ZA200200997B - Use of CGRP antagonists and CGRP release inhibitors for controlling menopausal hot flushes. - Google Patents
Use of CGRP antagonists and CGRP release inhibitors for controlling menopausal hot flushes. Download PDFInfo
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- ZA200200997B ZA200200997B ZA200200997A ZA200200997A ZA200200997B ZA 200200997 B ZA200200997 B ZA 200200997B ZA 200200997 A ZA200200997 A ZA 200200997A ZA 200200997 A ZA200200997 A ZA 200200997A ZA 200200997 B ZA200200997 B ZA 200200997B
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- South Africa
- Prior art keywords
- piperidinyl
- carbonyl
- dihydro
- dibromo
- amino
- Prior art date
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- 229940127597 CGRP antagonist Drugs 0.000 title claims description 16
- 108090000932 Calcitonin Gene-Related Peptide Proteins 0.000 title claims description 15
- 206010027304 Menopausal symptoms Diseases 0.000 title claims description 12
- 239000003112 inhibitor Substances 0.000 title claims description 9
- 102100025588 Calcitonin gene-related peptide 1 Human genes 0.000 title claims 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 106
- 239000013543 active substance Substances 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- -1 4-hydroxy-3,5-dimethylphenyl Chemical group 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 238000002657 hormone replacement therapy Methods 0.000 claims description 4
- 125000002435 L-phenylalanyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 238000009097 single-agent therapy Methods 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 7
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims 4
- 239000003735 calcitonin gene related peptide receptor antagonist Substances 0.000 claims 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 2
- GPASDLXNNAPVRX-UHFFFAOYSA-N 1-methyl-4-piperidin-1-ylpiperidine Chemical compound C1CN(C)CCC1N1CCCCC1 GPASDLXNNAPVRX-UHFFFAOYSA-N 0.000 claims 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- KGOJZYQQBKLMNZ-MUUNZHRXSA-N n-[(2r)-3-(4-amino-3,5-dibromophenyl)-1-oxo-1-(4-piperidin-1-ylpiperidin-1-yl)propan-2-yl]-4-(n-carbamoylanilino)piperidine-1-carboxamide Chemical compound C([C@@H](NC(=O)N1CCC(CC1)N(C(=O)N)C=1C=CC=CC=1)C(=O)N1CCC(CC1)N1CCCCC1)C1=CC(Br)=C(N)C(Br)=C1 KGOJZYQQBKLMNZ-MUUNZHRXSA-N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 239000013589 supplement Substances 0.000 claims 1
- 102000004414 Calcitonin Gene-Related Peptide Human genes 0.000 description 12
- 230000000694 effects Effects 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 3
- 206010060800 Hot flush Diseases 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 210000001044 sensory neuron Anatomy 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 102000003797 Neuropeptides Human genes 0.000 description 1
- 108090000189 Neuropeptides Proteins 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 229950002360 avitriptan Drugs 0.000 description 1
- WRZVGHXUPBWIOO-UHFFFAOYSA-N avitriptan Chemical compound C12=CC(CS(=O)(=O)NC)=CC=C2NC=C1CCCN(CC1)CCN1C1=NC=NC=C1OC WRZVGHXUPBWIOO-UHFFFAOYSA-N 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229960002472 eletriptan Drugs 0.000 description 1
- OTLDLQZJRFYOJR-LJQANCHMSA-N eletriptan Chemical compound CN1CCC[C@@H]1CC1=CN=C2[C]1C=C(CCS(=O)(=O)C=1C=CC=CC=1)C=C2 OTLDLQZJRFYOJR-LJQANCHMSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960005254 naratriptan Drugs 0.000 description 1
- UNHGSHHVDNGCFN-UHFFFAOYSA-N naratriptan Chemical compound C=12[CH]C(CCS(=O)(=O)NC)=CC=C2N=CC=1C1CCN(C)CC1 UNHGSHHVDNGCFN-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229960000425 rizatriptan Drugs 0.000 description 1
- TXHZXHICDBAVJW-UHFFFAOYSA-N rizatriptan Chemical compound C=1[C]2C(CCN(C)C)=CN=C2C=CC=1CN1C=NC=N1 TXHZXHICDBAVJW-UHFFFAOYSA-N 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000000952 serotonin receptor agonist Substances 0.000 description 1
- 229960003708 sumatriptan Drugs 0.000 description 1
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 229960001360 zolmitriptan Drugs 0.000 description 1
- UTAZCRNOSWWEFR-ZDUSSCGKSA-N zolmitriptan Chemical compound C=1[C]2C(CCN(C)C)=CN=C2C=CC=1C[C@H]1COC(=O)N1 UTAZCRNOSWWEFR-ZDUSSCGKSA-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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- 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
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
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- A61P5/00—Drugs for disorders of the endocrine system
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- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
- A61P5/22—Drugs for disorders of the endocrine system of the parathyroid hormones for decreasing, blocking or antagonising the activity of calcitonin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
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- A61P9/00—Drugs for disorders of the cardiovascular system
Description
. ® 2002/0997 * 72625pri
Boehringer Ingelheim Pharma KG Case 5/1268-Ro
D-55216 Ingelheim/Rhein foreign filing
Use of CGRP antagonists and CGRP release inhibitors for combating menopausal hot flushes
Hot flushes are a common symptom of peri/post-menopausal syndrome the physiology of which is still not fully understood. Apart from hormone replacement therapy, which is a complex intervention and frequently cannot be used long-term owing to its side effects, there has up until now been no simple therapy largely free from side effects for this generally troublesome condition. " Hot flushes are caused by vasodilatation and increased blood flow. A number of publications have mentioned the possibility that CGRP (calcitonin gene-related peptide) plays a part in the occurrence of menopausal hot flushes in oestrogen- deficient women owing to the vasodilatory properties of this neuropeptide ([1]: J. Endocrinol. (1995), 146(3), 431-437;
[2] : Acta Physiol. Scand. (1998), 162(4), 517-522; [3]: Am. J.
Obstet. Gynecol. (1996), 175(3, Pt. 1), 638-642). The therapeutic use of CGRP antagonists for treating menopausal syndrome has not previously been proposed in the literature.
It has now been found that the symptoms of menopausal hot flushes can be effectively prevented or their distressing effects substantially alleviated by substances which antagonise the effects of CGRP (CGRP antagonists) or inhibit or reduce the release of CGRP from sensory nerve endings (CGRP release inhibitors), this therapeutic approach being superior to hormone replacement therapy in particular because of its lack of side effects.
The present invention thus relates to the use of CGRP antagonists and/or CGRP release inhibitors for combating
Lo 200270997 _ < - 2 - menopausal hot flushes, including both prevention and acute treatment. The use according to the invention preferably comprises monotherapy with a single substance, but also includes combined therapy with a number of substances from the specified groups of active substances. Moreover, the treatment according to the invention may be carried out in addition to conventional hormone replacement therapy.
The invention also relates to the use of CGRP antagonists and/or CGRP release inhibitors for preparing a pharmaceutical composition for treating menopausal hot flushes as well as the corresponding pharmaceutical compositions containing as active substance one or more CGRP antagonists and/or CGRP release inhibitors. © Any pharmaceutically acceptable active substances which antagonise the known effects of CGRP or inhibit the release of
CGRP from sensory nerve endings may be used for the purposes of the present invention.
Examples of CGRP antagonists include the amino acid derivatives described in WO 98/11128 or DE 199 11 039, as well as the non-peptidic active substances described in WO 98/56779, WO 98/09630 and WO 97/09046.
Examples of CGRP release inhibitors include serotonin 5-HT,;- agonists such as avitriptan, eletriptan, naratriptan, rizatriptan, sumatriptan or zolmitriptan, as well as 5-HT- agonists or NPY-agonists.
Of the CGRP antagonists described in WO 98/11128, the following compounds, for example, may be used for the treatment of menopausal hot flushes, for the preparation of a corresponding pharmaceutical composition and as an ingredient of a corresponding pharmaceutical composition:
B - 3 - (B) 1-[N2-[3,5-dibromo-N- [[4-(3,4-dihydro-2 (1H) - oxoquinazolin-3-yl) -l-piperidinyl] carbonyl] -D-tyrosyl] -L- lysyl] -4- (4-pyridinyl) -piperazine, (B) 1-[4-amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2 (1H) - ox0-1,3-benzodiazepin-3-yl)-1-piperidinyl] carbonyl] -D-phenyl- alanyl] -4-(1-piperidinyl) -piperidine, (C) 1- [N2- [4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2 (1H) -oxo- quinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -L- lysyl]l -4- (4-pyridinyl) -piperazine, (D) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2 (1H) -oxo- quinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -L- lysyl] -4- (4-pyridinyl) -piperidine, (E) 1-[N2-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2 (2H) -oxo- imidazol-1-yl) -1-piperidinyl] carbonyl] -D-tyrosyl]-L-1lysyl] - 4- (4-pyridinyl) -piperazine, (F) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl- 2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenyl- alanyl] -L-1lysyl] -4- (4-pyridinyl) -piperazine, (G) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2 (1H) -oxothieno[3,4-d]- pyrimidin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (1- piperidinyl) -piperidine, (H) 1-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3 (3H) - oxo-1,2,4-triazol-2-yl)-1-piperidinyl] carbonyl] -D-phenyl- alanyl] -4- (1-methyl-4-piperidinyl) -piperidine, (1) 1-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3 (3H) - oxo-1,2,4-triazol-2-yl)-1-piperidinyl] carbonyl] -D-phenyl- alanyl] -4- (1-piperidinyl) -piperidine,
(J) 1- [4-amino-3,5-dibromo-N-{[4-(2,4-dihydro-5-phenyl-3 (3H) - oxo-1,2,4-triazol-2-yl) -1-piperidinyl] carbonyl] -D-phenyl- alanyl] -4- (1-methyl-4-piperidinyl) -piperazine, (K) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2 (1H) -oxo- thieno[3,2-d]pyrimidin-3-yl) -1-piperidinyl] carbonyl] -D-phenyl- alanyl]-4- (1-piperidinyl) -piperidine, (L) 1-{4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(tri- fluoromethyl) phenyl] -2 (2H) -oxoimidazol-1-yl] -1- piperidinyll carbonyl] -D-phenylalanyl] -4-(l-ethyl-4- piperidinyl) -piperidine, (M) 1-[4-amino-3,5-dibromo-N-[[4-([3,4-dihydro-2 (1H) - oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-hexyl-4-piperidinyl) -piperidine, (N) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2 (1H) - oxoquinazolin-3-yl]-1-piperidinyl] carbonyl] -D-phenylalanyl]-4- (1-cyclopropylmethyl-4-piperidinyl) -piperidine, (0) 1-[N-{[4-[3,4-dihydro-2 (1H) -~oxoquinazolin-3-yl]-1-pipe- ridinyl]) carbonyl] -3-ethenyl-D,L-phenylalanyl] -4- (hexahydro-1H- l-azepinyl) -piperidine, (P) (R,8)-1-[4-[4-(3,4-dihydro-2 (1H) -oxoquinazolin-3-yl)-1- piperidinyll]l-2-[(4-hydroxy-3,5-dimethylphenyl) methyl] -1,4-di- oxobutyl] -4- (1-piperidinyl) -piperidine, (Q) 1-[4-amino-3,5-dibromo-N-[ [4 -~ [N- (aminocarbonyl) -N-phenyl-
: amino] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-
piperidinyl) -piperidine, (R) 1- [4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2 (1H) - oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (5-methoxy-4-pyrimidinyl) -piperazine,
pt - 5 - (8S) 1-[4-amino-3,5-dibromo-N-[[4-(1,1-dioxido-3 (4H) -oxo- 1,2,4-benzothiadiazin-2-yl)-1-piperidinyl] carbonyl] -D- phenylalanyl] -4- (1-piperidinyl) -piperidine, (T) 1-[4-amino-3,5-dibromo-N-[[4-[2 (1H) -oxoquinolin-3-y1l]-1- piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) - piperidine, (U) 1-{4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2 (1H) - oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- [3- (dimethylamino) propyl] -piperazine, (Vv) 1-[4-amino-3,5-dibromo-N-[[4- [3,4-dihydro-2 (1H) - oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (4-methyl-1-piperazinyl) -piperidine, (W) 1-[4-amino-3,5-dibromo-N-{[4-[3,4-dihydro-2 (1H) - oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- [(1-methyl-4-piperidinyl) carbonyl] -piperazine, (X) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2 (1H) - oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- [(1-methyl-4-piperazinyl) carbonyl] -piperazine, (Y) 1-[4-amino-3,5-dibromo-N-[[4- (3,4-dihydro-2 (1H) -oxo- quinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] - 4-[4-[4- (dimethylamino)butyl]lphenyl] -piperazine, (2) 1-[4-amino-3,5-dibromo-N-[[4- (3,4-dihydro-2 (1H) -oxo- quinazolin-3-yl) -l-piperidinyl] carbonyl] -D-phenylalanyl] - 4-[4-(dimethylamino) -1-piperidinyl] -piperidine, (AA) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-y1) - 1l-piperidinyl] carbonyl] -N'-methyl-D-tryptyl] -4- (4-methyl-1- piperazinyl) -piperidine,
Claims (10)
1. Use of an active substance selected from CGRP antagonists and CGRP release inhibitors for treating menopausal hot flushes.
2. Use according to claim 1, characterised in that it is effected as a monotherapy with a single active substance.
3. Use according to claim 1, characterised in that it is effected as a supplement to hormone replacement therapy.
4. Use according to claim 1, characterised in that the active substance is a CGRP antagonist.
5. Use according to claim 4, characterised in that the CGRP antagonist is selected from among: (RA) 1- [N2- [3,5-dibromo-N- [[4- (3, 4-dihydro-2 (1H) - oxoquinazolin-3-yl)-1-piperidinyl] carbonyl] -D-tyrosyl] -L- lysyl]l -4- (4-pyridinyl) -piperazine, (B) 1-[4-amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2 (1H) - oxo-1,3-benzodiazepin-3-yl) -1-piperidinyl] carbonyl] -D-phenyl- alanyl] -4- (1-piperidinyl) -piperidine, (C) 1- [N2- [4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2 (1H) -oxo- quinazolin-3-yl)-1-piperidinyl] carbonyl] -D-phenylalanyl]-L- lysyll -4- (4-pyridinyl) -piperazine, (D) 1- [N2-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2 (1H) -oxo- quinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl]-L- lysyl] -4- (4-pyridinyl) -piperidine,
-~ - 31 - (E) 1- [N2-[3,5-dibromo-N-[[4- (1, 3-dihydro-4-phenyl-2 (2H) -oxo- imidazol-1-yl)-1-piperidinyl]} carbonyl} -D-tyrosyl] -L-1lysyl]-4- (4-pyridinyl) -piperazine, (F) 1- [N2- [4-amino-3,5-dibromo-N- [[4- (1,3-dihydro-4-phenyl- 2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenyl- alanyl] -L-1lysyl] -4- (4-pyridinyl) -piperazine, (G) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2 (1H) -oxothieno[3,4-d] - pyrimidin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4-(1- piperidinyl) -piperidine, (H) 1-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3 (3H) - oxo-1,2,4-triazol-2-yl)-1-piperidinyl] carbonyl] -D-phenyl- alanyl] -4- (1-methyl-4-piperidinyl) -piperidine, (1) 1-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3 (3H) - oxo-1,2,4-triazol-2-yl)-1-piperidinyl]l carbonyl] -D-phenyl- alanyl] -4- (1-piperidinyl) -piperidine, (J) 1-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3 (3H) - oxo-1,2,4-triazol-2-yl)-1-piperidinyl] carbonyl] -D-phenyl- alanyl] -4- (1-methyl-4-piperidinyl) -piperazine, (K) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2 (1H) -oxo- thieno([3,2-d]pyrimidin-3-yl)-1-piperidinyl] carbonyl] -D-phenyl- alanyl] -4- (1-piperidinyl) -piperidine, (L) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(tri- fluoromethyl) phenyl] -2 (2H) -oxoimidazol-1-yl] -1- piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-ethyl-4- piperidinyl) -piperidine, (M) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2 (1H) - oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-hexyl-4-piperidinyl) -piperidine,
(N) 1- [4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2 (1H) - oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl]-4- (1-cyclopropylmethyl-4-piperidinyl) -piperidine, (0) 1-[N-[[4-[3,4-dihydro-2 (1H) -oxoquinazolin-3-yl]-1-pipe- ridinyl] carbonyl] -3-ethenyl-D,L-phenylalanyl] -4- (hexahydro-1H- l-azepinyl) -piperidine, (P) (R,8)-1-[4-[4-(3,4-dihydro-2 (1H) -oxoguinazolin-3-yl)-1- piperidinyl] -2-[(4-hydroxy-3,5-dimethylphenyl) methyl] -1,4-di- oxobutyl] -4- (1-piperidinyl) -piperidine, (Q) 1-[4-amino-3,5-dibromo-N-[[4- [N- (aminocarbonyl) -N-phenyl- amino] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1- piperidinyl) -piperidine, (R) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2 (1H) - oxoquinazolin-3-yl) -1l-piperidinyl] carbonyl] -D-phenylalanyl] -4- (5-methoxy-4-pyrimidinyl) -piperazine, (8S) 1-[4-amino-3,5-dibromo-N-[[4-(1,1-dioxido-3 (4H) -oxo- 1,2,4-benzothiadiazin-2-yl) -1-piperidinyl] carbonyl] -D- phenylalanyl] -4- (1-piperidinyl) -piperidine,
(T) 1-[4-amino-3,5-dibromo-N-[[4-[2 (1H) -oxoquinolin-3-yl1]-1- piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) - piperidine,
(U) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2 (1H) - oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- [3- (dimethylamino) propyl] -piperazine,
(Vv) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2 (1H) - oxoquinazolin-3-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (4-methyl-1-piperazinyl) -piperidine,
N - 33 - (W) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2 (1H) - oxoguinazolin-3-yl]-1l-piperidinyl] carbonyl] -D-phenylalanyl]-4- [(1-methyl-4-piperidinyl) carbonyl] -piperazine, (X) 1-[4-amino-3,5-dibromo-N-[{4-[3,4-dihydro-2 (1H) - oxoquinazolin-3-yl]-1-piperidinyl] carbonyl] -D-phenylalanyl] -4- [(1-methyl-4-piperazinyl) carbonyl] -piperazine, (Y) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2 (1H) -oxo- quinazolin-3-yl) -l-piperidinyl] carbonyl] -D-phenylalanyl]-4- [4- [4- (dimethylamino)butyll phenyl] -piperazine, (z) 1-{4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2 (1H) -oxo- quinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl]-4- [4- (dimethylamino) -1-piperidinyl] -piperidine, (AA) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) - 1-piperidinyl] carbonyl] -N' -methyl-D-tryptyl] -4- (4-methyl-1- piperazinyl) -piperidine, (AB) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2 (2H) -oxoimidazol-1-yl) - l-piperidinyl]} carbonyl] -N'-(1,1-dimethylethoxycarbonyl) -D- tryptyl] -4- (1-methyl-4-piperidinyl) -piperidine, (AC) (R,S)-1-[4-[4-(3,4-dihydro-2(1H) -oxoquinazolin-3-yl)-1- piperidinyl] -2-[(3,5-dibromo-4-methylphenyl) methyl] -1,4-dioxo- butyl] -4- (4-methyl-1-piperazinyl) -piperidine, (AD) (R,S)-1-[4-[4-(3,4-dihydro-2(1H) -oxoquinazolin-3-yl)-1- piperidinyl] -2-[(3,5-dibromo-4-methoxyphenyl) methyl] -1,4- dioxobutyl] -4- (1-methyl-4-piperidinyl) -piperidine, (AE) (R,S)-1-[4-1[4-(3,4-dihydro-2 (1H) -oxoquinazolin-3-yl)-1- piperidinyl] -2-[(3,4-dibromophenyl)methyl] -1,4-dioxobutyl] -4- (4-methyl-1-piperazinyl) -piperidine,
(AF) 1-[N2-[N-[[4-(1,3-dihydro-2 (2H) -oxobenzimidazol-1-yl)- l-piperidinyl] carbonyl] -3,5~dibromo-D-tyrosyl] -L-1lysyl] - 4- (4-pyridinyl) -piperazine, (AG) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-6-hydroxy- 2 (2H) -oxobenzimidazol-1-yl) -1-piperidinyl] carbonyl] -D- phenylalanyl] -4- (1-piperidinyl) -piperidine, (AH) 1- [N2-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-2 (2H) -oxo- benzimidazol-1-yl)-1-piperidinyl] carbonyl] -D-phenylalanyl] - N6,N6-dimethyl-L-1lysyl]l -4- (4-pyridinyl) -piperazine, (AI) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2 (1H) -oxo- quinazolin-3-yl)-1-piperidinyl] carbonyl] -D-phenylalanyl] - N6,N6-dimethyl-L-1lysyl] -4- (4-pyridinyl) -piperazine, (AJ) (R,S8)-1-[2-(4-amino-3,5-dibromobenzoyl) -4- [4-(3,4- dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] -4-oxobutyl] - 4-(l-piperidinyl) -piperidine, (AK) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2,2-dioxido- 2,1,3-benzothiadiazin-3-yl) -1-piperidinyl] carbonyl] -D-phenyl- alanyl] -4- (1-piperidinyl) -piperidine, (AL) 1-{4-amino-3,5-dibromo-N-[{4-[1,3-dihydro-2 (2H) -oxoimi- dazo[4,5-clquinolin-3-yl] -1-piperidinyl] carbonyl] -D-phenyl- alanyl] -4- (1-piperidinyl) carbonyl] -piperidine, (AM) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2 (1H) - oxogquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine, (AN) 1-[N2-[3,5-dibromo-N-[{4-(3,4-dihydro-2 (1H) - oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -N6,N6- dimethyl-L-1lysyl]-4- (4-pyridinyl) ~piperazine,
@
(a0) 1-[4-amino-N-[[4-[4- (3-bromophenyl)-1,3-dihydro-2 (2H) - oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -3,5-dibromo-D- phenylalanyl] -4- (1-methyl-4-piperidinyl) -piperidine, (AP) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2 (2H) - oxoimidazol-1-yl]-1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (4-methyl-1-piperazinyl) -piperidine, (AQ) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(tri- fluoromethyl) phenyl] -2 (2H) -oxoimidazol-1-yl] -1- piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) - piperidine, (AR) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(tri- fluoromethyl) phenyl] -2 (2H) -oxoimidazol-1-yl]-1- piperidinyl] carbonyl] -D-phenylalanyl] -4- (exo-8-methyl-8- azabicyclo[3,2,1loct-3-yl) -piperazine, (AS) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2 (2H) -oxo- imidazol-1-yl) -1l-piperidinyl] carbonyl] -D-tyrosyl]-4-(1- piperidinyl) -piperidine, (AT) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3- (trifluoromethyl) phenyl] -2 (2H) -oxoimidazol-1-yl]-1- piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-ethyl-4- piperidinyl) -piperazine, (AU) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2 (2H) - oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl] -4- (hexahydro-4-methyl-1H-1,4-diazepin-1-yl)piperidine, (AV) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2 (1H) -oxoquinazolin-3- yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4-[1- (methylsulphonyl) - 4-piperidinyl] -piperidine,
(AW) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2 (2H) - oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl]-4- (1-methyl-4-piperidinyl) -piperidine, (AX) 1-[3,5-dibromo-N-[[4-[1,3-dihydro-4-[3- (trifluoromethyl) - phenyl] -2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D- tyrosyl] -4- (hexahydro-1H-1-azepinyl) -piperidine, (AY) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2 (1H) -oxoquinazolin-3- yl) -1-piperidinyl] carbonyl] -D-tyrosyl]-4- (1-methyl-4- piperidinyl) -piperidine, (AZ) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2 (1H) -oxo- quinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (exo-8-methyl-8-azabicyclo[3,2,1]loct-3-yl) -piperazine, (BA) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2 (2H) - oxoimidazol-1-yl)-1l-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4-piperidinyl) -piperazine, (BB) 1-[3,5-dibromo-N-[[4-[1,3-dihydro-4-[3- (trifluoromethyl) - phenyl] -2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D- tyrosyl] -4- (1-piperidinyl) -piperidine, (BC) 1- [N6-Acetyl-N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2 (1H) - oxoquinazolin-3-yl)-1-piperidinyl] carbonyl] -D-tyrosyl] -L- lysyl] -4- (4-pyridinyl) -piperazine, (BD) 1-[3,5-dibromo-N-[{4-(1,3-dihydro-4-phenyl-2 (2H) -oxoimi- dazol-1-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (hexahydro- 1H-1-azepinyl) -piperidine, (BE) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl) - 2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenyl- alanyl] -4- (1-methyl-4-piperidinyl) -piperidine,
@
(BF) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3- (trifluoromethyl) phenyl] -2 (2H) -oxoimidazol-1-yl] -1- piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-methyl-4- piperidinyl) -piperidine,
(BG) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2 (1H) -oxoquinazolin-3- yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- [1- (hydroxycarbonyl- methyl) -4-piperidinyl] -piperidine,
(BH) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2 (1H) -oxo-~ quinazolin-3-yl]-1l-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1- methylsulphonyl-4-piperidinyl) -piperidine,
(RI) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2 (1H) -oxoquinazolin-3- yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (4-piperidinyl) - piperidine,
(BJ) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H) - oxoimidazol-1-yl)-1-piperidinyl] carbonyl] -D-phenylalanyl] - 4-(l-ethyl-4-piperidinyl) -piperidine,
(BK) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-hydroxy- phenyl) -2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D- phenylalanyl] -4- (1-methyl-4-piperidinyl) -piperidine,
(BL) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2 (1H) -oxoquinazolin-3- yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (hexahydro-1H-1- azepinyl) -piperidine,
(BM) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2 (2H) - oxoimidazol-1-yl)-1l-piperidinyl] carbonyl] -D-phenylalanyl] -4- (1-piperidinyl) -piperidine,
(BN) 1-[4-amino-3,5-dibromo-N-{[4-[4- (3-bromophenyl)-1,3-di- hydro-2 (2H) -oxoimidazol-1-yl] ~1-piperidinyl] carbonyl] -D-phe- nylalanyl] -4- (exo-8-methyl-8-azabicyclo[3,2,1]loct-3-yl) - piperazine,
'@
(BO) 1- [4-amino-3,5-dibromo-N- [[4- (3,4-dihydro-2 (1H) -oxo- quinazolin-3-yl)-1l-piperidinyl] carbonyl] -D-phenylalanyl] - 4-(l-ethyl-4-piperidinyl) -piperidine, (BP) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2 (1H) -oxo- quinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] - 4-(l-ethyl-4-piperidinyl) -piperazine, (BQ) 1-[4-amino-3,5-dibromo-N-{{4-{1,3-dihydro-4-(3-methoxy- phenyl) -2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D- phenylalanyl] -4- (exo-8-methyl-8-azabicyclo[3,2,1]loct-3-yl) - piperazine, (BR) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2 (1H) -oxoquinazolin-3- yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4-[1- (cyclopropyl- methyl) -4-piperidinyl] -piperidine, (BS) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H) - oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (hexahydro-1H-1-azepinyl) -piperidine, (BT) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H) -oxo- quinazolin-3-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (4-piperidinyl) -piperidine, (BU) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2 (2H) -oxo- imidazol-1-yl) -1-piperidinyl] carbonyl] -D-tyrosyl]-4-(4- pyridinyl) -piperidine, (BV) 1-[3,5-dibromo-N-[[4-[1,3-dihydro-4-[3- (trifluoromethyl) - phenyl] -2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D- tyrosyl] -4- (1-methyl-4-piperidinyl) -piperazine, (BW) 1-[N2-[3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluorome- thyl) phenyl] -2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] - D-tyrosyl] -L-1ysyl] -4- (4-pyridinyl) -piperazine,
'@
YS - 39 - (BX) 1-1[3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-2(2H)- oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -4-(1- piperidinyl) -piperidine, (BY) 1-[4-amino-N-[[4-[4-(3-chlorophenyl)-1,3-dihydro-2 (2H) - oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -3,5-dibromo-D- phenylalanyl] -4- (1-methyl-4-piperidinyl) -piperidine, (BZ) 1-[4-amino-3,5-dibromo-N-{[4-(1,3-dihydro-4-[3- (trifluoromethyl) phenyl] -2 (2H) -oxoimidazol-1-yl] -1- piperidinyl] carbonyl] -D-phenylalanyl] -4- (hexahydro-1H-1- azepinyl) -piperidine, (CA) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3- (trifluoromethyl) phenyl] -2 (2H) -oxoimidazol-1-yl] -1- piperidinyl] carbonyl] -D-phenylalanyl] -4-(1-methyl-4- piperidinyl) -piperazine, (CB) 1-[4-amino-N-[[4-[4-(3-chlorophenyl)-1,3-dihydro-2(2H) - oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -3,5-dibromo-D- phenylalanyl] -4- (hexahydro-1H-1-azepinyl) -piperidine, (CC) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2 (2H) - oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- (4-pyridinyl) -piperazine, (cD) 1-[3,5-dibromo-N-{{4-(1,3-dihydro-4-phenyl-2 (2H) -oxoimi- dazol-1-yl) -1-piperidinyl] carbonyl] -D-tyrosyl]-4- (1-methyl-4- piperidinyl) -piperidine, (CE) 1-[4-amino-3,5-dibromo-N-[[4~[1,3-dihydro-4-phenyl-2 (2H) - oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D-phenylalanyl] -4- [4- (1-oxoethyl)phenyl] -piperazine,
"@ (CF) 1-[3,5-dibromo-N-[[4-[3,4-dihydro-2 (1H) -oxoquinazolin-3- yl] -1-piperidinyl] carbonyl] -D-tyrosyl] -4- (1-methyl-4- piperidinyl) -piperazine, (CG) 1-[4-amino-3,5-dibromo-N-[[4-([1,3-dihydro-4-(3-nitro- phenyl) -2 (2H) -oxoimidazol-1-yl] -1-piperidinyl] carbonyl] -D-phe- nylalanyl] -4- (1-methyl-4-piperidinyl) -piperidine, (CH) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2 (1H) -oxo- gquinazolin-3-yl]-1-piperidinyl]jcarbonyl]-D-phenylalanylj-4-(1- pyrrolidinyl) -piperidine, (CI) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2 (2H) - oxoimidazol-1-yl)-1l-piperidinyl] carbonyl] -D-phenylalanyl] -4- (hexahydro-1H-1-azepinyl) -piperidine and (¢J) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl) - 2 (2H) -oxoimidazol-1-yl) -1-piperidinyl] carbonyl] -D-phenyl- alanyl] -4- (1-methyl-4-piperidinyl) -piperazine, the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the physiologically acceptable salts thereof.
6. Use of an active substance selected from CGRP antagonists and CGRP release inhibitors for the preparation of a pharmaceutical composition for treating menopausal hot flushes.
7. Use according to claim 6, characterised in that the pharmaceutical composition contains only one active substance.
8. Use according to claim 6, characterised in that the active substance is a CGRP antagonist.
9. Use according to claim 8, characterised in that the CGRP antagonist is selected from the group according to claim 5.
< ee Yo WA : /
10. Pharmaceutical composition for treating menopausal hot flushes, containing as active substance one or more CGRP antagonists selected from the group according to claim 5 optionally together with one or more inert carriers and/or diluents. )
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19937304A DE19937304C2 (en) | 1999-08-10 | 1999-08-10 | Use of CGRP antagonists to combat menopausal hot flashes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200200997B true ZA200200997B (en) | 2002-10-30 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200200997A ZA200200997B (en) | 1999-08-10 | 2000-08-05 | Use of CGRP antagonists and CGRP release inhibitors for controlling menopausal hot flushes. |
Country Status (32)
| Country | Link |
|---|---|
| EP (1) | EP1207884B1 (en) |
| JP (1) | JP2003506403A (en) |
| KR (1) | KR100713573B1 (en) |
| CN (1) | CN1166361C (en) |
| AR (1) | AR025078A1 (en) |
| AT (1) | ATE281168T1 (en) |
| AU (1) | AU777709B2 (en) |
| BG (1) | BG65366B1 (en) |
| BR (1) | BR0013009A (en) |
| CA (1) | CA2378428C (en) |
| CZ (1) | CZ300513B6 (en) |
| DE (2) | DE19937304C2 (en) |
| EA (1) | EA007531B1 (en) |
| EE (1) | EE04928B1 (en) |
| ES (1) | ES2231243T3 (en) |
| HK (1) | HK1046854B (en) |
| HR (1) | HRP20020117A2 (en) |
| HU (1) | HUP0202397A3 (en) |
| IL (1) | IL148057A (en) |
| MX (1) | MXPA02001373A (en) |
| MY (1) | MY129668A (en) |
| NO (1) | NO20020605D0 (en) |
| NZ (1) | NZ517367A (en) |
| PL (1) | PL198483B1 (en) |
| PT (1) | PT1207884E (en) |
| SK (1) | SK285587B6 (en) |
| TR (1) | TR200200359T2 (en) |
| TW (1) | TWI285550B (en) |
| UA (1) | UA73137C2 (en) |
| WO (1) | WO2001010425A2 (en) |
| YU (1) | YU8302A (en) |
| ZA (1) | ZA200200997B (en) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19952147A1 (en) | 1999-10-29 | 2001-05-03 | Boehringer Ingelheim Pharma | New cyclopropanes, pharmaceutical compositions containing these compounds and process for their preparation |
| DE10139410A1 (en) * | 2001-08-17 | 2003-02-27 | Boehringer Ingelheim Pharma | Use of BIBN4096 in combination with other anti-migraine drugs for the treatment of migraines |
| AU2002359458A1 (en) | 2001-12-12 | 2003-06-23 | Eli Lilly And Company | Alanyl-piperidine heterocyclic derivatives useful against cardiovascular diseases |
| US6900317B2 (en) | 2002-02-19 | 2005-05-31 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Salts of the CGRP antagonist BIBN4096 and inhalable powdered medicaments containing them |
| DE10206770A1 (en) * | 2002-02-19 | 2003-08-28 | Boehringer Ingelheim Pharma | New, stable acid addition salts of the quinazolinone derivative CGRP antagonist BIBN4096, useful for the treatment of migraine, in the form of an inhalable powder |
| DE10207026A1 (en) * | 2002-02-20 | 2003-08-28 | Boehringer Ingelheim Kg | Stable inhalable powder of the calcitonin gene-related peptide antagonist, BIBN4096, useful for treating migraine, in the form of spherical nano-structured particles obtained by spray-drying |
| DE10227294A1 (en) * | 2002-06-19 | 2004-01-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Preparations for intranasal application of selected amino acid-derived CGRP antagonists and processes for their preparation |
| DE10250080A1 (en) * | 2002-10-25 | 2004-05-13 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Selected CGRP antagonists, process for their preparation and their use as pharmaceuticals |
| US7595312B2 (en) | 2002-10-25 | 2009-09-29 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Selected CGRP antagonists, processes for preparing them and their use as pharmaceutical compositions |
| DE10300973A1 (en) * | 2003-01-14 | 2004-07-22 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New carboxylic acids and their esters, medicaments containing these compounds and processes for their preparation |
| CA2531407A1 (en) * | 2003-07-07 | 2005-01-20 | Boehringer Ingelheim International Gmbh | Use of cgrp antagonists in treatment and prevention of hot flushes in prostate cancer patients |
| CN100418948C (en) * | 2003-07-15 | 2008-09-17 | 麦克公司 | Hydroxypyridine cgrp receptor antagonists |
| DE10338399A1 (en) * | 2003-08-18 | 2005-03-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Microparticles containing the CGRP antagonist 1- [N 2 - [3,5-dibromo-N - [[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine, process for their preparation and their use as inhalation powder |
| DE102004015723A1 (en) | 2004-03-29 | 2005-10-20 | Boehringer Ingelheim Pharma | Selected CGRP antagonists, process for their preparation and their use as pharmaceuticals |
| US7696195B2 (en) | 2004-04-22 | 2010-04-13 | Boehringer Ingelheim International Gmbh | Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions |
| DE102004019492A1 (en) * | 2004-04-22 | 2005-11-10 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Selected CGRP antagonists, process for their preparation and their use as pharmaceuticals |
| DE102004063752A1 (en) * | 2004-12-29 | 2006-07-13 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of selected CGRP antagonists to combat menopausal hot flashes |
| DE102004063755A1 (en) * | 2004-12-29 | 2006-07-20 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of CGRP antagonists for the treatment and prevention of hot flushes in patients with prostate cancer |
| EP1770091A1 (en) | 2005-09-29 | 2007-04-04 | Boehringer Ingelheim Pharma GmbH & Co. KG | CGRP-antagonists, process for their preparation as well as their use as medicaments |
| US7491717B2 (en) | 2005-03-23 | 2009-02-17 | Boehringer Ingelheim International Gmbh | Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions |
| US7439237B2 (en) | 2005-04-15 | 2008-10-21 | Boehringer Ingelheim International Gmbh | Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997009056A1 (en) * | 1995-09-07 | 1997-03-13 | L'oreal | Extract of iridaceae and compositions containing such extract |
| US5910482A (en) | 1996-03-19 | 1999-06-08 | Board Of Regents, The University Of Texas System | Treatment or prevention of preeclampsia, eclampsia with calcitonin gene related peptide, CGRP analog, progestational agent, nitric oxide source, and cyclooxygenase inhibitor |
| US5710024A (en) * | 1996-07-23 | 1998-01-20 | Smithkline Beecham Corporation | Polynucleotides that encode the calcitonin gene-related peptide receptor coponent factor (HOUNDC44) |
| SK285631B6 (en) * | 1996-09-10 | 2007-05-03 | Dr. Karl Thomae Gmbh | Modified amino acids, pharmaceutical composition comprising its and its use |
| DE19911039A1 (en) * | 1999-03-12 | 2000-09-14 | Boehringer Ingelheim Pharma | Modified amino acid amides, pharmaceutical compositions containing these compounds and process for their preparation |
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1999
- 1999-08-10 DE DE19937304A patent/DE19937304C2/en not_active Expired - Fee Related
-
2000
- 2000-05-08 UA UA2002031932A patent/UA73137C2/en unknown
- 2000-08-05 CN CNB008116156A patent/CN1166361C/en not_active Expired - Fee Related
- 2000-08-05 CA CA002378428A patent/CA2378428C/en not_active Expired - Fee Related
- 2000-08-05 AU AU69928/00A patent/AU777709B2/en not_active Ceased
- 2000-08-05 BR BR0013009-5A patent/BR0013009A/en active Pending
- 2000-08-05 ES ES00958385T patent/ES2231243T3/en not_active Expired - Lifetime
- 2000-08-05 SK SK197-2002A patent/SK285587B6/en unknown
- 2000-08-05 EA EA200200207A patent/EA007531B1/en not_active IP Right Cessation
- 2000-08-05 IL IL148057A patent/IL148057A/en not_active IP Right Cessation
- 2000-08-05 MX MXPA02001373A patent/MXPA02001373A/en active IP Right Grant
- 2000-08-05 NZ NZ517367A patent/NZ517367A/en unknown
- 2000-08-05 CZ CZ20020497A patent/CZ300513B6/en not_active IP Right Cessation
- 2000-08-05 DE DE50008527T patent/DE50008527D1/en not_active Expired - Lifetime
- 2000-08-05 YU YU8302A patent/YU8302A/en unknown
- 2000-08-05 PL PL364049A patent/PL198483B1/en not_active IP Right Cessation
- 2000-08-05 EP EP00958385A patent/EP1207884B1/en not_active Expired - Lifetime
- 2000-08-05 PT PT00958385T patent/PT1207884E/en unknown
- 2000-08-05 ZA ZA200200997A patent/ZA200200997B/en unknown
- 2000-08-05 JP JP2001514945A patent/JP2003506403A/en active Pending
- 2000-08-05 HU HU0202397A patent/HUP0202397A3/en unknown
- 2000-08-05 WO PCT/EP2000/007613 patent/WO2001010425A2/en active Application Filing
- 2000-08-05 KR KR1020027001796A patent/KR100713573B1/en not_active IP Right Cessation
- 2000-08-05 TR TR2002/00359T patent/TR200200359T2/en unknown
- 2000-08-05 EE EEP200200061A patent/EE04928B1/en not_active IP Right Cessation
- 2000-08-05 AT AT00958385T patent/ATE281168T1/en not_active IP Right Cessation
- 2000-08-08 MY MYPI20003601A patent/MY129668A/en unknown
- 2000-08-08 TW TW089115923A patent/TWI285550B/en not_active IP Right Cessation
- 2000-08-09 AR ARP000104098A patent/AR025078A1/en not_active Suspension/Interruption
-
2002
- 2002-02-06 BG BG106391A patent/BG65366B1/en active Active
- 2002-02-07 NO NO20020605A patent/NO20020605D0/en not_active Application Discontinuation
- 2002-02-07 HR HR20020117A patent/HRP20020117A2/en not_active Application Discontinuation
- 2002-11-19 HK HK02108347.1A patent/HK1046854B/en not_active IP Right Cessation
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