(2-萘氧基)醋酸N-羟基丁二酰亚胺酯 | 81012-92-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: (2-萘氧基)醋酸N-羟基丁二酰亚胺酯
• 中文别名: N-琥珀酰亚胺基-2-萘氧乙酸酯
• 英文名称: (2-naphthoxy)acetic acid N-hydroxysuccinimide ester
• 英文别名: Succinimidyl 2-naphthoxyacetate；(2,5-dioxopyrrolidin-1-yl) 2-naphthalen-2-yloxyacetate
• CAS: 81012-92-2
• 化学式: C₁₆H₁₃NO₅
• 分子量: 299.283
• InChiKey: CUSRGDOKYSVDPX-UHFFFAOYSA-N

物化性质

• 熔点：
  150-152 °C(lit.)
• 沸点：
  440.61°C (rough estimate)
• 密度：
  1.2365 (rough estimate)
• 稳定性/保质期：
  遵照规定使用和储存，则不会发生分解。

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.187
• 拓扑面积：
  72.9
• 氢给体数：
  0
• 氢受体数：
  5

安全信息

• 安全说明：
  S24/25
• 海关编码：
  2925190090
• 储存条件：
  存储于0至6℃的阴凉干燥处。

SDS

Name:	(2-Naphthoxy)Acetic Acid N-Hydroxysuccinimide Ester 98% Material Safety Data Sheet
Synonym:	None Known
CAS:	81012-92-2

Section 1 - Chemical Product MSDS Name:(2-Naphthoxy)Acetic Acid N-Hydroxysuccinimide Ester 98% Material Safety Data Sheet
Synonym:None Known

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Section 2 - COMPOSITION, INFORMATION ON INGREDIENTS

CAS#	Chemical Name	content	EINECS#
81012-92-2	(2-Naphthoxy)Acetic Acid, N-Hydroxysuc	98	279-655-1

Hazard Symbols: None Listed.
Risk Phrases: None Listed.

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Section 3 - HAZARDS IDENTIFICATION
EMERGENCY OVERVIEW
Moisture sensitive.The toxicological properties of this material have not been fully investigated.
Potential Health Effects
Eye:
May cause eye irritation.
Skin:
May cause skin irritation.
Ingestion:
May cause irritation of the digestive tract. The toxicological properties of this substance have not been fully investigated.
Inhalation:
May cause respiratory tract irritation. The toxicological properties of this substance have not been fully investigated.
Chronic:
No information found.

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Section 4 - FIRST AID MEASURES
Eyes: Flush eyes with plenty of water for at least 15 minutes, occasionally lifting the upper and lower eyelids. Get medical aid.
Skin:
Get medical aid. Flush skin with plenty of water for at least 15 minutes while removing contaminated clothing and shoes. Wash clothing before reuse.
Ingestion:
Never give anything by mouth to an unconscious person. Get medical aid. Do NOT induce vomiting. If conscious and alert, rinse mouth and drink 2-4 cupfuls of milk or water.
Inhalation:
Remove from exposure and move to fresh air immediately. If not breathing, give artificial respiration. If breathing is difficult, give oxygen. Get medical aid.
Notes to Physician:

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Section 5 - FIRE FIGHTING MEASURES
General Information:
As in any fire, wear a self-contained breathing apparatus in pressure-demand, MSHA/NIOSH (approved or equivalent), and full protective gear. During a fire, irritating and highly toxic gases may be generated by thermal decomposition or combustion. Runoff from fire control or dilution water may cause pollution.
Extinguishing Media:
In case of fire, use water, dry chemical, chemical foam, or alcohol-resistant foam. Use agent most appropriate to extinguish fire. Do NOT get water inside containers.

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Section 6 - ACCIDENTAL RELEASE MEASURES
General Information: Use proper personal protective equipment as indicated in Section 8.
Spills/Leaks:
Vacuum or sweep up material and place into a suitable disposal container. Clean up spills immediately, observing precautions in the Protective Equipment section. Avoid generating dusty conditions.
Provide ventilation. Do not get water inside containers.

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Section 7 - HANDLING and STORAGE
Handling:
Wash thoroughly after handling. Remove contaminated clothing and wash before reuse. Use with adequate ventilation. Minimize dust generation and accumulation. Avoid contact with eyes, skin, and clothing. Keep container tightly closed. Avoid ingestion and inhalation. Do not allow contact with water. Keep from contact with moist air and steam.
Storage:
Store in a tightly closed container. Keep refrigerated. (Store below 4C/39F.) Store protected from moisture.

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Section 8 - EXPOSURE CONTROLS, PERSONAL PROTECTION
Engineering Controls:
Facilities storing or utilizing this material should be equipped with an eyewash facility and a safety shower. Use process enclosure, local exhaust ventilation, or other engineering controls to control airborne levels.
Exposure Limits CAS# 81012-92-2: Personal Protective Equipment Eyes: Wear appropriate protective eyeglasses or chemical safety goggles as described by OSHA's eye and face protection regulations in 29 CFR 1910.133 or European Standard EN166.
Skin:
Wear appropriate protective gloves and clothing to prevent skin exposure.
Clothing:
Wear appropriate protective clothing to minimize contact with skin.
Respirators:
Follow the OSHA respirator regulations found in 29 CFR 1910.134 or European Standard EN 149. Use a NIOSH/MSHA or European Standard EN 149 approved respirator if exposure limits are exceeded or if irritation or other symptoms are experienced.

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Section 9 - PHYSICAL AND CHEMICAL PROPERTIES

Physical State: Powder
Color: white to off-white
Odor: None reported.
pH: Not available.
Vapor Pressure: Not available.
Viscosity: Not available.
Boiling Point: Not available.
Freezing/Melting Point: 150.00 - 152.00 deg C
Autoignition Temperature: Not available.
Flash Point: Not available.
Explosion Limits, lower: Not available.
Explosion Limits, upper: Not available.
Decomposition Temperature:
Solubility in water:
Specific Gravity/Density:
Molecular Formula: C16H13NO5
Molecular Weight: 299.27

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Section 10 - STABILITY AND REACTIVITY
Chemical Stability:
Stable under normal temperatures and pressures. May decompose on exposure to moist air or water.
Conditions to Avoid:
Incompatible materials, dust generation, moisture, excess heat, strong oxidants.
Incompatibilities with Other Materials:
Moisture, oxidizing agents, strong acids.
Hazardous Decomposition Products:
Nitrogen oxides, carbon monoxide, irritating and toxic fumes and gases, carbon dioxide, nitrogen.
Hazardous Polymerization: Has not been reported.

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Section 11 - TOXICOLOGICAL INFORMATION
RTECS#:
CAS# 81012-92-2 unlisted.
LD50/LC50:
Not available.
Carcinogenicity:
(2-Naphthoxy)Acetic Acid, N-Hydroxysuccinimide Ester - Not listed by ACGIH, IARC, or NTP.

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Section 12 - ECOLOGICAL INFORMATION

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Section 13 - DISPOSAL CONSIDERATIONS
Dispose of in a manner consistent with federal, state, and local regulations.

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Section 14 - TRANSPORT INFORMATION

IATA
Shipping Name: Not regulated.
Hazard Class:
UN Number:
Packing Group:
IMO
Shipping Name: Not regulated.
Hazard Class:
UN Number:
Packing Group:
RID/ADR
Shipping Name: Not regulated.
Hazard Class:
UN Number:
Packing group:

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Section 15 - REGULATORY INFORMATION

European/International Regulations
European Labeling in Accordance with EC Directives
Hazard Symbols: Not available.
Risk Phrases:
Safety Phrases:
S 24/25 Avoid contact with skin and eyes.
WGK (Water Danger/Protection)
CAS# 81012-92-2: No information available.
Canada
None of the chemicals in this product are listed on the DSL/NDSL list.
CAS# 81012-92-2 is not listed on Canada's Ingredient Disclosure List.
US FEDERAL
TSCA
CAS# 81012-92-2 is not listed on the TSCA inventory.
It is for research and development use only.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

反应信息

• 作为反应物：
  描述：

  (2-萘氧基)醋酸N-羟基丁二酰亚胺酯 在 potassium carbonate 、 四丁基溴化铵 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 丙酸 、 乙酸乙酯 为溶剂， 反应 10.5h， 生成 N-(2-(benzo[d]oxazol-2-yl)ethyl)-2-(naphthalen-2-yloxy)acetamide
  参考文献：
  名称：

  Synthesis, Biological Evaluation, and Structure–Activity Relationships of Potent Noncovalent and Nonpeptidic Cruzain Inhibitors as Anti-Trypanosoma cruzi Agents

  摘要：

  The development of cruzain inhibitors has been driven by the urgent need to develop novel and more effective drugs for the treatment of Chagas' disease. Herein, we report the lead optimization of a class of noncovalent cruzain inhibitors, starting from an inhibitor previously cocrystallized with the enzyme (K(i) = 0.8 μM). With the goal of achieving a better understanding of the structure-activity relationships, we have synthesized and evaluated a series of over 40 analogues, leading to the development of a very promising competitive inhibitor (8r, IC50 = 200 nM, K(i) = 82 nM). Investigation of the in vitro trypanocidal activity and preliminary cytotoxicity revealed the potential of the most potent cruzain inhibitors in guiding further medicinal chemistry efforts to develop drug candidates for Chagas' disease.

  DOI：

  10.1021/jm401709b
• 作为产物：
  描述：

  2-萘氧乙酸 在 草酰氯 、 三乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.25h， 生成 (2-萘氧基)醋酸N-羟基丁二酰亚胺酯
  参考文献：
  名称：

  Synthesis, Biological Evaluation, and Structure–Activity Relationships of Potent Noncovalent and Nonpeptidic Cruzain Inhibitors as Anti-Trypanosoma cruzi Agents

  摘要：

  The development of cruzain inhibitors has been driven by the urgent need to develop novel and more effective drugs for the treatment of Chagas' disease. Herein, we report the lead optimization of a class of noncovalent cruzain inhibitors, starting from an inhibitor previously cocrystallized with the enzyme (K(i) = 0.8 μM). With the goal of achieving a better understanding of the structure-activity relationships, we have synthesized and evaluated a series of over 40 analogues, leading to the development of a very promising competitive inhibitor (8r, IC50 = 200 nM, K(i) = 82 nM). Investigation of the in vitro trypanocidal activity and preliminary cytotoxicity revealed the potential of the most potent cruzain inhibitors in guiding further medicinal chemistry efforts to develop drug candidates for Chagas' disease.

  DOI：

  10.1021/jm401709b

文献信息

• Supramolecular hydrogels based on β-amino acid derivatives
  作者：Zhimou Yang、Gaolin Liang、Bing Xu

  DOI：10.1039/b516133a

  日期：——

  Here we report on a new class of supramolecular hydrogels based on dipeptides that consist of β-amino acids, which may confer proteolytic resistance to the hydrogels for biomedical applications.

  在此，我们报告了一类基于由δ-氨基酸组成的二肽的新型超分子水凝胶，这种水凝胶可赋予生物医学应用中的水凝胶抗蛋白水解性。
• Peptide enzyme inhibitors
  申请人：Merck & Co., Inc.

  公开号：EP0209897A2

  公开（公告）日：1987-01-28

  Enzyme peptides of the formula and analogs thereof which inhibit renin and are useful for treating various forms of renin-associated hypertension and hyperaldosteronism.

  式的酶肽 及其类似物，可抑制肾素，用于治疗各种肾素相关性高血压和高醛固酮症。
• Phosphorous containing enzyme inhibitors
  申请人：Merck & Co., Inc.

  公开号：EP0210545A2

  公开（公告）日：1987-02-04

  Dipeptides and amino acids of the formula A-E-G are disclosed wherein A is, e.g., hydrogen, or a-, RbCO or RbSO2- where Ra and Rb are e.g., alkyl, cycloalkyl, or aryl; wherein R' is, e.g., alkyl; n is 0, 1; R2 is, e.g., hydrogen or alkyl; R3 is OH, NH2, , , are e.g., alkyl; R4 is, e.g., hydrogen or alkyl R6 is H or methyl; R7 is, e.g., hydrogen or alkyl; R8 is, e.g., hydrogen, methyl or cycloalkyl such that when R8 is cycloalkyl, R6 and R7 are hydrogen; R9 is, e.g., hydroxy. The compounds have enzyme inhibitor activity e.g., renin inhibition angiotensin converting enzyme inhibition. BACKGROUND OF THE INVENTION The present invention is concerned with novel compounds (substituted amino acids and dipeptides) which inhibit renin and in some instances also inhibit angiotensin converting enzyme (ACE). The present invention is also concerned with pharmaceutical compositions containing the novel compounds of the present invention as active ingredients, with thier use for treating renin and/or ACE associated conditions, with diagnostic methods which utilize these compounds, and with processes for their preparation. Small peptide inhibitors of renin have been reported by Kokubu et al. (Biochem. Biophys. Res. Communs, 118, 929 (1984)) and by Fehrentz et al. (Febs. Letts., 167, 273 (1984)), who described peptide aldehyde inhibitors. R. Matsuda et al. in European Patent Application 128,762 (Sankyo Co., Ltd., 1984) also disclose tripeptide aldehydes as renin inhibitors. Some of the compounds disclosed in the present invention also inhibit angiotensin-converting enzyme. Peptides containing aminophosphonic acids as the carboxyl-terminal components, which are inhibitors of A.C.E. have previously been reported by Y. Kido et al., in J. Antibiot. (Tokyo), 37, 965-9 (1984) and in Japanese Patent J59187-790-A (Kyowa Hakko Kogyo KK) (1984). Also, phosphinylalkanoyl substituted proline analogs which inhibit A.C.E. have previously been described by E. Petrillo et al., U. S. Patents No 4,168,267; 4,337,201 (E. R. Squibb and Sons, 1979, 1982). Compounds of no more than two amino acids or the equivalent, which incorporate phosphorous-containing elements as the carboxyl-terminal or next-to carboxyl-terminal component have been discovered. They are potent renin inhibitors and may be orally acive. SUMMARY OF THE INVENTION Compounds which 1) include dipeptides and substituted amino acids and 2) contain phosphorous having renin inhibitory activity and which may be orally active. The present invention comprises compounds of the following formula: A-E-G (I) wherein: A is hydrogen, or Ra-, RbCO or RbSO2- where Ra and Rb are alkyl, cycloalkyl, aryl, heterocyclic, heterocyclic alkyl, heterocyclic aryl, aryloxy alkyl, heterocyclic aryloxy alkyl, aryl alkyl, heterocyclic aryl alkyl, heterocyclic oxyalkyl, and Ra and Rb may be substituted with up to three members selected from amino, carboxy, alkoxy carbonyl, hydroxy, alkyl, halo and alkoxy groups. E is G is -R3 or is wherein R1 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkyl alkyl, aryl alkyl, heterocyclic, heterocyclic alkyl, heterocyclic aryl alkyl, each of which may be substituted with up to three members selected from alkyl, halo, amino and alkoxy groups. n is 0, 1. R2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkyl alkyl, aryl, aryl alkyl, heterocyclic, heterocyclic alkyl, each of which may be substituted with up to three members selected from alkyl, hydroxy, halo, amino, alkylamino, dialkylamino, and alkoxy groups. R3 is OH, NH2, , , where , , and are separately alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkyl alkyl, aryl, aryl alkyl, heterocyclic, heterocyclic alkyl, each of which may be substituted with up to three groups selected from amino, alkylamino, dialkyl amino, trialkyl ammonium, hydroxy, alkoxy, aryloxy, aryl alkoxyl, or halo; R3 may also be -CO-V- wherein is alkyl or aryl; and are hydrogen or alkyl; and V is -O- or -NH-. R4 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, each of which may be substituted with up to three members selected from amino, alkylamino, dialkylamino, trialkyl ammonium, hydroxy, alkoxy, halo or alkyl groups; or -CO4V- wherein is alkyl or aryl; and are hydrogen or alkyl; and V is -O- or -NH-. R6 is H or methyl. R7 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, aryl, cycloalkyl alkyl, aryl alkyl, heterocyclic, heterocyclic alkyl, aryloxy alkyl, heterocyclic oxy alkyl, heterocyclic oxy, each of which may be substituted with up to three groups selected from amino, alkyl amino, dialkyl amino, trialkyl ammonium, hydroxy, alkoxy, carboxy, alkoxycarbonyl, alkylthio, arylthio, thiol, guanidino, carboxamido and alkanoylamino, and when taken together with NR8 may be a cyclic amino acid of the formula: where is hydrogen, phenyl, hydroxyphenyl; X is -S- or -CH2- or -CH-; m is 1 or 2; and is cyclohexyl, phenylthio; W and Z are single bonds or -CH2-, and R3 is as defined above. R8 is hydrogen, methyl and cycloalkyl (including cyclopentyl and indanyl) such that when R8 is cycloalkyl, R6 and R7 are hydrogen. R9 is hydroxy, , -NH2, , , where , and are as defined above such that when A is absent, R9 can be where R3, 1 R6 and R7 are as defined above. In the above definitions, the terms alkyl, alk, alkenyl, and alkynyl include hydrocarbon groups having up to 8 carbon atoms which groups may be straight chain or branched chain. Preferred alkyl or alk groups have 1-4 carbon atoms. Preferred alkenyl and alkynyl groups have 3 to 6 carbon atoms. The term halo means fluoro, chloro, bromo and iodo. The aryl substituent is a hydrocarbon having 6-12 carbon atoms exemplified by phenyl, naphthyl, biphenyl and cycloalkyl-fused derivatives thereof such as indanyl and tetralinyl. The heterocyclic substituents recited above represents any 5- or 6-membered ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein the nitrogen and sulfur heteroatoms may optionally be quaternized, and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring. Heterocyclic substituents in which nitrogen is the heteroatom are preferred; and of these, those containing a single nitrogen atom are preferred. Fully saturated and fully unsaturated heterocyclic substituents are also preferred. Thus, piperidine is a preferred saturated heterocyclic substituent. Other preferred heterocyclic substituents are pyrrolidinyl, imidazolidinyl, morpholinyl, tetrahydrofuranyl thienyl, pyrimidinyl, imidazolyl, indolyl, quinolinyl, isoquinolinyl and benzothieny groups and the like. Cycloalkyl and cycloalkenyl groups contain 3 to 12 carbon atoms and may be bridged. They are exemplified by cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl, nobornenyl, adamantyl, bicyclo[3.3.0]-octanyl and perhydronaphthyl groups and the like. Preferred A units include benzyloxycarbonyl, t-butoxycarbonyl, 1-naphthyloxyacetyl, and 1-naphthyl- acetyl. Preferred E units include those with the following formulae: Preferred G substituents include -OH, -OEt, -NH2. The compounds disclosed have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers. All isomeric forms are included in the present compounds as appropriate. The stereocenters present in the E unit of the peptides of formula I are in general of the chirality which corresponds to the naturally-occurring (L) amino acids. Thus, for example, the unit E of the formula below possesses the stereochemistry shown in the preferred form: The following are illustrative examples of peptides of the present invention: 1. (N-carbobenzoxy-l-amino-2-cyclohexylethyl) 2-carboxy-4-methylpentylphosphinic acid 2. (N-carbobenzoxy-l-amino-2-cyclohexylethyl) 2-carboxy-3-methylbutylphosphinic acid 3. (N-t-butoxycarbonyl-1-amino-2-cyclohexylethyl) 2-carboxy-3-methylbutylphosphinic acid 4. (N-carbobenzoxy-l-amino-2-cyclohexylethyl) 2-carbomethoxy-4-methylpentylphosphinic acid 5. (N-carbobenzoxy-1-amino-2-cyclohexylethyl) 2-carboxamido-4-methylpentylphosphinic acid 6. (N-t-butoxycarbonyl-1-amino-2-cyclohexylethyl) 2-(N-benzyl)carboxamido-3-methylbutylphosphinic acid 7. [N-(2-phenyl)ethyl-1-amino-2-cyclohexylethyl] 2-carboxy-4-methylpentylphosphinic acid 8. [N-(N-benzyl)carboxamidomethyl-l-amino-2-cyclohexylethyl] 2-carboxy-3-methylbutylphosphinic acid 9. [N-(1-carboethoxy-2-phenylethyl)-1-amino-2-cyclohexylethyl] 2-carboxy-3-methylbutylphosphinic acid 10. (N-carbobenzoxy-1-amino-2-cyclohexylethyl)carbo- methoxymethylphosphinic acid 11. (N-carbobenzoxy-l-amino-2-cyclohexylethyl)carboxy- methylphosphinic acid 12. (N-carbobenzoxy-l-amino-2-cyclohexylethyl) carbox- amidomethylphosphinic acid 13. (N-carbobenzoxy-l-amino-2-cyclohexylethyl) 2-carboxy-3-cyclohexylpropylphosphinic acid 14. [N-(3-phenyl)propionyl-l-amino-2-cyclohexylethyl] 2-carboxy-4-methylpentylphosphinic acid 15. (N-phenoxyacetyl-l-amino-2-cyclohexylethyl) 2-carboxy-3-methylbutylphosphinic acid 16. [N-(4-amino)butanoyl-1-amino-2-cyclohexylethyl] 2-carboxy-3-methylbutylphosphinic acid 17. (N-naphthyloxyacetyl)-1-amino-2-cyclohexylethyl) 2-carboxy-3-methylbutylphosphinic acid 18. Methyl (N-carbobenzoxy-l-amino-2-cyclohexylethyl) 2-carboxy-4-methylpentylphosphinate 19. Methyl (N-carbobenzoxy-l-amino-2-cyclohexylethyl)-carbomethoxymethylphosphinate 20. Ethyl [N-(3-phenyl)propionyl-l-amino-2-cyclohexylethyl] 2-carbomethoxy-3-methylbutylphosphinate 21. [N-(1-carboethoxy-5-aminopentyl)-1-amino-2-cyclohexylethyl] 2-carboxy-3-methylbutylphosphinic acid 22. [N-(1-carbobenzoxy-5-aminopentyl)-1-amino-2-cyclohexylethyl] 2-carboethoxy-3-methylbutylphosphinic acid 23. [N-carbobenzoxy-l-amino-2-cyclohexylethyl] 2-(N-(m-aminomethyl)benzyl)carboxamido-3-methyl- butylphosphinic acid Another group of illustrative compounds are: 24. (N-CBZ-1-amino-2-cyclohexylethyl) 2-carboxy-4-methylpentylphosphinic acid 25. (N-CBZ-1-amino-2-cyclohexylethyl) 2-carbomethoxy-4-methylpentylphosphinic acid 26. Methyl (N-CBZ-1-amino-2-cyclohexylethyl) 2-carbo- methoxy-4-methylpentylphosphinate 27. Methyl (N-BOC-1-amino-2-cyclohexylethyl) 2-carbo- methoxy-4-methylpentylphosphinate 28. (1-Amino-2-cyclohexylethyl) 2-carbomethoxy-4-methylpentylphosphinic acid hydrobromide 29. Methyl (1-amino-2-cyclohexylethyl) 2-carbomethoxy-4-methylpentylphosphinate hydrobromide 30. Trimethylacetoxymethyl (N-CBZ-1-amino-2-cyclohexylethyl) 2-carbomethoxy-4-methylpentylphosphinate 31. Methyl (N-BOC-1-amino-2-cyclohexylethyl) 2-carbo- methoxy-4-methyl-(E)-2-pentenylphosphinate 32. Methyl (N-BOC-l-amino-2-cyclohexylethyl) 2-carbo- methoxy-4-methyl-(Z)-2-pentenylphosphinate 33. (N-BOC-1-Amino-2-cyclohexylethyl) 2-carboxy-4-methyl-(E)-2-pentenylphosphinic acid 34. (N-BOC-l-Amino-2-cyclohexylethyl) 2-carboxy-4-methyl-(Z)-2-pentenylphosphinic acid 35. Methyl (N-CBZ-l-amino-2-cyclohexylethyl) 2-carbo- methoxy-3-cyclohexylphosphinate 36. Methyl (N-CBZ-1-amino-2-cyclohexylethyl) carbomethoxymethylphosphinate 37. (1-Amino-2-cyclohexylethyl) carbomethoxymethyl- phosphinic acid 38. Methyl (1-amino-2-cyclohexylethyl)carbomethoxymethylphosphinate hydrochloride 39. Methyl (N-CBZ-1-amino-3-methylbutyl)carbomethoxymethylphosphinate 40. Methyl (N-CBZ-l-amino-2-phenylethyl) 2-carbo- methoxy-3-phenylpropylphosphinate 41. (1-Amino-2-phenylethyl) 2-carbomethoxy-3-phenyl- propylphosphinate The Formula I compounds include many which bar acidic and/or basic groups. Pharmaceutically acceptable salts of these formula I compounds are also included. Among useful the acid addition salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Salts of the bases include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Conventional processes are used to prepare the pharmaceutically acceptable salts. The present invention is also directed to combinations of the novel renin-inhibitory compounds of Formula I with one or more antihypertensive agents selected from the group consisting of diuretics, a and/or B-adrenergic blocking agents, CNS-acting antihypertensive agents, adrenergic neuron blocking agents, vasodilators, angiotensin I converting enzyme inhibitors, calcium channel blockers and other antihypertensive agents. For example, the compounds of this invention can be given in combination with such compounds or salt or other derivative forms thereof as: Diuretics: acetazolamide; amiloride; bendroflumethiazide; benzthiazide; bumetanide; chlorothiazide; chlorthalidone; cyclothiazide; ethacrynic acid; furosemide; hydrochlorothiazide; hydroflumethiazide; indacrinone (racemic mixture, or as either the (+) or (-) enantiomer alone, or a manipulated ratio, e.g., 9:1 of said enantiomers, respectively); metolazone; methyclothiazide; muzolimine; polythiazide; quinethazone; sodium ethacrynate; sodium nitroprusside; spironolactone; ticrynafen; triamterene; trichlormethiazide; a-Adrenergic Blocking Agents: dibenamine; phentolamine; phenoxybenzamine; prazosin; tolazoline; B-Adrenergic Blocking Agents: atenolol; metoprolol; nadolol; propranolol; timolol; ((±)-2-[3-(tert-butylamino)-2-hydroxypropoxy]-2-furan- anilide) (ancarolol); (2-acetyl-7-(2-hydroxy-3-isopropylaminopropoxy)benzofuran HC1) (befunolol); ((+)-1-(isopropylamino)-3-(p-(2-cyclopropylmethoxyethyl)-phenoxy)-2-propranol HC1) (betaxolol); (1-[(3,4-dimethoxyphenethyl)amino]-3-(m-tolyloxy)-2-propanol HC1) (bevantolol); (((±)-1-(4-((2-isopropoxyethoxy)methyl)phenoxy)-3-iso- propylamino-2-propanol)fumarate) (bisoprolol); (4-(2-hydroxy-3-[4-(phenoxymethyl)-piperidino]-propoxy)-indole); (carbazolyl-4-oxy-5,2-(2-methoxyphenoxy)-ethylamino-2-propanol); (1-((1,1-dimethylethyl)amino)-3-((2-methyl-1H-indol-4-yl)oxy)-2-propanol benzoate) (bopindolol); (1-(2-exobicyclo[2.2.1]-hept-2-ylphenoxy)-3-[(1-methylethyl)-amino]-2-propanol HC1) (bornaprolol); (o-[2-hydroxy-3-[(2-indol-3-yl-1,1-dimethylethyl)-amino]propoxy]benzonitrile HC1) (bucindolol); (a-[(tert.butylamino)methyl]-7-ethyl-2-benzofuranmethanol) (bufuralol); (3-[3-acetyl-4-[3-(tert.butylamino)-2-hydroxypropyl]-phenyl]-1,1-diethylurea HC1) (celiprolol); ((+)-2-[2-13-[(1,1-dimethylethyl)amino]-2-hydroxy- propoxy]phenoxy]-N-methylacetamide HC1) (cetamolol); (2-benzimidazolyl-phenyl(2-isopropylaminopropanol)); ((+)-3'-acetyl-4'-(2-hydroxy-3-isopropylaminopropoxy)-acetanilide HC1) (diacetolol); (methyl-4-[2-hydroxy-3-[(l-methylethyl)aminopropoxy]]-benzenepropanoate HCl) (esmolol); (erythro-DL-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol); (1-(tert.butylamino)-3-[O-(2-propynyloxy)phenoxy]-2-propanol (pargolol); (1-(tert.butylamino)-3-[o-(6-hydrazino-3-pyridazinyl)-phenoxy]-2-propanol diHCl) (prizidilol); ((-)-2-hydroxy-5-[(R)-1-hydroxy-2-[(R)-(1-methyl-3-phenylpropyl)amino]ethyl]benzamide); (4-hydroxy-9-[2-hydroxy-3-(isopropylamino)-propoxy]-7-methyl-5H-furo[3,2-g][1]-benzopyran-5-one) (iprocrolol); ((-)-5-(tert.butylamino)-2-hydroxypropoxy]-3,4-dihydro-1-(2H)-naphthalenone HC1) (levobunolol); (4-(2-hydroxy-3-isopropylamino-propoxy)-1,2-benziso- thiazole HC1); (4-[3-(tert.butylamino)-2-hydroxypropoxy]-N-methylisocarbostyril HC1); ((+)-N-2-[4-(2-hydroxy-3-isopropyl aminopropoxy)-phenyl]ethyl-N'-isopropylurea) (pafenolol); (3-[[(2-trifluoroacetamido)ethyl]amino]-1-phenoxy- propan-2-ol); (N-(3-(o-chlorophenoxy)-2-hydroxypropyl)-N'-(4'-chloro-2,3-dihydro-3-oxo-5-pyridazinyl)ethylenediamine); ((±)-N-[3-acetyl-4-[2-hydroxy-3-[(1-methylethyl)amino]-propoxy]phenyl]butanamide) (acebutolol); ((+)-4'-[3-(tert-butylamino)-2-hydroxypropoxy]spiro-[cyclohexane-1,2'-indan]-1'-one) (spirendolol); (7-[3-[[2-hydroxy-3-[(2-methylindol-4-yl)oxy]propyl]-amino]butyl]thiophylline) (teoprolol); ((±)-1-tert.butylamino-3-(thiochroman-8-yloxy)-2-propanol) (tertatolol); ((±)-1-tert.butylamino-3-(2,3-xylyloxy)-2-propanol HC1) (xibenolol); (8-[3-(tert.butylamino)-2-hydroxypropoxy]-5-methyl- coumarin) (bucumolol); (2-(3-(tert.butylamino)-2-hydroxy-propoxy)benzonitrile HC1) (bunitrolol); ((+)-2'-[3-(tert-butylamino)-2-hydroxypropoxy-5'-fluorobutyrophenone) (butofilolol); (1-(carbazol-4-yloxy)-3-(isopropylamino)-2-propanol) (carazolol); (5-(3-tert.butylamino-2-hydroxy)propoxy-3,4-dihydro- carbostyril HC1) (carteolol); (1-(tert.butylamino)-3-(2,5-dichlorophenoxy)-2-propanol) (cloranolol); (1-(inden-4(or 7)-yloxy)-3-(isopropylamino)-2-propanol HC1) (indenolol); (1-isopropylamino-3-[(2-methylindol-4-yl)oxy]-2-propanol) (mepindolol); (l-(4-acetoxy-2,3,5-trimethylphenoxy)-3-isopropylaminopropan-2-ol) (metipranolol); (1-(isopropylamino)-3-(o-methoxyphenoxy)-3-[(1-methylethyl)amino]-2-propanol) (moprolol); ((1-tert.butylamino)-3-[(5,6,7,8-tetrahydro-cis-6,7-dihydroxy-l-naphthyl)oxy]-2-propanol) (nadolol); ((S)-1-(2-cyclopentylphenoxy)-3-[(1,1-dimethylethyl)-amino]-2-propanol sulfate (2:1)) (penbutolol); (4'-[1-hydroxy-2-(amino)ethyl]methanesulfonanilide) (sotalol); (2-methyl-3-[4-(2-hydroxy-3-tert.butylaminopropoxy)-phenyl]-7-methoxy-isoquinolin-1-(2H)-one); (1-(4-(2-(4-fluorophenyloxy)ethoxy)phenoxy)-3-iso- propylamino-2-propanol HC1); ((-)-p-[3-[(3,4-dimethoxyphenethyl)amino]-2-hydroxy- propoxy]-β-methylcinnamonitrile) (pacrinolol); ((+)-2-(3'-tert.butylamino-2'-hydroxypropylthio)-4-(5'-carbamoyl-2'-thienyl)thiazole HC1) (arotinolol); ((±)-1-[p-[2-(cyclopropylmethoxy)ethoxy]phenoxy]-3-(isopropylamino)-2-propanol) (cicloprolol); ((±)-1-[(3-chloro-2-methylindol-4-yl)oxy]-3-[(2-phenoxyethyl)amino]-2-propanol) (indopanolol); ((±)-6-[[2-[[3-(p-butoxyphenoxy)-2-hydroxypropyl]-amino]ethyl]amino]-1,3-dimethyluracil) (pirepolol); (4-(cyclohexylamino)-l-(l-naphtholenyloxy)-2-butanol); (1-phenyl-3-[2-[3-(2-cyanophenoxy)-2-hydroxypropyl]-aminoethyl]hydantoin HCl); (3,4-dihydro-8-(2-hydroxy-3-isopropylaminopropoxy)-3-nitroxy-2H-1-benzopyran) (nipradolol); a and B-Adrenergic Blocking Agents: ((±)-1-tert-butylamino)-3-[o-[2-(3-methyl-5-isoxazolyl)vinyl]phenoxy]-2-propanol) (isoxaprolol); (1-isopropylamino-3-(4-(2-nitroxyethoxy)phenoxy)-2-propanol HCl); (4-hydroxy-α-[[3-(4-methoxyphenyl)-1-methylpropyl]-aminomethyl]-3-(methylsulfinyl)-benzmethanol HC1) (sulfinalol); (5-[1-hydroxy-2-[[2-(o-methoxyphenoxy)ethyl]amino]-ethyl]-2-methylbenzenesulfonamide HC1); (5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]-salicylamide HC1) (labetalol); (1-((3-chloro-2-methyl-1H-inaol-4-yl)oxy)-3-((2-phenoxyethyl)amino)-2-propanol-hydrogenmalonate) (ifendolol); (4-(2-hydroxy-3-[(1-methyl-3-phenylpropyl)amino]-propoxy)benzeneacetamide); (1-[3-[[3-(1-naphthoxy)-2-hydroxypropyl]-amino]-3,3-dimethyl-propyl]-2-benzimidazolinone); (3-(l-(2-hydroxy-2-(4-chlorophenylethyl)-4-piperidyl)-3,4-dihydroxy)quinoxolin-2(lH)-one); CNS-Acting Agents: clonidine; methyldopa; Adrenergic Neuron Blocking Agents: guanethidine; reserpine and other rauwolfia alkaloids such as rescinnamine; Vasodilators: diazoxide; hydralazine; minoxidil; Angiotensin I Converting Enzyme Inhibitors: 1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline (captopril); (1-(4-ethoxycarbonyl-2,4(R,R)-dimethylbutanoyl)-indoline-2(S)-carboxylic acid); (2-[2-[[1-(ethoxycarbonyl)-3-phenyl-propyl]amino]-1- oxopropyl]-1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid); ((S)-1-[2-[[1-(ethaxycarbonyl)-3-phenylpropyl]amino]-1- oxopropyl]octahydro-lH-indole-2-carboxylic acid HCl); (N-cyclopentyl-N-(3-(2,2-dimethyl-l-oxopropyl)thiol-2-methyl-l-oxopropyl)glycine) (pivalopril); ((2R,4R)-2-(2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarboxylic acid); (1-(N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanyl)-cis,syn-octahydroindol-2(S)-carboxylic acid HC1); ((-)-(S)-1-[(S)-3-mercapto-2-methyl-1-oxopropyl]-indoline-2-carboxylic acid); ([1(S),4S]-1-[3-(benzoylthio)-2-methyl-1-oxopropyl]-4-phenylthio-L-proline; (3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-l-(3S)-benzazepine-l-acetic acid HC1); (N-(2-benzyl-3-mercaptopropanoyl)-S-ethyl-L-cysteine) and the S-methyl analogue; (N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate) (enalapril); N-[1-(S)-carboxy-3-phenylpropyl]-L-alanyl-1-proline; N2-[1-(S)-carboxy-3-phenylpropyl]-L-lysyl-L-proline (lysinopril); 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-(1S,3S,5S)-2-azabicyclo[3.3.0]actane-3-carboxylic acid; [1(S),4S]-1-(3-mercapto-2-methyl-1-oxoprapyl)-4-phenylthio-L-proline S-benzoyl calcium salt (zofenopril); [1-(+/-)4S]-4-cyclohexyl-1-[[2-methyl-1-[1-(1-(oxy- propoxy)propoxy](4-phenylbutyl)phosphinyl]acetyl]-L-proline sodium salt (fosfopril). Calcium Channel Blockers: nifedepine; nitrendipine, verapamil; diltiazam. Other Antihypertensive Agents: aminophylline; cryptenamine acetates and tannates; deserpidine; meremethoxylline procaine; pargyline; trimethaphan camsylate; and the like, as well as admixtures and combinations thereof. Typically, the individual daily dosages for these combinations can range from about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly. Coadministration is most readily accomplished by combining the active ingredients into a suitable unit dosage form containing the proper dosages of each. Other methods of coadministration are, of course, possible. The novel compounds of the present invention possess an excellent degree of activity in treating hypertension and congestive heart failure. For these purposes the compounds of the present invention may be administered orally, parenterally, by inhalation spray, or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the tr atment of warm- blooded animals such as mice, rats, horses, dogs, cats, etc., the compounds of the invention are effective in the treatment of humans. The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example as a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The peptides of this invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. Dosage levels of the order of 0.1 to 4.0 grams per daj parenterally are useful in the treatment of the above indicated conditions. Oral doses are 3-10 times higher. For example, renin- associated hypertension and hyperaldosteronism are effectively treated parenterally by the administration of from 1.0 to 50 milligrams of the compound per kilogram of body weight per day. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. Thus, in accordance with the present invention there is further provided a pharmaceutical composition for treating hypertension and congestive heart failure, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of the formula I. Also, in accordance with the present invention there is still further provided a method of treating hypertension and congestive heart failure, comprising administering to a patient in need of such treatment, a therapeutically effective amount of a compound of the formula I. The renin inhibitory compounds of the present invention may also be utilized in diagnostic methods for the purpose of establishing the significance of renin as a causative or contributory factor in hypertension or congestive heart failure in a particular patient. For this purpose the present compounds may be administered in a single dose of from 0.1 to 10 mg per kg of body weight. Both in vivo and in vitro methods may be employed. In the in vivo method, a novel peptide of the present invention is administered to a patient, preferably by intravenous injection, although other routes of parenteral administration are also suitable, at a hypotensive dosage level and as a single dose, and there may result a transitory fall in blood pressure. This fall in blood pressure, if it occurs, indicates supranormal plasma renin levels. Some of the compounds of formula I also have angiotensin converting enzyme (ACE) inhibitor activity. This activity augments renin inhibition in lowering blood pressure and in treating congestive heart failure. Treatment dosage and mode for this utility is generally the same as set out earlier. The preparation of the formula I compounds is illustrated in some of the examples below and in general proceeds as follows: a) Coupling of an amino-protected form of E to G, followed by b) amino protecting group removal from E-G and c) coupling A to the resulting amino group of E-G. The phosphorous-containing component E, as well as the component A may contain functionality which requires protection during the coupling reactions. Protecting groups, among those well-known in peptide synthesis, are chosen so as to be compatible with the coupling steps, yet easily removable afterwards. Among those utilized for amino group protection are the t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), 9-fluorenylmethyloxycarbonyl (FMOC), and benzyl groups. Carboxylic acids are protected as the methyl, ethyl, benzyl, or t-butyl esters. Phosphonic and phosphinic acids are protected as the methyl or ethyl esters. The coupling procedures referred to above include those brought about by use of dicyclohexylcarbodiimide/ 1-hydroxybenzotriazole and of disuccinimido oxallate (K. Takeda et al., Tetrahedron Lett., 24, 4451-54 (1983)). In many cases, both carboxylic and phosphonic (or phosphinic esters) may be hydrolyzed along with amino protecting groups as the last step in the synthesis. In these cases, treatment of the phosphorous-containing peptide analog with 30% hydrobromic acid in acetic acid, with 6N hydrochloric acid, or with aqueous sodium hydroxide, followed by purification of the resulting deprotected material by ion-exchange chromatography or reverse-phase HPLC, provides the desired product. In instances where A-E-G possesses a carboxyl-terminal amide function (R3=NH2, , or ), the fully coupled material A-E may be treated with 1 equivalent of lithium hydroxide (0.1 N) to hydrolyze selectively a carboxylic ester function in E. Standard coupling procedures may then be used to couple the resulting free carboxylic acid to an appropriate amine. This is followed by removal of the remaining protecting groups as described above. Alternatively the amide formation may be carried out prior to coupling of the component E-G to the A unit. Preparation of the phosphorous-containing components E are carried out as illustrated in the examples to follow. The 1-aminoalkylphosphonous acids used as starting materials in the examples below are prepared as illustrated in the examples and can be resolved to give optically active materials by the method of Baylis et al. (J. Chem. Soc. Perkin Trans 1, 2845-53 (1984)). Compounds derived from both the optically active and racemic materials are claimed in the present invention. The 1-aminoalkylphosphonic acids used in the examples below are prepared as described and can be resolved to give the optically active materials by the procedure of Kafarski et al., Can. J. Chem., 60, 3081-84 (1982), or can be prepared in optically active form by the method of Huber et al., Tetrahedron Lett., 3049-3052 (1979). Compounds derived from both the optically active and racemic materials are claimed in the present invention. When the amino group of the unit E which is to be coupled to A bears an N-methyl group (R6 = -CH3), procedures well known in peptide synthesis are used to couple A to E or E-G. In general, the mixed anhydride procedure (with pivaloyl chloride and N-methylmorpholine) is used, as illustrated by R. M. Wenger, Helv. Chem. Acta., 1984, 67, 502-525. This procedure is also utilized in formation of E-G when G is and R8 is other than hydrogen and in the preparation of G when R9 is and R6 R6 is methyl.

  本发明涉及具有以下公式的二肽和氨基酸：A-E-G，其中A可以是例如氢，或R aCO或R bSO2-，其中R a和R b例如是烷基、环烷基或芳基；R’是例如烷基；n是0或1；R2是例如氢或烷基；R3是例如OH、NH2等；R4是例如氢或烷基；R6是H或甲基；R7是例如氢或烷基；R8是例如氢、甲基或环烷基，使得当R8是环烷基时，R6和R7是氢；R9是例如羟基。这些化合物具有酶抑制活性，例如肾素抑制和血管紧张素转换酶抑制。 **发明背景** 本发明涉及一种新型化合物（取代氨基酸和二肽），所述化合物抑制肾素，并且在某些情况下还抑制血管紧张素转换酶（ACE）。本发明还涉及含有本发明新型化合物作为活性成分的药物组合物、用于治疗与肾素和/或ACE相关病症的方法、利用这些化合物的诊断方法，以及制备它们的工艺。Kokubu等人（Biochem. Biophys. Res. Commun., 118, 929 (1984))和Fehrentz等人（Febs. Lett., 167, 273 (1984))报道了小分子肽类肾素抑制剂。R. Matsuda等人在欧洲专利申请128,762（Sankyo Co., Ltd., 1984）中披露了三肽醛作为肾素抑制剂。 本发明中披露的一些化合物也抑制血管紧张素转换酶。Kido等人在J. Antibiot. (Tokyo), 37, 965-9 (1984)和日本专利J59187-790-A（Kyowa Hakko Kogyo KK，1984）中报道了含有氨基膦酸作为羧基末端组分的肽类，这些肽类是ACE抑制剂。此外，Petrillo等人在U.S.专利No. 4,168,267；4,337,201（E. R. Squibb and Sons，1979, 1982）中描述了抑制ACE的磷酰烷酸基脯氨酸类似物。 含有不超过两个氨基酸或其等效物的化合物，其中包含含有磷的元素作为羧基末端或次羧基末端组分，已经被发现。它们是强效的肾素抑制剂，并且可能是口服活性的。 **发明内容** 本发明包括以下形式的化合物： A-E-G (I) 其中： - **A**是氢，或R a-、R bCO或R bSO2-，其中R a和R b是烷基、环烷基、芳基、杂环、杂环烷基、杂环芳基、芳基氧烷基、杂环芳基氧烷基、芳基烷基、杂环芳基烷基、杂环氧烷基，且R a和R b可以被最多三个成员选自氨基、羧基、烷氧基羰基、羟基、烷基、卤素和烷氧基的基团取代。 - **E**是 - **G**是-R3或 其中R1是烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基烷基、杂环、杂环烷基、杂环芳基烷基，每种均可被最多三个选自烷基、卤素、氨基和烷氧基的基团取代。 - n是0或1。 - R2是氢、烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、芳基烷基、杂环、杂环烷基，每种均可被最多三个选自烷基、羟基、卤素、氨基、烷基氨基、二烷基氨基和烷氧基的基团取代。 - R3是OH、NH2、或 其中，所述基团各自是烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、芳基烷基、杂环、杂环烷基，每种均可被最多三个选自氨基、烷基氨基、二烷基氨基、三甲铵、羟基、烷氧基、芳氧基、芳烷基氧基和卤素的基团取代；R3也可以是-CO-V-，其中是烷基或芳基；和是氢或烷基；V是-O-或-NH-。 - R4是氢、烷基、烯基、炔基、芳基、芳烷基，每种均可被最多三个选自氨基、烷基氨基、二烷基氨基、三烷基铵、羟基、烷氧基、卤素或烷基的基团取代；或者-CO4V-，其中是烷基或芳基；和是氢或烷基；V是-O-或-NH-。 - R6是H或甲基。 - R7是氢、烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、芳烷基、杂环、杂环烷基、芳基氧烷基、杂环氧烷基、杂环氧基，每种均可被最多三个选自氨基、烷基氨基、二烷基氨基、三烷基铵、羟基、烷氧基、羧基、烷氧基羰基、烷硫基、芳硫基、巯基、胍基、羧酰氨基和烷酰氨基的基团取代。 - 当与NR8一起时，可能形成以下环状氨基酸： 其中是氢、苯基、羟基苯基；X是-S-、-CH2-或-CH-；m是1或2；是环己基、苯硫基；W和Z是单键或-CH2-；R3如上定义。 - R8是氢、甲基和环烷基（包括环戊基和茚基），使得当R8是环烷基时，R6和R7是氢。 - R9是羟基、NH2或 其中，如上定义，使得当A缺失时，R9可以是 其中R3、R6和R7如上定义。 中国命名法中的术语定义如下： - 烷基、烯基、炔基包括具有1-8个碳原子的直链或支链的烃基，优选烷基和烷基有1-4个碳原子，烯基和炔基有3-6个碳原子。 - 卤素指氟、氯、溴和碘。 - 芳基取代基是具有6-12个碳原子的烃基，例如苯基、萘基、联苯基及其与环烷基稠合的衍生物，如茚基和四氢萘基。 - 上述杂环取代基表示任何含有1至3个选自氮、氧和硫的异原子的5或6元环，其中氮和硫原子可以是季化的，包括任何与苯环稠合的杂环环。含氮的杂环基团是优选的，其中优选含有单个氮原子的杂环基团，如哌啶基、吡咯烷基、咪唑烷基、吗啉基、四氢甲基基、噻吩基、嘧啶基、咪唑基、吲哚基、喹啉基、异喹啉基和苯硫基。 - 环烷基和环烯基含有3-12个碳原子，可以是桥接的，例如环丙基、环戊基、环己基、环己烯基、bornen基、金刚烷基、双环[3.3.0]-辛基和降冰片基。 - 优选的A单元包括苯甲氧基羰基、叔丁氧基羰基、1-萘基氧乙酰基和1-萘基乙酰基。 - 优选的E单元包括以下结构： - 优选的G取代基包括-OH、-OEt、-NH2。 本发明所述化合物具有不对称中心，可以形成外消旋体、外消旋混合物和单个立体异构体。所有同分异构体均包括在本发明化合物中。 **具体实施方式** 本发明所述化合物在以下实施例中进行了说明： 1. (N-苯甲氧基羰基-L-氨基-2-环己基乙基) 2-羧基-4-甲基戊基膦酸 2. (N-苯甲氧基羰基-L-氨基-2-环己基乙基) 2-羧基-3-甲基丁基膦酸 3. (N-叔丁氧基羰基-1-氨基-2-环己基乙基) 2-羧基-3-甲基丁基膦酸 4. (N-苯甲氧基羰基-L-氨基-2-环己基乙基) 2-碳基 methoxymethyl 膦酸 5. (N-苯甲氧基羰基-1-氨基-2-环己基乙基) 2-羧酰氨基-4-甲基戊基膦酸 6. (N-叔丁氧基羰基-1-氨基-2-环己基乙基) 2-(N-苄基)羧酰氨基-3-甲基丁基膦酸 7. [N-(2-苯基)乙基-1-氨基-2-环己基乙基] 2-羧基-4-甲基戊基膦酸 8. [N-(N-苄基)羧酰甲基-1-氨基-2-环己基乙基] 2-羧基-3-甲基丁基膦酸 9. [N-(1-氨基乙氧基-2-苯基乙基)-1-氨基-2-环己基乙基] 2-羧基-3-甲基丁基膦酸 10. (N-苯甲氧基羰基-1-氨基-2-环己基乙基)甲氧羰甲基膦酸 11. (N-苯甲氧基羰基-L-氨基-2-环己基乙基)羧甲基膦酸 12. (N-苯甲氧基羰基-L-氨基-2-环己基乙基)羧酰甲基膦酸 13. (N-苯甲氧基羰基-L-氨基-2-环己基乙基) 2-羧基-3-环己基丙基膦酸 14. [N-(3-苯基)丙酰基-1-氨基-2-环己基乙基] 2-羧基-4-甲基戊基膦酸 15. (N-苯氧乙酰基-L-氨基-2-环己基乙基) 2-羧基-3-甲基丁基膦酸 16. [N-(4-氨基)丁酰基-1-氨基-2-环己基乙基] 2-羧基-3-甲基丁基膦酸 17. (N-萘基氧乙酰基-1-氨基-2-环己基乙基) 2-羧基-3-甲基丁基膦酸 18. 甲基 (N-苯甲氧基羰基-L-氨基-2-环己基乙基) 2-羧基-4-甲基戊基膦酸盐 19. 甲基 (N-苯甲氧基羰基-L-氨基-2-环己基乙基)-甲氧羰甲基膦酸盐 20. 乙基 [N-(3-苯基)丙酰基-1-氨基-2-环己基乙基] 2-甲氧羰基-3-甲基丁基膦酸盐 21. [N-(1-甲
• Eight-Membered Ring-Containing Jadomycins: Implications for Non-enzymatic Natural Products Biosynthesis
  作者：Andrew W. Robertson、Camilo F. Martinez-Farina、Deborah A. Smithen、Huimin Yin、Susan Monro、Alison Thompson、Sherri A. McFarland、Raymond T. Syvitski、David L. Jakeman

  DOI：10.1021/ja5114672

  日期：2015.3.11

  Jadomycin Oct (1) was isolated from Streptomyces venezuelae ISP5230 and characterized as a structurally unique eight-membered l-ornithine ring-containing jadomycin. The structure was elucidated through the semisynthetic derivatization of starting material via chemoselective acylation of the L-ornithine alpha-amino group using activated succinimidyl esters. Incorporation of 5-aminovaleric acid led to jadomycin AVA, a second eight-membered ring-containing jadomycin. These natural products illustrate the structural diversity permissible from a non-enzymatic step within a biosynthetic pathway and exemplifies the potential for discovery of novel scaffolds.
• Using affinity capillary electrophoresis to identify the peptide in a peptide library that binds most tightly to vancomycin
  作者：Yen Ho Chu、Luis Z. Avila、Hans A. Biebuyck、George M. Whitesides

  DOI：10.1021/jo00055a017

  日期：1993.1

  This paper describes a procedure, based on competitive binding, for identifying tight-binding ligand(s) for a receptor in mixtures of equimolar ligand candidates using affinity capillary electrophoresis (ACE). Vancomycin and a small library of 32 peptides were used as a model system to illustrate the procedure. This procedure should be applicable to peptide mixtures of greater complexity than the one used here, as well as to mixtures of nonpeptidic compounds. Limits and limitations to the procedure are described.

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