacêuticas compreendendo como ingrediente ativo uma quantidade eficaz de um ou mais derivados de 2-(3metilenodioxi)-benzoil indol, suas mistura em quaisquer proporções ou seus sais farmaceuticamente aceitáveis e excipientes farmaceuticamente aceitáveis. Mais especificamente, o ingrediente ativo é derivado (R)-3-((2(benzo[d][1,3]dioxol-5-carbonil)-lH-indol-3-il)metil)-1metilpiperazina-2,5-diona, seu enantiômero (5)-3-((2(benzo[d][1,3]dioxol-5-carbonil)-lH-indol-3-il)metil)-1metilpiperazina-2,5-diona ou suas misturas em quaisquer proporções.Pharmaceuticals comprising as an active ingredient an effective amount of one or more derivatives of 2- (3-methylenedioxy) benzoyl indole, their mixtures in any proportions or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients. More specifically, the active ingredient is derived (R) -3 - ((2 (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1methylpiperazine-2,5 -dione, its (5) -3 - ((2 (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1methylpiperazine-2,5-dione enantiomer or mixtures in any proportions.
Em alguns aspectos, a presente invenção provê um medicamento compreendendo como ingrediente ativo uma quantidade terapeuticamente eficaz de um ou mais derivados de 2-(3-metilenodioxi)-benzoil indol, suas misturas em quaisquer proporções ou seus sais farmaceuticamente aceitáveis. Mais especificamente, ditos medicamentos contêm como ingrediente ativo derivados ('J?)-3-((2-(benzo[d][l,3]dioxol-5-carbonil)-lHindol-3-il)metil)-l-metilpiperazina-2,5-diona, seu enantiômero (S)-3 -((2-(benzo[d] [1,3]dioxol-5-carbonil)-lH-indol-3il)metil)-l-metilpiperazina-2,5-diona ou suas misturas em quaisquer proporções.In some respects, the present invention provides a medicament comprising as a therapeutically effective amount of one or more derivatives of 2- (3-methylenedioxy) benzoyl indole, their mixtures in any proportions or their pharmaceutically acceptable salts. More specifically, said drugs contain ('J?) - 3 - ((2- (benzo [d] [1,3, dioxol-5-carbonyl) -lHindol-3-yl) methyl) -l- as an active ingredient. methylpiperazine-2,5-dione, its (S) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3yl) methyl) -l-methylpiperazine enantiomer- 2,5-dione or its mixtures in any proportions.
Em outro aspecto, a presente invenção provê o uso dos derivados de 2-(3-metilenodioxi)-benzoil indol, suas misturas em quaisquer proporções ou seus sais farmaceuticamente aceitáveis, para o tratamento curativo e/ou profilático, por via oral, da disfunção erétil e/ou sexual no homem. MaisIn another aspect, the present invention provides for the use of 2- (3-methylenedioxy) benzoyl indole derivatives, their mixtures in any proportions or their pharmaceutically acceptable salts, for the curative and / or prophylactic treatment, orally, of the dysfunction erectile and / or sexual in men. More
6/29 especificamente, o derivados de 2-(3-metilenodioxi)-benzoil indol é o derivado (R)-3-((2-(benzo[d][1,3]dioxol-5-carbonil)lH-indol-3-il)metil)-l-metilpiperazina-2,5-diona— e/ou seu enantiômero (Sj-3-((2-(benzo[d][1,3]dioxol-5-carbonil)-1Hindol-3-il)metil)-l-metilpiperazina-2,5-diona.6/29 specifically, the 2- (3-methylenedioxy) benzoyl indole derivative is the (R) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) 1H-indole derivative -3-yl) methyl) -l-methylpiperazine-2,5-dione— and / or its enantiomer (Sj-3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1Hindol -3-yl) methyl) -1-methylpiperazine-2,5-dione.
Breve Descrição das FigurasBrief Description of the Figures
Figura 1 - curva de concentração-resposta cumulativa do efeito relaxante do composto BL-122 (A) e do veículo (B) sobre o corpo cavernoso isolado de coelho. Os valores representam a média ± E.P.M. de 8 preparações, obtidas de 6 animais. Os asteriscos indicam o nível de significância *P<0.05, **P<0.01, comparado ao corpo cavernoso com 0% de relaxamento inicial, após prévia contração pela fenilefrina (3- 10 μΜ) correspondendo a 1,7 ± 0.07g de tensão.Figure 1 - Cumulative concentration-response curve of the relaxing effect of compound BL-122 (A) and vehicle (B) on the isolated cavernous body of a rabbit. Values represent the mean ± E.P.M. of 8 preparations, obtained from 6 animals. Asterisks indicate the level of significance * P <0.05, ** P <0.01, compared to the corpora cavernosa with 0% initial relaxation, after previous contraction by phenylephrine (3- 10 μΜ) corresponding to 1.7 ± 0.07g of tension .
Figura 2 - curva de dose-resposta cumulativa quanto ao efeito relaxante do composto BL-122 (A) e do veículo (B) sobre a aorta isolada de rato.Figure 2 - Cumulative dose-response curve for the relaxing effect of compound BL-122 (A) and vehicle (B) on the isolated rat aorta.
Figura 3 - teste de comportamento sexual de ratos sob efeito do composto BL-122 e veículo (salina contendo 10% de DMSO) administrados por via oral, na dose de 10 mg/kg. O parâmetro utilizado é referente às ereções espontâneas. Os resultados estão expressos como a média ± E.P.M. (erro padrão da média) de 9 animais. As diferenças estatísticas foram avaliadas através da análise de variância (ANOVA) seguida pelo teste de Newmann-Keuls. Valores de P menores que 0,05 (P < 0,05) foram considerados como indicativos de significância.Figure 3 - sexual behavior test of rats under the effect of compound BL-122 and vehicle (saline containing 10% DMSO) administered orally, at a dose of 10 mg / kg. The parameter used refers to spontaneous erections. The results are expressed as the mean ± E.P.M. (standard error of the mean) of 9 animals. Statistical differences were assessed using analysis of variance (ANOVA) followed by the Newmann-Keuls test. P values less than 0.05 (P <0.05) were considered as indicative of significance.
7/297/29
Descrição Detalhada da InvençãoDetailed Description of the Invention
A presente invenção fornece derivados de 2-(3metilenodioxi)-benzoil indol com estruturas de fórmula (I) (l)The present invention provides 2- (3-methylenedioxy) benzoyl indole derivatives with structures of formula (I) (1)
seus sais e solvatos, tais como hidratos, onde:its salts and solvates, such as hydrates, where:
R1 representa hidrogênio, halogênio, Ci_6 alquil ou O-R', ondeR 1 represents hydrogen, halogen, alkyl CI_ 6 or O-R 'where
R' representa hidrogênio ou alquilas inferiores;R 'represents hydrogen or lower alkyls;
n representa um número variando de 0 a 4;n represents a number ranging from 0 to 4;
R2 representa hidrogênio, Ci_6 alquil, C2-6 alquenil, C2_6 alquinil, haloCi_6alquil, C3-8 cicloalquil, C3-8 cicloalquilCi_3 alquil, aril Ci_3 alquil ou heteroaril Ci_3 alquil;R 2 is hydrogen, CI_ 6 alkyl, C 2 -6 alkenyl, C 2 _ 6 alkynyl, haloCi_ 6 alkyl, C 3-8 cycloalkyl, C 3-8 cicloalquilCi_ 3 alkyl, aryl alkyl or heteroaryl CI_ 3 CI_ 3 alkyl;
R3 representa hidrogênio, Ci_3 alquil ou R2 e R3 juntos representam um 3- ou 4- substituintes de um anel alquil ou alquenil;R 3 represents hydrogen, alkyl CI_ 3 or R 2 and R 3 together represent a 3- or 4- substituent of an alkyl or alkenyl ring;
R4 representa hidrogênio, Ci-6 alquil, C2_6 alquenil, C2_6 alquinil, haloCi_6alquil, C3_8 cicloalquil, C3-8 cicloalquilCi_3 alquil, aril Ci_3 alquil ou heteroaril Ci_3 alquil.R 4 represents hydrogen, Ci-6 alkyl, C2 _6 alkenyl, C2 _6 alkynyl, haloCi_6alquil, C 3 _ 8 cycloalkyl, C 3-8 cicloalquilCi_ 3 alkyl, aryl alkyl or heteroaryl CI_ 3 CI_ 3 alkyl.
R5 representa hidrogênio ou O-R', onde R' representa hidrogênio ou alquilas inferiores.R 5 represents hydrogen or O-R ', where R' represents hydrogen or lower alkyls.
8/298/29
Em R2 e R4, o termo aril do grupo aril Ci_3 alquil, representa o grupo fenil ou fenil substituído uma ou mais vezes por halogênio (por exemplo 1, 2 ou 3) ou Ci-6 alquil, Ci-6 alcóxi ou metilenedioxi. O termo heteroaril do grupo hetroaril Ci_3 alquil, representa o grupo furil ou piridil, opcionalmente substituídos uma ou mais vezes por halogênio, Ci6 alquil ou Ci_6 alcóxi. O termo C3_8 cicloalquil do grupo C3_8 cicloalquil Ci_3 alquil, representa um anel monocíclico contendo de 3 a 8 átomos de carbono. Exemplos adequados de anel cicloalquil incluem os anéis C3_6 cicloalquil: ciclopropil, ciclobutil, ciclopentil e ciclo hexil.In R 2 and R 4, the term aryl the aryl CI_ 3 -alkyl, represents phenyl or phenyl substituted one or more times by halogen (e.g. 1, 2 or 3) or Ci-6 alkyl, Ci-6 alkoxy , or methylenedioxy. The term heteroaryl hetroaril CI_ 3 alkyl group, represents pyridyl or furyl group, optionally substituted one or more times by halogen, Ci 6 alkyl or alkoxy CI_ 6. The term C 3 _ 8 cycloalkyl group of C 3 _ 8 cycloalkyl alkyl CI_ 3 represents a monocyclic ring containing from 3 to 8 carbon atoms. Examples of suitable cycloalkyl ring include the rings C 3 _ 6 cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Nas definições acima, o termo alquil representa a cadeia principal alquila ou, quando disponível, uma cadeia ramificada alquila dos grupos que ele representa. Por exemplo, o grupo Ci_ 4 alquil representa: metil, etil, n-propil, i-propil, n-butil, s-butil e t-butil. O termo alquenil empregado nas definições acima inclui grupos alquenil de cadeias reta e ramificada, como os grupos vinil e alil. 0 termo alquinil empregado nas definições acima inclui grupos alquinil de cadeias reta e ramificada, como o acetileno. O termo halogênio representa átomos de flúor, cloro, bromo ou iodo. O termo halo Ci~ 6alquil significa um grupo alquil conforme definido acima, contendo de um a seis átomos de carbono, substituído por um ou mais átomos de halogênio, por exemplo, 1, 2 ou 3.In the above definitions, the term alkyl represents the main alkyl chain or, when available, a branched alkyl chain of the groups it represents. For example, the C1-4 alkyl group represents: methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. The term alkenyl used in the definitions above includes straight and branched chain alkenyl groups, such as vinyl and allyl groups. The term alkynyl used in the above definitions includes straight and branched chain alkynyl groups, such as acetylene. The term halogen represents fluorine, chlorine, bromine or iodine atoms. The term C1-6alkyl halo means an alkyl group as defined above, containing from one to six carbon atoms, substituted by one or more halogen atoms, for example, 1, 2 or 3.
Quando R1 representar um átomo de halogênio ou um grupo OR' ou um grupo Ci-6 alquil, este substituinte pode estar ligado em qualquer posição disponível da porção fenil do indol e em mais de uma posição.When R 1 represents a halogen atom or an OR 'group or a C1-6 alkyl group, this substituent can be attached in any available position of the phenyl portion of the indole and in more than one position.
podem conter um ou maismay contain one or more
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Os compostos de fórmula (I) centros assimétricos, assim podem existir enantiômeros e/ou diastereoisômeros.The compounds of formula (I) are asymmetric centers, so there can be enantiomers and / or diastereoisomers.
Em particular, na fórmula (I) acima um centro quiral é evidenciado com um asterisco. Isto implica que a invenção inclui a mistura dos enantiômeros e suas formas individuais separadas.In particular, in formula (I) above a chiral center is highlighted with an asterisk. This implies that the invention includes mixing the enantiomers and their separate individual forms.
Os compostos de fórmula (I) podem existir com diferentes formas tautoméricas e a invenção inclui a mistura das formas tautoméricas e suas formas individuais separadas.The compounds of formula (I) can exist in different tautomeric forms and the invention includes mixing the tautomeric forms and their separate individual forms.
Os sais farmaceuticamente aceitáveis dos compostos de fórmula (I) , os quais possuem um centro básico, podem ser formados pela adição de ácidos farmaceuticamente aceitáveis. Alguns exemplos incluem sais de: cloridrato, bromoidrato, sulfato ou bisulfato, fosfato ou hidrogênio-fosfato, acetato, benzoato, succinato, fumarato, maleato, lactato, citrato, tartarato, gluconato, metassulfonato, benzenossulfonato e ptoluenossulfonato. Os compostos de fórmula (I) podem fornecer sais de metais farmaceuticamente aceitáveis, em particularPharmaceutically acceptable salts of the compounds of formula (I), which have a basic center, can be formed by the addition of pharmaceutically acceptable acids. Some examples include salts of: hydrochloride, bromohydrate, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, metasulfonate, benzenesulfonate and ptoluenesulfonate. The compounds of formula (I) can provide pharmaceutically acceptable metal salts, in particular
hidrogênios e R2 é um grupo Ci_6 aquil. Mais especificamente, os derivados (R)-3-((2-(benzo[d][1,3]dioxol-5-carbonil)-lH-indol10 / 29hydrogens and R 2 is a group CI_ 6 Aquil. More specifically, derivatives (R) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol10 / 29
3-il)metil)-l-metilpiperazina-2,5-diona e seu enantiômero (S)3- ( (2- (benzo [d] [1,3]dioxol-5-carbonil) -lH-indol-3-il)inetil) -1metilpiperazina-2,5-diona, respectivamente compostos de fórmula Ib e Ic abaixo:3-yl) methyl) -1-methylpiperazine-2,5-dione and its (S) enantiomer 3- ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indole-3 -yl) inethyl) -1methylpiperazine-2,5-dione, respectively compounds of formula Ib and Ic:
presente intermediários para acimapresent intermediaries for above
invençãoinvention
a preparação dosthe preparation of
ExemplosExamples
contempla compostos de compostos compostos fórmulacontemplates compounds of compound compounds formula
II
intermediários de fórmula II:intermediates of formula II:
e suas misturas, incluindo misturas racêmicas ou sais ou / 29 solvatos destes compostos, onde R1, R3 e R4 são definidos na reivindicação 1, alq representa o grupo Ci_6a.lqu.il e Hal representa um átomo de halogênio.and mixtures thereof, including racemic mixtures or salts or solvates of these compounds, where R 1 , R 3 and R 4 are defined in claim 1, al represents the group C1-6a.lqu.il and Hal represents a halogen atom.
Outros exemplos de compostos intermediários são os de fórmula (III):Other examples of intermediate compounds are those of formula (III):
e suas misturas, incluindo misturas racêmicas ou sais ou solvatos destes compostos, onde R1, R2, R3 R4, R5, e n são definidos na reivindicação 1, alq representa o grupo Ci_6alquil e Hal representa um átomo de halogênio.and mixtures thereof, including racemic mixtures or salts or solvates of these compounds, where R 1 , R 2 , R 3 R 4 , R 5 , and n are defined in claim 1, al represents the C1-6 alkyl group and Hal represents a halogen atom.
Vantajosamente, o derivado (R)-3-((2-(benzo[d][1,3]dioxol5-carbonil)-lH-indol-3-il)metil)-l-metilpiperazina-2,5-diona, segundo a presente invenção pode ser preparado a partir de (6R, trans)-6-(1,3-benzodioxol-5-il)-2,3,6,7,12,12a-hexahidro2-metil-pirazino[1',2':1,6]pirido[3,4-b]indol-1,4-diona, conforme reação abaixo (Procedimento 1):Advantageously, the (R) -3 - ((2- (benzo [d] [1,3] dioxol5-carbonyl) -1H-indol-3-yl) methyl) -1-methylpiperazine-2,5-dione derivative, according to the present invention can be prepared from (6R, trans) -6- (1,3-benzodioxol-5-yl) -2,3,6,7,12,12a-hexahidro2-methyl-pyrazino [1 ' , 2 ': 1,6] pyrido [3,4-b] indole-1,4-dione, as shown below (Procedure 1):
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(Procedimento 1)(Procedure 1)
Uma rota alternativa para a preparação do derivado (R)-3((2-(benzo[d][1,3]dioxol-5-carbonil)-lH-indol-3-il)metil)-1metilpiperazina-2,5-diona, segundo a presente invenção, a partir de (6R, trans)-6-(l,3-benzodioxol-5-il)-2,3,6,7,12,12ahexahidro-2-metil-pirazino[1' , 2 ' : 1,6 ]pirido[3,4-b]indol-1,4diona, é através da reação abaixo (Procedimento 2):An alternative route for the preparation of derivative (R) -3 ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1methylpiperazine-2,5 -dione, according to the present invention, from (6R, trans) -6- (1,3-benzodioxol-5-yl) -2,3,6,7,12,12ahexahidro-2-methyl-pyrazino [1 ', 2': 1,6] pyrido [3,4-b] indole-1,4dione, is via the reaction below (Procedure 2):
(Procedimento 2)(Procedure 2)
Ainda, o derivado (R)-3-((2-(benzo[d][1,3]dioxol-5carbonil)-lH-indol-3-il)metil)-l-metilpiperazina-2,5-diona, segundo a presente invenção pode ser preparado a partir de (1R,3R)-1-(benzo[d][1,3]dioxol-5-il)-2-(2-cloroacetil)2,3,4,9-tetrahidro-lH-pirido[3,4-b]indol-3-carboxilato de metila, conforme as reações abaixo (Procedimento 3):In addition, the derivative (R) -3 - ((2- (benzo [d] [1,3] dioxol-5carbonyl) -1H-indol-3-yl) methyl) -1-methylpiperazine-2,5-dione, according to the present invention can be prepared from (1R, 3R) -1- (benzo [d] [1,3] dioxol-5-yl) -2- (2-chloroacetyl) 2,3,4,9- methyl tetrahydro-1H-pyrido [3,4-b] indole-3-carboxylate, according to the reactions below (Procedure 3):
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(Procedimento 3) enantiômero (S)-3-((2-(benzo[d][1,3]dioxol-5-carbonil)lH-indol-3-il)metil)-l-metilpiperazina-2,5-diona e a mistura racêmica foram preparados utilizando os procedimentos descritos acima e empregando matérias primas com configuração correspondente a configuração desejada para o produto, e as reações às quais as matérias primas são submetidas não alteraram a configuração do centro assimétrico desejado.(Procedure 3) (S) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) 1H-indol-3-yl) methyl) -1-methylpiperazine-2,5- enantiomer diona and the racemic mixture were prepared using the procedures described above and using raw materials with a configuration corresponding to the desired configuration for the product, and the reactions to which the raw materials are subjected did not change the configuration of the desired asymmetric center.
Os exemplos a seguir ilustram, de forma não limitativa, os processos de preparação do composto (R)-3-({2(benzo[d][1,3]dioxol-5-carbonil)-lH-indol-3-il)metil)-1metilpiperazina-2,5-diona, ou composto BL-122, de acordo com os procedimentos 1, 2 e 3 acima citados.The following examples illustrate, but are not limited to, the processes for preparing compound (R) -3 - ({2 (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3-yl ) methyl) -1methylpiperazine-2,5-dione, or compound BL-122, according to procedures 1, 2 and 3 above.
Exemplo 1Example 1
Procedimento 1:Procedure 1:
3,5g do composto (6R, trans)-6-(1,3-benzodioxol-5-il)2,3,6,7,12,12a-hexahidro-2-metilpirazino[1',2':1,6]pirido[3,4-b]indol-1,4-diona foram / 29 misturadas a 205g de DDQ a temperatura ambiente. Em seguida, essa mistura foi adicionada à 100 ml de uma mistura de THF:H20 (9:1) . A mistura reacional foi mantida sob agitação durante 8 horas à temperatura ambiente, sendo monitorada por TLC. Porções adicionais de DDQ foram adicionadas até que todo o (6R, trans)-6-(1,3-benzodioxol-5-il) - 2,3,6,7,12,12a hexahidro - 2 - metilpirazino[1',2':1,6Jpirido[3,4-b]indol1,4-diona fosse consumido. Após completada a reação, a mistura foi lavada com água e o produto extraído em acetato de etila. As fases orgânicas foram reunidas e secas em MgSO4. O solvente foi parcialmente removido, levando à precipitação do produto, que foi filtrado e seco em estufa a 602 C. O produto obtido como sólido de coloração branca (composto BL-122) apresentou3.5g of compound (6R, trans) -6- (1,3-benzodioxol-5-yl) 2,3,6,7,12,12a-hexahydro-2-methylpyrazino [1 ', 2': 1, 6] pyrido [3,4-b] indole-1,4-dione were mixed with 205g DDQ at room temperature. Then, this mixture was added to 100 ml of a THF: H2 O mixture (9: 1). The reaction mixture was kept under stirring for 8 hours at room temperature, being monitored by TLC. Additional portions of DDQ were added until all (6R, trans) -6- (1,3-benzodioxol-5-yl) - 2,3,6,7,12,12a hexahydro - 2 - methylpyrazine [1 ', 2 ': 1,6Jpirido [3,4-b] indol1,4-dione was consumed. After the reaction was completed, the mixture was washed with water and the product extracted in ethyl acetate. The organic phases were combined and dried over MgSO 4 . The solvent was partially removed, causing the product to precipitate, which was filtered and dried in an oven at 60 2 C. The product obtained as a white colored solid (compound BL-122) showed
Exemplo 2Example 2
Procedimento 2: * il) Procedure 2: * il)
1,4g de dióxido de selênio foram adicionadas em uma solução contendo 2,4g de (6R, trans) - 6 - (1,3 - benzodioxol - 5 il) -2,3,6,7,12,12a - hexahidro - 2 - metil pirazino[1',2':1,6]pirido[3,4-b]indol-1,4-diona e 60ml de dioxano. A mistura reacional foi mantida sob agitação e refluxo durante 4 horas. Ao final desse período a mistura reacional foi filtrada em celite/sílica e o solvente / 29 rotoevaporado. O produto sólido foi recristalizado em1.4 g of selenium dioxide were added in a solution containing 2.4 g of (6R, trans) - 6 - (1.3 - benzodioxol - 5 yl) -2,3,6,7,12,12a - hexahydro - 2 - methyl pyrazine [1 ', 2': 1.6] pyrido [3,4-b] indole-1,4-dione and 60 ml of dioxane. The reaction mixture was kept under stirring and reflux for 4 hours. At the end of this period, the reaction mixture was filtered through celite / silica and the solvent / rotoevaporated. The solid product was recrystallized from
CH2C12/MeOH e seco em estufa a uma temperatura de 602 C. 0 produto obtido como sólido de coloração branca, composto BL122, apresentou as seguintes características: p.f. 219-2212C e [cx]d 25= +12 (c 0,8; DMSO) . RMN XH (500MHz - DMSO) = 11,52 (1H,CH2C12 / MeOH and kiln dried at a temperature of 60 2 C. The product obtained as a white solid, compound BL122, had the following characteristics: mp 219-221 2 C and [cx] d 25 = +12 (c 0 , 8; DMSO). X H NMR (500MHz - DMSO) = 11.52 (1H,
s); 7,95 (1H, d, J = 3Hz); 7,61 (1H, d, J = 8Hz); 7,43 (1H, d, J = 8Hz); 7,34 (1H, dd, J = 8Hz e J = 1,5Hz); 7,25-7,28 (2H, m) ; 7,07-7,10 (2H, m) ; 6,17 (2H, s); 4,00-4,03 (1H, m) ; 3,333,48 (3H, m); 2,98 (1H, d, J = 17,5Hz); 2,53 (3H, s).s); 7.95 (1H, d, J = 3 Hz); 7.61 (1H, d, J = 8 Hz); 7.43 (1H, d, J = 8 Hz); 7.34 (1H, dd, J = 8Hz and J = 1.5Hz); 7.25-7.28 (2H, m); 7.07-7.10 (2H, m); 6.17 (2H, s); 4.00-4.03 (1H, m); 3,333.48 (3H, m); 2.98 (1H, d, J = 17.5 Hz); 2.53 (3H, s).
Exemplo 3Example 3
Procedimento 3:Procedure 3:
32g de dióxido de selênio foram adicionadas a uma solução contendo 107g de 1- (benzo[d] [1,3]dioxol-5-il)-2-(2cloroacetil)-2,3,4,9-tetrahidro-lH-pirido[3,4-b]indol-3carboxilato de metila em 1.250ml de tetrathidrofurano (THF). A mistura reacional foi mantida sob agitação e refluxo durante32g of selenium dioxide were added to a solution containing 107g of 1- (benzo [d] [1,3] dioxol-5-yl) -2- (2chloroacetyl) -2,3,4,9-tetrahydro-1H- pyrido [3,4-b] methyl indole-3 carboxylate in 1,250 ml of tetrathidrofuran (THF). The reaction mixture was kept under stirring and reflux for
I, 5 horas. Ao final desse período, a mistura reacional foi filtrada em celite/sílica e cerca de 30% do solvente foi removido. À mistura reacional, foram adicionados l.OOOml de etanol absoluto e 200ml de uma solução a 30% de metilamina em etanol. Essa mistura foi mantida sob refluxo durante 4 horas. O solvente foi parcialmente removido, levando a precipitação do produto final, o qual foi filtrado e seco em estufa a 60a C. O produto obtido como sólido de coloração branca, composto BL-122, apresentou as seguintes características: p.f. 219221aC e [a]D 25= +12 (c 0,8; DMSO). RMN XH (500MHz - DMSO) =I, 5 hours. At the end of that period, the reaction mixture was filtered over celite / silica and about 30% of the solvent was removed. To the reaction mixture, 100 ml of absolute ethanol and 200 ml of a 30% solution of methylamine in ethanol were added. This mixture was kept under reflux for 4 hours. The solvent was partially removed, leading to precipitation of the final product, which was filtered and dried in an oven at 60 C. The product obtained as a white colored solid, BL-122 compound had the following characteristics: mp 219 221 C and [a] D 25 = +12 (c 0.8; DMSO). NMR X H (500MHz - DMSO) =
II, 52 (1H, s); 7,95 (1H, d, J = 3Hz); 7,61 (1H, d, J = 8Hz) ;II, 52 (1H, s); 7.95 (1H, d, J = 3 Hz); 7.61 (1H, d, J = 8 Hz);
7,43 (1H, d, J7.43 (1H, d, J
8Hz) ; 7,34 (1H, dd, J8Hz); 7.34 (1H, dd, J
8Hz e J8Hz and J
1,5Hz);1.5Hz);
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7,25-7,28 (2Η, m); 7,07-7,10 (2H, (1H, m) ; 3,33-3,48 (3H, m) ; 2,98 (3H, S); RMN 13C (125MHz - DMSO) = 147,4; 136,3; 132,9; 132,8; 127,5; 116,1; 112,6; 109,1; 108,0; 102,0;7.25-7.28 (2Η, m); 7.07-7.10 (2H, (1H, m); 3.33-3.48 (3H, m); 2.98 (3H, S); 13 C NMR (125MHz - DMSO) = 147.4 ; 136.3; 132.9; 132.8; 127.5; 116.1; 112.6; 109.1; 108.0; 102.0;
m) ; 6,17 (2H, s); 4,00-4,03 (1H, d, J = 17,5Hz) ; 2,53m); 6.17 (2H, s); 4.00-4.03 (1H, d, J = 17.5 Hz); 2.53
186,9; 165,9; 164,8; 151,0; 125,8; 124,9; 120,7; 119,8;186.9; 165.9; 164.8; 151.0; 125.8; 124.9; 120.7; 119.8;
55,7; 50,6; 33,0; 29,1.55.7; 50.6; 33.0; 29.1.
Os compostos da presente invenção, assim como seus sais farmaceuticamente aceitáveis, são potenciais estimuladores de expressão de NO em tecidos e potenciais inibidores seletivos de PDE específica para cGMP. Assim, os compostos da fórmula (I) e seus sais farmaceuticamente aceitáveis são de interesse na terapia, especificamente no tratamento e profilaxia, de uma variedade de condições em que a estimulação da expressão de NO em tecidos ou a inibição de PDE específica para cGMP são consideradas benéficas.The compounds of the present invention, as well as their pharmaceutically acceptable salts, are potential stimulators of NO expression in tissues and potential selective inhibitors of cGMP-specific PDE. Thus, the compounds of formula (I) and their pharmaceutically acceptable salts are of interest in the therapy, specifically in the treatment and prophylaxis, of a variety of conditions in which the stimulation of NO expression in tissues or the inhibition of cGMP-specific PDE are considered beneficial.
Como uma resposta da inibição seletiva para PDE-5 apresentada pelos compostos da presente invenção, os níveis de cGMP são elevados, o que por sua vez, pode promover as atividades anti-plaquetárias, anti-neutrófilas, antivasoespásticas, vasodilatadoras, natriuréticas e diuréticas, bem como a efeitos do fator relaxante derivado de nitrovasodilatadores, fator natriurético atrial (ANF), peptídeo natriurético do cérebro (BNP), peptídeos natriuréticos tipo C (CNP) e agentes relaxantes dependentes de endotélio, como bradicinina, acetilcolina e 5-HTi.As a selective inhibition response to PDE-5 presented by the compounds of the present invention, cGMP levels are high, which in turn can promote anti-platelet, anti-neutrophil, anti-spasmodic, vasodilatory, natriuretic and diuretic activities, as well as the effects of nitrovasodilator-derived relaxing factor, atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), type C natriuretic peptides (CNP) and endothelium-dependent relaxing agents, such as bradykinin, acetylcholine and 5-HTi.
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Os compostos da fórmula (I) segundo a presente invenção têm utilidade no tratamento e prevenção em uma quantidade de distúrbios, incluindo angina estável, instável e variável, hipertensão, hipertensão pulmonar, falha cardíaca congestiva, falha renal, aterosclerose, estados doentios de desobstrução reduzida dos vasos sanguíneos, doença vascular periférica, distúrbios vasculares, como a doença de Raynaud, disfunção erétil, disfunção sexual, doenças inflamatórias, ataque cardíaco, bronquite, asma crônica, asma alérgica, rinite alérgica, glaucoma e doenças caracterizadas por distúrbios de motilidade intestinal.The compounds of formula (I) according to the present invention are useful in the treatment and prevention in a number of disorders, including stable, unstable and variable angina, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, unhealthy states of reduced clearance blood vessels, peripheral vascular disease, vascular disorders such as Raynaud's disease, erectile dysfunction, sexual dysfunction, inflammatory diseases, heart attack, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma and diseases characterized by intestinal motility disorders.
Os compostos de fórmula (I) e seus sais farmaceuticamente aceitáveis, segundo a presente invenção, podem ser administrados por qualquer via adequada, como por exemplo, por via oral, bucal, sublingual, retal, vaginal, nasal, tópica, intraperitoneal ou parenteral. Prefere-se geralmente a administração oral.The compounds of formula (I) and their pharmaceutically acceptable salts, according to the present invention, can be administered by any suitable route, for example, by oral, buccal, sublingual, rectal, vaginal, nasal, topical, intraperitoneal or parenteral route. Oral administration is generally preferred.
As composições farmacêuticas compreendendo como ingrediente ativo uma quantidade eficaz de um dos derivados da fórmula (I) podem ser apresentadas em diversos tipos de formulações farmacêuticas, tais como, mas não limitadas a: (i) comprimido, opcionalmente revestido, mastigável, efervescente, multicamadas ou solúvel; (ii) pílulas; (iii) pó opcionalmente dispersível ou efervescente; (iv) cápsulas de qualquer tipo, como por exemplo, cápsula gelatinosa dura, cápsula gelatinosa mole e amilácia; (v) pastilhas; (vi) granulados, opcionalmente na forma de micropartículas ou de microcápsulas, ou em / 29 preparações vetorizadas, como por exemplo, os lipossomos;Pharmaceutical compositions comprising as an active ingredient an effective amount of one of the derivatives of formula (I) can be presented in several types of pharmaceutical formulations, such as, but not limited to: (i) optionally coated, chewable, effervescent, multilayered tablet or soluble; (ii) pills; (iii) optionally dispersible or effervescent powder; (iv) capsules of any kind, for example, hard gelatin capsule, soft gelatin capsule and starch; (v) lozenges; (vi) granules, optionally in the form of microparticles or microcapsules, or in vectorized preparations, such as liposomes;
(vii) supositórios, (viii) soluções opcionalmente oral, nasal, oftálmica; (ix) injetável incluindo subcutânea, intradérmica, intramuscular e intravenosa; (x) suspensões; (xi) xaropes;(vii) suppositories, (viii) optionally oral, nasal, ophthalmic solutions; (ix) injectable including subcutaneous, intradermal, intramuscular and intravenous; (x) suspensions; (xi) syrups;
(xii) infusão; dentre outras.(xii) infusion; among others.
Caso a forma farmacêutica seja uma solução ou suspensão de administração oral, o veículo farmaceuticamente aceitável pode incluir solventes e co-solventes, tampões, conservantes, corantes, flavorizantes adoçantes, agentes de redução, agentes espessantes, agentes sequestrantes, tensoativos, substâncias para o ajuste de pH (por exemplo, ácido clorídrico, hidróxido de sódio), agentes de suspensão, antioxidantes, dentre outros. Os solventes ou meios de suspensão podem ser: água purificada e/ou outros solventes hidrofílicos (por exemplo, etanol, DMSO, propileno glicol, PEG) ou hidrofóbicos (por exemplo, óleos). Os co-solventes podem ser o etanol, propileno glicol, glicerol, dentre outros. Os conservantes podem ser os fenóis, parabenos, ácido benzóico. Os agentes redutores podem ser a vitamina E, ácido ascórbico, etc. É desejável que quaisquer desses excipientes ou aditivos estejam dentro das exigências de qualidade para uso farmacêutico e veterinário estabelecidas pelas autoridades competentes.If the pharmaceutical form is a solution or suspension for oral administration, the pharmaceutically acceptable carrier may include solvents and co-solvents, buffers, preservatives, dyes, sweetening flavors, reducing agents, thickening agents, sequestering agents, surfactants, substances for adjustment pH (for example, hydrochloric acid, sodium hydroxide), suspending agents, antioxidants, among others. The solvents or suspending means can be: purified water and / or other hydrophilic solvents (for example, ethanol, DMSO, propylene glycol, PEG) or hydrophobic (for example, oils). Co-solvents can be ethanol, propylene glycol, glycerol, among others. Preservatives can be phenols, parabens, benzoic acid. The reducing agents can be vitamin E, ascorbic acid, etc. It is desirable that any of these excipients or additives are within the quality requirements for pharmaceutical and veterinary use established by the competent authorities.
No caso de a forma farmacêutica da composição segundo a presente invenção seja em comprimido, ela pode incluir um ou mais excipientes selecionados do grupo consistindo de diluentes, desintegrantes, aglutinantes, corantes e agentes f lavorizantes. O diluente pode ser um ou mais entre carbonato / 29 de cálcio, fosfato dibásico de cálcio, fosfato tribásico de cálcio, sulfato de cálcio, celulose microcristalina, dextratos, dextrinas, excipientes de dextrose, frutose, caulim, lactitol, lactose, manitol, sorbitol, amido, amido pré-gelatinizado, sacarose, açúcar compress^el . e açúcar de confeiteiro, e em particular pode ser lactose. 0 aglutinante pode ser um ou mais entre metilcelulose, hidroxipropilcelulose, hidróxipropil metilcelulose, polivinilpirrolidona, gelatina, goma arábica, etilcelulose, álcool polvinílico, pululana, amido pré-gelatinizado, ágar, goma draganta, derivados de ácido alginíco e propileno glicol, e alginato, e em particular pode ser polivinilpirrolidona. 0 desintegrante pode ser um ou mais entre hidroxipropilcelulose substituída de baixo peso molecular, carboximetil celulose, carboximetil celulose de cálcio, carboximetil celulose de sódio, croscarmelose de sódio, amido, amidoglicolato de sódio, celulose cristalina, hidróxipropil amido, e amido parcialmente pré-gelatinizado.If the pharmaceutical form of the composition according to the present invention is in tablet form, it can include one or more excipients selected from the group consisting of diluents, disintegrants, binders, dyes and flavoring agents. The diluent may be one or more of calcium carbonate / 29, calcium dibasic phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol , starch, pregelatinized starch, sucrose, compressed sugar. and powdered sugar, and in particular it can be lactose. The binder can be one or more of methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethylcellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, dragant gum, alginic acid and propylene glycol derivatives, and algin, glycol, and algin, glycol, and alginate, and alginate. and in particular it can be polyvinylpyrrolidone. The disintegrant may be one or more of substituted low molecular weight hydroxypropylcellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, sodium croscarmellose, starch, sodium starch glycolate, crystalline cellulose, hydroxypropyl starch, and partially pregelatinized starch .
As soluções, suspensões ou xaropes de administração oral, por exemplo, são em apresentações farmacêuticas do tipo flaconetes, frascos e ampolas.Solutions, suspensions or syrups for oral administration, for example, are in pharmaceutical presentations such as flaconettes, flasks and ampoules.
Também estão incluídas na presente invenção as composições de ação rápida, as de ação prolongada e as de liberação retardada. As formas farmacêuticas preferidas da invenção são o comprimido simples, comprimido revestido e cápsula.Also included in the present invention are fast-acting, long-acting and delayed-release compositions. Preferred dosage forms of the invention are the single tablet, coated tablet and capsule.
/ 29/ 29
As composições farmacêuticas compreendendo como ingrediente ativo uma quantidade eficaz de um dos derivados da fórmula (I) podem ser apresentadas com o referido derivado sozinho ou em associação com outro ingrediente ativo.Pharmaceutical compositions comprising as an active ingredient an effective amount of one of the derivatives of formula (I) can be presented with said derivative alone or in combination with another active ingredient.
As composições farmacêuticas, assim como o medicamento compreendendo como ingrediente ativo uma quantidade eficaz de um dos derivados da fórmula (I) têm usos especialmente para o tratamento e prevenção em uma quantidade de distúrbios, incluindo angina estável, instável e variável, falha renal, aterosclerose, estados doentios de desobstrução reduzida dos vasos sanguíneos, doença vascular periférica, distúrbiosThe pharmaceutical compositions, as well as the medicament comprising as an active ingredient an effective amount of one of the derivatives of formula (I) have uses especially for the treatment and prevention in a number of disorders, including stable, unstable and variable angina, renal failure, atherosclerosis , unhealthy states of reduced blood vessel clearance, peripheral vascular disease, disorders
glaucoma e doenças caracterizadas por distúrbios de motilidade intestinal.glaucoma and diseases characterized by disorders of intestinal motility.
Para a administração a animal de sangue quente no tratamento curativo ou profilático dos distúrbios definidos acima, as dosagens orais dos compostos de fórmula (I) podem estar na faixa de 0,l-900mg diários para um paciente que deles necessite. Na prática, o médico deverá determinar o regime de dosagens unitárias mais adequadas para cada paciente, o que variará em relação à idade, peso e resposta individual do paciente.For administration to warm-blooded animals in the curative or prophylactic treatment of the disorders defined above, the oral dosages of the compounds of formula (I) can be in the range of 0.900 mg daily for a patient who needs them. In practice, the physician should determine the most appropriate unit dosage regimen for each patient, which will vary in relation to the patient's age, weight and individual response.
Exemplos de algumas formulações farmacêuticas orais / 29 compreendendo os compostos de fórmula (I) segundo a presente invenção estão abaixo definidas.Examples of some oral pharmaceutical formulations / 29 comprising the compounds of formula (I) according to the present invention are defined below.
Exemplo 4Example 4
Exemplo 5Example 5
/ 29/ 29
Exemplo 6Example 6
Exemplo 7Example 7
/ 29/ 29
Exemplo 8Example 8
Exemplo 9Example 9
/ 29/ 29
Exemplo 10Example 10
As técnicas de preparação dessas formulações são conhecidas dos farmacotécnicos e conhecidos no estado da técnica.The techniques for preparing these formulations are known to pharmacotechnicians and known in the art.
A atividade inibitória dos compostos da presente invenção foi mensurada por meio de análise in vitro da potência e eficácia do efeito relaxante do composto BL-122 em tecido muscular. 0 efeito inibitório do composto BL-122 no relaxamento muscular foi testado em corpo cavernoso de coelho e rato, como mostrado nos Exemplos 11 e 12, respectivamente.The inhibitory activity of the compounds of the present invention was measured by means of in vitro analysis of the potency and effectiveness of the relaxing effect of the compound BL-122 in muscle tissue. The inhibitory effect of compound BL-122 on muscle relaxation was tested in the rabbit and rat cavernous body, as shown in Examples 11 and 12, respectively.
Exemplo 11Example 11
11.1. Isolamento e montagem das preparações11.1. Isolation and assembly of preparations
Para a realização dos experimentos foram utilizados coelhos machos pesando entre 3,5 a 4,0 Kg. Os animais foram anestesiados com pentabarbital sódico (40 mg/kg, i.p), a cavidade abdominal foi aberta para a retirada do pênis dos animais. Os tecidos foram colocados em placa de Petri contendo / 29 solução de Krebs -Henseleit pH 7,4 ( NaCl 118 mM; KC1 4,8 mM; CaCl2 2,5 mM; MgSCU 1,2 mM; KH2PO4 0,9 mM; NaHCCh 25 mM; glicose 11 mM) aquecida à 37°C, sendo que a cartilagem e os tecidos aderentes foram cuidadosamente removidos. Em geral 3 segmentos contendo aproximadamente 2 cm de comprimento do corpo cavernoso foram obtidos de cada animal. As preparações foram montadas em cubas de vidro contendo 5 ml de solução de Krebs contendo indometacina (5,6 μΜ) mantida à 37°C, continuamente aerada com uma mistura de 95% de O2 e 5% de CO2.To carry out the experiments, male rabbits weighing between 3.5 and 4.0 kg were used. The animals were anesthetized with sodium pentabarbital (40 mg / kg, ip), the abdominal cavity was opened for the removal of the animals' penis. The tissues were placed in a Petri dish containing / 29 Krebs -Henseleit solution pH 7.4 (118 mM NaCl; 4.8 mM KCl; 2.5 mM CaCl 2 ; 1.2 mM MgSCU; 0.9 mM KH2PO4; NaHCCh 25 mM; glucose 11 mM) heated to 37 ° C, and the cartilage and adherent tissues were carefully removed. In general, 3 segments containing approximately 2 cm in length of the cavernous body were obtained from each animal. The preparations were assembled in glass vats containing 5 ml of Krebs' solution containing indomethacin (5.6 μΜ) maintained at 37 ° C, continuously aerated with a mixture of 95% O 2 and 5% CO 2 .
As preparações foram submetidas a um período de equilíbrio de pelo menos 90 minutos, sob tensão de 2 g, tempo durante o qual a solução do banho foi renovada a cada 15 minutos. As mudanças de tensão isométrica foram registradas através de transdutor de força TRI-201 (Letica Scientific Instruments, Espanha) acoplado a um polígrafo.The preparations were subjected to an equilibrium period of at least 90 minutes, under tension of 2 g, during which time the bath solution was renewed every 15 minutes. Changes in isometric tension were recorded using a TRI-201 force transducer (Letica Scientific Instruments, Spain) coupled to a polygraph.
11.2. Análise do efeito de relaxante para os compostos estudados no corpo cavernoso isolado de coelho11.2. Analysis of the relaxant effect for the studied compounds in the isolated cavernous body of a rabbit
Decorrido o período de estabilização, as preparações foram expostas a concentrações únicas de 3 a 10 μΜ de fenielefrina. Após a completa estabilização das respostas contrateis à fenilefrina (cerca de 5 minutos), as preparações foram novamente expostas a concentrações crescentes e cumulativas (1 a 1000 nM) para cada um dos compostos testados. Após o relaxamento completo dos tecidos, os órgãos foram lavados várias vezes com solução de Krebs e deixado em repouso por pelo menos 60 minutos, antes da realização de nova curva doseresposta os mesmos compostos.After the stabilization period, the preparations were exposed to unique concentrations of 3 to 10 μΜ of phenielephrine. After complete stabilization of contractile responses to phenylephrine (about 5 minutes), the preparations were again exposed to increasing and cumulative concentrations (1 to 1000 nM) for each of the tested compounds. After complete relaxation of the tissues, the organs were washed several times with Krebs' solution and left to rest for at least 60 minutes, before performing a new curve of response to the same compounds.
/ 29/ 29
As respostas relaxantes causadas pelos compostos foram calculadas em função da resposta contrátil causado pela fenilefrina considerada como 100% de contração.The relaxing responses caused by the compounds were calculated as a function of the contractile response caused by phenylephrine considered as 100% contraction.
O composto BL-122 foi diluído em 10 mM de DMSO seguindo diluição seriada. Visando avaliar o efeito do veículo usado (DMSO) foram realizados experimentos controles paralelos utilizando os mesmos volumes das diversas diluições de DMSO (veiculo).The BL-122 compound was diluted in 10 mM DMSO following serial dilution. In order to evaluate the effect of the used vehicle (DMSO) parallel control experiments were carried out using the same volumes of the different dilutions of DMSO (vehicle).
A análise do efeito relaxante em corpo cavernoso de coelho mostrou que a. adição de concentrações cumulativas de 1 a 1000 nM do composto BL-122 promoveu relaxamento nas preparações de corpo cavernoso previamente contraídas pela felnilefrina (3-10 μΜ) , conforme ilustração da Figura 1. A taxa CE50s do composto BL-122 foi de 15,9 (1,8 - 29,9) μΜ, e o relaxamento máximo (eficácia) foi de 63,1 ± 7,8 %. O controle realizado por meio de tratamento com o veículo demonstra que o mesmo não promove relaxamento nos referidos tecidos.The analysis of the relaxing effect in the cavernous body of a rabbit showed that the. addition of cumulative concentrations of 1 to 1000 nM of the BL-122 compound promoted relaxation in the preparations of the corpora cavernosa previously contracted by felnilefrina (3-10 μΜ), as shown in Figure 1. The EC 50 s rate of the BL-122 compound was 15.9 (1.8 - 29.9) μΜ, and the maximum relaxation (efficacy) was 63.1 ± 7.8%. The control carried out by means of treatment with the vehicle demonstrates that it does not promote relaxation in the referred tissues.
Exemplo 12Example 12
12.1. Isolamento e montagem das preparações12.1. Isolation and assembly of preparations
Para a realização dos experimentos foram utilizados ratos Wistar machos pesando entre 300 - 350 g. Os animais foram mantidos em ambiente com umidade (60-80%) e temperatura controladas (22 ± 22C), com ciclo claro-escuro de 12 horas e livre acesso à água e ração. Tintes dos experimentos, os animais foram aclimatizados no laboratório durante um período / 29 mínimo de 1 hora. Cada animal foi utilizado apenas uma vez em cada teste.To carry out the experiments, male Wistar rats weighing between 300 - 350 g were used. The animals were kept in an environment with humidity (60-80%) and temperature controlled (22 ± 2 2 C), with a 12-hour light-dark cycle and free access to water and food. In the experiments, the animals were acclimatized in the laboratory for a minimum period of 29 hours. Each animal was used only once in each test.
Os animais foram sacrificados por aprofundamento da anestesia com quetamina e cloridrato de xilazina, seguido de exsanguinação feita pela secção da artéria carótida. Após a abertura da cavidade torácica, a aorta foi cuidadosamente removida e transferida para uma placa de Petri contendo solução de Krebs-Henseleit, com a seguinte composição (mM) :The animals were sacrificed by deepening anesthesia with ketamine and xylazine hydrochloride, followed by exsanguination performed by the section of the carotid artery. After opening the chest cavity, the aorta was carefully removed and transferred to a Petri dish containing Krebs-Henseleit solution, with the following composition (mM):
NaCl 118; KC1 4,7; CaC12 2,5; MgSO4 1,2; KH2PO4 0,9; NaHCO3NaCl 118; KC1 4.7; CaC12 2.5; MgSO4 1.2; KH2PO4 0.9; NaHCO3
25; glicose 11. A seguir retirou-se cuidadosamente os tecidos adiposos e conectivo adjacentes.25; glucose 11. Next, the adipose and adjacent connective tissues were carefully removed.
O vaso foi seccionado na forma de anéis com aproximadamente 3 a 4 mm de comprimento, os quais foram transferidos para cubas de vidro com volume total de 5 mL contendo solução de Krebs-Henseleit, mantida à 37°C, pH 7,4 e continuamente aerada com uma mistura de 95% de O2 e 5% de CO2. Duas hastes metálicas foram inseridas na luz dos mesmos, sendo uma delas adaptada a um transdutor de tensão isométrica acoplado a um polígrafo (TRI-201 - Letica Scientific Instruments). A tensão de repouso aplicada às preparações correspondeu a 1,0 g e a solução nutriente foi substituída a cada 15 minutos.The vessel was sectioned in the form of rings approximately 3 to 4 mm in length, which were transferred to glass vats with a total volume of 5 ml containing Krebs-Henseleit solution, maintained at 37 ° C, pH 7.4 and continuously aerated with a mixture of 95% O 2 and 5% CO 2 . Two metallic rods were inserted in their light, one of which was adapted to an isometric tension transducer coupled to a polygraph (TRI-201 - Letica Scientific Instruments). The resting tension applied to the preparations corresponded to 1.0 g and the nutrient solution was replaced every 15 minutes.
Após o período de equilíbrio de 60 minutos, as preparações foram contraídas com fenilefrina (0,3 - 1 μΜ) e a após a estabilização da contração tônica da preparação, a integridade do endotélio vascular foi avaliada pela capacidade da / 29 acetilcolina (ACh, 1 μΜ) induzir relaxamento das preparações. Somente as preparações que apresentaram relaxamento igual ou superior a 75% foram consideradas com endotélio íntegro e, portanto, foram selecionadas para a realização dos experimentos. Em seguida, a solução de Krebs- Henseleit foi renovada seguida por um período de equilíbrio de 30 minutos.After the equilibrium period of 60 minutes, the preparations were contracted with phenylephrine (0.3 - 1 μΜ) and after stabilizing the tonic contraction of the preparation, the integrity of the vascular endothelium was assessed by the capacity of / 29 acetylcholine (ACh, 1 μΜ) induce relaxation of the preparations. Only the preparations that presented relaxation equal to or greater than 75% were considered to have an intact endothelium and, therefore, were selected for carrying out the experiments. Then, the Krebs-Henseleit solution was renewed followed by an equilibrium period of 30 minutes.
12.2. Análise do efeito de relaxante para os compostos estudados no corpo cavernoso Isolado de rato12.2. Analysis of the relaxant effect for the studied compounds in the corpora cavernosa
Após os 3 0 minutos de repouso, as preparações foram contraídas pela fenilefrina (0.3 - 1 μΜ) e assim as contrações tônicas foram estabilizadas, sendo realizadas curvas doseresposta (DCR) de relaxamento usando o composto BL-122 (0,001 - 100 μΜ), na presença do endotélio. Experimentos paralelos utilizando somente o solvente DMSO usado para diluir o composto BL-122 foram realizados em tecidos montados a partir dos mesmos animais.After the 30 minutes of rest, the preparations were contracted by phenylephrine (0.3 - 1 μΜ) and thus the tonic contractions were stabilized, with relaxation response curves (DCR) being performed using the compound BL-122 (0.001 - 100 μΜ), in the presence of the endothelium. Parallel experiments using only the DMSO solvent used to dilute the BL-122 compound were performed on tissues assembled from the same animals.
Os resultados ilustrados na Figura 2 mostram que a adição de concentrações cumulativas de 1 a 1000 nM de composto BL-122 promoveu relaxamento nas preparações de aorta de rato previamente contraídas pela fenilefrina.The results illustrated in Figure 2 show that the addition of cumulative concentrations of 1 to 1000 nM of BL-122 compound promoted relaxation in the preparations of rat aorta previously contracted by phenylephrine.
A atividade dos compostos da presente invenção no comportamento sexual foi mensurada por meio de análise in vivo da eficácia do efeito do composto BL-122 em ereções espontâneas, como mostrado no Exemplo 13.The activity of the compounds of the present invention on sexual behavior was measured by in vivo analysis of the effectiveness of the effect of compound BL-122 on spontaneous erections, as shown in Example 13.
/ 29/ 29
Exemplo 13Example 13
13.1. Isolamento e montagem das preparações protocolo utilizado foi adaptado a partir de artigos da literatura (Hosseinzadeh et al., 2008; Rizzo et al., 2008).13.1. Isolation and assembly of the preparations used protocol was adapted from literature articles (Hosseinzadeh et al., 2008; Rizzo et al., 2008).
Dois dias antes da realização dos experimentos, casais de machos e fêmeas foram isolados em caixas plásticas. Neste mesmo período, os machos foram habituados durante 1 hora por dia em gaiolas aramadas de metal, retangulares e com dimensões de 40 x 23 x 33 cm. No dia do teste, os ratos machos foram tratados com 10 mg/kg (v.o.) do composto BL-122 ou somente com o veículo (salina contendo 10 % de DMSO). Imediatamente após, os animais foram colocados nas gaiolas de observação. Os ratos que receberam tratamento por via oral permaneceram em jejum por 4 horas antes do teste. Decorrida 1,5 horas após o tratamento por via oral, as fêmeas foram colocadas com os respectivos machos nas gaiolas. O comportamento de ereção espontânea foi observado durante 1 hora.Two days before the experiments, couples of males and females were isolated in plastic boxes. In this same period, the males were accustomed for 1 hour a day in metal wire cages, rectangular and with dimensions of 40 x 23 x 33 cm. On the test day, male rats were treated with 10 mg / kg (v.o.) of compound BL-122 or only with the vehicle (saline containing 10% DMSO). Immediately afterwards, the animals were placed in the observation cages. The rats that received oral treatment remained fasting for 4 hours before the test. After 1.5 hours after oral treatment, the females were placed with their males in the cages. Spontaneous erection behavior was observed for 1 hour.
13.2. Efeito do composto BL-122 sobre o comportamento sexual de ratos na presença de fêmeas quando administrados oralmente.13.2. Effect of compound BL-122 on the sexual behavior of rats in the presence of females when administered orally.
O tratamento por via oral com o composto BL-122 na dose de 10 mg/kg aumentou significativamente o parâmetro referente às ereções espontâneas quando comparado com o veículo, cerca de 6,4 ± 2,0 conforme ilustrado na Figura 3.Oral treatment with compound BL-122 at a dose of 10 mg / kg significantly increased the parameter referring to spontaneous erections when compared with the vehicle, about 6.4 ± 2.0 as illustrated in Figure 3.
Claims (13)
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