US2944079A - Nn-di-chloroethylaminobutyrates and preparation thereof - Google Patents
Nn-di-chloroethylaminobutyrates and preparation thereof Download PDFInfo
- Publication number
- US2944079A US2944079A US391134A US39113453A US2944079A US 2944079 A US2944079 A US 2944079A US 391134 A US391134 A US 391134A US 39113453 A US39113453 A US 39113453A US 2944079 A US2944079 A US 2944079A
- Authority
- US
- United States
- Prior art keywords
- parts
- aminophenylbutyrate
- acid
- chloroethyl
- growth
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000002360 preparation method Methods 0.000 title description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 230000012010 growth Effects 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 229940127089 cytotoxic agent Drugs 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- SUFDVCVFTSHFJT-UHFFFAOYSA-N 2-(4-aminophenyl)-2-methylbutanoic acid Chemical compound CCC(C)(C(O)=O)C1=CC=C(N)C=C1 SUFDVCVFTSHFJT-UHFFFAOYSA-N 0.000 description 1
- XBGNOMBPRQVJSR-UHFFFAOYSA-N 2-(4-nitrophenyl)butanoic acid Chemical compound CCC(C(O)=O)C1=CC=C([N+]([O-])=O)C=C1 XBGNOMBPRQVJSR-UHFFFAOYSA-N 0.000 description 1
- VKPPFDPXZWFDFA-UHFFFAOYSA-N 2-chloroethanamine Chemical compound NCCCl VKPPFDPXZWFDFA-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- TXFLGZOGNOOEFZ-UHFFFAOYSA-N bis(2-chloroethyl)amine Chemical class ClCCNCCCl TXFLGZOGNOOEFZ-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- -1 di (2 chloroethyl) aminophenylbutyric acid Chemical compound 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- OXUCBZMQKBXZIC-UHFFFAOYSA-N ethyl 2-(4-aminophenyl)butanoate Chemical compound CCOC(=O)C(CC)C1=CC=C(N)C=C1 OXUCBZMQKBXZIC-UHFFFAOYSA-N 0.000 description 1
- LBEVBNULNXDPFP-UHFFFAOYSA-N ethyl 2-(4-nitrophenyl)butanoate Chemical compound CCOC(=O)C(CC)C1=CC=C([N+]([O-])=O)C=C1 LBEVBNULNXDPFP-UHFFFAOYSA-N 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 230000002710 gonadal effect Effects 0.000 description 1
- 230000009422 growth inhibiting effect Effects 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- YDFUBDXOHRVZLD-UHFFFAOYSA-N methyl 2-(4-aminophenyl)butanoate Chemical compound COC(=O)C(CC)C1=CC=C(N)C=C1 YDFUBDXOHRVZLD-UHFFFAOYSA-N 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
Definitions
- This invention relates to chemotherapeutic agents and has as an object to provide improved compounds having tumour growth inhibitory action.
- Bis-chloroethylamines of the general formula RN( CH CH CI) 2 (I) are well known as cytotoxic agents which are capable of arresting the growth of transplanted animal tumours (see Haddow, Brit. Med. Bull. (1947), 4, 422.
- chemotherapeutic agents are well known as cytotoxic agents which are capable of arresting the growth of transplanted animal tumours (see Haddow, Brit. Med. Bull. (1947), 4, 422.
- One disadvantage of the compounds so far examined which limits their use as chemotherapeutic agents is the non-specificity of their action. They are toxic to all types of rapidly proliferating tissue, e.g. bone marrow, gonadal tissue and gastric mucosa, as well as towards neoplastic tissue.
- R is hydrogen or an alkyl group, preferably one containing not more than eight carbon atoms.
- the preferred compound is p-NN-di-(Z-chloroethyl)-aminophenylbutyric acid of the formula:
- the growth-inhibitory effect is not accompanied by serious depression of the bone-marrow such as may be induced by alky1'bis-2- chloroethylamines and many other aryl bis-2-chloroethylamines, so far tested;
- the present invention also includes a process for the manufacture of compounds of the general Formula 111 above wherein an alkyl NN-di-(Z-hydroxyethyl)-aminophenylbutyrate is treated with phosphorus oxychloride to form an alkyl NN-di-(Z-chloroethyl)-aminophenylbutyrate which is, if desired, converted by hydrolysis in an acid medium into a NN-di-(2-chloroethyl-aminophenylbutyric acid.
- the process of the example may be modified by treating the methyl-p-aminophenylbutyrate with ethylene oxide (25 parts) in N acetic acid (50 parts) at room temperature for 4 hours.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB322814X | 1952-11-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US2944079A true US2944079A (en) | 1960-07-05 |
Family
ID=10336169
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US391134A Expired - Lifetime US2944079A (en) | 1952-11-20 | 1953-11-09 | Nn-di-chloroethylaminobutyrates and preparation thereof |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US2944079A (de) |
| CH (1) | CH322814A (de) |
| DE (1) | DE939507C (de) |
| FR (1) | FR1093021A (de) |
| GB (1) | GB727336A (de) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3335176A (en) * | 1962-04-13 | 1967-08-08 | Allied Chem | Aminomethyl carboxy dibenzyl amines and preparation thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4835182A (en) * | 1987-08-21 | 1989-05-30 | The United States Of America As Represented By The Department Of Health And Human Services | Enhancing drug delivery to the brain |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB128912A (en) * | 1918-06-26 | 1919-10-30 | Ste Chim Usines Rhone | Manufacture of New Substituted Benzoic Acid Esters. |
| GB653452A (en) * | 1947-04-12 | 1951-05-16 | Goodrich Co B F | Improvements in or relating to a method of preparing an (n,n-diaryl) amino acid ester |
-
1952
- 1952-11-20 GB GB29401/52A patent/GB727336A/en not_active Expired
-
1953
- 1953-11-06 CH CH322814D patent/CH322814A/de unknown
- 1953-11-09 US US391134A patent/US2944079A/en not_active Expired - Lifetime
- 1953-11-18 FR FR1093021D patent/FR1093021A/fr not_active Expired
- 1953-11-19 DE DEN8044A patent/DE939507C/de not_active Expired
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB128912A (en) * | 1918-06-26 | 1919-10-30 | Ste Chim Usines Rhone | Manufacture of New Substituted Benzoic Acid Esters. |
| GB653452A (en) * | 1947-04-12 | 1951-05-16 | Goodrich Co B F | Improvements in or relating to a method of preparing an (n,n-diaryl) amino acid ester |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3335176A (en) * | 1962-04-13 | 1967-08-08 | Allied Chem | Aminomethyl carboxy dibenzyl amines and preparation thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| GB727336A (en) | 1955-03-30 |
| FR1093021A (fr) | 1955-04-29 |
| DE939507C (de) | 1956-02-23 |
| CH322814A (de) | 1957-06-30 |
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