WO1995019356A1 - Inhibiteur de l'endopepsidase 24.15 - Google Patents

Inhibiteur de l'endopepsidase 24.15 Download PDF

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Publication number
WO1995019356A1
WO1995019356A1 PCT/JP1995/000020 JP9500020W WO9519356A1 WO 1995019356 A1 WO1995019356 A1 WO 1995019356A1 JP 9500020 W JP9500020 W JP 9500020W WO 9519356 A1 WO9519356 A1 WO 9519356A1
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WO
WIPO (PCT)
Prior art keywords
group
lower alkyl
hydrogen atom
alkyl group
hydroxy
Prior art date
Application number
PCT/JP1995/000020
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English (en)
Japanese (ja)
Inventor
Shiro Mita
Kyurin Ri
Yuko Fujita
Susumu Ito
Original Assignee
Santen Pharmaceutical Co., 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.)
Filing date
Publication date
Application filed by Santen Pharmaceutical Co., Ltd. filed Critical Santen Pharmaceutical Co., Ltd.
Publication of WO1995019356A1 publication Critical patent/WO1995019356A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an endopeptidase 24.15 inhibitor containing a thiazolidincarbonylamino acid derivative as an active ingredient.
  • Endopeptidase one of the neutral endopeptidases
  • Endopeptidase 24.15 is a thiol-dependent neutral metal-containing beptidase, which was also called Pz-peptidase or CL-peptidase.
  • Endopeptidase 24.15 is an enzyme that exists in the body, such as the brain (particularly the hypothalamus) and the testicles, and is involved in various biological functions. It is known that a therapeutic effect is exhibited. For example, analgesic effects, effects on rheumatism, effects on osteoporosis, and effects on dementia such as Alzheimer's disease. Specifically, the analgesic effect of a compound that inhibits endopeptidase 24.15 was confirmed by a hot plate test, a ligation test and a tilofrick test (J. Med.
  • Endopeptidase 2 4. 15 Compounds that inhibit N- [1— (R, S) -carboxy-3-phenylphenyl] —L-alanyl-L-alanyl-L-tyro-silyl 4-amino Benzoic acid, N— [1 — (R, S) 1-carboxy-3- 3-phenylpropyl] 1 L- 1-alanyl- L- 1-alanyl- L-phenylanilanyl 4- 1-aminobenzoic acid, etc. have been reported (Bioche mistry , 27, 597-602 (1988)). However, there is no report that it inhibits endopeptidase 24.15 in smaller compounds.
  • the present inventors searched for a compound that inhibits a new endopeptidase 24.15, and as a result, thiazolidin carbonyl, which is a compound having an angiotensin converting enzyme inhibitory action and being a therapeutic agent for hypertension, has been found.
  • An amino acid derivative (see Japanese Patent Application Laid-Open No. 56-139455) was found to inhibit endopeptidase 24.15.
  • These compounds are especially useful for analgesics, anti-rheumatic drugs, osteoporosis drugs and Alzheimer's disease. It is expected to be useful as a therapeutic agent for dementia. Disclosure of the invention
  • the present invention relates to an endopeptidase 24.15 inhibitor comprising a compound represented by the following general formula [I] or a salt thereof (hereinafter referred to as the compound of the present invention) as an active ingredient, and a compound represented by the following general formula [IV] It relates to the novel compounds or their salts shown.
  • R 1 represents a hydrogen atom, a lower alkyl group, a hydroxy group or a lower alkanoyloxy group.
  • R 2 represents a hydrogen atom, a lower alkanol group or a benzoyl group.
  • R 3 represents a hydrogen atom.
  • R 4 represents a hydrogen atom, a lower alkyl group or a phenyl lower alkyl group; R 4 and R 4 may be combined at any time to form a pyrrolidine ring; and the lower alkyl group may be a hydroxy group, It may be substituted with a carboxy group, a mercapto group, a lower alkylthio group, an imidazolyl group or an indolyl group, and the phenyl ring of the phenyl lower alkyl group is a hydroxy group or a lower alkoxy group. May be substituted with a group.
  • R 5 represents a carboxyl group which may be converted to an ester or an amide.
  • ⁇ is a linear or branched alkyl having 1 to 3 carbon atoms Represents a len group.
  • R 6 represents a lower alkyl group.
  • R 7 represents a hydrogen atom, a lower alkanol group or a benzoyl group.
  • A represents a linear or branched alkylene group having 1 to 3 carbon atoms.
  • the lower alkyl group is defined as 1 to 6 such as methyl, ethyl, propyl, hexyl, isopropyl, tert.-butyl and (dimethyl) ethyl.
  • the lower alkanoyloxy group means a linear or branched alkanoyloxy group having 2 to 6 carbon atoms such as acetyloxy, propionyloxy, hexanoyloxy, and vivaloyloxy.
  • the lower alkanoyl group means a straight-chain or branched alkanoyl group having 2 to 6 carbon atoms such as cetyl, propionyl, hexanoyl, and vivaloyl.
  • a lower alkylthio group is a straight-chain or branched alkylthio having 1 to 6 carbon atoms such as methylthio, ethylthio, propylthio, hexylthio, isopropylthio, tert.-butylthio, (dimethyl) ethylthio and the like. Represents a group.
  • a lower alkoxy group is a straight chain having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, hexyloxy, isopropoxy, tert.-butoxy and the like. Shows a branched alkoxy group.
  • Esters are commonly used as esters of carboxylic acids, such as lower alkyl esters such as methyl ester, ethyl ester, hexyl ester, isopropyl ester, tert.-butyl ester, and phenyl lower alkyl ester such as benzyl ester. Indicates what is done.
  • Amides are amides with ammonia, amides with lower alkylamines such as methylamine, ethylamine and dimethylamine, and amides with phenyl lower alkylamines such as benzylamine.
  • the salts in the compound of the present invention are not particularly limited as long as they are pharmaceutically acceptable salts.
  • salts with alkaline metals such as sodium, potassium, calcium and the like or alkaline earth metals can be used.
  • Salts, salts with organic amines such as ammonium, getylamine, triethanolamine and the like can be mentioned.
  • the compounds of the present invention include stereoisomers and optical isomers, all of which are included in the present invention.
  • R 1 is a lower alkyl group or a hydroxy group
  • R 2 is a hydrogen atom, a lower alkanol group or a benzoyl group
  • R 3 is a hydrogen atom
  • R 4 represents a hydrogen atom, a lower alkyl group or a phenyl lower alkyl group, and the lower alkyl group may be substituted with a hydroxy group or an indolyl group
  • R 5 is an ester or amide.
  • A represents a straight-chain or branched alkylene group having 1 to 3 carbon atoms, and a carboxyl group which may be converted to N are preferred.
  • Examples of the compound (N) include those in which R 5 is a carboxyl group, R 1 is a hydroxy group, R 5 is a carboxyl group, R 1 is a hydroxy group, R 2 is a hydrogen atom, 5 is Cal Those that are boxyl groups are preferred.
  • R ⁇ Chikarakuhi mud alkoxy group, R 2 and R is then preferred correct examples, R ⁇ Chikarakuhi mud alkoxy group, R 2 and R.
  • R 4 is a phenyl lower alkyl group, especially a benzyl group
  • R 5 is a carboxyl group compound and R 1 is a hydroxy group
  • R 2 and R 3 are hydrogen atoms
  • R 4 is a hydroxy lower alkyl group.
  • a compound having a hydroxymethyl group and a carboxyl group for R 5 can be mentioned.
  • the lower alkylene group for A an ethylene group is preferred.
  • Preferred examples of the compound represented by the general formula [IV] include a compound in which R 6 is a methyl group and R 7 is a hydrogen atom. Further, as the lower alkylene group of A, a propylene group is preferable.
  • N— [3 -— (3-mercapto-12-methylpropionyl) -12— (4-—) represented by the following formula [V] is exemplified.
  • Endopeptidase 24.15 is an enzyme that exists in the body and is involved in various biological functions. Endopeptidase 2 4.15 The compound that inhibits 15 exerts an analgesic effect (J. Med. Chem., 36, 1369-1379 (1993)), indicating that endopeptidase is present in synovial fluid from rheumatic patients. 5Specifically high activity (C1 in. Chim. Acta, 170, 291-296 (1987)). Inhibition of endopeptidase 2.4.15 can be used as a therapeutic agent for osteoporosis. Luteinizing protein that intrinsically increases Increasing the amount of lemon-releasing hormone (J. Pharmacol. Ex P.
  • endopeptidase 24.15 was also present in Alzheimer's disease patients. It has been reported that it is involved in the formation of amyloid protein (Biochem. Biophys. Res. Commun., 185, 746-752 (1992)).
  • the present inventors searched for a compound that inhibits a new endopeptidase 24.15.
  • the compound of the present invention inhibits endopeptidase 24.15, and is especially useful for analgesics, antirheumatic agents, osteoporosis treatment agents and It is expected to be useful as a therapeutic agent for dementia such as Ruzheimer's disease.
  • the compound of the present invention has an angiotensin-converting enzyme inhibitory activity and can be used as a therapeutic agent for hypertension (Japanese Patent Application Laid-Open No. 56-139455). Is not disclosed.
  • the method of administration of the compound of the present invention may be oral or parenteral, and examples of dosage forms include tablets, capsules, capsules, granules, powders, and injections.
  • the preparation of the compound of the present invention may be prepared according to a conventional method by adding necessary additives to the compound of the present invention according to the dosage form.
  • necessary additives for example, in the case of oral preparations such as tablets, capsules, soft capsules, granules and powders, Bulking agents such as lactose, crystalline cellulose, starch, vegetable oil, etc.
  • Lubricants such as magnesium phosphate and talc; binders such as hydroxyquine propylcellulose and polyvinylpyrrolidone; disintegrants such as carboxymethylcellulose calcium and low-substituted hydroxypropylmethylcellulose; and hydroxypropylmethylate Coating agents such as norecellulose, macrogol, silicone tree B, etc., and film agents such as gelatin film may be added as needed.
  • the dose of the compound of the present invention in the present invention can be appropriately selected depending on the condition, age, dosage form, etc., and is 0.1 to 500 mg per day, preferably 1 to: once or several times LOOO mg. It may be administered separately.
  • Compound of the present invention 1 mg Lactose 66.4 mg Corn starch 20 mg Carboxymethylcellulose Calcium 6 mg Hydroxypropyl pilsesolerose 4 mg Magnesium stearate 0.6 mg Tablets of the above formulation are coated with a coating agent (for example, , Hydroxypropylmethylcellulose, macrogol, silicon resin, etc.) (2 mg) to obtain the desired coating tablets (the same formulation is used for tablets with the following formulation) )
  • a coating agent for example, Hydroxypropylmethylcellulose, macrogol, silicon resin, etc.
  • Compound of the present invention 50 mg Lactose 55 mg Mg potato starch 20 mg Hydroxypropyl pircellose: L 4 mg Talc trace amount
  • Endopeptidase 2 4.15
  • benzoinolegri-silyl L-aranyl-L-aranyl-l-L-phenylaranyl-l-4-aminobenzoic acid B z — GAAF—p AB
  • Orlowski et al. which measures enzymatic activity by using as a substrate, is known (Eur. J. Biochem., 81-88 (1983)). Therefore, according to the method described in this document, The effect of the product on endopeptidase 24.5 was examined (experimental method).
  • the reaction was performed under the following reaction conditions.
  • Tris-HCl buffer pH 7.0 200 mM
  • Test compound 0 to: L 0, M endopeptidase 2 4.151 ⁇ g
  • the above solution 2501 was incubated at 37 ° C for 15 minutes. Twenty-five percent trichloroacetic acid was added, followed by two-hundred and one-half percent sodium nitrite aqueous solution. Three minutes later, add 0.25% of a 1.25% ammonium sulfamate solution, and after another two minutes, 0.1% 1— (1 naphthyl) monoethylene diamine dihydrochloride ethanol Solution was added to 500 ⁇ 1. After standing for 10 minutes or more, the absorbance was measured at a wavelength of 555.5 nm.
  • the degree of inhibitory effect of the test compound on endopeptidase 24.15 was determined using the inhibition rate determined by the following formula.
  • compound 2 The concentration required to inhibit 50% of endopeptidase 24.5 in 1 L-phenylanilanine (compound 2) (I
  • the compounds of the present invention were found to significantly inhibit endopeptidase 24.15 activity at low concentrations.
  • the compound of the present invention is an excellent endeptidase It has an activity of inhibiting 24.15, and is expected to be particularly useful as an analgesic, an antirheumatic agent, a therapeutic agent for osteoporosis, and a therapeutic agent for dementia such as Alzheimer's disease.
  • the present invention relates to an endopeptidase 24.4.15 inhibitor containing a thiazolidincarbonylcarbonylamino acid derivative as an active ingredient.
  • the compound has excellent endopeptidase 24.15 inhibitory activity and is expected to be useful for analgesics, antirheumatic agents, osteoporosis treatment, and treatment of dementia. .

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Inhibiteur de l'endopepsidase 24.15 dont le principe actif est un composé représenté par la formule générale (1) dans laquelle R1 représente hydrogène, alkyle inférieur, hydroxy ou alcanoyloxy inférieur; R2 représente hydrogène, alcanoyle inférieur ou benzoyle; R3, représente hydrogène; R4 représente hydrogène, alkyle inférieur ou alkyle inférieur phénylé sous réserve que R3 et R4 puissent se combiner entre eux pour former un cycle de pyrolidine, que l'alkyle inférieur puisse être substitué par un hydroxy, un carboxy, un mercapto, un alkylthyo, un imidazolyle ou un indolyle et que le phényle de l'alkyle inférieur phénylé puisse être substitué par hydroxy ou alcoxy inférieur; R5 représente carboxyl sous la forme d'un ester ou d'une amide et A représente un alkylène C¿1?-C3 linéaire ou ramifié. Ce composé présente une excellente activité inhibitrice de l'endopepsidase 24.15 et une efficacité prometteuse comme analgésique et anti-rhumatismal et contre l'ostéoporose et la démence.
PCT/JP1995/000020 1994-01-18 1995-01-11 Inhibiteur de l'endopepsidase 24.15 WO1995019356A1 (fr)

Applications Claiming Priority (2)

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JP6003351A JP2973271B2 (ja) 1994-01-18 1994-01-18 エンドペプチダーゼ２４．１５阻害剤
JP6/3351 1994-01-18

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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999035163A1 (fr) * 1998-01-08 1999-07-15 Celltech Therapeutics Limited Derives de phenylalanine
US6274577B1 (en) 1998-09-30 2001-08-14 Celltech Therapeutics Limited Benzodiazepines
US6319922B1 (en) 1998-11-23 2001-11-20 Celltech Therapeutics Limited Propanoic acid derivatives
US6329362B1 (en) 1998-03-16 2001-12-11 Celltech Therapeutics Limited Cinnamic acid derivatives
US6329372B1 (en) 1998-01-27 2001-12-11 Celltech Therapeutics Limited Phenylalanine derivatives
US6348463B1 (en) 1998-09-28 2002-02-19 Celltech Therapeutics Limited Phenylalanine derivatives
US6362204B1 (en) 1998-05-22 2002-03-26 Celltech Therapeutics, Ltd Phenylalanine derivatives
US6369229B1 (en) 1998-06-03 2002-04-09 Celltech Therapeutics, Limited Pyridylalanine derivatives
US6403608B1 (en) 2000-05-30 2002-06-11 Celltech R&D, Ltd. 3-Substituted isoquinolin-1-yl derivatives
US6455539B2 (en) 1999-12-23 2002-09-24 Celltech R&D Limited Squaric acid derivates
US6465471B1 (en) 1998-07-03 2002-10-15 Celltech Therapeutics Limited Cinnamic acid derivatives
US6469025B1 (en) 2000-08-02 2002-10-22 Celltech R&D Ltd. 3-substituted isoquinolin-1-yl derivatives
US6518283B1 (en) 1999-05-28 2003-02-11 Celltech R&D Limited Squaric acid derivatives
US6521626B1 (en) 1998-03-24 2003-02-18 Celltech R&D Limited Thiocarboxamide derivatives
US6534513B1 (en) 1999-09-29 2003-03-18 Celltech R&D Limited Phenylalkanoic acid derivatives
US6545013B2 (en) 2000-05-30 2003-04-08 Celltech R&D Limited 2,7-naphthyridine derivatives
US6555562B1 (en) 1998-02-26 2003-04-29 Celltech R&D Limited Phenylalanine derivatives
US6610700B2 (en) 2000-04-17 2003-08-26 Celltech R & D Limited Enamine derivatives
US6740654B2 (en) 2000-07-07 2004-05-25 Celltech R & D Limited Squaric acid derivatives
US6911451B1 (en) 1998-06-05 2005-06-28 Celltech R&D Limited Phenylalanine derivatives
US6953798B1 (en) 1998-11-30 2005-10-11 Celltech R&D Limited β-alanine derivates

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BRPI0816807A2 (pt) * 2007-09-12 2017-05-16 Dr Reddy's Laboratories Inc bortezomib e processo para a produção do mesmo

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56139455A (en) * 1980-04-02 1981-10-30 Santen Pharmaceut Co Ltd Sulfur-containing acylaminoacid
JPS57112381A (en) * 1980-12-29 1982-07-13 Santen Pharmaceut Co Ltd Five-membered heterocyclic compound
JPS646263A (en) * 1987-02-23 1989-01-10 Ono Pharmaceutical Co Novel thiazolidine derivative, its production and antiamnestic agent containing same
JPS6442475A (en) * 1987-08-08 1989-02-14 Kissei Pharmaceutical Thiazolidine derivative
JPH01250370A (ja) * 1987-12-23 1989-10-05 Zeria Pharmaceut Co Ltd 新規アミノ酸イミド誘導体、製法ならびに用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56139455A (en) * 1980-04-02 1981-10-30 Santen Pharmaceut Co Ltd Sulfur-containing acylaminoacid
JPS57112381A (en) * 1980-12-29 1982-07-13 Santen Pharmaceut Co Ltd Five-membered heterocyclic compound
JPS646263A (en) * 1987-02-23 1989-01-10 Ono Pharmaceutical Co Novel thiazolidine derivative, its production and antiamnestic agent containing same
JPS6442475A (en) * 1987-08-08 1989-02-14 Kissei Pharmaceutical Thiazolidine derivative
JPH01250370A (ja) * 1987-12-23 1989-10-05 Zeria Pharmaceut Co Ltd 新規アミノ酸イミド誘導体、製法ならびに用途

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6197794B1 (en) 1998-01-08 2001-03-06 Celltech Therapeutics Limited Phenylalanine derivatives
WO1999035163A1 (fr) * 1998-01-08 1999-07-15 Celltech Therapeutics Limited Derives de phenylalanine
US6329372B1 (en) 1998-01-27 2001-12-11 Celltech Therapeutics Limited Phenylalanine derivatives
US6555562B1 (en) 1998-02-26 2003-04-29 Celltech R&D Limited Phenylalanine derivatives
US6329362B1 (en) 1998-03-16 2001-12-11 Celltech Therapeutics Limited Cinnamic acid derivatives
US6521626B1 (en) 1998-03-24 2003-02-18 Celltech R&D Limited Thiocarboxamide derivatives
US6362204B1 (en) 1998-05-22 2002-03-26 Celltech Therapeutics, Ltd Phenylalanine derivatives
US6369229B1 (en) 1998-06-03 2002-04-09 Celltech Therapeutics, Limited Pyridylalanine derivatives
US6911451B1 (en) 1998-06-05 2005-06-28 Celltech R&D Limited Phenylalanine derivatives
US6465471B1 (en) 1998-07-03 2002-10-15 Celltech Therapeutics Limited Cinnamic acid derivatives
US6348463B1 (en) 1998-09-28 2002-02-19 Celltech Therapeutics Limited Phenylalanine derivatives
US6677339B2 (en) 1998-09-28 2004-01-13 Celltech R & D Limited Phenylalanine derivatives
US6274577B1 (en) 1998-09-30 2001-08-14 Celltech Therapeutics Limited Benzodiazepines
US6319922B1 (en) 1998-11-23 2001-11-20 Celltech Therapeutics Limited Propanoic acid derivatives
US6953798B1 (en) 1998-11-30 2005-10-11 Celltech R&D Limited β-alanine derivates
US6518283B1 (en) 1999-05-28 2003-02-11 Celltech R&D Limited Squaric acid derivatives
US6534513B1 (en) 1999-09-29 2003-03-18 Celltech R&D Limited Phenylalkanoic acid derivatives
US6455539B2 (en) 1999-12-23 2002-09-24 Celltech R&D Limited Squaric acid derivates
US6610700B2 (en) 2000-04-17 2003-08-26 Celltech R & D Limited Enamine derivatives
US6545013B2 (en) 2000-05-30 2003-04-08 Celltech R&D Limited 2,7-naphthyridine derivatives
US6403608B1 (en) 2000-05-30 2002-06-11 Celltech R&D, Ltd. 3-Substituted isoquinolin-1-yl derivatives
US6740654B2 (en) 2000-07-07 2004-05-25 Celltech R & D Limited Squaric acid derivatives
US6469025B1 (en) 2000-08-02 2002-10-22 Celltech R&D Ltd. 3-substituted isoquinolin-1-yl derivatives

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JPH07206677A (ja) 1995-08-08

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