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1. (EP0979273) MODIFIED ANTISENSE NUCLEOTIDES COMPLEMENTARY TO A SECTION OF THE HUMAN Ha-Ras GENE

Office : European Patent Office
Application Number: 98925504 Application Date: 30.04.1998
Publication Number: 0979273 Publication Date: 16.02.2000
Publication Kind : A1
Designated States: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LI, LU, MC, NL, PT, SE
Prior PCT appl.: Application Number:EP1998002546 ; Publication Number: Click to see the data
IPC:
A 61K
C 12N
C12N 15/09
A 61K
A61K 31/133
C 07H
A61K 31/175
A61K 31/407
A61K 31/513
A61K 31/519
A61K 31/664
A61K 31/675
A61K 31/70
A61K 31/704
A61K 31/711
A61K 33/24
A61K 38/00
A61K 45/06
A61P 35/00
C07H 21/00
C07H 21/02
C12N 15/113
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
70
Carbohydrates; Sugars; Derivatives thereof
C CHEMISTRY; METALLURGY
12
BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
N
MICRO-ORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICRO-ORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
15
Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
09
Recombinant DNA-technology
11
DNA or RNA fragments; Modified forms thereof
C CHEMISTRY; METALLURGY
12
BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
N
MICRO-ORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICRO-ORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
15
Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
09
Recombinant DNA-technology
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
45
Medicinal preparations containing active ingredients not provided for in groups A61K31/-A61K41/132
06
Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
13
Amines, e.g. amantadine
133
having hydroxy groups, e.g. sphingosine
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
H
SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
21
Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
16
Amides, e.g. hydroxamic acids
17
having the group N-C(O)-N or N-C(S)-N, e.g. urea, thiourea, carmustine
175
having the group , N-C(O)-NN- or , e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
33
Heterocyclic compounds
395
having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
40
having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
407
condensed with heterocyclic ring systems, e.g. ketorolac, physostigmine
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
33
Heterocyclic compounds
395
having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
495
having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
505
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
513
having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
33
Heterocyclic compounds
395
having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
495
having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
505
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
519
ortho- or peri-condensed with heterocyclic rings
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
66
Phosphorus compounds
664
Amides of phosphorus acids
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
66
Phosphorus compounds
675
having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
70
Carbohydrates; Sugars; Derivatives thereof
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
70
Carbohydrates; Sugars; Derivatives thereof
7028
Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
7034
attached to a carbocyclic compound, e.g. phloridzin
704
attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin, digitoxin
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
70
Carbohydrates; Sugars; Derivatives thereof
7088
Compounds having three or more nucleosides or nucleotides
711
Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
33
Medicinal preparations containing inorganic active ingredients
24
Heavy metals; Compounds thereof
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
38
Medicinal preparations containing peptides
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
45
Medicinal preparations containing active ingredients not provided for in groups A61K31/-A61K41/132
06
Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
P
SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
35
Antineoplastic agents
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
H
SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
21
Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
H
SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
21
Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
02
with ribosyl as saccharide radical
C CHEMISTRY; METALLURGY
12
BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
N
MICRO-ORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICRO-ORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
15
Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
09
Recombinant DNA-technology
11
DNA or RNA fragments; Modified forms thereof
113
Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides
CPC:
C07H 21/02
A61K 38/00
C12N 15/1135
C12N 2310/11
C12N 2310/315
C12N 2310/322
C12N 2310/345
C12N 2310/351
C12N 2310/3531
Applicants: HOECHST MARION ROUSSEL DE GMBH
Inventors: UHLMANN EUGEN
PEYMAN ANUSCHIRWAN
WILL DAVID WILLIAM
CHANG ESTHER
PIROLLO KATHLEEN
RAIT ANTONINA
Priority Data: 97107404 05.05.1997 EP
9802546 30.04.1998 EP
98925504 30.04.1998 EP
Title: (DE) MODIFIZIERTE ANTISENSE OLIGONUKLEOTIDE, DIE KOMPLEMENTÄR ZU EINEM ABSCHNITT DES MENSCHLICHEN HA-RAS GEN SIND
(EN) MODIFIED ANTISENSE NUCLEOTIDES COMPLEMENTARY TO A SECTION OF THE HUMAN Ha-Ras GENE
(FR) NUCLEOTIDES ANTISENS MODIFIES COMPLEMENTAIRES D'UNE SECTION DU GENE HUMAIN Ha-Ras
Abstract:
(EN) The invention relates to a specific modified oligonucleotide complementary to a section of the human Ha-ras gene and mRNA, and its use to specifically regulate, modulate or inhibit expression of the Ha-ras gene, and its use as a pharmaceutical for the treatment of conditions arising from abnormal expression of the Ha-ras gene, in particular in combination with chemotherapy and radiotherapy. The modified oligodeoxynucleotide according to the invention has the sequence: 5'-TxAxTxTxCxCxGxTxCxAxT-3'-O-PO2-O-R, wherein X is o or s, with the proviso that x is 4 to 9 times equal to s and o means a phosphodiester internucleoside linkage, s means a phosphorothioate internucleoside linkage, R means a C8-C21 alkyl group, -(CH2-CH2O)n-(CH2)m-CH3 or -CH2-CH(OH)CH2O-(CH2)q-CH3 wherein n is an integer from 1 to 6, m is an integer from 0 to 20 and q is an integer from 7 to 20 and A is 2'-deoxyadenosine, G is 2'-deoxyguanosine, C is 2'-deoxycytidine and T is thymidine.
(FR) L'invention concerne un oligonucléotide modifié spécifique, complémentaire d'une section du gène humain Ha-ras et mARN, et son utilisation pour réguler, moduler ou inhiber de manière spécifique, l'expression du gène Ha-ras. L'invention concerne également son utilisation comme produit pharmaceutique pour traiter les conditions provenant de l'expression anormale du gène Ha-ras, en particulier, en association avec la chimiothérapie et la radiothérapie. L'oligodésoxynucléotide modifié, selon l'invention, présente la séquence 5'-TxAxTxTxCxCxGxTxCxAxT-3'-O-PO2-O-R x représente o ou s, à condition que x soit 4 à 9 fois égal à s et o représente une liaison d'internucléoside de phosphodiester, s représente une liaison d'internucléoside de phosphorothioate. R représente un groupe alkyle C8-C21, -(CH2-CH2O)n-(CH2)m-CH3 ou -CH2-CH(OH)CH2O-(CH2)q-CH3 où n est un nombre entier compris entre 1 et 6, m est un nombre entier compris entre 0 et 20 et q est un nombre entier compris entre 7 et 20 et A représente 2'-désoxyadénosine, G représente 2'-désoxyguanosine, C est 2'-désoxycytidine et T est thymidine.
Also published as:
CZPV1999-3910MXPA/a/1999/010132KR1020010012238US20030064514US20050020523JP2002501505
CN1255164CA2288946AU1998077602WO/1998/050540