CA1243034A - Compose anti-prolyl endopeptidase - Google Patents

Compose anti-prolyl endopeptidase

Info

Publication number: CA1243034A
Authority: CA; Canada
Prior art keywords: compounds; compound; general formula; prolyl endopeptidase; lower alkyl
Prior art date: 1984-05-17
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

Application number

CA000487839A

Other languages

English (en)

Inventor

Takaharu Tanaka

Naoki Higuchi

Masaki Hashimoto

Masayuki Saito

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Suntory Ltd

Original Assignee

Suntory Ltd

Priority date (The priority date 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 date listed.)

1984-05-17

Filing date

1985-07-31

Publication date

1988-10-11

1985-07-31 Application filed by Suntory Ltd filed Critical Suntory Ltd

1988-10-11 Application granted granted Critical

1988-10-11 Publication of CA1243034A publication Critical patent/CA1243034A/fr

Status Expired legal-status Critical Current

Links

150000001875 compounds Chemical class 0.000 title claims abstract description 78
230000000694 effects Effects 0.000 title description 13
102000005593 Endopeptidases Human genes 0.000 title description 11
108010059378 Endopeptidases Proteins 0.000 title description 11
238000000034 method Methods 0.000 claims abstract description 21
125000005907 alkyl ester group Chemical group 0.000 claims abstract description 7
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 3
ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 3
150000001244 carboxylic acid anhydrides Chemical class 0.000 claims 1
150000001732 carboxylic acid derivatives Chemical class 0.000 claims 1
230000003647 oxidation Effects 0.000 claims 1
238000007254 oxidation reaction Methods 0.000 claims 1
230000003496 anti-amnesic effect Effects 0.000 abstract description 12
102000056251 Prolyl Oligopeptidases Human genes 0.000 abstract description 9
101710178372 Prolyl endopeptidase Proteins 0.000 abstract description 9
239000003795 chemical substances by application Substances 0.000 abstract description 7
239000002475 cognitive enhancer Substances 0.000 abstract description 7
230000002401 inhibitory effect Effects 0.000 abstract description 4
125000003172 aldehyde group Chemical group 0.000 abstract description 3
231100000053 low toxicity Toxicity 0.000 abstract description 3
229940122210 Prolyl endopeptidase inhibitor Drugs 0.000 abstract 1
ORZXYSPOAVJYRU-UHFFFAOYSA-N benzyl 2-(2-formylpyrrolidine-1-carbonyl)pyrrolidine-1-carboxylate Chemical compound O=CC1CCCN1C(=O)C1N(C(=O)OCC=2C=CC=CC=2)CCC1 ORZXYSPOAVJYRU-UHFFFAOYSA-N 0.000 abstract 1
239000003649 prolyl endopeptidase inhibitor Substances 0.000 abstract 1
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
239000000203 mixture Substances 0.000 description 16
239000002904 solvent Substances 0.000 description 14
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
238000003786 synthesis reaction Methods 0.000 description 12
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
241000700159 Rattus Species 0.000 description 11
230000015572 biosynthetic process Effects 0.000 description 11
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 9
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
239000000243 solution Substances 0.000 description 9
238000012360 testing method Methods 0.000 description 9
229930000680 A04AD01 - Scopolamine Natural products 0.000 description 8
208000000044 Amnesia Diseases 0.000 description 8
208000031091 Amnestic disease Diseases 0.000 description 8
STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 8
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 8
DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
230000006986 amnesia Effects 0.000 description 8
STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 8
229960002646 scopolamine Drugs 0.000 description 8
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
238000004440 column chromatography Methods 0.000 description 7
239000012043 crude product Substances 0.000 description 7
239000007788 liquid Substances 0.000 description 7
239000000741 silica gel Substances 0.000 description 7
229910002027 silica gel Inorganic materials 0.000 description 7
239000012267 brine Substances 0.000 description 6
238000006243 chemical reaction Methods 0.000 description 6
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
239000000725 suspension Substances 0.000 description 6
229940086542 triethylamine Drugs 0.000 description 6
241000699670 Mus sp. Species 0.000 description 5
238000001816 cooling Methods 0.000 description 5
229920006395 saturated elastomer Polymers 0.000 description 5
235000017557 sodium bicarbonate Nutrition 0.000 description 5
229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 4
-1 CHO Compound Chemical class 0.000 description 4
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
238000000605 extraction Methods 0.000 description 4
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 4
238000010992 reflux Methods 0.000 description 4
KDYAXCPAROXQHG-ZDUSSCGKSA-N 1-[(2s)-2-(hydroxymethyl)pyrrolidin-1-yl]-3-phenylpropan-1-one Chemical compound OC[C@@H]1CCCN1C(=O)CCC1=CC=CC=C1 KDYAXCPAROXQHG-ZDUSSCGKSA-N 0.000 description 3
239000004480 active ingredient Substances 0.000 description 3
125000000217 alkyl group Chemical group 0.000 description 3
230000037396 body weight Effects 0.000 description 3
238000001035 drying Methods 0.000 description 3
230000005764 inhibitory process Effects 0.000 description 3
HQEIPVHJHZTMDP-JEDNCBNOSA-N methyl (2s)-pyrrolidine-2-carboxylate;hydrochloride Chemical compound Cl.COC(=O)[C@@H]1CCCN1 HQEIPVHJHZTMDP-JEDNCBNOSA-N 0.000 description 3
239000002504 physiological saline solution Substances 0.000 description 3
229910000033 sodium borohydride Inorganic materials 0.000 description 3
239000012279 sodium borohydride Substances 0.000 description 3
239000007858 starting material Substances 0.000 description 3
UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 3
DQAMUVCRKGSGKA-LBPRGKRZSA-N 1-[(2s)-2-(hydroxymethyl)pyrrolidin-1-yl]-2-phenylethanone Chemical compound OC[C@@H]1CCCN1C(=O)CC1=CC=CC=C1 DQAMUVCRKGSGKA-LBPRGKRZSA-N 0.000 description 2
XNSAINXGIQZQOO-UHFFFAOYSA-N L-pyroglutamyl-L-histidyl-L-proline amide Natural products NC(=O)C1CCCN1C(=O)C(NC(=O)C1NC(=O)CC1)CC1=CN=CN1 XNSAINXGIQZQOO-UHFFFAOYSA-N 0.000 description 2
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
239000004365 Protease Substances 0.000 description 2
239000000627 Thyrotropin-Releasing Hormone Substances 0.000 description 2
102400000336 Thyrotropin-releasing hormone Human genes 0.000 description 2
101800004623 Thyrotropin-releasing hormone Proteins 0.000 description 2
231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 2
238000011047 acute toxicity test Methods 0.000 description 2
235000019628 coolness Nutrition 0.000 description 2
239000003814 drug Substances 0.000 description 2
239000011874 heated mixture Substances 0.000 description 2
239000003112 inhibitor Substances 0.000 description 2
238000005259 measurement Methods 0.000 description 2
XVFKQIPKRSNKQQ-LBPRGKRZSA-N methyl (2s)-1-(2-phenylacetyl)pyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1CCCN1C(=O)CC1=CC=CC=C1 XVFKQIPKRSNKQQ-LBPRGKRZSA-N 0.000 description 2
NMASVINVCBNPBF-ZDUSSCGKSA-N methyl (2s)-1-(3-phenylpropanoyl)pyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1CCCN1C(=O)CCC1=CC=CC=C1 NMASVINVCBNPBF-ZDUSSCGKSA-N 0.000 description 2
239000012044 organic layer Substances 0.000 description 2
230000003449 preventive effect Effects 0.000 description 2
XNSAINXGIQZQOO-SRVKXCTJSA-N protirelin Chemical compound NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H]1NC(=O)CC1)CC1=CN=CN1 XNSAINXGIQZQOO-SRVKXCTJSA-N 0.000 description 2
239000011541 reaction mixture Substances 0.000 description 2
239000012258 stirred mixture Substances 0.000 description 2
238000003756 stirring Methods 0.000 description 2
VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
229940034199 thyrotropin-releasing hormone Drugs 0.000 description 2
GURJOLXDTNHEOL-LBPRGKRZSA-N (2s)-1-(2-phenylacetyl)pyrrolidine-2-carbaldehyde Chemical compound O=C[C@@H]1CCCN1C(=O)CC1=CC=CC=C1 GURJOLXDTNHEOL-LBPRGKRZSA-N 0.000 description 1
AGRIQBHIKABLPJ-UHFFFAOYSA-N 1-Pyrrolidinecarboxaldehyde Chemical compound O=CN1CCCC1 AGRIQBHIKABLPJ-UHFFFAOYSA-N 0.000 description 1
VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 1
FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
108010004032 Bromelains Proteins 0.000 description 1
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
108090000317 Chymotrypsin Proteins 0.000 description 1
102000004190 Enzymes Human genes 0.000 description 1
108090000790 Enzymes Proteins 0.000 description 1
241000699666 Mus <mouse, genus> Species 0.000 description 1
102400001103 Neurotensin Human genes 0.000 description 1
101800001814 Neurotensin Proteins 0.000 description 1
CQGRLHBOVUGVEA-UHFFFAOYSA-N OOOOOOOOOOOOOOO Chemical compound OOOOOOOOOOOOOOO CQGRLHBOVUGVEA-UHFFFAOYSA-N 0.000 description 1
108090000526 Papain Proteins 0.000 description 1
108090001109 Thermolysin Proteins 0.000 description 1
239000013504 Triton X-100 Substances 0.000 description 1
229920004890 Triton X-100 Polymers 0.000 description 1
102000004142 Trypsin Human genes 0.000 description 1
108090000631 Trypsin Proteins 0.000 description 1
GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 description 1
108010004977 Vasopressins Proteins 0.000 description 1
102000002852 Vasopressins Human genes 0.000 description 1
238000002835 absorbance Methods 0.000 description 1
239000008351 acetate buffer Substances 0.000 description 1
231100000403 acute toxicity Toxicity 0.000 description 1
230000007059 acute toxicity Effects 0.000 description 1
125000003158 alcohol group Chemical group 0.000 description 1
230000003109 amnesic effect Effects 0.000 description 1
KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 1
238000006664 bond formation reaction Methods 0.000 description 1
235000019835 bromelain Nutrition 0.000 description 1
239000000872 buffer Substances 0.000 description 1
239000002775 capsule Substances 0.000 description 1
229910052799 carbon Inorganic materials 0.000 description 1
150000001735 carboxylic acids Chemical class 0.000 description 1
239000007810 chemical reaction solvent Substances 0.000 description 1
229960002376 chymotrypsin Drugs 0.000 description 1
229940125782 compound 2 Drugs 0.000 description 1
230000001143 conditioned effect Effects 0.000 description 1
238000007796 conventional method Methods 0.000 description 1
201000010099 disease Diseases 0.000 description 1
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
239000002552 dosage form Substances 0.000 description 1
229940079593 drug Drugs 0.000 description 1
239000003937 drug carrier Substances 0.000 description 1
229940088598 enzyme Drugs 0.000 description 1
125000004185 ester group Chemical group 0.000 description 1
150000002148 esters Chemical class 0.000 description 1
238000011156 evaluation Methods 0.000 description 1
239000007924 injection Substances 0.000 description 1
238000002347 injection Methods 0.000 description 1
230000035987 intoxication Effects 0.000 description 1
231100000566 intoxication Toxicity 0.000 description 1
238000007912 intraperitoneal administration Methods 0.000 description 1
238000001990 intravenous administration Methods 0.000 description 1
230000007787 long-term memory Effects 0.000 description 1
229910052943 magnesium sulfate Inorganic materials 0.000 description 1
235000019341 magnesium sulphate Nutrition 0.000 description 1
230000015654 memory Effects 0.000 description 1
CWWARWOPSKGELM-SARDKLJWSA-N methyl (2s)-2-[[(2s)-2-[[2-[[(2s)-2-[[(2s)-2-[[(2s)-5-amino-2-[[(2s)-5-amino-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s)-1-[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)OC)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 CWWARWOPSKGELM-SARDKLJWSA-N 0.000 description 1
150000004702 methyl esters Chemical class 0.000 description 1
238000002156 mixing Methods 0.000 description 1
PCJGZPGTCUMMOT-ISULXFBGSA-N neurotensin Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 PCJGZPGTCUMMOT-ISULXFBGSA-N 0.000 description 1
239000002858 neurotransmitter agent Substances 0.000 description 1
231100000956 nontoxicity Toxicity 0.000 description 1
229940055729 papain Drugs 0.000 description 1
235000019834 papain Nutrition 0.000 description 1
239000000546 pharmaceutical excipient Substances 0.000 description 1
239000008363 phosphate buffer Substances 0.000 description 1
125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
239000004094 surface-active agent Substances 0.000 description 1
239000003826 tablet Substances 0.000 description 1
239000012588 trypsin Substances 0.000 description 1
229960003726 vasopressin Drugs 0.000 description 1

Landscapes

Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Medicinal Preparation (AREA)
Compositions Of Macromolecular Compounds (AREA)

CA000487839A 1984-05-17 1985-07-31 Compose anti-prolyl endopeptidase Expired CA1243034A (fr)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
JP9941984A JPS60243140A (ja)	1984-05-17	1984-05-17	ゲルプレ−ト
JP160994/1984		1984-07-31

Publications (1)

Publication Number	Publication Date
CA1243034A true CA1243034A (fr)	1988-10-11

Family

ID=14246947

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA000487839A Expired CA1243034A (fr)	1984-05-17	1985-07-31	Compose anti-prolyl endopeptidase

Country Status (2)

Country	Link
JP (1)	JPS60243140A (fr)
CA (1)	CA1243034A (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
CN1124127C (zh)	1998-12-03	2003-10-15	花王株式会社	片状化妆品
US20150250644A1 (en) *	2012-09-05	2015-09-10	The Better Bandage Company	Prefilled Poultice Wraps and Systems

1984
- 1984-05-17 JP JP9941984A patent/JPS60243140A/ja active Pending
1985
- 1985-07-31 CA CA000487839A patent/CA1243034A/fr not_active Expired

Also Published As

Publication number	Publication date
JPS60243140A (ja)	1985-12-03

Legal Events

Date	Code	Title	Description
2005-10-11	MKEX	Expiry

Publication	Publication Date	Title
EP0172458B1 (fr)	1989-11-02	Composés biologiquement actifs à activité anti-prolyl endopeptidase
CA1267149A (fr)	1990-03-27	Derive de n-acylpyrrolidine, methode de synthese et application
SU860697A1 (ru)	1981-08-30	Способ получени производных дегидроциклических иминокислот
US5081284A (en)	1992-01-14	Proteinase inhibitor
US9499849B2 (en)	2016-11-22	Processes for preparing tubulysins
KR0167101B1 (ko)	1999-01-15	[r-(r,r)]-2-(4-플루오로페닐)-베타, 델타-디히드록시-5-(1-메틸에틸)-3-페닐-4-[(페닐아미노)카르보닐]-1h-피롤-1-헵탄산, 그의 락톤형 및 염류
US5091406A (en)	1992-02-25	Prolinal derivatives
US4916146A (en)	1990-04-10	Amino acid imide derivatives, usage thereof, and medicinal composition containing the same
DD283998A5 (de)	1990-10-31	Verfahren zur herstellung von prolinderivaten und verwandten verbindungen
DD129442B3 (de)	1990-01-10	Verfahren zur herstellung von captopril und vertraeglichen salzen
GB2054586A (en)	1981-02-18	Antihypertensive amides
CA2131367A1 (fr)	1993-09-16	Nouveaux derives peptidiques anticoagulants et compositions pharmaceutiques en contenant; procede de fabrication
DE3000628C2 (fr)	1988-09-08
US4757083A (en)	1988-07-12	Novel pyrrolidinylamide ester derivatives having anti-prolyl endopeptidase activity and synthesis and use thereof
KR100469028B1 (ko)	2005-07-07	선택적트롬빈억제제로유용한방향족아미딘유도체
CA2023522A1 (fr)	1991-02-19	2-(rs)-substituts de 2,3-dihydro-5-oxy-4,6,7-trimethylbenzofuranes utiles comme produits pharmaceutiques antioxydants ayant des proprietes anti-ischemiques et regulatrices de la secretion muqueuse
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DE69130605T2 (de)	1999-05-20	Antihypertensive N-(alpha-substituiertes Pyridyl)-carbonyldipeptide
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AU611796B2 (en)	1991-06-20	Amides of cyclomethylen-1, 2-bicarboxylic acids having therapeutical activity, processes for their preparation and pharmaceutical compositions containing them
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ES2346964T3 (es)	2010-10-22	Derivados del acido hidroxamico.
CA1280428C (fr)	1991-02-19	Derive d'un ester de pyrrolidinylamide ayant une activite anti-prolyl endopeptidase, sa synthese et son utilisation
WO2004060862A2 (fr)	2004-07-22	Composes presentant un effet inhibiteur sur la prolyl-oligopeptidase
JP2674703B2 (ja)	1997-11-12	新規チアゾリジン誘導体及びその用途