β-Carboline derivatives useful as inhibitors of phosphodiesterase

专利摘要:
The present invention relates to novel beta-carboline derivatives of the general formula (I), wherein all the variables are as described within the specification, useful as phosphodiesterase inhibitors. The present invention further relates to use of the described derivatives for the treatment of diseases and conditions related to PDE, for example male erectile dysfunction.
公开号:KR20020095481A
申请号:KR1020027015583
申请日:2001-05-03
公开日:2002-12-26
发明作者:수이지후아；매실랙마크제이.
申请人:오르토-맥네일 파마슈티칼, 인코퍼레이티드；
IPC主号:

专利说明:

Β-Carboline derivatives useful as inhibitors of phosphodiesterase}
[1] [Cross-References to Related Applications]
[2] This invention claims priority to Provisional Application Serial No. 60 / 204,667, filed May 17, 2000, the contents of which are incorporated herein by reference.
[4] Erectile dysfunction (ED) is defined as being unable to achieve or maintain an erection hard enough for satisfactory intercourse. Currently, approximately 7-8% of the male population has some ED, at least 20 million in the United States alone. Since the likelihood of ED increases with age, the incidence of this symptom increases further as the average age of the population increases.
[5] Male erectile dysfunction may be the result of mental and / or biological factors. Although ED has several causes, certain classes of the male population are more prone to the symptoms of the disease. In particular, patients with diabetes, hypertension, heart disease, and multiple sclerosis are particularly at risk of ED. In addition, patients taking certain classes of drugs such as antihypertensives, antidepressants, sedatives, stabilizers are more likely to suffer ED.
[6] Treatments for ED include various types of pharmacological agents, vacuum devices, and penile inserts. Among the pharmacological agents, papaverine, phentolamine, and alprostadil are currently used in practice. These drugs are only effective after direct intra- penis or intra-bladder injection and have side effects such as persistent penile erection, fibrosis, penile pain and hematoma at the injection site. The vacuum device is a non-invasive replacement therapy for ED. These devices create an erection by generating negative pressure around the penis axis, thereby increasing blood flow to the corpus cavernosum through passive vasodilation. Although this type of treatment is often successful in ED of biological origin, there are complaints including the lack of time involved in using spontaneous and mechanical devices, and difficulty and discomfort of ejaculation. Various semi-fixed or swelling penile inserts are successfully used in some cases, especially in men with diabetes. These devices are generally considered when other methods of treatment fail and have the side effects of increased risk of infection and ischemia.
[7] Recently, phosphodiesterase V (PDEV) inhibitor, sildenafil (Viagra ™), has been approved by the FDA as an effective oral treatment for ED treatment. Sildenafil, 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3-n-propyl-6,7-dihydro-1H-pyrazolo- [ 4,3-d] pyrimidin-7one and many related analogues and their use as antianginal agents are described in earlier patents 5,250,534 and 5,346,901. The use of sildenafil and related analogs for the treatment of male erectile dysfunction is described in PCT International Publication No. WO 94/28902, published December 22, 1994. In clinical studies, the drug improved sexual function in approximately 70% of men who suffered ED of psychological or biological causes. However, this drug was less effective in patients undergoing radical prostatectomy, with 43% of patients receiving sildenafil and 15% of patients receiving placebo improved their erection. In addition, the use of sildenafil is associated with several undesirable side effects, including headache, redness and color confusion due to non-selective effects on various tissues. Despite these drawbacks, the drug is preferred by the patient over other therapies including the direct introduction of drugs into the penis through insertion, the use of external devices or surgical procedures.
[8] Daugan et al., In US Pat. Nos. 5,859,009 (EP 0740668 B1 and WO 9519978), describe tetracycline derivatives as cyclic guanosine 3 ′, 5′-monophosphate, in particular phosphodiesterase inhibitors, and those in the treatment of cardiovascular disorders. Describe the purpose of use. Daugan et al. Teach the use of such tetracytoline derivatives for the treatment of impotents in WO97 / 03675.
[9] Bombrun et al. Disclose in WO 97/43287 a series of carboline derivatives, more particularly 2- (substituted alkyl carbonyl) substituted carboline derivatives and cyclic guanosine 3,5-monophosphates, in particular phosphodiesterases. It relates to their use in cardiovascular disorders as inhibitors.
[10] Ellis et al. Describe in WO 94/28902 and EP 0702555 B1 a series of pyrazolepyrimidinone derivatives and their use in the treatment of erectile dysfunction. Campbell, S. F. teaches the use of bicyclic heterocyclic compounds (pyrazolopyrimidones) in the treatment of impotence in WO96 / 16657; Campbell et al., On the other hand, teach the use of selective cGMP PDE inhibitors for the treatment of erectile dysfunction in WO96 / 16644.
[11] Ohashi et al. Disclose a tetracyclic pyridocarbazole derivative having a cGMP PDE inhibitory action in WO9745427.
[12] Fourtillan et al. Disclose in WO 96/08490 A1 a series of carboline derivatives and their use in the treatment of diseases associated with melatonin activity disorders. Ueki et al. Describe pyridine and 1,2,3,4-tetrahydropyridine derivatives useful as antipsychotic drugs in US Pat. No. 5,126,448. Atkinson et al. Disclose in US Pat. No. 3,328,412 1-aryl and heteroaryl-2-acyl-1,2,3,4-tetrahydro-β-carboline derivatives with long lasting analgesic properties.
[13] Erectile erection of sexually excited penis occurs due to the complex interactions of physiological processes including the central nervous system, peripheral nervous system and smooth muscle. In particular, release of nitric oxide from non-adrenergic, non-cholinergic nerves and endothelium activates guanyl cyclase in the corpus cavernosum and increases intracellular cGMP levels. Increasing intracellular cGMP reduces intracellular calcium levels, which lead to columnar smooth muscle relaxation, which in turn leads to cavernous volume expansion and compression of sub-tunical venules leading to penile erection.
[14] PDEV has been found in human platelets and vascular smooth muscle, and a role for this enzyme in the regulation of intracellular concentrations of cGMP in cardiovascular tissues has been proposed. In fact, PDEV inhibitors are known to enhance endothelial cGMP-induced increases in intracellular cGMP, resulting in endothelial vasodilation. Moreover, PDEV inhibitors selectively lower pulmonary arterial pressure in animal models of congestive heart failure and pulmonary hypertension. Thus, in addition to its utility in ED, PDEV inhibitors will be therapeutically useful in conditions such as heart failure, pulmonary hypertension, and angina pectoris.
[15] Drugs that increase the concentration of cGMP in the penis tissue, or increase the release of cGMP or reduce degradation are expected to be an effective treatment of ED. Intracellular levels of cGMP are regulated by enzymes involved in their formation and degradation, namely guanylate cyclase and cyclic nucleotide phosphodiesterases (PDEs). To date, at least nine mammalian PDEs have been described, of which five hydrolyze active cGMP under physiological conditions to make inactive GMP (PDEs I, II, V, VI, and IX). PDE V is an isoform superior to the human corpus cavernosum. Therefore, inhibitors of PDEV are expected to increase the concentration of cGMP in the corpus cavernosum and increase the duration and frequency of penile erection.
[16] Additionally, selective PDE inhibitors include male erectile dysfunction (ED), female sexual excitability, nitric oxide production in tissues of the vagina and clitoris and female sexual dysfunction associated with blood flow, preterm birth, menopause, cardiovascular disorders, atherosclerosis, It is known to be useful for the treatment of various disorders including arterial obstruction, thrombosis, coronary rest stenosis, angina pectoris, myocardial infarction, heart failure, ischemic heart disorder, hypertension, pulmonary hypertension, asthma, intermittent claudication and diabetes complications. .
[17] Accordingly, it is an object of the present invention to identify compounds that increase the concentration of cGMP in penile tissues through inhibition of phosphodiesterases, particularly PDEV. Another object of the present invention is to identify compounds useful for sexual dysfunction, especially erectile dysfunction and / or impotence in male animals and sexual dysfunction in female animals. Another object of the present invention is to identify methods of treating sexual dysfunction, in particular erectile dysfunction, using the compounds of the present invention.
[18] Another object of the present invention is male erectile dysfunction, female sexual dysfunction, penis disorder, atherosclerosis, arterial obstruction disorder, thrombosis, coronary rest stenosis, angina pectoris, myocardial infarction, heart failure, ischemic heart disorder, hypertension, pulmonary hypertension, asthma, To identify compounds that are useful in the treatment of disorders mediated by PDEV, such as intermittent claudication and diabetic complications.
[19] We describe a series of β-carboline derivatives that have the ability to inhibit phosphodiesterase type V in enzyme tests and increase the concentration of cGMP in penile tissues in vitro.
[20] Summary of the Invention
[21] The present invention provides novel β-carboline derivative compounds useful as phosphodiesterase inhibitors. More specifically, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof:
[22]
[23] In the above formula,
[24] R ¹ is independently halogen, nitro, hydroxy, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -NH ₂ , -NHR ^A , -N (R ^A ) ₂ , -OR ^A , -C (O ) NH ₂ , -C (O) NHR ^A , -C (O) N (R ^A ) ₂ , -NC (O) -R ^A , -SO ₂ NHR ^A , -SO ₂ N (R ^A ) ₂ , phenyl (Optionally substituted by 1 to 3 R ^B ) and heteroaryl (optionally substituted by 1 to 3 R ^B );
[25] Wherein each R ^A is independently C ₁ -C ₈ alkyl, aryl (optionally substituted by 1 to 3 R ^B ), C ₁ -C ₈ aralkyl (optionally substituted by 1 to 3 R ^B ) ) And heteroaryl (optionally substituted by 1 to 3 R ^B );
[26] Wherein each R ^B is independently halogen, hydroxy, nitro, cyano, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkoxycarbonyl, carboxyC ₁ -C ₈ alkyl, C ₁ -C ₈ alkylsulfonyl, trifluoromethyl, trifluoromethoxy, amino, acetylamino, di (C ₁ -C ₈ alkyl) amino, di (C ₁ -C ₈ alkyl) aminoC ₁ -C ₈ Alkoxy, di (C ₁ -C ₈ alkyl) aminoacetylC ₁ -C ₈ alkyl, di (C ₁ -C ₈ alkyl) aminoacetylamino, carboxyC ₁ -C ₈ alkylcarbonylamino, hydroxyC ₁ -C ₈ alkylamino, NHR ^A , N (R ^A ) ₂ and heterocycloalkylC ₁ -C ₈ alkoxy;
[27] n is an integer from 0 to 4;
[28] X is selected from the group consisting of O, S and NR ^D ;
[29] Wherein R ^D is hydrogen, hydroxy, -OR ^A , C ₁ -C ₈ alkyl, wherein alkyl is halogen, carboxy, amino, C ₁ -C ₈ alkylamino, di (C ₁ -C ₈ alkyl) amino, Optionally substituted by 1 to 3 substituents independently selected from C ₁ -C ₈ alkoxycarbonyl, heteroaryl or heterocycloalkyl; heteroaryl and heteroarylcarbonyl, wherein heteroaryl is substituted for phenyl or substituted phenyl May be optionally substituted, wherein the phenyl substituent is 1 to 3 R ^B );
[30] R ² is optionally substituted by C ₅ -C ₁₀ alkyl (optionally substituted by 1 to 3 R ^C ), aryl (optionally substituted by 1 to 3 R ^B ), heteroaryl (optionally by 1 to 3 R ^B Substituted) and heterocycloalkyl (optionally substituted by 1 to 3 R ^B );
[31] Wherein each R ^C is independently selected from the group consisting of halogen, hydroxy, nitro, NH ₂ , NHR ^A and N (R ^A ) ₂ ;
[32] Z is selected from the group consisting of CH ₂ , CHOH and C (O); Provided that when Z is CHOH or C (O) X is NH;
[33] R ⁴ is hydrogen, hydroxy, carboxy, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, di (C ₁ -C ₈ alkyl) aminoalkoxycarbonyl, di (C ₁ -C ₈ alkyl ) AminoC ₁ -C ₈ alkylaminocarbonyl, and -COR ^F ;
[34] R here^FIs C_One-C₈Alkyl, NH₂, NHR^A, NR^A ₂, -C_One-C₈Alkyl-NH₂, -C_One-C₈Alkyl-NHR^A, -C_One-C₈Alkyl-NR^A ₂And -NH-C_One-C₈Alkyl-NR^A ₂Is selected from the group consisting of;
[35] a is an integer from 0 to 1;
[36] Y is selected from the group consisting of CH ₂ , C (O), C (O) O, C (O) —NH and SO ₂ ;
[37] Is selected from the group consisting of naphthyl, heteroaryl and heterocycloalkyl;
[38] m is an integer from 0 to 2;
[39] R ³ is independently halogen, nitro, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, trifluoromethyl, trifluoromethoxy, phenyl (optionally substituted by 1 to 3 R ^B ), phenylsul Polyvinyl, naphthyl, C ₁ -C ₈ aralkyl, heteroaryl (optionally substituted by one to three R ^B ), NH ₂ , NHR ^A , and N (R ^A ) ₂ ;
[40] only, If this is 2-furyl or 2-thienyl, m is an integer of 1-2.
[41] The present invention provides a pharmaceutical composition containing a pharmaceutically acceptable carrier and the aforementioned compounds. The present invention provides a pharmaceutical composition prepared by mixing the above-mentioned compound with a pharmaceutically acceptable carrier. The present invention also provides a method for preparing a pharmaceutical composition, characterized in that the above-mentioned compound is mixed with a pharmaceutically acceptable carrier.
[42] The present invention is characterized by administering to a patient in need thereof a therapeutically effective amount of the above-mentioned compound or pharmaceutical composition, for example, sexual dysfunction, for example male impotence, impotence, female sexual dysfunction, for example female sexual arousal. Examples are methods of treating female sexual dysfunction, premature birth and / or menstrual irregularities associated with dysfunction, vaginal and clitoris tissues with blood flow and nitric oxide production.
[43] The present invention illustrates a method of increasing the concentration of cGMP in penile tissues via inhibition of phosphodiesterases, particularly PDEV, by administering an effective amount of the compound or pharmaceutical composition to a male patient in need of treatment.
[44] The present invention also illustrates a method for providing endothelial dependent vasodilation by increasing an intracellular cGMP induced by nitric oxide, by administering an effective amount of the compound or pharmaceutical composition to a patient in need thereof. .
[45] The present invention is also characterized by administering to a patient in need of such treatment an effective amount of the above-mentioned compound or pharmaceutical composition, male impotence (ED), impotence, female sexual dysfunction, female sexual dysfunction, vagina And sexual dysfunction, premature birth, menstrual disorders, cardiovascular disease, atherosclerosis, obstructive arterial disease, thrombosis, coronary rest stenosis, angina pectoris, myocardial infarction, heart failure associated with blood flow and nitric oxide production in clitoris tissues And ischemic heart disease, hypertension, pulmonary hypertension, asthma, intermittent claudication and diabetic complications.
[46] The present invention provides an increase in the concentration of cGMP in penile tissues through (a) treatment of hypogonadism, especially male impotence, (b) treatment of impotence, (c) inhibition of phosphodiesterases, especially PDEV, in patients in need of treatment. And / or (d) preterm birth, dysmenorrhea, cardiovascular disease, atherosclerosis, obstructive artery disease, thrombosis, coronary restenosis, angina pectoris, myocardial infarction, heart failure, ischemic heart disease, hypertension, pulmonary hypertension, asthma, intermittent claudication And the use of the aforementioned compounds in the manufacture of a medicament for the treatment of a condition selected from the group consisting of diabetic complications.
[3] The present invention relates to novel β-carboline derivatives, useful as phosphodiesterase inhibitors. The present invention further relates to the synthesis of β-carboline derivatives and to the synthesis of intermediates used in the preparation thereof. The present invention further relates to the use of the above-described derivatives for the treatment of diseases and conditions associated with PDE, for example male erectile dysfunction.
[47] The present invention provides novel β-carboline derivatives useful for the treatment of sexual dysfunction, especially male impotence (ED). Although the compounds of the present invention are primarily useful for the treatment of male hypogonadism or impotence, they also include, for example, female sexual dysfunction, female sexual dysfunction associated with blood flow and nitrate production in the vagina and clitoris tissue, And the treatment of female sexual dysfunction such as premature birth and menstrual irregularities.
[48] In particular, the compounds of the present invention may be represented by the following general formula (I):
[49]
[50] Wherein all substituents are as defined above.
[51] Preferably n is zero. Preferably m is an integer from 0 to 1.
[52] In one embodiment of the invention X is selected from S or NR ^D , wherein R ^D is hydrogen, haloC ₁ -C ₆ alkyl, di (C ₁ -C ₄ alkyl) aminoC ₁ -C ₆ alkyl, heteroaryl, HeteroarylC ₁ -C ₄ alkyl, heterocycloalkylC ₁ -C ₄ alkyl, carboxyC ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxycarbonylC ₁ -C ₄ alkyl and heteroarylcarbonyl Selected; Heteroaryl here is also optionally substituted by phenyl or substituted phenyl, wherein the phenyl substituent is one or two independently selected from R ^B ; Wherein each R ^B is independently halogen, nitro, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, trifluoromethyl, trifluoromethoxy, amino and di (C ₁ -C ₄ alkyl) amino It is selected from the configured group. Preferably, X is selected from S or NR ^D , wherein R ^D is hydrogen, di (methyl) aminoethyl, di (methyl) amino-n-propyl, di (ethyl) aminoethyl, di (ethyl) amino -n-butyl, N-pyrrolidinylethyl, N-morpholinylethyl, 2-pyridylmethyl, 4-pyridylmethyl, 5- (4-methylphenyl) -2-pyrimidinyl, carboxymethyl, carboxyethyl , 4-chloro-n-butyl, 2- (5- (3-trifluoromethylphenyl) furyl) carbonyl, 2- (5- (3-nitrophenyl) furyl) carbonyl, methoxycarbonylmethyl, meth It is selected from the group consisting of oxycarbonylethyl and 2-benzoxazolyl. More preferably, X is NR ^D , wherein R ^D is hydrogen, di (methyl) aminoethyl, 4-pyridylmethyl, 2-pyridylmethyl, N-morpholinylethyl, carboxyethyl, carboxymethyl, Di (ethyl) aminoethyl, N-pyrrolidinylethyl and 5- (4-methylphenyl) -2-pyrimidinyl. Most preferably, X is NR ^D , wherein R ^D is selected from the group consisting of hydrogen, di (methyl) aminoethyl, N-morpholinylethyl, carboxymethyl and N-pyrrolidinylethyl.
[53] Preferably, Z is selected from the group consisting of CH ₂ and C (O); Provided that when Z is C (O), X is NH.
[54] Preferably, Y is selected from the group consisting of C (O), SO ₂ and CH ₂ . More preferably, Y is selected from the group consisting of C (O) and CH ₂ . Most preferably, Y is C (O).
[55] In one example according to the invention Is selected from the group consisting of naphthyl and heteroaryl. Preferably, Is naphthyl, 2-pyrimidinyl, 2-furyl, 3-furyl, 2-benzofuryl, 2-thienyl, 2-benzothienyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-benzimi Dazolyl, 4-thiazolyl, 2-thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3- (1,2,5-triazolyl), 4-isoxazolyl, 2-pyri It is selected from the group consisting of dill and 3-pyridyl. More preferably, Is naphthyl, 2-pyrimidinyl, 2-furyl, 2-benzofuryl, 2-thienyl, 2-benzothienyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-thiazolyl, 4-thia It is selected from the group consisting of zolyl and 2-pyridyl. Most preferably, Is selected from the group consisting of 2-pyrimidinyl, 2-furyl, 2-benzofuryl, 2-benzoxazolyl, 2-thiazolyl and 2-pyridyl.
[56] In one example according to the invention, R ² is 3,4-methylenedioxyphenyl, 3,4- (difluoro) methylenedioxyphenyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo- [1,4] -dioxin-6-yl, pyridyl, phenyl and substituted phenyl; Wherein the phenyl substituent is halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, trifluoromethyl, cyano, nitro, C ₁ -C ₄ alkoxycarbonyl, di (C ₁ -C ₄ alkyl) amino Or di (C ₁ -C ₄ alkyl) aminoC ₁ -C ₄ alkoxy independently one or two. Preferably, R ² is phenyl, 3,4-methylenedioxyphenyl, 3,4- (difluoro) methylenedioxyphenyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo- [ 1,4] -dioxin-6-yl, 4-pyridyl, 3-pyridyl, 4-cyanophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl , 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3,4-dimethoxyphenyl, 3-trifluoromethyl-4-chlorophenyl, 3,4-dichlorophenyl, 4-chlorophenyl, 4-meth Oxycarbonylphenyl, 3,4-dimethoxyphenyl, 4- (dimethylamino) phenyl and 4- (N- (3-dimethylamino) -n-propoxy) phenyl. More preferably, R ² is selected from the group consisting of 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl and 2,3-dihydrobenzo- [1,4] -dioxin-6-yl do. Most preferably, R ² is selected from the group consisting of 3,4-methylenedioxyphenyl and 2,3-dihydrobenzofuryl.
[57] Preferably, R ⁴ is hydrogen, carboxy, C ₁ -C ₄ alkoxycarbonyl, di (C ₁ -C ₄ alkyl) aminoC ₁ -C ₄ alkoxycarbonyl and di (C ₁ -C ₄ alkyl) aminoC _It is selected from the group consisting of _1- C ₄ alkylaminocarbonyl. More preferably, R ⁴ is selected from the group consisting of hydrogen, carboxy, dimethylaminoethoxycarbonyl, dimethylaminoethylaminocarbonyl and methoxycarbonyl. Most preferably, R ⁴ is hydrogen.
[58] In one example according to the invention, R ³ is independently halogen, nitro, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, trifluoromethyl, C ₁ -C ₄ aralkyl, pyrazinyl, pyridyl, halogen It is selected from the group consisting of substituted pyridyl, dimethyl substituted imidazolyl, phenyl, phenylsulfonyl and substituted phenyl; Wherein the phenyl substituent is halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, trifluoromethyl, trifluoromethoxy, nitro, amino, acetylamino, C ₁ -C ₄ alkylsulfonyl, CarboxyC ₁ -C ₄ alkylcarbonylamino, hydroxyC ₁ -C ₄ alkylamino, di (C ₁ -C ₄ alkyl) aminoC ₁ -C ₄ alkoxy, di (C ₁ -C ₄ alkyl) aminoacetylamino Or one or two independently selected from heterocycloalkylC ₁ -C ₄ alkoxy. Preferably, R ³ is chloro, bromo, methyl, n-propyl, t-butyl, methoxy, trifluoromethyl, nitro, phenyl, benzyl, phenylsulfonyl, 4-hydroxyphenyl, 4-chlorophenyl , 4-methylphenyl, 3,4-dimethoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 5-trifluoromethylphenyl, 4-methoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-aminophenyl, 4-aminophenyl, 2-nitro-4-chlorophenyl, 2-nitro-4-methylphenyl, 2-nitro-4-methylsulfonylphenyl, 3-acetylaminophenyl, 4 -Acetylaminophenyl, 4- (3-carboxy-n-propyl) carbonylaminophenyl, 2-chloro-5-trifluoromethylphenyl, 4- (4-hydroxy-n-butyl) aminophenyl, 2- ( Dimethylamino) acetylaminophenyl, 4- [2- (N-pyrrolidinyl) ethoxy] phenyl, 4- [2- (4-morpholinyl) ethoxy] phenyl, 4- (2- (dimethylamino) Ethoxy) phenyl, 4-pyrazinyl, 2,3-dimethyl-3H-imidazolyl, 2-pyridyl and 3- Independently selected from the group consisting of pyridyl. More preferably, R ³ is bromo, t-butyl, methoxy, trifluoromethyl, nitro, phenyl, 4-chlorophenyl, 3,4-dimethoxyphenyl, 3-trifluoromethylphenyl, 4-methylphenyl , 4-methoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-aminophenyl, 2-nitro-4-chlorophenyl, 2-nitro-4-methylphenyl, 2-nitro-4- Methylsulfonylphenyl, 4- (3-carboxy-n-propyl) carbonylaminophenyl, 2-chloro-5-trifluoromethylphenyl, 4- (4-hydroxy-n-butyl) aminophenyl, 2-2 -(Dimethylamino) acetylaminophenyl, 4-pyrazinyl, 2-pyridyl and 2,3-dimethyl-3H-imidazol-4-yl. Most preferably, R ³ is t-butyl, methoxy, nitro, phenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3-trifluoromethylphenyl, 2 -Nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-aminophenyl, 2-nitro-4-methylsulfonylphenyl, 2- (dimethylamino) acetylaminophenyl, 2-pyridyl and 2,3-dimethyl Is selected from the group consisting of -3H-imidazol-4-yl.
[59] For medical purposes, salts of the compounds of the invention refer to salts that are acceptable as nontoxic pharmaceuticals. However, other salts may be useful for the preparation of the compounds according to the invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include, for example, pharmaceutically acceptable acids such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carboxylic acid or phosphoric acid. It can be formed by mixing with a solution of which includes acid addition salts. In addition, when the compound of the present invention carries an acidic moiety, suitable pharmaceutically acceptable salts thereof include alkali metal salts such as sodium or potassium salts; Alkaline earth metal salts such as calcium or magnesium salts; And salts formed as suitable organic ligands, for example quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include:
[60] Acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, chamlate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edicyl Latex, estolate, ecylate, fumarate, glutceptate, gluconate, glutamate, glycolylarsanylate, hexylsorbinate, hydravamin, hydrobromide, hydrochloride, hydroxynaphthoate, yo Odide, Isothionate, Lactate, Lactiobionate, Laurate, Maleate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate, Mucate, Naphsylate, Nitrate, N -Methylglucamine ammonium salt, oleate, pamoate (embonate), palmi Tate, Pantothenate, Phosphate / Diphosphate, Polygalacturonate, Salicylate, Stearate, Sulfate, Subacetate, Succinate, Tannate, Tartrate, Theoclate, Tosylate, Triethiodide And valerate.
[61] The present invention includes within its scope prodrugs of the compounds of the present invention. In general, such prodrugs will be functional derivatives of compounds that can be readily converted to the desired compound in vivo. Thus, in the methods of treatment of the present invention, the term “administration” encompasses the treatment of various diseases described as compounds that are specifically disclosed or that are not specifically disclosed, but which are converted to specific compounds in vivo after administration to a patient. do. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design o Prodrugs', ed. H. Bundgaard, Elsevier, 1985).
[62] If the compounds according to the invention have at least one chiral center, they can thus exist as enantiomers. If the compounds have two or more chiral centers, they may additionally exist as diastereomers. It will be understood that all such isomers and mixtures are included within the scope of the present invention. In addition, some of the crystalline forms for the compounds may exist as polymorphs and are intended to be included in the present invention as they are. In addition, some compounds may form solvates with water (ie, hydrates) or common organic solvents, which solvates are also intended to be within the scope of the present invention.
[63] As used herein, unless otherwise indicated, "halogen" will mean chlorine, bromine, fluorine and iodine.
[64] The term "alkyl", when used alone or as part of a substituent group, shall mean 1 to 10 carbon atoms, or any number of straight or branched chain alkanes within this range. For example, alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl and 2-methylpentyl.
[65] The term "alkoxy" will refer to the oxygen ether radicals of the straight or branched chain alkyl groups described above. For example, alkoxy radicals include methoxy, ethoxy, n-propoxy, n-butoxy, sec-butoxy, tert-butoxy, and the like.
[66] The term "aryl" refers to an aromatic group such as phenyl, naphthyl, and the like.
[67] The term "aralkyl" refers to an alkyl group substituted with an aryl group. For example, benzyl, phenylethyl, etc.
[68] As used herein, the term “heteroaryl” refers to a stable 5 or 5 membered monocyclic aromatic ring system containing 1 to 3 heteroatoms independently selected from N, O or S; And 9 or 10 membered bicyclic aromatic ring systems containing 1 to 4 heteroatoms independently selected from carbon atoms and N, O or S. Heteroaryl groups may be bonded to heteroatoms or carbon atoms to produce stable structures. Examples of heteroaryl groups include pyridyl, pyrimidinyl, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyrrolyl, thiazolyl, thiadiazolyl, thiazolyl, benzimi Including dazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, indazolyl, indolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl or isoquinolinyl, It is not limited to these. Particularly preferred heteroaryl groups are pyridyl, pyrazolyl, furyl, thiazolyl, thienyl, imidazolyl, isoxazolyl, pyrazinyl, pyrimidinyl, triazolyl, benzofuryl, benzothienyl, benzimidazolyl, Benzothiazolyl and benzoxazolyl.
[69] As used herein, “cycloalkyl” refers to a stable 3-8 membered monocyclic ring structure composed of saturated carbon atoms. Suitable examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
[70] The term “heterocycloalkyl” refers to a stable saturated or partially unsaturated, 3-8 membered monocylic group containing carbon atoms and heteroatoms independently selected from 1 to 4, preferably 1 to 2 N, O or S. Click ring structure; And a stable saturated, partially unsaturated or partially aromatic 9 to 10 membered bicyclic ring system containing carbon atoms and heteroatoms independently selected from 1 to 4 N, O or S. Heterocycloalkyl may be bonded to any carbon atom or heteroatom that results in a stable structure. Suitable examples of heterocycloalkyl groups include pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, ditianyl, tritianyl, dioxolanyl, dioxanyl, thiomorpholinyl, 3, 4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo- [1,4] -dioxin-6-yl, 2,3-dihydro-furo [2,3- b] pyridyl, 1,2- (methylenedioxy) cyclohexane, and the like. Particularly preferred heterocycloalkyl groups are pyrrolidinyl, morpholinyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl and 2,3-dihydrobenzo- [1,4] -dioxin- 6-day.
[71] As used herein, the symbol " ^* " shall mean the presence of stereoisomeric centers.
[72] Under the standard nomenclature used throughout this specification, the terminal sites of designated side chains are described first, followed by adjacent functional groups towards the point of attachment. Thus, for example, a "phenylC ₁ -C ₆ alkylaminocarbonylC ₁ -C ₆ alkyl" substituent means a group of the formula:
[73]
[74] The definition of a substituent or variable at a particular position within a molecule is intended to be independent of the definition anywhere else in this molecule. It is understood that substituents and substitution patterns on the compounds of the present invention can be selected by those skilled in the art to provide compounds that are chemically stable and can be readily synthesized by techniques known in the art, in addition to the methods set forth herein. Will be. It is also intended that when n or m is> 1, the corresponding R ¹ or R ³ substituents may be the same or different.
[75] As used herein, "sexual dysfunction" refers to female sexual dysfunction, male erectile dysfunction, impotence, female sexual dysfunction, female sexual arousal disorder, and female sexual dysfunction related to blood flow and nitric oxide production in tissues of the vagina and clitoris. Include.
[76] As used herein, the term “subject” refers to an animal, preferably a mammal, most preferably a human being, who has been the subject of treatment, observation or experiment.
[77] As used herein, the term “therapeutically effective amount” refers to the biological or medical response of a tissue system, animal or human, that a researcher, veterinarian, doctor or other clinician would like to know, which includes alleviation of the symptoms of the disease or condition being treated Refers to the amount of active compound or agent.
[78] As used herein, the term "composition" includes a product comprising a specific component in a specific amount in addition to a product which directly or indirectly results in a combination of the specific component in a specific amount.
[79] The abbreviations used herein, particularly in the reactions and examples, are as follows:
[80] Cmpd # = compound ID number
[81] DCC = 1,3-dicyclohexylcarbodiimide
[82] DCM = dichloromethane
[83] DDQ = dichlorodicyanoquinone
[84] DIC = diisopropylcarbodiimide
[85] DIPEA = diisopropylethylamine
[86] DMF = N, N-dimethylformamide
[87] DMSO = dimethyl sulfoxide
[88] dppp = 1,3-bis (diphenylphosphino) propane
[89] EDTA = ethylenedinitrotetraacetic acid
[90] Fmoc = 9-fluorenylmethoxycarbonyl
[91] Fmoc-NCS = 9-fluorenylmethoxycarbonyl isothiocyanate
[92] HEPES = 2- [4- (2-hydroxyethyl) -piperazinyl] -ethanesulfonic acid
[93] LAH = lithium aluminum hydride
[94] PDE = phosphodiesterase
[95] Pd ₂ dba ₃ = tris (dibenzylidene acetone) dipaladium (0)
[96] Pd (OAc) ₂ = palladium (II) acetate
[97] Pd (PPh ₃ ) ₄ = palladium tetrakis (triphenyl phosphine)
[98] Ph = phenyl
[99] PMSF = phenylmethane sulfonyl fluoride
[100] PPh ₃ = triphenyl phosphine
[101] PyBop = (1-hydroxy-1H-benzotriazolato-O) tri-1-pyrrolidinyl phosphorus
[102] PyBrop = Bromo-tri-1-pyridinyl phosphorus
[103] SNP = Sodium Nitroproside
[104] TEA = triethylamine
[105] TFA = trifluoroacetic acid
[106] THF = tetrahydrofuran
[107] TsOH = tomic acid
[108] Compounds of formula (I) may be prepared according to the methods summarized in more detail below.
[109] Compounds of formula (I) wherein (Y) _a is C (O) can be prepared according to the method outlined in Scheme 1.
[110]
[111]
[112] More specifically, a compound of formula (II) wherein X is O, S or NH, i.e., a known compound or a compound prepared by a known method, is prepared in the presence of an acid catalyst such as TFA, tomic acid, or the like, DCM, THF, toluene. The corresponding tricyclic compound of formula (IV) is prepared by reaction with an appropriately substituted aldehyde of formula (III) in an organic solvent such as the like.
[113] The compound of formula (IV) was converted to triethylamine (TEA), diisopropylethyl in an organic solvent such as dichloromethane (DCM), N, N'-dimethylformamide (DMF), tetrahydrofuran (THF), and the like. In the presence of a base such as an amine (DIPEA), sodium carbonate or the like with an appropriately substituted compound of formula (V) wherein A is halogen; In organic solvents such as dichloromethane (DCM), N, N'-dimethylformamide (DMF), tetrahydrofuran (THF), and the like, A is hydroxy in the presence of a coupling agent such as DCC, DIC, PyBop, PyBrop, and the like. Reaction with a suitably substituted compound of formula (V) affords the corresponding compound of formula (Ia).
[114] Alternatively, compounds of formula (I) wherein X is O, S, or NH and (Y) _a is C (O) can be prepared according to the method outlined in Scheme 2.
[115]
[116]
[117] More specifically, a compound of formula (II) wherein X is O, S, or NH is suitably substituted in formula (VI) in which A is halogen or hydroxy in an organic solvent such as DCM, THF, DMF, or the like. Reaction with a compound of affords the corresponding compound of formula (VII).
[118] The compound of formula (VII) is treated with POCl _{3 in} an organic solvent such as toluene, benzene, and the like, and then reduced to NaBH ₄ in an organic solvent such as ethanol, isopropanol, and the like to cyclize the corresponding compound of formula (IV). To prepare.
[119] The compound of formula (IV) is then reacted with an appropriately substituted compound of formula (V) to produce a compound of formula (Ia) as outlined in Scheme 1.
[120] Compounds of formula (I) wherein X is O, S or NH and (Y) _a is SO ₂ can be prepared according to the method outlined in Scheme 3.
[121]
[122] Thus, an appropriately substituted compound of formula (IV) is an appropriately substituted compound of formula (VIII), ie a known compound, wherein A is halogen or hydroxy in an organic solvent such as DCM, chloroform, DMF, THF, and the like. Reaction with a compound prepared by known methods affords the corresponding compound of formula (lb).
[123] Compounds of formula (I) wherein X is O, S or NH and (Y) _a is CH ₂ can be prepared according to the method outlined in Scheme 4.
[124]
[125] Thus, a suitably substituted compound of general formula (Ia) is used in an organic solvent such as methanol, THF, diethyl ether, and the like, preferably a reducing agent such as LAH, diborone, and the like, preferably at a temperature of about -20 to 40 ° C. Is treated with LAH to produce the corresponding compound of formula (Ic).
[126] (Y) Compounds of general formula (I) wherein _a is CH ₂ and X is NH can be prepared separately according to the method outlined in Scheme 5.
[127]
[128] Thus, a compound of formula (IVa) is reacted with an appropriately substituted compound of formula (IX) wherein Q is halogen, O-tosylate or O-mesoleate in an organic solvent such as DCM, THF, or the like To prepare a compound of formula (Id).
[129] Compounds of formula (I) wherein X is O, S or NH and (Y) _a is (Y) ₀ (ie a is 0 such that Y is absent) can be prepared according to the method outlined in Scheme 6. have.
[130]
[131]
[132] More specifically, the compound of formula (IV), i.e., a known compound or a compound prepared by a known method, is preferably used in an organic solvent such as toluene, DMF, 1-methyl-2-pyrrolidinone, or the like, preferably about 80 The corresponding compound of formula (Ie) is prepared by reaction with an appropriately substituted halide of formula (X), ie a known compound or a compound prepared by a known method, at a temperature of from 250 ° C.
[133] Compounds of formula (I) wherein X is NR ^D can be prepared according to the method outlined in Scheme 7.
[134]
[135] Thus, the compound of formula (If) may be prepared in a solvent such as DMF, 1-methyl-2-pyrrolidinone, or the like, in which Z is halogen, hydroxy, O-tosylate or O-mesoleate. The compound is reacted with a base such as sodium hydride, potassium t-butoxide, and the like to produce the corresponding compound of formula (Ig).
[136] Compounds of formula (I) wherein Z is CH-OH or C (O) can be prepared according to the method outlined in Scheme 8.
[137]
[138] More specifically, the compound of formula (If) is treated in an solvent such as THF, methanol, water, and the like with an oxidizing agent such as DDQ, chloranyl, and the like, preferably at a temperature of about -78 to about 30 ° C. A mixture of compounds of formula (Ih) and (Ii) is prepared. Preferably, compounds of formulas (Ih) and (Ii) are separated by known methods, such as recrystallization, column chromatography, and the like.
[139] Compounds of formula (I) wherein is 2-thiazolyl can be prepared according to the method outlined in Scheme 9.
[140]
[141] Thus, the appropriately substituted compound of formula (IVa) is reacted with Fmoc-NCS in an organic solvent such as DCM, DMF, THF, and the like, preferably at room temperature, to prepare the corresponding compound of formula (XII).
[142] Compound (XII) is reacted with 20% piperidine in alcohols such as methanol, ethanol, and the like to produce the corresponding amine of formula (XIII).
[143] General formula wherein the amine of formula (XIII) is suitably substituted in the presence of an organic solvent or mixture such as DMF, ethanol: dioxane, and the like, in the presence of a base such as TEA, DIPEA, and the like, preferably at a temperature of about 70 ° C. Reaction with α-halo methyl ketone of (XIV) affords the corresponding compound of formula (Ij).
[144] Compounds of formula (I) wherein (Y) _a is C (O) O can be prepared according to the method outlined in Scheme 10.
[145]
[146] More specifically, the compound of formula (IV) is reacted with an anhydride of formula (XV) or an anhydride of formula (XVI), suitably substituted in an organic solvent such as DCM, DMF, THF, or the like. To prepare a compound of formula (Ik).
[147] Compounds of formula (I) wherein (Y) _a is C (O) -NH can be prepared according to the method outlined in Scheme 11.
[148]
[149] Thus, the compound of formula (IV) is reacted with a compound of formula (XVII), which is suitably substituted in an organic solvent such as DCM, DMF, THF, and the like to produce the corresponding compound of formula (Im).
[150] When the process for the preparation of the compounds according to the invention produces a mixture of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form or each enantiomer may be prepared by enantiomeric synthesis or cleavage. The compound can be salted and then fractionated with standard techniques, such as optically active acids, such as (-)-di-p-toluoyl-d-tartaric acid and / or (+)-di-p-toluoyl l-tartaric acid. It can be cleaved into its component enantiomers by formation of diastereomeric pairs by regeneration of crystals and free bases. The compounds may also be cleaved by the formation of diastereomeric esters or amides, followed by chromatographic separation and removal of chiral aids. Alternatively, compounds can be partitioned using chiral HPLC columns.
[151] During the preparation of the compounds of the present invention, it may be necessary and / or desirable to protect the sensitive or reactive groups of the molecules concerned. This is known from conventional protection groups, such as Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; And T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991]. The protecting group can be removed in a convenient subsequent step using methods known from the art.
[152] The usefulness of a compound in treating sexual dysfunction can be measured according to the procedures described in Examples 10, 11 and 12 of the present invention.
[153] The present invention therefore provides a method of treating sexual dysfunction in a patient in need thereof, which method comprises administering a compound as defined herein in an amount effective to treat sexual dysfunction. The compound can be administered to a patient by conventional routes of administration, including but not limited to intravenous, oral, subcutaneous, intramuscular, intraepithelial and parenteral. The amount of compound effective to treat sexual dysfunction is from 0.1 mg to 20 mg per kg body weight of the patient.
[154] The invention also provides pharmaceutical compositions comprising one or more compounds of the invention in combination with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage form such as tablets, pills, capsules, powders, granules, sterile parenteral liquids or suspensions, metered aerosols or liquid sprays, drops, ampoules, injector devices or suppositories ; For oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or aeration. Alternatively, the composition may be present in a form suitable for once-weekly or once-monthly administration; For example, insoluble salts of the active compounds, such as decanoate salts, may be suitable for providing depot preparations for intramuscular injection. To prepare a solid composition such as a tablet, the main active ingredient is a pharmaceutical carrier such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum. It is admixed with tableting components and other pharmaceutical diluents such as water to form a solid preformulation composition containing a homogeneous mixture of a compound of the invention, or a pharmaceutically acceptable salt thereof. When these preformulation compositions are mentioned to be homogeneous, it means that the active ingredients are evenly distributed throughout the composition so that the composition can be easily subdivided into equally effective dosage forms such as tablets, pills and capsules. Such solid preformulation compositions are then subdivided into unit dosage forms of the form described above containing 1 to about 1000 mg of the active ingredient of the invention. Coating or otherwise combining tablets or pills of the novel compositions can provide dosage forms that confer the benefit of sustained action. For example, a tablet or pill can include an internal dosage component and an external dosage component, wherein the external dosage component is in the form of an envelope over the internal dosage component. The two components have a role in resisting degradation in the stomach and can be separated by an enteric layer that allows internal components to pass through or delayed release into the duodenum. Various materials can be used in such enteric layers or coatings, which include various polymeric acids and materials such as cellac, cetyl alcohol and cellulose acetate.
[155] Liquid forms in which the novel compositions of the present invention may be incorporated for oral administration or by injection include, in addition to elixirs and similar pharmaceutical excipients, aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and cottonseed oil, sesame oil, coconut oil. Or emulsions flavored with an edible oil such as peanut oil. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
[156] The method of treating sexual dysfunction, in particular male erectile dysfunction (ED), as described herein, can also be carried out using a pharmaceutical composition comprising a compound as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain about 1 mg to 1000 mg, preferably about 10 to 500 mg of the compound, and may be in any form suitable for the selected dosage form. Carriers include, but are not limited to, essential and inert pharmaceutical additives, including but not limited to binders, suspending agents, lubricants, flavoring agents, sweetening agents, preservatives, dyes, and coatings. Compositions suitable for oral administration include, but are not limited to, solid forms such as pills, tablets, caplets, capsules (each including immediate release formulations, timed release formulations and sustained release formulations), granules, and powders, and liquid forms, such as liquid formulations. , Syrups, elixirs, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
[157] Advantageously, the compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in two, three or four separate doses per day. In addition, the compounds of the present invention may be administered in intranasal form by topical use of suitable intranasal excipients or by transdermal skin patches well known to those skilled in the art. For administration in the form of a transdermal dispensing system, of course, dosage administration will be continuous rather than intermittent throughout the dosage regimen.
[158] For example, for oral administration in the form of tablets or capsules, the active drug component may be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders are not limited and include natural and synthetic gums such as starch, gelatin, glucose or beta-lactose, corn sweeteners, acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium Benzoate, sodium acetate, sodium chloride and the like. Disintegrants include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
[159] Liquid forms include synthetic and natural gums, such as appropriately suspended suspensions or dispersants, such as tragacanth, acacia, methylcellulose, and the like. For parenteral administration, sterile suspensions and solutions are preferred. In general, isotonic agents containing suitable preservatives are used when intravenous administration is desired.
[160] The compounds of the present invention may also be administered in the form of liposome distribution systems, such as small unilamellar vesicles, large single vesicles, and multilayer vesicles. Liposomes can be administered from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholine. Can be formed.
[161] Compounds of the invention can also be dispensed by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidephenols, polyhydroxyethyl aspartamide phenols, or polyethylene oxide polylysine substituted with palmitoyl moieties. In addition, the compounds of the present invention are biodegradable polymer classes useful for achieving controlled release of drugs such as polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polishes It can be coupled to a crosslinked or amphipatic block copolymer of ananoacrylate and hydrogel.
[162] The compounds of the present invention may be administered in previous compositions and according to the dosage regimens achieved in the art whenever the treatment of sexual dysfunction, especially male erectile dysfunction (ED), is required.
[163] The daily dosage of the product can vary widely from 1 to 1,000 mg per day for adults. For oral administration, the composition is preferably provided to the patient to be treated in the form of tablets containing the active ingredients 5.0, 10.0, 15.0, 25,0, 25.0, 50,0, 100, 250 and 500 mg for symptom adjustment. do. An effective amount of drug is usually supplied at a dosage level of about 0.1 mg / kg body weight to about 20 mg / kg per day. Preferably, this range is from about 0.2 mg / kg body weight to about 10 mg / kg per day, in particular from about 0.5 mg / kg body weight to about 10 mg / kg per day. The compound may be administered in one to four regimens per day.
[164] The optimal dosage to be administered can be readily determined by one skilled in the art and will depend on the particular compound used, the dosage form, the strength of the formulation, the dosage form, and the progression of the disease symptom. In addition, factors associated with the particular patient to be treated, including the patient's age, weight, diet and time of administration, will result in the need to adjust the dosage.
[165] The following examples are presented to aid the understanding of the present invention and are not intended to and in no way limit the invention set forth in the claims that follow.
[166] Unless otherwise indicated, ¹ H NMR was measured on Bruker AC-300.
[167] Example 1
[168] 1- (3,4-methylenedioxyphenyl) -2- [5- (3-trifluoromethylphenyl) furoyl] -2,3,4,9-tetrahydro-1H-β-carboline (No. 58 )
[169] To a suspension of 5- (3-trifluoromethylphenyl) furonic acid (256 mg, 1 mmol) in DCM (20 ml, anhydrous) was added oxalyl chloride (165 mg, 1.3 mmol) followed by the addition of 2 drops of DMF. . The mixture was stirred at rt for 1 h. 1- (3,4-methylenedioxyphenyl) -2,3,4,9-tetrahydro-1H-β-carboline (292 mg, 1 mmol) in DCM (10 ml, anhydrous) (WO 97/43287 , Prepared according to the method described in Intermediate 7, page 24) and triethylamine (0.4 ml), and the mixture is stirred at room temperature for 16 hours, sequentially NaHCO ₃ aqueous solution, brine (2X), 1N Washed with HCl and brine (2X) and dried using MgSO ₄ . After evaporation of the solvent a white solid was obtained.
[170] mp: 126-129 ° C.
[171]
[172] Example 2
[173] 9- [2- (pyrrolidin-1-yl) -ethyl] -1- (3,4-methylenedioxyphenyl) -2- [5- (3-trifluoromethyl-phenyl) furoyl]- 2,3,4-trihydro-1H-β-carboline (No. 75)
[174] 1- (3,4-methylenedioxyphenyl) -2- [5- (3-trifluoromethylphenyl) furoyl] -2,3,4,9-tetrahydro-1H in DMF (15 ml, anhydrous) To a solution of -β-carboline (prepared in Example 1) (600 mg, 1.14 mmol) was added sodium hydride (60%, 105 mg, 2.6 mmol) at room temperature. The mixture was stirred for 30 minutes at room temperature. N-chloroethylpyrrolidine hydrochloride (214 mg, 1.26 mmol) and 15-crown ether-5 (1 drop) were added. The mixture was stirred for 16 h at rt, quenched with NH ₄ Cl, extracted with ethyl acetate and dried over MgSO ₄ . After evaporating the solvent, the residue was purified by column chromatography (silica gel, ethyl acetate: hexane = 3: 1) to give a white solid.
[175]
[176] The corresponding methanesulfonic acid salt was prepared by adding 1.0 equivalent of methanesulfonic acid to a solution of the title compound in DCM to produce the product for biological testing.
[177] mp: 122-124 ° C.
[178] Example 3
[179] 1- (3,4-methylenedioxyphenyl) -2- [5- (3,4-dimethoxyphenyl) pyrimidin-2-yl] -2,3,4,9-tetrahydro-1H-β- Caboline (No. 7)
[180] 1- (3,4-methylenedioxyphenyl) -2,3,4,9-tetrahydro-1H-β-carboline (3.73 g, 12.8 mmol) in DMF (50 ml, anhydrous) with stirring for 16 hours (Prepared according to the method disclosed in WO 97/43287, intermediate 7, page 24) and a solution of 2-chloro-5- (3,4-dimethoxyphenyl) pyrimidine (1.6 g, 6.4 mmol) at 120 ° C. Heated. The reaction mixture was quenched with NH ₄ Cl and extracted with ethyl acetate. The organic phase was washed with brine (2X) and dried using MgSO ₄ . Column chromatography (silica gel, ethyl acetate: hexane = 2: 3) gave a white solid.
[181]
[182] Example 4
[183] 1- (3,4-methylenedioxyphenyl) -2- [5- (3,4-dimethoxyphenyl) pyrimidin-2-yl] -9-dimethylaminoethyl-2,3,4-trihydro- 1H-β-carboline (No. 5)
[184] 1- (3,4-methylenedioxyphenyl) -2- [5- (3,4-dimethoxyphenyl) pyrimidin-2-yl] -2,3,4 according to the procedure described in Example 2 , 9-tetrahydro-1H-β-carboline (prepared in Example 3) (1.0 g, 1.97 mmol), 2-chloro-N, N-dimethylethylamine hydrochloride (0.342 g, 2.37 mmol), hydrogenation Sodium (60%, 0.190 g, 4.74 mmol) and 15-crown ether-5 were reacted to give the product as a slightly yellow solid (after column chromatography with silica gel, ethyl acetate).
[185]
[186] Example 5
[187] 1- (3,4-methylenedioxyphenyl) -2- [5- (4-methoxyphenyl) -pyrimidin-2-yl] -4-oxo-2,3,4,9-tetrahydro-1H -β-carboline (No. 157) & 1- (3,4-methylenedioxy-phenyl) -2- [5- (4-methoxyphenyl) -pyrimidin-2-yl] -4-hydroxy- 2,3,4,9-tetrahydro-1H-β-carboline (No. 158)
[188] DDQ (113.5 mg, 0.5 mmol) and 1- (3,4-methylenedioxyphenyl) -2- [5- (3,4-dimethoxyphenyl) pyrimidin-2-yl] -2,3,4, To a mixture of 9-tetrahydro-1H-β-carboline (prepared in Example 3) (51 mg, 0.1 mmol) was added a mixed solvent of THF: water (9: 1) at -78 ° C. The mixture was stirred at 0 ° C and warmed to room temperature over 15 hours. Column chromatography (silica gel, hexane: ethyl acetate = 1: 1) gave the above oxo- and hydroxy derivatives as white solids, respectively.
[189] 157 times
[190]
[191] 158 times
[192]
[193] Example 6
[194] 1- (3,4-methylenedioxyphenyl) -2- [4- (4-methoxyphenyl) thiazol-2-yl] -2,3,4,9-tetrahydro-1H-β-carboline (No.169)
[195] A. 1- (3,4-Methylenedioxyphenyl) -2- [3- (fluorenylmethyloxycarbonyl) thiocarbamoyl] -2,3,4,9-tetrahydro-1H-β-car Bolin
[196] 1- (3,4-methylenedioxyphenyl) -2,3,4,9-tetrahydro-1H-β-carboline (2.66 g, 9.08 mmol) (WO 97/43287, intermediate 7, disclosed on page 24 Prepared according to the method) and Fmoc-isothiocyanate (2.82 g, 10.14 mmol) was dissolved in dry dichloromethane (50 ml). The mixture was stirred at ambient temperature for 16 hours and then concentrated in vacuo. Purification by flash chromatography (0-10% methanol in dichloromethane) gave thiourea protected as a pale yellow solid.
[197]
[198] B. 1- (3,4-Methylenedioxyphenyl) -2-thiocarbamoyl) -2,3,4,9-tetrahydro-1H-β-carboline
[199] The protected thiourea (4.78 g, 8.33 mmol) solution obtained in Part A dissolved in 20% (v / v) piperidine in methanol was heated to reflux for 5 hours. The mixture was concentrated in vacuo to afford a crude residue which was purified by flash chromatography (SiO ₂ , 0-10% methanol in dichloromethane) to give a yellow solid.
[200]
[201] C. 1- (3,4-Methylenedioxyphenyl) -2- [4- (4-methoxyphenyl) thiazol-2-yl] -2,3,4,9-tetrahydro-1H-β- Caboline (No. 169)
[202] To a solution of thiourea (223 mg, 0.63 mmol) obtained in Part B in a dioxane: ethanol (5 ml) 1: 1 mixture was 4-methoxyphenyl-2'-bromoacetophenone (175 mg, 0.76 mmol) and Triethylamine (0.40 ml) was added. The mixture was heated to 70 ° C. for 3 hours, cooled to room temperature and concentrated on a rotary evaporator. The residue was purified by flash chromatography (SiO ₂ , 0-10% methanol in dichloromethane) to give a colorless solid.
[203]
[204] Example 7
[205] 1- (3,4-methylenedioxyphenyl) -2- [4-phenylthiazol-2-yl] -2,3,4,9-tetrahydro-1H-β-carboline (No. 170)
[206] A. 1- (3,4-Methylenedioxyphenyl) -2- [3- (fluorenylmethyloxycarbonyl) thiocarbamoyl] -2,3,4,9-tetrahydro-1H-β-car Bolin
[207] 1- (3,4-methylenedioxyphenyl) -2,3,4,9-tetrahydro-1H-β-carboline (2.66 g, 9.08 mmol) (WO 97/43287, intermediate 7, disclosed on page 24 Prepared according to the method) and Fmoc-isothiocyanate (2.82 g, 10.14 mmol) was dissolved in dry dichloromethane (50 ml). The mixture was stirred at ambient temperature for 16 hours and then concentrated in vacuo. Purification by flash chromatography (0-10% methanol in dichloromethane) gave thiourea protected as a pale yellow solid.
[208]
[209] B. 1- (3,4-Methylenedioxyphenyl) -2- (thiocarbamoyl) -2,3,4,9-tetrahydro-1H-β-carboline
[210] A solution of the protected thiourea (4.78 g, 8.33 mmol) of Part A dissolved in 20% (v / v) piperidine in methanol was heated to reflux for 5 hours. The mixture was concentrated in vacuo to afford a crude residue which was purified by flash chromatography (SiO ₂ , 0-10% methanol in dichloromethane) to give a yellow solid.
[211]
[212] C. 1- (3,4-Methylenedioxyphenyl) -2- [4-phenylthiazol-2-yl] -2,3,4,9-tetrahydro-1H-β-carboline (No. 170)
[213] To the thiourea (227 mg, 0.65 mmol) solution obtained in Part B was added β-bromoacetophenone (159 mg, 0.80 mmol) and triethylamine (0.40 ml). The mixture was heated to 70 ° C. for 3 hours, cooled to room temperature and concentrated on a rotary evaporator. The residue was purified by flash chromatography (SiO ₂ , 0-10% methanol in dichloromethane) to give a pale yellow solid.
[214]
[215] Example 8
[216] 1- (2,3-dihydro-benzofuran-5-yl) -2- [5- (2,3-dimethyl-3H-imidazol-4-yl) -pyrimidin-2-yl] -2, 3,4,9-tetrahydro-1H-β-carboline (No. 190)
[217] 2- (5-bromo-2-pyrimidinyl) -1- (2,3-dihydro-5-benzofuranyl) -2,3,4,9-tetrahydro-1H-β-carboline ( 0.45 g, 1.00 mmol), 1,2-dimethyl-1H-imidazole (0.18 g, 1.87 mmol), Pd (OAc) ₂ (12 mg, 0.05 mmol), PPh ₃ (26 mg, 0.1 mmol) and K ₂ CO ₃ (0.28 g, 2 mmol) was stirred in 3.5 ml DMF at 140 ° C. for 14 h. The mixture was poured into 10% aqueous NaOH solution (50 ml). The resulting solution was extracted with CH ₂ Cl ₂ (3 × 50 ml) and dried over Na ₂ SO ₄ . Purification by preparative TLC gave the title product as a yellow powder.
[218]
[219] Example 9
[220] 2- [2,3 '] bipyridinyl-6'-yl-1- (2,3-dihydro-benzofuran-5-yl) -2,3,4,9-tetrahydro-1H-β- Caboline (No. 191)
[221] A. 2- (5-Bromo-pyridin-2-yl) -1- (2,3-dihydro-benzofuran-5-yl) -2,3,4,9-tetrahydro-1H-β- Kaboline
[222] 1- (2,3-dihydro-5-benzofuranyl) -2,3,4,9-tetrahydro-1H-β-carboline (11.6 g, 40 mmol), 2,5-dibromopyridine (10.42 g, 44 mmol), Pd ₂ dba ₃ (1.465 g, 1.6 mmol), dppp (1.32 g, 3.2 mmol) and NaO t Bu (5.38 g, 56 mmol) in 60 ml DMF at 80 ° C for 3 days. Stirred. The reaction mixture was filtered through a plug of celite using CH ₂ Cl ₂ . The reaction mixture was then concentrated and the crude mixture was loaded on a Foxy column (110 g silica gel) and eluted with ethyl acetate / hexanes (3: 7). The product was crystallized in a test tube. The product was concentrated and then recrystallized with THF to give the product as yellow crystals.
[223]
[224] B. 2- [2,3 '] bipyridinyl-6'-yl-1- (2,3-dihydro-benzofuran-5-yl) -2,3,4,9-tetrahydro-1H- β-carboline
[225] The product obtained from step A (0.4 g, 0.896 mmol), 2-tributylstananyilpyridine (0.8 g, 2.17 mmol) and Pd (PPh ₃ ) ₄ (0.12 g, 0.104 mmol) were added at 88 ° C. for 24 hours. Stir in, 4-dioxane (5 ml). The reaction mixture was filtered through a plug of celite using CH ₂ Cl ₂ and concentrated to a small volume. Preparative TLC (3: 7 ethyl acetate / hexanes then 5% CH ₃ OH / CH ₂ Cl ₂ ) gave the product as a yellow solid.
[226]
[227] The compounds listed in Tables 1-6 were prepared according to the procedures described herein.
[228] TABLE 1
[229]
[230]
[231]
[232]
[233]
[234] TABLE 2
[235]
[236]
[237]
[238]
[239]
[240]
[241]
[242]
[243]
[244]
[245]
[246]
[247] TABLE 3
[248]
[249]
[250] TABLE 4
[251]
[252]
[253] TABLE 5
[254]
[255]
[256]
[257] Example 10
[258] In vitro test
[259] Cyclic Nucleotide Phosphodiesterase (PDE) Assays
[260] PDEV Isolation
[261] International Journal of Impotence Research 1996 by Boolell et al. ( Boolell, M., Allen, MJ, Ballard, SA, Ge [o-Attee, S., Muirhead, GJ, Naylor, AM, Osterloh, IH, and Gingell, C ) The protocol described in 8, 47-52 was slightly modified to isolate PDEV from rabbit and human tissues.
[262] Briefly, rabbit or human tissue was homogenized in ice cooling buffer containing 20 mM HEPES (pH 7.2), 0.25 M sucrose, 1 mM EDTA and 1 mM phenylmethylsulfonyl fluoride (PMSF). Homogenates were centrifuged at 100,000 g for 60 minutes at 4 ° C. The supernatant was filtered through a 0.2 μM filter and loaded onto a Pharmacia Mono Q anion exchange column (1 mL bed volume) equilibrated with 20 mM HEPES, 1 mM EDTA and 0.5 mM PMSF. After washing the unbound protein, the enzyme was eluted by linear gradient with 100-600 mM NaCl in the same buffer (total 35-50 ml depending on tissue. Enzymes were 35, 40, 45, 50 and 50 ml eluted). The column was run at a flow rate of 1 ml / min to recover the 1 ml fraction. Fractions containing various PDE activities were collected separately and used for later testing.
[263] PDEV Inhibition Measurement
[264] As described below, the PDE assay was performed with minor modifications to the description of Thompson and Appleman, Biochemistry 1971 10, 311-316.
[265] It was assayed to conform to the 96-well format. Enzyme was transferred to 5 mM MgCl ₂ , 15 mM Tris HCl (pH 7.4), 0.5 mg / ml bovine serum albumin, 1 μM cGMP or cAMP, 0.1 μCi [ ³ H] -cGMP or [ ³ H] -cAMP and 2-10 μl column eluate. Assayed. The total volume of assay solution is 100 μl. The reaction mixture was incubated at 30 ° C. for 30 minutes. Boil for 1 minute to stop the reaction and cool on ice. 25 μl 1 mg / ml Ophiophagus hannah was added to the obtained [ ³ H] 5′-mononucleotide to convert it to uncharged [ ³ H] 5′-nucleoside and for 10 minutes at 30 ° C. Incubated. The reaction was stopped by addition of 1 ml Bio-Rad AG1-X2 resin slurry (1: 3). After centrifugation, all occupied nucleotides were bound by resin and only supernatant [ ³ H] -nucleosides remained. 200 μl aliquots were taken and counted by liquid scintillation. PDE activity is expressed in ml of hydrolyzed cyclic nucleotide pmol / min / enzyme sample.
[266] Inhibitor studies were performed in assay buffer at a final concentration of 10% DMSO. Under these conditions, hydrolysis of the product increased linearly with time and enzyme concentration.
[267] Example 11
[268] In vitro determination of K _i for phosphodiesterase inhibitors
[269] It was assayed to conform to the 96-well format. Phosphodiesterases were assayed for 5 mM MgCl ₂ , 15 mM Tris HCl, pH 7.4, 0.5 mg / ml bovine serum albumin, 30 nM ³ H-cGMP and various concentrations of test compounds. The amount of enzyme used in each reaction was supposed to convert less than 15% of the initial substrate during the assay. In all measurements, test compounds were dissolved and diluted in 100% DMSO (2% DMSO in assay). The total volume of assay solution was 100 μl. The reaction mixture was incubated at 30 ° C. for 90 minutes. The reaction was terminated by boiling for 1 minute and then immediately transferred to an ice bath. 25 μl of 1 mg / ml snakehead ( Ophiophagus hannah ) was then added to each well and the reaction mixture was incubated at 30 ° C. for 10 minutes. 1 ml of Bio-Rad AG1-X2 resin slurry (1: 3) was added to terminate the reaction. An aliquot of 200 μl was taken and counted by liquid scintillation.
[270] Percent inhibition of maximal substrate conversion (inhibition by enzymes without inhibitor) was calculated for each concentration of test compound. IC ₅₀ was determined using the GraphPad Prism nonlinear regression assay (Type S dose response) by plotting the percent inhibition versus the log value of the test compound concentration. K _m of the enzyme substrate concentration << under the conditions of (herein, K _m = substrate concentration at the time of reaching the half of the maximum enzyme rate) K _i is consistent with the IC ₅₀ value.
[271] Mass spectrum and PDEV inhibitory activity of the representative compounds according to the present invention are shown in Table 6-7. Inhibition data is expressed as IC ₅₀ (μM) or expressed as Ki value as percent inhibition at a given concentration of test compound.
[272] TABLE 6
[273]
[274]
[275]
[276]
[277]
[278]
[279] TABLE 7
[280]
[281]
[282]
[283] Example 12
[284] In vivo testing
[285] The compounds according to the invention were tested for in vivo effects by Carter et al. (Carter, A.J., Ballard, S. A., and Naylor, A.M.) according to the methods described in The Journal of Urology 1998, 160, 242-246.
[286] Example 13
[287] As a specific embodiment of the oral composition, 100 mg of the compound of Example 7 was formulated with a total amount of 580-590 mg to fill O size hard gel capsules with sufficiently finely divided lactose.
[288] While the foregoing specification discloses the principles of the invention by providing examples for purposes of illustration, the practice of the invention will then encompass all routine variations, adaptations and / or modifications within the scope of the claims and their equivalents. .

权利要求:
Claims (14)
[1" claim-type="Currently amended] A compound of formula (I) and a pharmaceutically acceptable salt thereof:

In the above formula
R ¹ is independently halogen, nitro, hydroxy, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -NH ₂ , -NHR ^A , -N (R ^A ) ₂ , -OR ^A , -C (O ) NH ₂ , -C (O) NHR ^A , -C (O) N (R ^A ) ₂ , -NC (O) -R ^A , -SO ₂ NHR ^A , -SO ₂ N (R ^A ) ₂ , phenyl (Optionally substituted by 1 to 3 R ^B ) and heteroaryl (optionally substituted by 1 to 3 R ^B );
Wherein each R ^A is independently C ₁ -C ₈ alkyl, aryl (optionally substituted by 1 to 3 R ^B ), C ₁ -C ₈ aralkyl (optionally substituted by 1 to 3 R ^B ) ) And heteroaryl (optionally substituted by 1 to 3 R ^B );
Wherein each R ^B is independently halogen, hydroxy, nitro, cyano, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkoxycarbonyl, carboxyC ₁ -C ₈ alkyl, C ₁ -C ₈ alkylsulfonyl, trifluoromethyl, trifluoromethoxy, amino, acetylamino, di (C ₁ -C ₈ alkyl) amino, di (C ₁ -C ₈ alkyl) aminoC ₁ -C ₈ Alkoxy, di (C ₁ -C ₈ alkyl) aminoacetylC ₁ -C ₈ alkyl, di (C ₁ -C ₈ alkyl) aminoacetylamino, carboxyC ₁ -C ₈ alkylcarbonylamino, hydroxyC ₁ -C ₈ alkylamino, NHR ^A , N (R ^A ) ₂ and heterocycloalkylC ₁ -C ₈ alkoxy;
n is an integer from 0 to 4;
X is selected from the group consisting of O, S and NR ^D ;
Wherein R ^D is hydrogen, hydroxy, -OR ^A , C ₁ -C ₈ alkyl, wherein alkyl is halogen, carboxy, amino, C ₁ -C ₈ alkylamino, di (C ₁ -C ₈ alkyl) amino, Optionally substituted by 1 to 3 substituents independently selected from C ₁ -C ₈ alkoxycarbonyl, heteroaryl or heterocycloalkyl; heteroaryl and heteroarylcarbonyl, wherein heteroaryl is substituted for phenyl or substituted phenyl May be optionally substituted, wherein the phenyl substituent is 1 to 3 R ^B );
R ² is optionally substituted by C ₅ -C ₁₀ alkyl (optionally substituted by 1 to 3 R ^C ), aryl (optionally substituted by 1 to 3 R ^B ), heteroaryl (optionally by 1 to 3 R ^B Substituted) and heterocycloalkyl (optionally substituted by 1 to 3 R ^B );
Wherein each R ^C is independently selected from the group consisting of halogen, hydroxy, nitro, NH ₂ , NHR ^A and N (R ^A ) ₂ ;
Z is selected from the group consisting of CH ₂ , CHOH and C (O); Provided that when Z is CHOH or C (O) X is NH;
R ⁴ is hydrogen, hydroxy, carboxy, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, di (C ₁ -C ₈ alkyl) aminoalkoxycarbonyl, di (C ₁ -C ₈ alkyl ) AminoC ₁ -C ₈ alkylaminocarbonyl, and -COR ^F ;
R here^FIs C_One-C₈Alkyl, NH₂, NHR^A, NR^A ₂, -C_One-C₈Alkyl-NH₂, -C_One-C₈Alkyl-NHR^A, -C_One-C₈Alkyl-NR^A ₂And -NH-C_One-C₈Alkyl-NR^A ₂Is selected from the group consisting of;
a is an integer from 0 to 1;
Y is selected from the group consisting of CH ₂ , C (O), C (O) O, C (O) —NH and SO ₂ ;
Is selected from the group consisting of naphthyl, heteroaryl and heterocycloalkyl;
m is an integer from 0 to 2;
R ³ is independently halogen, nitro, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, trifluoromethyl, trifluoromethoxy, phenyl (optionally substituted by 1 to 3 R ^B ), phenylsul Polyvinyl, naphthyl, C ₁ -C ₈ aralkyl, heteroaryl (optionally substituted by one to three R ^B ), NH ₂ , NHR ^A , and N (R ^A ) ₂ ;
only, If this is 2-furyl or 2-thienyl, m is an integer of 1-2.
[2" claim-type="Currently amended] The method of claim 1,
n is 0;
X is selected from S or NR ^D , wherein R ^D is hydrogen, haloC ₁ -C ₆ alkyl, di (C ₁ -C ₄ alkyl) aminoC ₁ -C ₆ alkyl, heteroaryl, heteroarylC _1- C ₄ alkyl, heterocycloalkylC ₁ -C ₄ alkyl, carboxyC ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxycarbonylC ₁ -C ₄ alkyl and heteroarylcarbonyl; Heteroaryl here is also optionally substituted by phenyl or substituted phenyl, wherein the phenyl substituent is one or two independently selected from R ^B ;
Wherein each R ^B is independently halogen, nitro, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, trifluoromethyl, trifluoromethoxy, amino and di (C ₁ -C ₄ alkyl) amino Is selected from the configured group;
R ² is 3,4-methylenedioxyphenyl, 3,4- (difluoro) methylenedioxyphenyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo- [1,4] -di It is selected from the group consisting of auxin-6-yl, pyridyl, phenyl and substituted phenyl; Wherein the phenyl substituent is halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, trifluoromethyl, cyano, nitro, C ₁ -C ₄ alkoxycarbonyl, di (C ₁ -C ₄ alkyl) amino Or one or two independently selected from di (C ₁ -C ₄ alkyl) aminoC ₁ -C ₄ alkoxy;
R ⁴ is hydrogen, carboxy, C ₁ -C ₄ alkoxycarbonyl, di (C ₁ -C ₄ alkyl) aminoC ₁ -C ₄ alkoxycarbonyl and di (C ₁ -C ₄ alkyl) aminoC ₁ -C ₄ Selected from the group consisting of alkylaminocarbonyl;
Y is selected from the group consisting of C (O), SO ₂ and CH ₂ ;
Is selected from the group consisting of naphthyl and heteroaryl;
R ³ is independently halogen, nitro, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, trifluoromethyl, C ₁ -C ₄ aralkyl, pyrazinyl, pyridyl, halogen substituted pyridyl, dimethyl substitution Imidazolyl, phenyl, phenylsulfonyl and substituted phenyl; Wherein the phenyl substituent is halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, trifluoromethyl, trifluoromethoxy, nitro, amino, acetylamino, C ₁ -C ₄ alkylsulfonyl, CarboxyC ₁ -C ₄ alkylcarbonylamino, hydroxyC ₁ -C ₄ alkylamino, di (C ₁ -C ₄ alkyl) aminoC ₁ -C ₄ alkoxy, di (C ₁ -C ₄ alkyl) aminoacetylamino Or one or two independently selected from heterocycloalkylC ₁ -C ₄ alkoxy;
only, If this is 2-furyl or 2-thienyl, m is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein m is an integer from 1 to 2.
[3" claim-type="Currently amended] The method of claim 2,
X is selected from S or NR ^D , wherein R ^D is hydrogen, di (methyl) aminoethyl, di (methyl) amino-n-propyl, di (ethyl) aminoethyl, di (ethyl) amino-n-butyl , N-pyrrolidinylethyl, N-morpholinylethyl, 2-pyridylmethyl, 4-pyridylmethyl, 5- (4-methylphenyl) -2-pyrimidinyl, carboxymethyl, carboxyethyl, 4-chloro -n-butyl, 2- (5- (3-trifluoromethylphenyl) furyl) carbonyl, 2- (5- (3-nitrophenyl) furyl) carbonyl, methoxycarbonylmethyl, methoxycarbonylethyl And 2-benzoxazolyl;
R ² is phenyl, 3,4-methylenedioxyphenyl, 3,4- (difluoro) methylenedioxyphenyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo- [1,4] -Dioxin-6-yl, 4-pyridyl, 3-pyridyl, 4-cyanophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 3,4 -Dimethylphenyl, 3,5-dimethylphenyl, 3,4-dimethoxyphenyl, 3-trifluoromethyl-4-chlorophenyl, 3,4-dichlorophenyl, 4-chlorophenyl, 4-methoxycarbonylphenyl , 3,4-dimethoxyphenyl, 4- (dimethylamino) phenyl and 4- (N- (3-dimethylamino) -n-propoxy) phenyl,
R ⁴ is selected from the group consisting of hydrogen, carboxy, dimethylaminoethoxycarbonyl, dimethylaminoethylaminocarbonyl and methoxycarbonyl;
Is naphthyl, 2-pyrimidinyl, 2-furyl, 3-furyl, 2-benzofuryl, 2-thienyl, 2-benzothienyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-benzimi Dazolyl, 4-thiazolyl, 2-thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3- (1,2,5-triazolyl), 4-isoxazolyl, 2-pyri Is selected from the group consisting of dill and 3-pyridyl;
R ³ is chloro, bromo, methyl, n-propyl, t-butyl, methoxy, trifluoromethyl, nitro, phenyl, benzyl, phenylsulfonyl, 4-hydroxyphenyl, 4-chlorophenyl, 4-methylphenyl , 3,4-dimethoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 5-trifluoromethylphenyl, 4-methoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl , 3-aminophenyl, 4-aminophenyl, 2-nitro-4-chlorophenyl, 2-nitro-4-methylphenyl, 2-nitro-4-methylsulfonylphenyl, 3-acetylaminophenyl, 4-acetylaminophenyl , 4- (3-carboxy-n-propyl) carbonylaminophenyl, 2-chloro-5-trifluoromethylphenyl, 4- (4-hydroxy-n-butyl) aminophenyl, 2- (dimethylamino) acetyl Aminophenyl, 4- [2- (N-pyrrolidinyl) ethoxy] phenyl, 4- [2- (4-morpholinyl) ethoxy] phenyl, 4- (2- (dimethylamino) ethoxy) phenyl , 4-pyrazinyl, 2,3-dimethyl-3H-imidazolyl, 2-pyridyl and 3-pyridyl It is selected from the group;
only, If this is 2-furyl or 2-thienyl, m is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein m is an integer from 1 to 2.
[4" claim-type="Currently amended] The method of claim 3,
X is NR ^D , wherein R ^D is hydrogen, di (methyl) aminoethyl, 4-pyridylmethyl, 2-pyridylmethyl, N-morpholinylethyl, carboxyethyl, carboxymethyl, di (ethyl) amino Is selected from the group consisting of ethyl, N-pyrrolidinylethyl and 5- (4-methylphenyl) -2-pyrimidinyl;
R ² is selected from the group consisting of 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl and 2,3-dihydrobenzo- [1,4] -dioxin-6-yl;
R ⁴ is hydrogen;
Y is selected from the group consisting of C (O) and CH ₂ ;
Is naphthyl, 2-pyrimidinyl, 2-furyl, 2-benzofuryl, 2-thienyl, 2-benzothienyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-thiazolyl, 4-thia Is selected from the group consisting of zolyl and 2-pyridyl;
m is an integer from 0 to 1;
R ³ is bromo, t-butyl, methoxy, trifluoromethyl, nitro, phenyl, 4-chlorophenyl, 3,4-dimethoxyphenyl, 3-trifluoromethylphenyl, 4-methylphenyl, 4-methoxy Phenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-aminophenyl, 2-nitro-4-chlorophenyl, 2-nitro-4-methylphenyl, 2-nitro-4-methylsulfonylphenyl, 4- (3-carboxy-n-propyl) carbonylaminophenyl, 2-chloro-5-trifluoromethylphenyl, 4- (4-hydroxy-n-butyl) aminophenyl, 2-2- (dimethylamino) Acetylaminophenyl, 4-pyrazinyl, 2-pyridyl and 2,3-dimethyl-3H-imidazol-4-yl;
only, If this is 2-furyl or 2-thienyl, m is 1, or a pharmaceutically acceptable salt thereof.
[5" claim-type="Currently amended] The method of claim 4, wherein
X is NR ^D , wherein R ^D is selected from the group consisting of hydrogen, di (methyl) aminoethyl, N-morpholinylethyl, carboxymethyl and N-pyrrolidinylethyl;
R ² is selected from the group consisting of 3,4-methylenedioxyphenyl and 2,3-dihydrobenzofuryl;
Z is selected from the group consisting of CH ₂ and C (O); Provided that when Z is C (O) X is NH;
Y is C (O);
Is selected from the group consisting of 2-pyrimidinyl, 2-furyl, 2-benzofuryl, 2-benzoxazolyl, 2-thiazolyl and 2-pyridyl;
R ³ is t-butyl, methoxy, nitro, phenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3-trifluoromethylphenyl, 2-nitrophenyl, 3 -Nitrophenyl, 4-nitrophenyl, 3-aminophenyl, 2-nitro-4-methylsulfonylphenyl, 2- (dimethylamino) acetylaminophenyl, 2-pyridyl and 2,3-dimethyl-3H-imidazole Selected from the group consisting of -4-yl;
only, If this is 2-furyl, m is 1 or a pharmaceutically acceptable salt thereof.
[6" claim-type="Currently amended] The method of claim 3,
1- (3,4-methylenedioxyphenyl) -2-[(5-phenyl-2-furyl) carbonyl] -2,3,4,9-tetrahydro-1H-β-carboline;
1- (3,4-methylenedioxyphenyl) -2- [5- (2-pyridyl) -2-pyrimidinyl] -9-di (methyl) aminoethyl-2,3,4,9-tetra Hydro-1H-β-carboline;
1- (3,4-methylenedioxyphenyl) -2- [5- (3,4-dimethoxyphenyl) -2-pyrimidinyl] -1,2,3,9-tetrahydro-4-oxo- 4H-β-carboline;
1- (3,4-methylenedioxyphenyl) -2- [5- (4-methylphenyl) -2-pyrimidinyl] -1,2,3,9-tetrahydro-4-oxo-4H-β- Carboline;
1- (3,4-methylenedioxyphenyl) -2- [5- (4-methoxyphenyl) -2-pyrimidinyl] -1,2,3,4-tetrahydro-4-oxo-4H- β-carboline;
1- (3,4-methylenedioxyphenyl) -2- [4- (4-methoxyphenyl) -2-thiazolyl] -2,3,4,9-tetrahydro-1H-β-carboline;
1- (3,4-methylenedioxyphenyl) -2- (4-phenyl-2-thiazolyl) -2,3,4,9-tetrahydro-1H-β-carboline;
2- [2,3 '] bipyridinyl-6'-yl-1- (2,3-dihydro-benzofuran-5-yl) -2,3,4,9-tetrahydro-1H-β- Carboline; And
1- (2,3-dihydrobenzofuran-5-yl) -2- [5- (2,3-dimethyl-3H-imidazol-4-yl) -2,3-2,3,4,9 A compound selected from the group consisting of tetrahydro-1H-β-carboline and a pharmaceutically acceptable salt thereof.
[7" claim-type="Currently amended] A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1.
[8" claim-type="Currently amended] A pharmaceutical composition prepared by mixing the compound of claim 1 and a pharmaceutically acceptable carrier.
[9" claim-type="Currently amended] A method for preparing a pharmaceutical composition, characterized in that the compound of claim 1 and a pharmaceutically acceptable carrier are mixed.
[10" claim-type="Currently amended] A method of treating sexual dysfunction characterized by administering an effective amount of a compound of claim 1 to a patient in need thereof.
[11" claim-type="Currently amended] The method of claim 10, wherein the sexual dysfunction is male impotence.
[12" claim-type="Currently amended] 11. The method of claim 10, wherein the sexual dysfunction is in a group consisting of male hypogonadism, male impotence, impotence, female sexual dysfunction, female sexual arousal dysfunction, and female sexual dysfunction associated with blood flow and nitrate production in the vaginal and clitoris tissues. The method selected.
[13" claim-type="Currently amended] A method for increasing the concentration of cGMP in penile tissues comprising administering to a male patient in need thereof an effective amount of the compound of claim 1.
[14" claim-type="Currently amended] A female in need of treatment for administering an effective amount of the compound of claim 1, characterized by impotence in males (ED), impotence, female sexual dysfunction, and women involved in blood flow and nitrate production in the vagina and clitoris tissue. Sexual dysfunction, premature birth, dysmenorrhea, cardiovascular disease, atherosclerosis, obstructive artery disease, thrombosis, coronary rest stenosis, angina pectoris, myocardial infarction, heart failure, ischemic heart disease, hypertension, pulmonary hypertension, asthma, intermittent A method for treating a symptom selected from the group consisting of claudication and diabetes complications.

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同族专利:

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公开号 | 公开日

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KR100852366B1|2008-08-14|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2000-05-17|Priority to US60/204,667

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2001-05-03|Application filed by 오르토-맥네일 파마슈티칼, 인코퍼레이티드

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2001-05-03|Priority to KR20027015583A

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2002-12-26|Publication of KR20020095481A

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2008-08-14|Application granted

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2008-08-14|Publication of KR100852366B1

优先权:

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申请号 | 申请日 | 专利标题

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US60/204,667|2000-05-17|

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KR20027015583A|KR100852366B1|2000-05-17|2001-05-03|Carboline derivatives useful as inhibitors of phosphodiesterase T|