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【结 构 式】 
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【药物名称】HMR-4902, KW-3902 【化学名称】8-(Octahydro-2,5-methanopentalen-3a-yl)-1,3-dipropylxanthine 【CA登记号】136199-02-5 【 分 子 式 】C20H28N4O2 【 分 子 量 】356.47176 |
【开发单位】Kyowa Hakko (Originator), Aventis Pharma (Licensee), NovaCardia (Licensee) 【药理作用】CARDIOVASCULAR DRUGS, Diuretics, Heart Failure Therapy, Renal Failure, Agents for, RENAL-UROLOGIC DRUGS, Treatment of Renal Diseases, Adenosine A1 Antagonists |
合成路线1
a) A synthetic method is presented: Acylation of 1,3-dipropyl-5,6-diaminouracil (I) with a 3-noradamantane carboxylic acid (II) gave (III). Treatment of (III) with aqueous NaOH afforded the cyclized product KW-3902.
| 【1】 Suzuki, F.; Shimada, J.; Kubo, K.; Ohno, T.; Karasawa, A.; Ishii, A.; Hiromi, N. (Kyowa Hakko Kogyo Co., Ltd.); Xanthine derivs. EP 0386675; JP 1991173888; US 5068236 . |
| 【2】 Ohno, T.; Nonaka, H.; Karasawa, A.; Kubo, K.; Suzuki, F.; Mizumoto, H.; Shimada, J.; Ishii, A.; 8-(Dicyclopropylmethyl)-1,3-dipropylxanthine: A potent and selective adenosine A1 antagonist with renal protective and diuretic activities. J Med Chem 1991, 34, 1, 466-9. |
| 【3】 Suzuki, F.; KW-3902. Drugs Fut 1992, 17, 10, 876. |
| 【4】 Ohno, T.; Ishii, A.; Suzuki, F.; Karasawa, A.; Nonaka, H.; Kubo, K.; Shimada, J.; Mizumoto, H.; 8-Polycycloalkyl-1,3-dipropylxanthines as potent and selective antagonists for A1-adenosine receptors. J Med Chem 1992, 35, 5, 924. |
| 【5】 Karasawa, A.; Nonaka, H.; Suzuki, F.; Ishii, A.; Mizumoto, H.; Shimada, J.; Kubo, K.; A. Structure-activity relationships on diuretic activities and protective effects against acute renal failure. J Med Chem 1992, 35, 16, 3066. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 14628 | 5,6-diamino-1,3-dipropyl-2,4(1H,3H)-pyrimidinedione | C10H18N4O2 | 详情 | 详情 | |
| (II) | 14629 | tricyclo[3.3.1.0(3,7)]nonane-3-carboxylic acid; 3-Noradamantanecarboxylic acid | 16200-53-6 | C10H14O2 | 详情 | 详情 |
| (III) | 14630 | N-(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-5-pyrimidinyl)tricyclo[3.3.1.0(3,7)]nonane-3-carboxamide | C20H30N4O3 | 详情 | 详情 |
合成路线2
The oxidation of tricyclo[3.3.1.03,7]nonane-3-carboxylic acid methyl ester (I) with CrO3 in acetic anhydride/acetic acid gives a mixture of the 9-oxo and 6-oxo isomers (II), which is condensed with 5,6-diamino-1,3-dipropylpyrimidine-2,4(1H,3H)-dione (III) by means of LiOH, and after HPLC separation yields the 9-oxo isomer (IV) of the condensation product. The cyclization of (IV) by means of Ca(OH)2 affords the 1,3-dipropylxanthine derivative (V), which is finally reduced with LiBH4 to a mixture of isomers that is separated by HPLC yielding finally metabolite M1.
| 【1】 Shimada, J.; Eguchi, T.; Yasuzawa, T.; Nakamura, A.; Horiguchi, A.; Mochida, K.; Suzuki, F.; Synthesis of rat metabolites of a adenosine A1 antagonist, KW-3902. Symp Med Chem 1996, Abst 1-P-24. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIa) | 20541 | methyl 9-oxotricyclo[3.3.1.0(3,7)]nonane-3-carboxylate | C11H14O3 | 详情 | 详情 | |
| (IIb) | 20542 | methyl 6-oxotricyclo[3.3.1.0(3,7)]nonane-3-carboxylate | C11H14O3 | 详情 | 详情 | |
| M1 | 63837 | 8-(9-hydroxytricyclo[3.3.1.0~3,7~]non-3-yl)-1,3-dipropyl-3,7-dihydro-1H-purine-2,6-dione | C20H28N4O3 | 详情 | 详情 | |
| (I) | 20540 | methyl tricyclo[3.3.1.0(3,7)]nonane-3-carboxylate | C11H16O2 | 详情 | 详情 | |
| (III) | 14628 | 5,6-diamino-1,3-dipropyl-2,4(1H,3H)-pyrimidinedione | C10H18N4O2 | 详情 | 详情 | |
| (IV) | 20544 | N-(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-5-pyrimidinyl)-9-oxotricyclo[3.3.1.0(3,7)]nonane-3-carboxamide | C20H28N4O4 | 详情 | 详情 | |
| (V) | 20545 | 8-(9-oxotricyclo[3.3.1.0(3,7)]non-3-yl)-1,3-dipropyl-3,7-dihydro-1H-purine-2,6-dione | C20H26N4O3 | 详情 | 详情 |
合成路线3
The condensation of 9-oxotricyclo[3.3.1.03,7]nonane-3-carboxylic acid methyl ester (II) with 5,6-diamino-1-propylpyrimidine-2,4(1H,3H)-dione (VI) by means of LiOH gives the expected condensation product (VII), which by reduction with NaBH4 and HPLC separation yields the exo-hydroxy isomer (VIII). The condensation of (VIII) with bromoacetone (IX) by means of cesium carbonate affords compound (X), which is cyclized with Ca(OH)2 as before to give metabolite M3. Finally, this compound is reduced with NaBH4 to afford metabolite M2.
| 【1】 Shimada, J.; Eguchi, T.; Yasuzawa, T.; Nakamura, A.; Horiguchi, A.; Mochida, K.; Suzuki, F.; Synthesis of rat metabolites of a adenosine A1 antagonist, KW-3902. Symp Med Chem 1996, Abst 1-P-24. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIa) | 20541 | methyl 9-oxotricyclo[3.3.1.0(3,7)]nonane-3-carboxylate | C11H14O3 | 详情 | 详情 | |
| M3 | 63838 | 8-(9-hydroxytricyclo[3.3.1.0~3,7~]non-3-yl)-1-(2-oxopropyl)-3-propyl-3,7-dihydro-1H-purine-2,6-dione | C20H26N4O4 | 详情 | 详情 | |
| M2 | 63839 | 1-(2-hydroxypropyl)-8-(9-hydroxytricyclo[3.3.1.0~3,7~]non-3-yl)-3-propyl-3,7-dihydro-1H-purine-2,6-dione | C20H28N4O4 | 详情 | 详情 | |
| (V) | 20545 | 8-(9-oxotricyclo[3.3.1.0(3,7)]non-3-yl)-1,3-dipropyl-3,7-dihydro-1H-purine-2,6-dione | C20H26N4O3 | 详情 | 详情 | |
| (VI) | 20546 | 5,6-diamino-1-propyl-2,4(1H,3H)-pyrimidinedione | C7H12N4O2 | 详情 | 详情 | |
| (VII) | 20547 | N-(6-amino-2,4-dioxo-1-propyl-1,2,3,4-tetrahydro-5-pyrimidinyl)-9-oxotricyclo[3.3.1.0(3,7)]nonane-3-carboxamide | C17H22N4O4 | 详情 | 详情 | |
| (VIII) | 20548 | N-(6-amino-2,4-dioxo-1-propyl-1,2,3,4-tetrahydro-5-pyrimidinyl)-9-hydroxytricyclo[3.3.1.0(3,7)]nonane-3-carboxamide | C17H24N4O4 | 详情 | 详情 | |
| (IX) | 20549 | 1-bromoacetone | 598-31-2 | C3H5BrO | 详情 | 详情 |
| (X) | 20550 | N-[6-amino-2,4-dioxo-3-(2-oxopropyl)-1-propyl-1,2,3,4-tetrahydro-5-pyrimidinyl]-9-hydroxytricyclo[3.3.1.0(3,7)]nonane-3-carboxamide | C20H28N4O5 | 详情 | 详情 |
合成路线4
The selective biological hydroxylation of compounds (XI) by means of Absidia ramosa FERM BP-4605 in corn steep liquor, glucose, Brig 35 at 28 C, 5-7 days gives metabolites M3.
| 【1】 Shimada, J.; Eguchi, T.; Yasuzawa, T.; Nakamura, A.; Horiguchi, A.; Mochida, K.; Suzuki, F.; Synthesis of rat metabolites of a adenosine A1 antagonist, KW-3902. Symp Med Chem 1996, Abst 1-P-24. |
合成路线5
The selective biological hydroxylation of compounds (XII) by means of Absidia ramosa FERM BP-4605 in corn steep liquor, glucose, Brig 35 at 28 C, 5-7 days gives metabolites M1.
| 【1】 Shimada, J.; Eguchi, T.; Yasuzawa, T.; Nakamura, A.; Horiguchi, A.; Mochida, K.; Suzuki, F.; Synthesis of rat metabolites of a adenosine A1 antagonist, KW-3902. Symp Med Chem 1996, Abst 1-P-24. |
合成路线6
The selective biological hydroxylation of compounds (XIII) by means of Absidia ramosa FERM BP-4605 in corn steep liquor, glucose, Brig 35 at 28 C, 5-7 days gives metabolites M2.
| 【1】 Shimada, J.; Eguchi, T.; Yasuzawa, T.; Nakamura, A.; Horiguchi, A.; Mochida, K.; Suzuki, F.; Synthesis of rat metabolites of a adenosine A1 antagonist, KW-3902. Symp Med Chem 1996, Abst 1-P-24. |