Claims
- 1. A pyrrolidine derivative of the formula: ##STR136## wherein Z represents a methylene group, R represents the general formula:
- G--E--D--B--A--
- wherein A represents a linkage which contains no atom, an alkylene group of from 1 to 6 carbon atoms(s), an alkenylene group of from 2 to 6 carbon atoms, a group of the formula: ##STR137## wherein Y represents an alkylene group of from 1 to 4 carbon atom(s) or an alkenylene group of from 2 to 4 carbon atoms, a saturated hydrocarbon ring of from 4 to 7 carbon atoms or a heterocyclic mono ring containing 3 to 7 ring members including 1 or 2 hetero atom(s) selected from N, O and S atoms which may be partially or fully saturated or aromatic,
- B represents a linkage which contains no atom or an alkylene group of from 1 to 6 carbon atom(s),
- D represents a group of the formula:
- --NR.sup.1 --CO--
- wherein R.sup.1 represents a hydrogen atom, an alkyl group of from 1 to 6 carbon atom(s), a phenyl group or a benzyl group,
- E represents a linkage which contains no atom, an alkylene group of from 1 to 8 carbon atom(s) or an alkylene group of from 1 to 8 carbon atom(s) substituted or by a phenyl or benzyl group,
- G represents a mono-, bi- or tri-carbocyclic ring(s) containing not more than 15 carbon atoms which may be partially or fully saturated or aromatic, or mono-, bi- or tri-heterocyclic ring(s) containing not more than 15 ring members including carbon and 1 or 2 hetero atoms selected from N, O and S atoms which may be partially or fully saturated or aromatic wherein said carbocyclic or heterocyclic ring(s) represented by G is unsubstituted or substituted by 1-3 of an alkyl group of from 1 to 6 carbon atoms(s), an alkoxy group of from 1 to 6 carbon atom(s), a halogen atom, a trifluoromethyl group or a nitro group, and L represents a group of the formula:
- --CO--COR.sup.2
- --CO--CH.sub.2 --COR.sup.2
- --CO--CF.sub.2 --COR.sup.2
- --CO--CO--NR.sup.5 R.sup.6
- or
- --CO--CH.sub.2 --CO--NR.sup.5 R.sup.6
- wherein, R.sup.2 represents a hydrogen atom, a hydroxy group, an alkyl group of from 1 to 6 carbon atom(s), an alkoxy group of from 1 to carbon atom(s), a phenyl group, an alkyl group of from 1 to 6 carbon atom(s) substituted by a phenyl group, or an alkoxy group of from 1 to 6 carbon atom(s) substituted by a phenyl group,
- R.sup.5 and R.sup.6 independently represent a hydrogen atom, an alkyl group of from 1 to 6 carbon atom(s), a phenyl group, or an alkyl group of from 1 to 6 carbon atom(s) substituted by a phenyl group, with the proviso that the following compounds are excluded:
- (i) compounds wherein both of A and B are a linkage which contains no atom
- or a non-toxic salt or hydrate thereof.
- 2. A compound according to claim 1, wherein G is phenyl, naphthyl or fluorenyl group which is unsubstituted or substituted.
- 3. A compound according to claim 1, of general formula: ##STR138## wherein L.sup.1 represents a group of general formula:
- --CO--CH.sub.2 --COR.sup.2
- --CO--CF.sub.2 --COR.sup.2
- --CO--CO--NR.sup.5 R.sup.6
- or
- wherein all of the symbols are the same meaning as defined in claim 1.
- 4. A compound according to claim 1 or 3, which is:
- 3-((2S)-1-{3-(N-benzyl-N-methylcarbamoyl)propanoyl)pyrrolidin-2-yl)-3-oxopropionic acid
- or ethyl ester thereof,
- 3-((2S)-1-{3-(N-benzyl-N-methylcarbamoyl)propanoyl)pyrrolidin-2-yl}-3-oxo-2, 2-difluoropropionic acid
- or ethyl ester thereof,
- 2-{(2S)-1-{3-(N-benzyl-N-methylcarbamoyl)propanoyl)pyrrolidin-2 yl}-2-oxo-N-ethylacetamide,
- 2-{(2S-1-{3-(N-benzyl-N-methylcarbamoyl)propanoyl}pyrrolidin-2-yl}-2-oxoacetamide
- or
- 2-{(2S)-1-{3-(N-benzyl-N-methylcarbamoyl)propanoyl)pyrrolidin-2-yl}-2-oxo-N-methyl-N-benzylacetamide.
- 5. A compound according to claim 1 of general formula: ##STR139##
- --CO--COR.sup.2
- wherein all of the symbols are the same meaning as defined in claim 1.
- 6. A compound according to claim 1 or 5, which is:
- 2-{(2S)-1-{3-(N-benzyl-N-methylcarbamoyl)propanoyl}pyrrolidin-2-yl)-2-oxoacetic acid,
- 2-{(2S)-1-{3-{N-(4-chlorophenylmethyl) carbamoyl}propanoyl}pyrrolidin-2-yl}-2-oxoacetic acid,
- 2-{(2S)-1-{3-{N-(9-fluorenyl)carbamoyl}propanoyl}pyrrolidin-2-yl }-2-oxoacetic acid,
- 2-{(2S)-1-{3-{N-(4-trifluoromethylphenylmethyl)-N-phenylcarbamoyl propanoyl}pyrrolidin-2-yl}-2-oxoacetic acid,
- 2-{(2S)-1-(3-(N-benzyl-N-t-butylcarbamoyl) propanoyl}pyrrolidin-2-yl}-2-oxoacetic acid,
- 2-{(2S)-1-{3-(N-benzyl-N-phenylcarbamoyl}propanoyl}pyrrolidin-2-yl}-2-oxoacetic acid,
- 2-{(2S)-1-{3-{N-(1-naphthy)methyl-N-methylcarbamoyl) propanoyl)pyrrolidin-2-yl)-2-oxocetic acid,
- 2-{(2S)-1-{3-{N-(2,4-dichlorophenylmethyl) carbamoyl}propanoyl}pyrrolidin-2-yl)-2-oxoacetic acid,
- 2-{(2S-1-{3-(N-(2-naphthyl)methyl-N-methylcarbamoyl}propanyl}pyrrolidin-2-yl}-2-oxoacetic acid,
- 2-{(2S)-1-{(1RS, 2R)-2-(N-benzylcarbamoyl)cyclopentanecarbonyl}pyrrolidin-2-yl}-2-oxoacetic acid,
- 2-{(2S)-1-{3-{N-(4-methylphenylmethyl)carbamoyl}propanoyl}pyrrolidin-2-yl)-2-oxoacetic acid,
- 2-{(2S)-1-{3-{N-(4-chlorophenylmethyl)-N-phenylcarbamoyl}propanoyl}pyrrolidin-2-yl)-2-oxoacetic acid
- or
- 2-{(2S)-1-{3-{N-(4-chlorophenylmethyl)-N-methylcarbamoyl}propanoyl}pyrrolidin-2-yl}-2-oxoacetic acid
- 2-{(2S)-1-(3-(N-benzyl-N-methylcarbamoyl)propanoyl}pyrrolidin-2-yl}-2-hydroxyacetic acid,
- 2-{(2S)-1-{3-(N-(4-chlorophenylmethyl) carbamoyl}propanoyl}pyrrolidin-2-yl)-2-hydroxyacetic acid,
- 2-{(2S)-1-{3-{N-(9-fluorenyl)carbamoyl}propanoyl}pyrrolidin-2-yl}-2-hydroxyacetic acid,
- {(2S)-1-{3-(N-benzyl-N-methylcarbamoyl)propanoyl}pyrrolidin-2-yl}dimethoxymethane,
- 2-{(2S)-1-{3-(N-benzyl-N-methylcarbamoyl)propanoyl}pyrrolidin-2-yl}-2-1,3-dioxolan,
- (1RS)-1-{(2S)-1-(3-(N-benzyl-N-methylcarbamoyl) propanoyl}pyrrolidin-2-yl}propan-1-ol
- or
- (1RS)-1-phenyl-1-{(2S)-1-{3-(N-benzyl-N-methylcarbamoyl) propanoyl}pyrrolidin-2-yl)methanol].
- 7. A compound which is:
- 2-{(2S)-1-{(1RS, 2R)-2-(3-phenylpropanoyl) cyclopentanecarbonyl}pyrrolidin-2-yl}-2-oxoacetic acid
- or
- ethyl ester thereof.
- 8. A compound which is:
- 2-{(2S)-1-{3-(4-(4-phenylbutoxy)phenyl}propenoyl}pyrrolidin-2-yl}-2-oxoacetic acid
- or ethyl ester thereof.
- 9. A pharmaceutical composition for treating amnesia which comprises, as active ingredient, a therpeutically effective amount of pyrrolidine derivative of the following general formula (I) and pharmaceutically acceptable carrier and/or coating: ##STR140## wherein Z represents a methylene group, R represents the general formula:
- G--E--D--B--A--
- wherein A represents a linkage which contains no atom, an alkylene group of from 1 to 6 carbon atoms(s), an alkenylene group of from 2 to 6 carbon atoms, a group of the formula: ##STR141## wherein Y represents an alkylene group of from 1 to 4 carbon atom(s) or an alkenylene group of from 2 to 4 carbon atoms, a saturated hydrocarbon ring of from 4 to 7 carbon atoms or a heterocyclic mono ring containing 3 to 7 ring members including 1 or 2 hetero atom(S) selected from N, O and S atoms which may be partially or fully saturated or aromatic,
- B represents a linkage which contains no atom or an alkylene group of from 1 to 6 carbon atom(s),
- D represents a group of the formula:
- --NR.sup.1 --CO--
- wherein R.sup.1 represents a hydrogen atom, an alkyl group of from 1 to 6 carbon atom(s), a phenyl group or a benzyl group,
- E represents a linkage which contains no atom, an alkylene group of from 1 to 8 carbon atom(s) or an alkylene group of from 1 to 8 carbon atom(s) substituted or by a phenyl or benzyl group,
- G represents a mono-, bi- or tri-carbocyclic ring(s) containing not more than 15 carbon atoms which may be partially or fully saturated or aromatic, or mono-, bi- or tri-heterocyclic ring(s) containing not more than 15 ring members including carbon and 1 or 2 hetero atoms selected from N, O and S atoms which may be partially or fully saturated or aromatic wherein said carbocyclic or heterocyclic ring(s) represented by G is unsubstituted or substituted by 1-3 of an alkyl group of from 1 to 6 carbon atoms(s), an alkoxy group of from 1 to 6 carbon atom(s), a halogen atom, a trifluoromethyl group or a nitro group, and L represents a group of the formula:
- --CO--COR.sup.2
- --CO--CH.sub.2 --COR.sup.2
- --CO--CF.sub.2 --COR.sup.2
- --CO--CO--NR.sup.5 R.sup.6
- or
- --CO--CH.sub.2 --CO--NR.sup.5 R.sup.6
- wherein, R.sup.2 represents a hydrogen atom, a hydroxy group, an alkyl group of from 1 to 6 carbon atom(s), an alkoxy group of from 1 to 6 carbon atom(s), a phenyl group, an alkyl group of from 1 to 6 carbon atom(s) substituted by a phenyl group, or an alkoxy group of from 1 to 6 carbon atom(s) substituted by a phenyl group,
- R.sup.5 and R.sup.6 independently represent a hydrogen atom, an alkyl group of from 1 to 6 carbon atom(s), a phenyl group, or an alkyl group of from 1 to 6 carbon atom(s) substituted by a phenyl group,
- with the proviso that compounds wherein both of A and B are a linkage which contains no atom are excluded; or a non-toxic salt or hydrate thereof.
- 10. A method for prevention and treatment of amnesia which comprises administration of a therapeutically effective amount of pyrrolidine derivative of the general formula (I): ##STR142## wherein Z represents a methylene group, R represents the general formula:
- G--E--D--B--A--
- wherein A represents a linkage which contains no atom, an alkylene group of from 1 to 6 carbon atoms(s), an alkenylene group of from 2 to 6 carbon atoms, a group of the formula: ##STR143## wherein Y represents an alkylene group of from 1 to 4 carbon atom(s) or an alkenylene group of from 2 to 4 carbon atoms, a saturated hydrocarbon ring of from 4 to 7 carbon atoms or a heterocyclic mono ring containing 3 to 7 ring members including 1 or 2 hetero atom(s) selected from N, O and S atoms which may be partially or fully saturated or aromatic,
- B represents a linkage which contains no atom or an alkylene group of from 1 to 6 carbon atom(s),
- D represents a group of the formula:
- --NR.sup.1 --CO--
- wherein R.sup.1 represents a hydrogen atom, an alkyl group of from 1 to 6 carbon atom(s), a phenyl group or a benzyl group,
- E represents a linkage which contains no atom, an alkylene group of from 1 to 8 carbon atom(s) or an alkylene group of from 1 to 8 carbon atom(s) substituted or by a phenyl or benzyl group,
- G represents a mono-, bi- or tri-carbocyclic ring(s) containing not more than 15 carbon atoms which may be partially or fully saturated or aromatic, or mono-, bi- or tri-heterocyclic ring(s) containing not more than 15 ring members including carbon and 1 or 2 hetero atoms selected from N, O and S atoms which may be partially or fully saturated or aromatic wherein said carbocyclic or heterocyclic ring(s) represented by G is unsubstituted or substituted by 1-3 of an alkyl group of from 1 to 6 carbon atoms(s), an alkoxy group of from 1 to 6 carbon atom(s), a halogen atom a trifluoromethyl group or a nitro group, and L represents a group of the formula:
- --CO--COR.sup.2
- --CO--CH.sub.2 --COR.sup.2
- --CO--CF.sub.2 --COR.sup.2
- --CO--CO--NR.sup.5 R.sup.6
- or
- --CO--CH.sub.2 --CO--NR.sup.5 R.sup.6
- wherein, R.sup.2 represents a hydrogen atom, a hydroxy group, an alkyl group of from 1 to 6 carbon atom(s), an alkoxy group of from 1 to 6 carbon atom(s), a phenyl group, an alkyl group of from 1 to 6 carbon atom(s) substituted by a phenyl group, or an alkoxy group of from 1 to 6 carbon atom(s) substituted by a phenyl group,,
- R.sup.5 and R.sup.6 independently represent a hydrogen atom, an alkyl group of from 1 to 6 carbon atom(s), a phenyl group, or an alkyl group of from 1 to 6 carbon atom(s) substituted by a phenyl group,
- with the proviso that compounds wherein both of A and B are a linkage which contains no atom are excluded; or a non-toxic salt or hydrate thereof.
Priority Claims (1)
Number |
Date |
Country |
Kind |
63-85288 |
Apr 1988 |
JPX |
|
Parent Case Info
This is a a divisional application of prior application No. 08/008,365, filed Jan. 22, 1993, now U.S. Pat. No. 5,401,760, which is a divisional application of 07/700,299, filed May 15, 1991, now U.S. Pat. No. 5,212,191, which is a divisional of 07/333,227, filed on Apr. 5, 1989, now U.S. Pat. No. 5,053,414.
US Referenced Citations (10)
Foreign Referenced Citations (5)
Number |
Date |
Country |
0238319 |
Sep 1987 |
EPX |
0268190 |
May 1988 |
EPX |
0384341 |
Aug 1990 |
EPX |
0414903 |
Mar 1991 |
EPX |
155267 |
Jul 1987 |
JPX |
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Entry |
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Divisions (3)
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Number |
Date |
Country |
Parent |
08365 |
Jan 1993 |
|
Parent |
700299 |
May 1991 |
|
Parent |
333227 |
Apr 1989 |
|