CA2562529A1 - Selected cgrp antagonists, methods for the production thereof, and use thereof as medicaments - Google Patents
Selected cgrp antagonists, methods for the production thereof, and use thereof as medicaments Download PDFInfo
- Publication number
- CA2562529A1 CA2562529A1 CA002562529A CA2562529A CA2562529A1 CA 2562529 A1 CA2562529 A1 CA 2562529A1 CA 002562529 A CA002562529 A CA 002562529A CA 2562529 A CA2562529 A CA 2562529A CA 2562529 A1 CA2562529 A1 CA 2562529A1
- Authority
- CA
- Canada
- Prior art keywords
- general formula
- piperidine
- amino
- oxospiro
- chloro
- Prior art date
- 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.)
- Abandoned
Links
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229940086766 sodium chloride 180 mg Drugs 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 229960000651 tasosartan Drugs 0.000 description 1
- ADXGNEYLLLSOAR-UHFFFAOYSA-N tasosartan Chemical compound C12=NC(C)=NC(C)=C2CCC(=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 ADXGNEYLLLSOAR-UHFFFAOYSA-N 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
- 229960002871 tenoxicam Drugs 0.000 description 1
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229960004394 topiramate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 1
- 125000004784 trichloromethoxy group Chemical group ClC(O*)(Cl)Cl 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 238000005533 tritiation Methods 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 229940102566 valproate Drugs 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 1
- 229960005318 vigabatrin Drugs 0.000 description 1
- PJDFLNIOAUIZSL-UHFFFAOYSA-N vigabatrin Chemical compound C=CC(N)CCC(O)=O PJDFLNIOAUIZSL-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229960001360 zolmitriptan Drugs 0.000 description 1
- ULSDMUVEXKOYBU-ZDUSSCGKSA-N zolmitriptan Chemical compound C1=C2C(CCN(C)C)=CNC2=CC=C1C[C@H]1COC(=O)N1 ULSDMUVEXKOYBU-ZDUSSCGKSA-N 0.000 description 1
- ZXVNMYWKKDOREA-UHFFFAOYSA-N zomepirac Chemical compound C1=C(CC(O)=O)N(C)C(C(=O)C=2C=CC(Cl)=CC=2)=C1C ZXVNMYWKKDOREA-UHFFFAOYSA-N 0.000 description 1
- 229960003414 zomepirac Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- 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
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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
- A61P25/06—Antimigraine agents
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
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- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A61P37/08—Antiallergic agents
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- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
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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
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- Health & Medical Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Pulmonology (AREA)
- Endocrinology (AREA)
- Dermatology (AREA)
- Biomedical Technology (AREA)
- Immunology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Addiction (AREA)
- Neurology (AREA)
- Heart & Thoracic Surgery (AREA)
- Psychiatry (AREA)
- Toxicology (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Reproductive Health (AREA)
- Cardiology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to the CGRP antagonists of general formula (I), wherein A and R1 to R3 are defined as indicated in claim 1, the tautomers, diastereomers, enantiomers, hydrates, mixtures and salts thereof, the hydrates of the salts, especially the physiologically acceptable salts thereof with inorganic or organic acids, medicaments containing said compounds, the use thereof, and methods for the production thereof.
Description
WO w05/100360 PCT/EP2005/0038 86983pct Selected CGRP antagonists, methods for the production thereof, and use thereof as medicaments The present invention relates to the GGRP antagonists of general formula A
N O N~Rs O
R
the tautomers, the diastereomers, the enantiomers, the hydrates thereof, the mixtures thereof and the salts thereof as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids, pharmaceutical compositions containing these compounds, their use and processes for preparing them.
In the above general formula (I) A denotes a group of formula NHz ~ NHZ ~ OH ~ NCH
CI ~ / CF3 ~ / CI ~ / CI
CH
NN2 ~ ~ NHZ ~ NHZ ~ NHZ
Br / CI ~ / CI Qr ~ / CI
> >
N- Z
the group R denotes a group of formula N N N
\ N~H \
N' ' O
N_ 'O
N O
H H H
or and -NR2R3 denotes a group of formula ~N~N~ ~N~ UN-CHs '~N O
U
' ~ , ~N CH3 ~N~ ~ H ~-N N CH3 ' ' , ~N~ ~/N H ~N~NCH ~N~N
N O N~Rs O
R
the tautomers, the diastereomers, the enantiomers, the hydrates thereof, the mixtures thereof and the salts thereof as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids, pharmaceutical compositions containing these compounds, their use and processes for preparing them.
In the above general formula (I) A denotes a group of formula NHz ~ NHZ ~ OH ~ NCH
CI ~ / CF3 ~ / CI ~ / CI
CH
NN2 ~ ~ NHZ ~ NHZ ~ NHZ
Br / CI ~ / CI Qr ~ / CI
> >
N- Z
the group R denotes a group of formula N N N
\ N~H \
N' ' O
N_ 'O
N O
H H H
or and -NR2R3 denotes a group of formula ~N~N~ ~N~ UN-CHs '~N O
U
' ~ , ~N CH3 ~N~ ~ H ~-N N CH3 ' ' , ~N~ ~/N H ~N~NCH ~N~N
3 s CH3 , -N~N~ -~ ~ ~ ~N -~-N~N N-CH3 ' ~ , ~N~N\~N-CH3 ~' ~ --C~ ~N~N
N
' ~ , --~ N N I ~
N~ ~ N N -~-N N I
CHs ~/ ~ ~N
,.
Hs H.,C .CH3 -~-N, r--N N-CH3 ..~-N N~-=~N-CH3 ~--N N N---H3 ~ H
' r ~N, /- N - /~ -~N
~/ r N N N~
N
, ~ H /~ N
~N CH3 ~-N~ CH3 -~N N-H
or Particularly preferred compounds of the above general formula (I) are as follows, for example:
N
CI /
1 \ I N~O~N~N 2 N
N
O
o c1 F
F \
F
,r] 6 O N~O~N~N-N~ O
'\
g 10 .N
F
F
F
11 12 0 ~~N~.N~N
N~~ O 0 ~~'~\
.N CI
F
F
F
N N 14 N N ~N~N
~/\
N
' ~ , --~ N N I ~
N~ ~ N N -~-N N I
CHs ~/ ~ ~N
,.
Hs H.,C .CH3 -~-N, r--N N-CH3 ..~-N N~-=~N-CH3 ~--N N N---H3 ~ H
' r ~N, /- N - /~ -~N
~/ r N N N~
N
, ~ H /~ N
~N CH3 ~-N~ CH3 -~N N-H
or Particularly preferred compounds of the above general formula (I) are as follows, for example:
N
CI /
1 \ I N~O~N~N 2 N
N
O
o c1 F
F \
F
,r] 6 O N~O~N~N-N~ O
'\
g 10 .N
F
F
F
11 12 0 ~~N~.N~N
N~~ O 0 ~~'~\
.N CI
F
F
F
N N 14 N N ~N~N
~/\
N~-N
~N ~ ~ N
N\~N
N N CI
F F \
29 - = 30 F
N O'r0 N-~ ~'N N-~N-O
~N ~ ~ N
N\~N
N N CI
F F \
29 - = 30 F
N O'r0 N-~ ~'N N-~N-O
~N CI
F
31 FF \ /
N ~N 32 j~-0 N o N ~N
N O
~N CI
F
33 F F \ ~
34 N o N~O~ ~N~N
35 ~ 36 N
O CI
F
F \ I
37 3$ F
O~-O N-~ ~--N N~N-N OO ~
F F
N
F
39 F F \ I
0 0;
N N~ ~N~
N \J 0 O
N~--N ~
N CI
F
F \/
~ ~N~-~N-N~~ O O
F
31 FF \ /
N ~N 32 j~-0 N o N ~N
N O
~N CI
F
33 F F \ ~
34 N o N~O~ ~N~N
35 ~ 36 N
O CI
F
F \ I
37 3$ F
O~-O N-~ ~--N N~N-N OO ~
F F
N
F
39 F F \ I
0 0;
N N~ ~N~
N \J 0 O
N~--N ~
N CI
F
F \/
~ ~N~-~N-N~~ O O
o c1 F
47 F F \ /
48 O N~ ~N~~-- N
N~ 00 I \
N
G I ~ .
55 - .
\ I ~O~~N / \N 56 N
h- ~Jo II
N
~i -NVN
O
II
N
CI I \
~~ ~N~N
N J\J 00 -O
N ) II
N
G /
\ / N~~~~N N
N~O 00 O
N
67 6g N CI
F
F \ I
0 0 N, 70 N ~O~N~~ ~ w F F
N
F
75 76 F F \ /
O ' O '~O~ ~N \ ~N
/ \
O CI N CI
F F
F \ I F \ /
77 F : F
O O N/ 7$ O
N N~O~N~~ N O N~O~N~ N~
/ \ / \
.N CI
F
N ~ - $O p/ 0 N~p~N~ UN-I \
N
w N
F F
N
F
87 $$ F F \ /
O O , N~O~N~N
N~ ~lO
F F
N
F F \ /
89 gp F
O O .
N N- N.IO~N~N
N /\ J OO
I
F F
N
F
91 g2 F F \ /
O N~-N ~0~~ U
_g_ F F
N
F
95 F \ /
c 96 F
ON O N~ ~ N~N
O
/ \
F F
N
F
97 g8 F F \ /
~/N- O~ O N-~ ~ NxN
/ \
F
F F
N
100 F F \ /
0 ~ /~
O 'N O O N ~N
/ \
N
G I \.
103 - - _ 104 N / N~O~ ~N
-O
O
N N
U
II
N
~N~~N~N-N~O 00 O
O G
F F \ I
N N~O~- VN
N~-N~N-121 ~ , 122 N
O CI
F
F \ I
123 124 F : _ 0 ~
ON O N~O~ UN~
N~-N~N-VN--~N' N
G / \
131 - : 132 ~N-N I N~O
O
N Br F
F \ I
~O~- ~N-~N
/ \
135 , 136 N r F
F \ I
139 ~N~ 140 o F
0 ~--N~ N~ N O N ~O~ N~ UN
/ \
N N r \ F F \ I
CI /
141 - : 142 F
\ / ~ ~ ~ O~'O N-~ ~N N~N
N 00 UN N O O v.J
O O / \
N
G I \ ' 143 - . 144 \ o /''~
-~ ~~N~N-N~O 00 O
//
N
CI /
\ ~ -~ ~N N-N~p 00 O
p G
F
F \/
O N~ ~N~N~ 158 N~ 00 N r F
F
161 162 F : _ N N~O~N~ UN-N
G / \ ' -~ ~-N N-N~ 00 ~O
N N r F -G F \
165 \ ~ p : ~ 166 o F o N O O ~--~ N p O
O
167 ~ 168 N
O CI
F
F \
N~ ~N~- ~ 170 ~\
N
G
-~ ~~N~-N~o 00 N
G
173 - : 174 -~ ~--N N-N~O 00 O
N
CI /
175 - = 176 0 ~
N / ~O~ N~.IN
-O
O
N
G / \
177 - : 178 \ / -~ _a--N~- ~ , N /\ J 00 ~O
F F
N
F
~N, 180 F p 0 ~~--~, r N N N~O~N~ ~
\
F F
N
181 182 F F \ ~
p o N p N-I ~--N~-N
N r F
F \ I
185 F : _ N O N~O~N~./N
N
/ \
N r F F \ I
189 190 F : _ ON O N~O~ UN~
/ \
II N Br N F
G I \ F \ I
191 _ o ; _ 192 o F
0 ~-N / N~p~ ~N N N~p~N~ ~ w O I \
O CI F
F N F F
F \ / F
F ; F \ /
193 ON O N~o~ ~N \ ~N 194 O FN~O~~N
I \ N/ \ OO
II N r N F
/ \ F \ /
195 _ G - , _ 196 F o \ / ~ ~N N O/ O N~ ~N~N
N~O 00 U N/ \ O O
O
N CI
F F F
N
F \ I F
197 o F ' 198 F F \ /
N ~~N~N~ O~-O -10~-t~N~
N O
/ \ / \
N CI r _ N
F F
F \ I F \ I
199 o F o ' 200 F o ~N-N N~O~N~N O ~O~NVN~
/ \ N/ \
_N CI r _ N
F F _ F \ I F \ I
201 F = F
N~o~N~.N 2O2 0~o N~o~ VN
N
/ \ ~ \
p CI N CI
F F
F \ I F \ I
203 F ' F
N~O~N~ ~ 204 ON O N~O
/ \ / \\
O CI N CI
F F
F \ I F \ I
205 o F o ' 206 F
N N~O~N~N O! O N-(O~N~
/ \ N/ \
207 ~ 208 ~N~
N
211 - _ o - 212 VN
N J\J 00 ~O
O CI N CI
F F
F \ I F \ I
213 F ' F
o ,--~ 214 N O p N~ U O~'O N O ~.JN
\-' N O
N CI
F
F \/
N~ -~N~N 22O
O
221 ~ 222 N
223 ~ 224 N N
O CI
F
F \ I
N~ -~N~--~N 226 /\
N CI
F
F \ I
227 ,-~ 228 F
UN N~ ~N~
/ \
N CI
F
F \ I
229 230 o F
~O~N~ UN~
N U
I \
N O
~J
N CI
F
F \ I
F
N
N O O ~ N
/ \\
239 ~ 240 N CI
F
F \ I
0 ~
O N-I ~N~
N~ O p0 / \
N CI
F
F \
p o N -~O~ N
/ \ _ N G F F
F N F
F \ ~ ~ \
2 F a~
47 : 248 N
N \/
j'~~ ~ N~l-N
O
N G
F F
F N F
F \ / ~ \
F G
249 ~ 250 _ _.
NT' N N \ / /O N
~N~O~
N N
O
N CI F
F
F N F
F \ / ~ \
251 F a~
o = _ 252 HON N O N H \ / ~O~ ~N~N
N
~.-N
O
N CFs F F
\ N F
G G ~ \
o _ N / ~O~p -~- ~N-~N Ii \ / N~ ~ ~ -N N N
N~ 00 O
O
F F F
N F F
N F
G / \
255 256 G _ N H \ / ~ ~j-N N
N 00 N 00 ~--~ N
~N ~N
O O
F F F F
N F N F
G /~ G / \
/o ' ,-~
' N N
N~ ~ N N-H \ /~
N~ 00 ~ N N~~ ~ ~N~
O O
the tautomers, the diastereomers, the enantiomers, the hydrates thereof, the mixtures thereof and the salts thereof as well as the hydrates of the salts, while the compounds (1) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-yl)-piperidin-1-yl]-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate, (2) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-methyl-piperidin-yl)-piperazin-1-yl]-2-oxo-ethyl 1',2'-d ihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate, (3) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1'-methyl [4,4']bipiperidinyl-1-yl)-2-oxo-ethyl1',2'-dihydro-2'-oxospiro-4H-3',1 quinazoiine'-4,4'-piperidine-1-carboxylate, (4) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1,4']bipiperidinyl-1'-yl-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-2o carboxylate, (5) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-y1 )-piperidin-1-yl]-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate, (6) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-methyl-piperidin-yl)-piperazin-1-yl]-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate, (7) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1'-methyl-[4,4']bipiperidinyl-1-yl)-2-oxo-ethyl1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate, (8) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1,4']bipiperidinyl-1'-yl-2 oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1 1 o carboxylate, the tautomers, the diastereomers, the enantiomers, the hydrates thereof, the mixtures thereof and the salts thereof as well as the hydrates of the salts are of exceptional importance.
The compounds of general formula (I) are prepared by methods known in principle.
The following methods have proved particularly useful for preparing the compounds of general formula (I) according to the invention:
(a) In order to prepare compounds of general formula A
N ~ N~Rs R
wherein A and R~ to R3 are as hereinbefore defined:
reacting a piperidine of general formula NH , (1l) wherein R' is as hereinbefore defined, with a carbonic acid derivative of general formula O
G~G
, (III) wherein G denotes a nucleofugic group which may be identical or different, preferably the chlorine atom, the p-nitrophenoxy or trichloromethoxy group, and with a compound of general formula I
N~Rs O , (IV) wherein A, R2 and R3 are as hereinbefore defined, with the proviso that R2 and R3 do ~5 not contain any other free, unprotected, primary or secondary aliphatic amino function.
The reactions which are theoretically two-step reactions are usually carried out as one-pot processes, preferably by reacting one of the two components (II) or (IV) with 2o equimolar quantities of the carbonic acid derivative of general formula (III) in a suitable solvent at lower temperature in the first stage, then adding at least equimolar amounts of the other component (II) or (!V) and finishing the reaction at elevated temperature. The reactions with bis-(trichioromethyl)-carbonate are preferably carried out in the presence of at least 2 equivalents (based on bis-(trichloromethyl)-25 carbonate) of a tertiary base, e.g. triethylamine, N-ethyl-diisopropylamine, pyridine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane or 1,8-diazabicyclo[5.4.0]undec-7-ene. Examples of solvents, which should be anhydrous, include tetrahydrofuran, dioxane, dimethyl formamide, dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone or acetonitrile; if bis-(trichloromethyl)-carbonate is used as the carbonyl component anhydrous chlorohydrocarbons such as dichloromethane, 1,2-dichloroethane or trichloroethylene are preferred. The reaction temperatures for the first reaction step are between -30 and +25°C, preferably -5 and +10°C, for the second reaction step they are between +15°C and the boiling temperature of the solvent used, preferably between +20°C
and +70°C (cf.
also: H. A. Staab and W. Rohr, "Synthesen mit heterocyclischen Amiden (Azoliden)", Neuere Methoden der Praparativen Organischen Chemie, Vol. V, p. 53 - 93, Verlag Chemie, WeinheimlBergstr., 1967; P. Majer and R.S. Randad, J. Org. Chem. 59, 1937 - 1938 (1994); K. Takeda, Y. Akagi, A. Saiki, T. Sukahara and H. Ogura, 1o Tetrahedron Letters 24 (42), 4569 - 4572 (1983); S.R. Sandier and W. Karo in "Organic Functional Group Preparations", Vol. II, p. 223-245, Academis Press, New York 1971 ).
(b) In order to prepare compounds of general formula A
O Rz N O N~Rs R , (I) wherein A and R1 to R3 are as hereinbefore defined:
2o coupling a carboxylic acid of general formula A
O
OH
N~O
R ,(V) wherein A and R1 are as hereinbefore defined, with an amine of general formula HNR2R3, wherein R2 and R3 are as hereinbefore defined, with the proviso that they do not contain any other free unprotected primary or secondary aliphatic amino function.
Any primary or secondary amino function additionally present in the group -NR2R3 is in each case provided with a suitable protective group.
The coupling is preferably carried out using methods known from peptide chemistry (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example using carbodiimides such as e.g. dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide, O-(1 H-benzotriazol-1-yl)- N,N-N;N'-tetramethyluronium hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP). By adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt) the reaction speed can be increased. The couplings are normally carried out with equimolar amounts of the coupling components as well as the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethyl ~5 formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between -30 and +30°C, preferably -20 and +25°C. If necessary, N-ethyl-diisopropylamine (Hunig base) is preferably used as an additional auxiliary base.
2o The so-called anhydride process is used as a further coupling method for synthesising compounds of general formula (I) (cf. also: M. Bodanszky, "Peptide Chemistry", Springer-Verlag 1988, p. 58-59; M. Bodanszky, "Principles of Peptide Synthesis", Springer-Verlag 1984, p. 21-27). The Vaughan variant of the mixed anhydride process is preferred (J.R. Vaughan Jr., J. Amer. Chem.Soc. 73, 3547 25 (1951 )), in which the mixed anhydride is obtained from the carboxylic acid of general formula (V) which is to be coupled and monoisobutyl carbonate, using isobutyl chlorocarbonate in the presence of bases such as 4-methylmorpholine or 4-ethylmorpholine. The preparation of this mixed anhydride and the coupling with the amines of general formula HNR2R3 are carried out in a one-pot process, using the 3o above-mentioned solvents and at temperatures between -20 and +25°C, preferably between 0°C and +25°C.
(c) In order to prepare compounds of general formula A
I
N O N~Rs R~ O
(I) wherein A and R~ to R3 are as hereinbefore defined:
coupling a compound of general formula A
O
~ Nu N_ -O
O
R , (VI) wherein A and R' are as hereinbefore defined and Nu denotes a leaving group, for example a halogen atom, such as the chlorine, bromine or iodine atom, an alkyl-sulphonyloxy group with 1 to 10 carbon atoms in the alkyl moiety, a phenylsulphonyloxy or naphthylsulphonyloxy group optionally mono-, di- or trisubstituted by chlorine or bromine atoms, by methyl or nitro groups, while the substituents may be identical or different, a 1H-imidazol-1-yl, a 1H-pyrazol-1-yl ~5 optionally substituted by one or two methyl groups in the carbon skeleton, a 1 H-1,2,4-triazol-1-yl, 1 H-1,2,3-triazol-1-yl, 1 H-1,2,3,4-tetrazol-1-yl, a vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, pentafluorophenyl, pyranyl or pyridinyl, a dimethylaminyloxy, 2(1H)-oxopyridin-1-yl-oxy, 2,5-dioxopyrrolidin-1-yloxy, phthalimidyloxy, 1 H-benzo-triazol-1-yloxy or azide 2o group, with an amine of general formula HNR2R3, wherein R2 and R3 are as hereinbefore defined, with the proviso that no other free, unprotected, primary or secondary aliphatic amino function is present.
The reaction is carried out under Schotten-Baumann or Einhorn conditions, i.e.
the components are reacted in the presence of at least one equivalent of an auxiliary base at temperatures between -50°C and +120°C, preferably -10°C and +30°C, and optionally in the presence of solvents. The auxiliary bases used are preferably alkali metal and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, e.g. sodium carbonate, potassium carbonate or caesium carbonate, alkali metal acetates, e.g. sodium or potassium acetate, as well as tertiary amines, e.g. pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine, 1,4-diazabicyclo[2.2.2]octane or 1,8-diazabicyclo[5.4.0]undec-7-ene, the solvents used may be, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methyl-pyrrolidone or mixtures thereof; if alkali metal or alkaline earth metal hydroxides, alkali metal carbonates or acetates are used as the auxiliary bases, water may also be added to the reaction mixture as co-solvent.
~5 The new compounds of general formula (I) according to the invention contain one or more chiral centres. If for example there are two chiral centres the compounds may occur in the form of two pairs of diastereomeric antipodes. The invention covers the individual isomers as well as the mixtures thereof.
2o The diastereomers may be separated on the basis of their different physico-chemical properties, e.g. by fractional crystallisation from suitable solvents, by high pressure liquid or column chromatography, using chiral or preferably non-chiral stationary phases.
25 Racemates covered by general formula (I) may be separated for example by HPLC
on suitable chiral stationary phases (e.g. Chiral AGP, Chiralpak AD).
Racemates which contain a basic function can also be separated via the diastereomeric, optically active salts which are produced on reacting with an optically active acid, for example (+) or (-)-tartaric acid, (+) or (-)-diacetyl tartaric acid, (+) or (-)-monomethyl tartrate or 30 (+)-camphorsulphonic acid.
According to a conventional method of separating isomers, the racemate of a compound of general formula (I) is reacted with one of the above-mentioned optically active acids or bases in equimolar amounts in a solvent and the resulting crystalline, diastereomeric, optically active salts thereof are separated using their different solubilities. This reaction may be carried out in any type of solvent provided that it is sufficiently different in terms of the solubility of the salts. Preferably, methanol, ethanol or mixtures thereof, for example in a ratio by volume of 50:50, are used.
Then each of the optically active salts is dissolved in water, carefully neutralised with a base such as sodium carbonate or potassium carbonate, or with a suitable acid, e.g. dilute hydrochloric acid or aqueous methanesulphonic acid, and in this way the corresponding free compound is obtained in the (+) or (-) form.
The (R) or (S) enantiomer alone or a mixture of two optically active diastereomeric compounds covered by general formula (I) may also be obtained by performing the syntheses described above with a suitable reaction component in the (R) or (S) configuration.
15 The starting compounds of general formula (II) may be obtained, if they are not already known from the literature, according to the methods described in International Patent Application WO 03/104236. The starting compounds of general formula (Ill) are commercially obtainable. Compounds of general formula (IV) may be obtained by methods familiar to the peptide chemist from hydroxycarboxylic acids 2o and amines of general formula HNR2R3 .
To prepare compounds of general formula (IV), the hydroxycarboxylic acids of general formula A
H~O OH
25 O , (VII) wherein the group A is as hereinbefore defined, which are needed for the synthesis, may be obtained from compounds of general formula A
H~N OH
I
H O , (VIII) wherein A is as hereinbefore defined.
With the proviso that the group A does not contain an amino or methylamino group, by diazotising compounds of general formula (VIII) with a suitable diazotising reagent, preferably sodium nitrite in an acid medium, it is possible to obtain the compounds of general formula (VII). If enantiomerically pure compounds are used the corresponding enantiomerically pure hydroxycarboxylic acid compounds are obtained, the configuration being retained as the reaction proceeds.
Another method of obtaining compounds of general formula (VII) wherein the groups A are as hereinbefore defined comprises alkylating the compound O O
, (IX) with correspondingly substituted benzylchlorides, benzylbromides or benzyliodides of general formula A
zo X ,(X) wherein A is as hereinbefore defined and X denotes a chlorine, bromine or iodine atom, analogously to methods known from the literature (Michael T. Crimmins, Kyle A. Emmitte and Jason D. Katz, Org. Lett. 2, 2165-2167 [2000)).
The diastereomeric products formed may then be separated using physicochemical methods, preferably chromatographic methods. The hydrolytic cleaving of the chiral auxiliary, coupling with amines of general formula HNR2R3 and cleaving of the benzyl protective group also provides a way of obtaining enantiomerically pure hydroxycarboxylic acid compounds of general formula (IV).
Compounds of general formula (VII) wherein the groups A are as hereinbefore defined may also be obtained by boiling down 2-acetylamino-3-phenyl-acrylic acids of general formula A
O
~ OH
H C' _N
H
O , (XI) ~5 using strong acids and subsequently reducing the 2-hydroxy-3-phenyl-acrylic acids formed.
The compounds of general formula (I) obtained may, if they contain suitable basic functions, be converted, particularly for pharmaceutical use, into their physiologically 2o acceptable salts with inorganic or organic acids. Suitable acids include for example hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid or malefic acid.
The present invention relates to racemates if the compounds of general formula (I) have only one chiral element. However, the application also includes the individual diastereomeric pairs of antipodes or mixtures thereof which are obtained if there is more than one chiral element in the compounds of general formula (I), as well as the 3o individual optically active enantiomers of which the above-mentioned racemates are made up.
Also included in the subject matter of this invention are the compounds according to the invention, including the salts thereof, in which one or more hydrogen atoms, for example one, two, three, four or five hydrogen atoms, are replaced by deuterium.
The new compounds of general formula (I) and the physiologically acceptable salts thereof have valuable pharmacological properties, based on their selective CGRP-antagonistic properties. The invention further relates to pharmaceutical compositions containing these compounds, their use and the preparation thereof.
The new compounds mentioned above and the physiologically acceptable salts thereof have CGRP-antagonistic properties and exhibit good affinities in CGRP
receptor binding studies. The compounds display CGRP-antagonistic properties in the pharmacological test systems described hereinafter.
The following experiments were carried out to demonstrate the affinity of the above-mentioned compounds for human CGRP-receptors and their antagonistic properties:
A. Binding studies with SK-N-MC cells (expressing the human CGRP receptor) SK-N-MC cells are cultivated in "Dulbecco's modified Eagle medium". The medium is removed from confluent cultures. The cells are washed twice with PBS buffer (Gibco 041-04190 M), detached by the addition of PBS buffer mixed with 0.02% EDTA, and isolated by centrifuging. After resuspension in 20 ml of "Balanced Salts Solution"
[BSS (in mM): NaCI 120, KCI 5.4, NaHC03 16.2, MgS04 0.8, NaHP04 1.0, CaCl2 1.8, D-glucose 5.5, HEPES 30, pH 7.40] the cells are centrifuged twice at 100 x g and resuspended in BSS. After the number of cells has been determined, the cells are homogenised using an Ultra-Turrax and centrifuged for 10 minutes at 3000 x g.
The supernatant is discarded and the pellet is recentrifuged in Tris buffer (10 mM
Tris, 50 3o mM NaCI, 5 mM MgCl2, 1 mM EDTA, pH 7.40) enriched with 1 % bovine serum albumin and 0.1 % bacitracin, and resuspended (1 ml / 1000000 cells). The homogenised product is frozen at -80°C. The membrane preparations are stable for more than 6 weeks under these conditions.
After thawing, the homogenised product is diluted 1:10 with assay buffer (50 mM
Tris, 150 mM NaCI, 5 mM MgCl2, 1 mM EDTA, pH 7.40) and homogenised for 30 seconds with an Ultra-Turrax. 230 p1 of the homogenised product are incubated for 180 minutes at ambient temperature with 50 pM'251-iodotyrosyl-Calcitonin-Gene Related Peptide (Amersham) and increasing concentrations of the test substances in a total volume of 250 p1. The incubation is ended by rapid filtration through GF/B
glass fibre filters treated with polyethyleneimine (0.1 %) using a cell harvester. The protein-bound radioactivity is measured using a gamma counter. Non-specific binding is defined as the bound radioactivity in the presence of 1 pM human CGRP-alpha during incubation.
The concentration binding curves are analysed using computer-aided non-linear curve matching.
The compounds mentioned hereinbefore show ICSO values <_ 10000 nM in the test described.
B. CGRP Antagonism in SK-N-MC cells 2o SK-N-MC cells (1 million cells) are washed twice with 250 NI incubation buffer {Hanks' HEPES, 1 mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4) and pre-incubated at 37°C for 15 minutes. After the addition of CGRP (10 NI) as agonist in increasing concentrations (1 O-'~ to 10-6 M), or additionally the substance in 3 to 4 different concentrations, the mixture is incubated for another 15 minutes.
Intracellular cAMP is then extracted by the addition of 20 NI of 1 M HCI and centrifugation (2000 x g, 4°C, for 15 minutes). The supernatants are frozen in liquid nitrogen and stored at -20°C.
3o The cAMP contents of the samples are determined by radioimmunoassay (Messrs.
Amersham) and the pA2 values of antagonistically acting substances are determined graphically.
The compounds of general formula (I) exhibit CGRP-antagonistic properties in the in vitro test model described, in a dosage range befinreen 10-'2 and 10-5 M.
In view of their pharmacological properties the compounds of general formula (I) and the salts thereof with physiologically acceptable acids are thus suitable for the acute and prophylactic treatment of headaches, particularly migraine or cluster headaches.
Moreover, the compounds of general formula (I) also have a positive effect on the following diseases: non-insulin-dependent diabetes mellitus ("NIDDM"), complex regional pain syndrome (CRPS1 ), cardiovascular diseases, morphine tolerance, diarrhoea caused by clostridium toxin, skin diseases, particularly thermal and radiation-induced skin damage including sunburn, inflammatory diseases, e.g.
inflammatory diseases of the joints (arthritis), neurogenic inflammation of the oral mucosa, inflammatory lung diseases, allergic rhinitis, asthma, diseases accompanied by excessive vasodilatation and resultant reduced blood supply to the tissues, e.g.
shock and sepsis. In addition, the compounds according to the invention have a general pain-relieving effect.
The symptoms of menopausal hot flushes caused by vasodilatation and increased blood flow in oestrogen-deficient women and hormone-treated patients with prostate 2o carcinoma are favourably affected by the CGRP-antagonists of the present application in a preventive and acute-therapeutic capacity, this therapeutic approach being distinguished from hormone replacement by the absence of side effects.
The dosage required to achieve a corresponding effect is conveniently 0.01 to 25 mg/kg of body weight, preferably 0.01 to 1 mg/kg of body weight, when administered intravenously or subcutaneousiy and 0.01 to 20 mg/kg of body weight, preferably 0.1 to 10 mg/kg of body weight when administered orally, and 0.01 to 10 mg/kg of body weight, preferably 0.1 to 10 mglkg of body weight when administered nasally or by inhalation, 1 to 3 x a day in each case.
If the treatment with CGRP antagonists and/or CGRP release inhibitors is given as a supplement to conventional hormone replacement, it is advisable to reduce the doses specified above, in which case the dosage may be from 1/5 of the lower limits mentioned above up to 1l1 of the upper limits specified.
The compounds prepared according to the invention may be administered either on their own or optionally in combination with other active substances for the treatment of migraine by intravenous, subcutaneous, intramuscular, intrarectal, intranasal route, by inhalation, transdermally or orally, while aerosol formulations are particularly suitable for inhalation. The combinations may be administered either simultaneously or sequentially.
Categories of active substance which may be used in the combination include e.g.
1o angiotensin II receptor antagonists, a-agonists and a-antagonists, 5-HT~B,~o agonists, AMPA antagonists, mild analgesics, antidepressants, antiemetics, anti-convulsants, antimuscarinics, ~i-blockers, calcium antagonists, corticosteroids, ergot alkaloids, histamine-H1 receptor antagonists, neurokinine antagonists, neurofeptics, non-steroidal antiinflammatories, NO-synthase inhibitors, prokinetics, selective ~s serotonin reuptake inhibitors or other anti-migraine agents, which may be formulated together with one or more inert conventional carriers and/or diluents, e.g.
with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, 2o carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, into conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, metered dose aerosols or suppositories.
Thus other active substances which may be used for the combinations mentioned 2s above include for example the non-steroidal antiinflammatories aceclofenac, acemetacin, acetylsalicylic acid, azathioprine, diclofenac, diflunisal, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, leflunomide, lornoxicam, mefenamic acid, naproxen, phenylbutazone, piroxicam, sulphasalazine, tenoxicam, zomepirac or the pharmaceutically acceptable salts thereof as well as meloxicam and so other selective COX2-inhibitors, such as for example rofecoxib and celecoxib.
It is also possible to use candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, valsartan, duloxetine, ergotamine, dihydroergotamine, metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine, chlorpromazine, vigabatrin, timolol, isometheptene, pizotifen, botox, gabapentin, topiramate, riboflavin, montelukast, lisinopril, prochloroperazine, dexamethasone, flunarizine, dextropropoxyphene, meperidine, metoprolol, propranolol, nadolol, atenolol, clonidine, indoramin, carbamazepine, phenytoin, valproate, amitryptiline, lidocaine or diltiazem and other 5-HT~B,»-agonists such as, for example, almotriptan, avitriptan, donitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan and the physiologically acceptable salts thereof.
The dosage of these active substances is expediently 1/5 of the lowest recommended dose to 1/1 of the normally recommended dose, i.e. for example 20 to 100 mg of sumatriptan.
The invention further relates to the use of the compounds according to the invention as valuable adjuvants for the production and purification (by affinity chromatography) of antibodies as well as in RIA and ELISA assays, after suitable radioactive labelling, for example by tritiation of suitable precursors, for example by catalytic hydrogenation with tritium or replacing halogen atoms with tritium, and as a diagnostic or analytical adjuvant in neurotransmitter research.
2o Experimental section As a rule, IR,'H-NMR and/or mass spectra have been obtained for the compounds prepared.
Unless otherwise stated, Rf values are obtained using ready-made silica gel TLC
plates 60 F254 (E. Merck, Darmstadt, Item no. 1.05714) without chamber saturation.
The ratios given for the eluants relate to units by volume of the solvent in question.
The units by volume specified for NH3 refer to a concentrated solution of NH3 in water.
Unless otherwise stated, the acid, base and salt solutions used for working up the 3o reaction solutions are aqueous systems of the concentrations specified.
For chromatographic purification, silica gel made by Millipore (MATREXT"", 35-70 pm) is used.
If there are no details of the configuration, it is unclear whether the substances are pure enantiomers or whether partial or even total racemisation has taken place.
The following abbreviations are used in the experimental descriptions:
Cyc cyclohexane DCM dichloromethane DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide EtOAc ethyl acetate HCI hydrochloric acid Hunig base ethyldiisopropylamine 1o LiOH lithium hydroxide MeOH methanol RT ambient temperature TBME tert.-butyl-methylether TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate THF tetrahydrofuran Example 1 (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-2o piperidin-1-yl]-2-oxo-ethyl1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate Fs NHZ
v 'CI
O N N O~-N~~N-v v0 HN
(1a) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-methoxycarbonyl-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate A mixture of 0.62 g (5.07 mmol) DMAP, 1.02 g (5.06 mmol) 4-nitrophenyl chloroformate and 20 mL pyridine was stirred for 40 min at RT, 1.50 g (5.04 mmol) methyl (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-hydroxy-propionate, so dissolved in 20 mL pyridine, was added dropwise thereto and the mixture was stirred for 2 h at RT. After the addition of 1.2 g (5.52 mmol) 2',3'-dihydro-2'-oxospiro-piperidin-4,4'(1'H)-quinazoline the mixture was stirred overnight at RT, combined with 60 mL TBME, washed three times with 1 M KHS04 solution and six times with 15%
K2C03 solution . The organic phase was dried over MgS04, filtered and evaporated down under reduced pressure. The residue was purified by column chromatography over silica gel.
Yield: 1.20 g (44% of theory) MS: (M+H)+ = 541/543 (CI) Rf = 0.61 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2) (1b) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate A mixture of 1.20 g (2.22 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-methoxycarbonyl-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate and 50 ml THF was combined with an aqueous solution of 100 mg (4.09 mmol) LiOH and stirred for 4 hours at RT. The reaction mixture was evaporated down under reduced pressure, combined with water and the aqueous phase was extracted twice with EtOAc . Then the aqueous phase was acidified by the addition of 1 molar hydrochloric acid and exhaustively extracted with DCM. The combined organic phases were dried over sodium sulphate and evaporated down under reduced pressure.
Yield: 0.90 g (77% of theory) MS: (M+H)+ = 5251527 (CI) Rf = 0.17 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2) (1c) (R)-1-(4-amino-3-chloro-5-triffuoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 1',2'-d ihydro-2'oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate 80 mg (0.24 mmol) TBTU and 0.05 mL (0.28 mmol) Hunig base were added to a 3o solution of 100 mg (0.19 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate in 15 mL THF and stirred for 30 min at RT . Then the mixture was combined with 40 mg (0.21 mmol) 1-methyl-4-piperidin-4-yl-piperazine dissolved in 5 mL THF and the reaction mixture was stirred for 4 h at RT . After the addition of 30 mL EtOAc the reaction mixture was washed twice with 20 mL 15% K2C03 solution.
The organic phase was dried over MgS04, filtered and evaporated down under reduced pressure. The residue was purified by column chromatography (silica gel, gradient DCM to DCM/MeOH/NH3 50:45:5).
Yield: 40 mg (31 % of theory) MS: (M+H)+ = 692/694 (CI) Rf = 0.36 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2) Example 2 (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-( 1-methyl-piperidin-4-yl)-piperazin-1-yIJ-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate Analogously to Example (1c) the product was obtained from 100 mg (0.19 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 1',2'-dihydro-2'-oxospiro-4H 3',1-quinazoline'-4,4'-piperidine-1-carboxylate and 40 mg (0.22 mmol) 1-(1-methyl-piperidin-4-yl)-piperazine.
Yield: 20 mg (15% of theory) MS: (M+H)+ = 692/694 (CI) 15 Rf = 0.30 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2) Example 3 (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1'-methyl-[4,4'Jbipiperidinyl-1-yl)-20 2-oxo-ethyl1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carbvxylate NHz CI
O N N~O~-N\_~N-O
HN
Analogously to Example (1 c) the product was obtained from 100 mg (0.19 mmol) (R)-25 2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate and 40 mg (0.22 mmol) 1-methyl-[4,4'Jbipiperidinyl.
Yield: 10 mg (8% of theory) MS: (M+H)+ = 691/693 (CI) Rf = 0.37 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2) Example 4 (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1,4')bipiperidinyl-1'-yl-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate NHz CI
O N N~O~N
~--~ ~O
HN
~l Analogously to Example (1 c) the product was obtained from 100 mg (0.19 mmol) (R)-~5 2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate and 40 mg (0.23 mmol) [1,4'Jbipiperidinyl.
Yield: 40 mg (31 % of theory) MS: (M+H)+ = 677/679 (CI) 2o Rf = 0.46 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2) Example 5 (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-2s piperidin-1-yIJ-2-oxo-ethyl1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate NHZ
v 'CI _ O O N O~~ N-HN
(5a) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-methoxycarbonyl-ethyl 1',2'-dihyd ro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate s Analogously to Example (1 a) the product was obtained from 1.5 g (5.04 mmol) methyl (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-hydroxy-propionate and 1.2 g (5.50 mmol) 1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine.
Yield: 0.85 g (31 % of theory) MS: (M+H)+ = 542/544 (CI) Rf = 0.56 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2) (5b) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate Analogously to Example (1 b) the product was obtained from 850 mg (1.57 mmol) (R)-~5 2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-methoxycarbonyl-ethyl1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate and 80 mg (3.27 mmol) LiOH.
Yield: 570 mg (69% of theory) MS: (M+H)+ = 528/530 (CI) 2o R, = 0.10 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2) (5c) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 1',2'-d ihyd ro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate 25 Analogously to Example (1c) the product was obtained from 100 mg (0.19 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 1',2'-d ihyd ro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate and 40 mg (0.21 mmol) 1-methyl-4-piperidin-4-yl-piperazine.
Yield: 70 mg (53% of theory) 3o MS: (M+H)+ = 693/695 (CI) Rf = 0.46 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2) Example 6 (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate F~
NHZ
v 'CI
O O N O~--~N~N-vO
HN
~l Analogously to Example (1 c) the product was obtained from 100 mg (0.19 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate and 40 mg (0.22 mmol) 1-( 1-methyl-piperidin-4-yl )-piperazine.
Yield: 50 mg (38% of theory) MS: (M+H)+ = 693/695 (C1) Rf = 0.34 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2) Example 7 (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1'-methyl-[4,4']bipiperidinyl-1-yl)-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate Analogously to Example (1c) the product was obtained from 100 mg (0.19 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate and 40 mg (0.22 mmol) 1-methyl-[4,4']bipiperidinyl.
Yield: 40 mg (30% of theory) MS: (M+H)+ = 692/694 (CI) Rf = 0.38 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2) Example 8 (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1,4']bipiperidinyl-1'-yl-2-oxo-ethyl 1',2'-d ihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate Analogously to Example (1c) the product was obtained from 100 mg (0.19 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 1',2'-d ihyd ro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate and 40 mg (0.23 mmol) [1,4']bipiperidinyl.
2o Yield: 40 mg (31 % of theory) MS: (M+H)+ = 678/680 (CI) Rf = 0.44 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2) The following Examples describe the preparation of pharmaceutical formulations which contain as active substance any desired compound of general formula (1):
Example I
Capsules for powder inhalation containing 1 mdof active ingredient Composition:
1 capsule for powder inhalation contains:
active ingredient 1.0 mg lactose 20.0 mg hard gelatine capsules 50.0 ma 71.0 mg ~5 Method of preparation:
The active ingredient is ground to the particle size required for inhaled substances.
The ground active ingredient is homogeneously mixed with the lactose. The mixture is transferred into hard gelatine capsules.
20 Example II
lnhalable solution for Respimat~ containing 1 ma of active ingredient Composition:
25 1 puff contains:
active ingredient 1.0 mg benzalkonium chloride 0.002 mg disodium edetate 0.0075 mg purified water ad 15.0 NI
Method of preparation:
The active ingredient and benzalkonium chloride are dissolved in water and transferred into Respimat~ cartridges.
Example III
Inhalable solution for nebulisers containing 1 mg of active ingredient Composition:
1 vial contains:
active ingredient 0.1 g sodium chloride 0.18 g benzalkonium chloride 0.002 g 1o purified water ad 20.0 ml Method of preparation:
The active ingredient, sodium chloride and benzalkonium chloride are dissolved in wate r.
Example IV
Propellant gas-operated metering aerosol containing 1 mg of active ingredient 2o Composition:
1 pufF contains:
active ingredient 1.0 mg lecithin 0.1 propellant gas ad 50.0 NI
Method of preparation:
The micronised active ingredient is homogeneously suspended in the mixture of lecithin and propellant gas. The suspension is transferred into a pressurised 3o container with a metering valve.
Example V
Nasal spray containing 1 mg of active in redient Composition:
active ingredient 1.0 mg sodium chloride 0.9 mg benzalkonium chloride 0.025 mg disodium edetate 0.05 mg 1o purified water ad 0.1 ml Method of preparation:
The active ingredient and the excipients are dissolved in water and transferred into a suitable container.
Example VI
Injectable solution containing 5 mg of active substance per 5 ml 2o Composition:
active substance 5 mg glucose 250 mg human serum albumin 10 mg glycofurol 250 mg water for injections ad 5 ml Preparation:
Glycofurol and glucose are dissolved in water for injections (Wfl); human serum 3o albumin is added; active ingredient is dissolved with heating; made up to specified volume with Wfl; transferred into ampoules under nitrogen gas.
Example VII
Iniectable solution containingi 100 mg of active substance per 20 ml Composition:
active substance 100 mg monopotassium dihydrogen phosphate = KH2P04 12 mg disodium hydrogen phosphate = Na2HP04~2H20 2 mg sodium chloride 180 mg 1o human serum albumin 50 mg Polysorbate 80 20 mg water for injections ad 20 ml Preparation:
Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate are dissolved in water for injections (Wfl); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with Wfl; transferred into ampoules.
Example VIII
Lyophilisate containing 10 mg of active substance Composition:
Active substance 10 mg Mannitol 300 mg human serum albumin 20 mg 3o Preparation:
Mannitol is dissolved in water for injections (Wfl); human serum albumin is added;
active ingredient is dissolved with heating; made up to specified volume with Wfl;
transferred into vials; freeze-dried.
Solvent for lyophilisate:
Polysorbate 80 = Tween 80 20 mg mannitol 200 mg water for injections ad 10 ml Preparation:
Polysorbate 80 and mannitol are dissolved in water for injections (Wfl);
transferred into ampoules.
Example IX
Tablets containinc~20 mq of active substance Composition:
~ 5 active substance 20 mg lactose 120 mg maize starch 40 mg magnesium stearate 2 mg Povidone K 25 18 mg Preparation:
Active substance, lactose and maize starch are homogeneously mixed; granulated with an aqueous solution of Povidone; mixed with magnesium stearate;
compressed in a tablet press; weight of tablet 200 mg.
Example X
Capsules containing 20 mgi active substance Composition:
active substance 20 mg maize starch 80 mg highly dispersed silica 5 mg magnesium stearate 2.5 mg Preparation:
Active substance, maize starch and silica are homogeneously mixed; mixed with magnesium stearate; the mixture is packed into size for 3 hard gelatine capsules in a capsule filling machine.
Example XI
Suppositories containinct 50 mg of active substance Composition:
active substance 50 mg hard fat (Adeps solidus) q.s. ad 1700 mg Preparation:
Hard fat is melted at about 38°C; ground active substance is homogeneously dispersed in the molten hard fat; after cooling to about 35°C it is poured into chilled moulds.
Exam~~le XII
Injectable solution containing 10 ma of active substance aer 1 ml Composition:
active substance 10 mg mannitol 50 mg human serum albumin 10 mg water for injections ad 1 ml Preparation:
Mannitol is dissolved in water for injections (Wfl); human serum albumin is added;
active ingredient is dissolved with heating; made up to specified volume with Wfl;
transferred into ampoules under nitrogen gas.
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the tautomers, the diastereomers, the enantiomers, the hydrates thereof, the mixtures thereof and the salts thereof as well as the hydrates of the salts, while the compounds (1) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-yl)-piperidin-1-yl]-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate, (2) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-methyl-piperidin-yl)-piperazin-1-yl]-2-oxo-ethyl 1',2'-d ihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate, (3) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1'-methyl [4,4']bipiperidinyl-1-yl)-2-oxo-ethyl1',2'-dihydro-2'-oxospiro-4H-3',1 quinazoiine'-4,4'-piperidine-1-carboxylate, (4) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1,4']bipiperidinyl-1'-yl-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-2o carboxylate, (5) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-y1 )-piperidin-1-yl]-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate, (6) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-methyl-piperidin-yl)-piperazin-1-yl]-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate, (7) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1'-methyl-[4,4']bipiperidinyl-1-yl)-2-oxo-ethyl1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate, (8) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1,4']bipiperidinyl-1'-yl-2 oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1 1 o carboxylate, the tautomers, the diastereomers, the enantiomers, the hydrates thereof, the mixtures thereof and the salts thereof as well as the hydrates of the salts are of exceptional importance.
The compounds of general formula (I) are prepared by methods known in principle.
The following methods have proved particularly useful for preparing the compounds of general formula (I) according to the invention:
(a) In order to prepare compounds of general formula A
N ~ N~Rs R
wherein A and R~ to R3 are as hereinbefore defined:
reacting a piperidine of general formula NH , (1l) wherein R' is as hereinbefore defined, with a carbonic acid derivative of general formula O
G~G
, (III) wherein G denotes a nucleofugic group which may be identical or different, preferably the chlorine atom, the p-nitrophenoxy or trichloromethoxy group, and with a compound of general formula I
N~Rs O , (IV) wherein A, R2 and R3 are as hereinbefore defined, with the proviso that R2 and R3 do ~5 not contain any other free, unprotected, primary or secondary aliphatic amino function.
The reactions which are theoretically two-step reactions are usually carried out as one-pot processes, preferably by reacting one of the two components (II) or (IV) with 2o equimolar quantities of the carbonic acid derivative of general formula (III) in a suitable solvent at lower temperature in the first stage, then adding at least equimolar amounts of the other component (II) or (!V) and finishing the reaction at elevated temperature. The reactions with bis-(trichioromethyl)-carbonate are preferably carried out in the presence of at least 2 equivalents (based on bis-(trichloromethyl)-25 carbonate) of a tertiary base, e.g. triethylamine, N-ethyl-diisopropylamine, pyridine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane or 1,8-diazabicyclo[5.4.0]undec-7-ene. Examples of solvents, which should be anhydrous, include tetrahydrofuran, dioxane, dimethyl formamide, dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone or acetonitrile; if bis-(trichloromethyl)-carbonate is used as the carbonyl component anhydrous chlorohydrocarbons such as dichloromethane, 1,2-dichloroethane or trichloroethylene are preferred. The reaction temperatures for the first reaction step are between -30 and +25°C, preferably -5 and +10°C, for the second reaction step they are between +15°C and the boiling temperature of the solvent used, preferably between +20°C
and +70°C (cf.
also: H. A. Staab and W. Rohr, "Synthesen mit heterocyclischen Amiden (Azoliden)", Neuere Methoden der Praparativen Organischen Chemie, Vol. V, p. 53 - 93, Verlag Chemie, WeinheimlBergstr., 1967; P. Majer and R.S. Randad, J. Org. Chem. 59, 1937 - 1938 (1994); K. Takeda, Y. Akagi, A. Saiki, T. Sukahara and H. Ogura, 1o Tetrahedron Letters 24 (42), 4569 - 4572 (1983); S.R. Sandier and W. Karo in "Organic Functional Group Preparations", Vol. II, p. 223-245, Academis Press, New York 1971 ).
(b) In order to prepare compounds of general formula A
O Rz N O N~Rs R , (I) wherein A and R1 to R3 are as hereinbefore defined:
2o coupling a carboxylic acid of general formula A
O
OH
N~O
R ,(V) wherein A and R1 are as hereinbefore defined, with an amine of general formula HNR2R3, wherein R2 and R3 are as hereinbefore defined, with the proviso that they do not contain any other free unprotected primary or secondary aliphatic amino function.
Any primary or secondary amino function additionally present in the group -NR2R3 is in each case provided with a suitable protective group.
The coupling is preferably carried out using methods known from peptide chemistry (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example using carbodiimides such as e.g. dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide, O-(1 H-benzotriazol-1-yl)- N,N-N;N'-tetramethyluronium hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP). By adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt) the reaction speed can be increased. The couplings are normally carried out with equimolar amounts of the coupling components as well as the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethyl ~5 formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between -30 and +30°C, preferably -20 and +25°C. If necessary, N-ethyl-diisopropylamine (Hunig base) is preferably used as an additional auxiliary base.
2o The so-called anhydride process is used as a further coupling method for synthesising compounds of general formula (I) (cf. also: M. Bodanszky, "Peptide Chemistry", Springer-Verlag 1988, p. 58-59; M. Bodanszky, "Principles of Peptide Synthesis", Springer-Verlag 1984, p. 21-27). The Vaughan variant of the mixed anhydride process is preferred (J.R. Vaughan Jr., J. Amer. Chem.Soc. 73, 3547 25 (1951 )), in which the mixed anhydride is obtained from the carboxylic acid of general formula (V) which is to be coupled and monoisobutyl carbonate, using isobutyl chlorocarbonate in the presence of bases such as 4-methylmorpholine or 4-ethylmorpholine. The preparation of this mixed anhydride and the coupling with the amines of general formula HNR2R3 are carried out in a one-pot process, using the 3o above-mentioned solvents and at temperatures between -20 and +25°C, preferably between 0°C and +25°C.
(c) In order to prepare compounds of general formula A
I
N O N~Rs R~ O
(I) wherein A and R~ to R3 are as hereinbefore defined:
coupling a compound of general formula A
O
~ Nu N_ -O
O
R , (VI) wherein A and R' are as hereinbefore defined and Nu denotes a leaving group, for example a halogen atom, such as the chlorine, bromine or iodine atom, an alkyl-sulphonyloxy group with 1 to 10 carbon atoms in the alkyl moiety, a phenylsulphonyloxy or naphthylsulphonyloxy group optionally mono-, di- or trisubstituted by chlorine or bromine atoms, by methyl or nitro groups, while the substituents may be identical or different, a 1H-imidazol-1-yl, a 1H-pyrazol-1-yl ~5 optionally substituted by one or two methyl groups in the carbon skeleton, a 1 H-1,2,4-triazol-1-yl, 1 H-1,2,3-triazol-1-yl, 1 H-1,2,3,4-tetrazol-1-yl, a vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, pentafluorophenyl, pyranyl or pyridinyl, a dimethylaminyloxy, 2(1H)-oxopyridin-1-yl-oxy, 2,5-dioxopyrrolidin-1-yloxy, phthalimidyloxy, 1 H-benzo-triazol-1-yloxy or azide 2o group, with an amine of general formula HNR2R3, wherein R2 and R3 are as hereinbefore defined, with the proviso that no other free, unprotected, primary or secondary aliphatic amino function is present.
The reaction is carried out under Schotten-Baumann or Einhorn conditions, i.e.
the components are reacted in the presence of at least one equivalent of an auxiliary base at temperatures between -50°C and +120°C, preferably -10°C and +30°C, and optionally in the presence of solvents. The auxiliary bases used are preferably alkali metal and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, e.g. sodium carbonate, potassium carbonate or caesium carbonate, alkali metal acetates, e.g. sodium or potassium acetate, as well as tertiary amines, e.g. pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine, 1,4-diazabicyclo[2.2.2]octane or 1,8-diazabicyclo[5.4.0]undec-7-ene, the solvents used may be, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methyl-pyrrolidone or mixtures thereof; if alkali metal or alkaline earth metal hydroxides, alkali metal carbonates or acetates are used as the auxiliary bases, water may also be added to the reaction mixture as co-solvent.
~5 The new compounds of general formula (I) according to the invention contain one or more chiral centres. If for example there are two chiral centres the compounds may occur in the form of two pairs of diastereomeric antipodes. The invention covers the individual isomers as well as the mixtures thereof.
2o The diastereomers may be separated on the basis of their different physico-chemical properties, e.g. by fractional crystallisation from suitable solvents, by high pressure liquid or column chromatography, using chiral or preferably non-chiral stationary phases.
25 Racemates covered by general formula (I) may be separated for example by HPLC
on suitable chiral stationary phases (e.g. Chiral AGP, Chiralpak AD).
Racemates which contain a basic function can also be separated via the diastereomeric, optically active salts which are produced on reacting with an optically active acid, for example (+) or (-)-tartaric acid, (+) or (-)-diacetyl tartaric acid, (+) or (-)-monomethyl tartrate or 30 (+)-camphorsulphonic acid.
According to a conventional method of separating isomers, the racemate of a compound of general formula (I) is reacted with one of the above-mentioned optically active acids or bases in equimolar amounts in a solvent and the resulting crystalline, diastereomeric, optically active salts thereof are separated using their different solubilities. This reaction may be carried out in any type of solvent provided that it is sufficiently different in terms of the solubility of the salts. Preferably, methanol, ethanol or mixtures thereof, for example in a ratio by volume of 50:50, are used.
Then each of the optically active salts is dissolved in water, carefully neutralised with a base such as sodium carbonate or potassium carbonate, or with a suitable acid, e.g. dilute hydrochloric acid or aqueous methanesulphonic acid, and in this way the corresponding free compound is obtained in the (+) or (-) form.
The (R) or (S) enantiomer alone or a mixture of two optically active diastereomeric compounds covered by general formula (I) may also be obtained by performing the syntheses described above with a suitable reaction component in the (R) or (S) configuration.
15 The starting compounds of general formula (II) may be obtained, if they are not already known from the literature, according to the methods described in International Patent Application WO 03/104236. The starting compounds of general formula (Ill) are commercially obtainable. Compounds of general formula (IV) may be obtained by methods familiar to the peptide chemist from hydroxycarboxylic acids 2o and amines of general formula HNR2R3 .
To prepare compounds of general formula (IV), the hydroxycarboxylic acids of general formula A
H~O OH
25 O , (VII) wherein the group A is as hereinbefore defined, which are needed for the synthesis, may be obtained from compounds of general formula A
H~N OH
I
H O , (VIII) wherein A is as hereinbefore defined.
With the proviso that the group A does not contain an amino or methylamino group, by diazotising compounds of general formula (VIII) with a suitable diazotising reagent, preferably sodium nitrite in an acid medium, it is possible to obtain the compounds of general formula (VII). If enantiomerically pure compounds are used the corresponding enantiomerically pure hydroxycarboxylic acid compounds are obtained, the configuration being retained as the reaction proceeds.
Another method of obtaining compounds of general formula (VII) wherein the groups A are as hereinbefore defined comprises alkylating the compound O O
, (IX) with correspondingly substituted benzylchlorides, benzylbromides or benzyliodides of general formula A
zo X ,(X) wherein A is as hereinbefore defined and X denotes a chlorine, bromine or iodine atom, analogously to methods known from the literature (Michael T. Crimmins, Kyle A. Emmitte and Jason D. Katz, Org. Lett. 2, 2165-2167 [2000)).
The diastereomeric products formed may then be separated using physicochemical methods, preferably chromatographic methods. The hydrolytic cleaving of the chiral auxiliary, coupling with amines of general formula HNR2R3 and cleaving of the benzyl protective group also provides a way of obtaining enantiomerically pure hydroxycarboxylic acid compounds of general formula (IV).
Compounds of general formula (VII) wherein the groups A are as hereinbefore defined may also be obtained by boiling down 2-acetylamino-3-phenyl-acrylic acids of general formula A
O
~ OH
H C' _N
H
O , (XI) ~5 using strong acids and subsequently reducing the 2-hydroxy-3-phenyl-acrylic acids formed.
The compounds of general formula (I) obtained may, if they contain suitable basic functions, be converted, particularly for pharmaceutical use, into their physiologically 2o acceptable salts with inorganic or organic acids. Suitable acids include for example hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid or malefic acid.
The present invention relates to racemates if the compounds of general formula (I) have only one chiral element. However, the application also includes the individual diastereomeric pairs of antipodes or mixtures thereof which are obtained if there is more than one chiral element in the compounds of general formula (I), as well as the 3o individual optically active enantiomers of which the above-mentioned racemates are made up.
Also included in the subject matter of this invention are the compounds according to the invention, including the salts thereof, in which one or more hydrogen atoms, for example one, two, three, four or five hydrogen atoms, are replaced by deuterium.
The new compounds of general formula (I) and the physiologically acceptable salts thereof have valuable pharmacological properties, based on their selective CGRP-antagonistic properties. The invention further relates to pharmaceutical compositions containing these compounds, their use and the preparation thereof.
The new compounds mentioned above and the physiologically acceptable salts thereof have CGRP-antagonistic properties and exhibit good affinities in CGRP
receptor binding studies. The compounds display CGRP-antagonistic properties in the pharmacological test systems described hereinafter.
The following experiments were carried out to demonstrate the affinity of the above-mentioned compounds for human CGRP-receptors and their antagonistic properties:
A. Binding studies with SK-N-MC cells (expressing the human CGRP receptor) SK-N-MC cells are cultivated in "Dulbecco's modified Eagle medium". The medium is removed from confluent cultures. The cells are washed twice with PBS buffer (Gibco 041-04190 M), detached by the addition of PBS buffer mixed with 0.02% EDTA, and isolated by centrifuging. After resuspension in 20 ml of "Balanced Salts Solution"
[BSS (in mM): NaCI 120, KCI 5.4, NaHC03 16.2, MgS04 0.8, NaHP04 1.0, CaCl2 1.8, D-glucose 5.5, HEPES 30, pH 7.40] the cells are centrifuged twice at 100 x g and resuspended in BSS. After the number of cells has been determined, the cells are homogenised using an Ultra-Turrax and centrifuged for 10 minutes at 3000 x g.
The supernatant is discarded and the pellet is recentrifuged in Tris buffer (10 mM
Tris, 50 3o mM NaCI, 5 mM MgCl2, 1 mM EDTA, pH 7.40) enriched with 1 % bovine serum albumin and 0.1 % bacitracin, and resuspended (1 ml / 1000000 cells). The homogenised product is frozen at -80°C. The membrane preparations are stable for more than 6 weeks under these conditions.
After thawing, the homogenised product is diluted 1:10 with assay buffer (50 mM
Tris, 150 mM NaCI, 5 mM MgCl2, 1 mM EDTA, pH 7.40) and homogenised for 30 seconds with an Ultra-Turrax. 230 p1 of the homogenised product are incubated for 180 minutes at ambient temperature with 50 pM'251-iodotyrosyl-Calcitonin-Gene Related Peptide (Amersham) and increasing concentrations of the test substances in a total volume of 250 p1. The incubation is ended by rapid filtration through GF/B
glass fibre filters treated with polyethyleneimine (0.1 %) using a cell harvester. The protein-bound radioactivity is measured using a gamma counter. Non-specific binding is defined as the bound radioactivity in the presence of 1 pM human CGRP-alpha during incubation.
The concentration binding curves are analysed using computer-aided non-linear curve matching.
The compounds mentioned hereinbefore show ICSO values <_ 10000 nM in the test described.
B. CGRP Antagonism in SK-N-MC cells 2o SK-N-MC cells (1 million cells) are washed twice with 250 NI incubation buffer {Hanks' HEPES, 1 mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4) and pre-incubated at 37°C for 15 minutes. After the addition of CGRP (10 NI) as agonist in increasing concentrations (1 O-'~ to 10-6 M), or additionally the substance in 3 to 4 different concentrations, the mixture is incubated for another 15 minutes.
Intracellular cAMP is then extracted by the addition of 20 NI of 1 M HCI and centrifugation (2000 x g, 4°C, for 15 minutes). The supernatants are frozen in liquid nitrogen and stored at -20°C.
3o The cAMP contents of the samples are determined by radioimmunoassay (Messrs.
Amersham) and the pA2 values of antagonistically acting substances are determined graphically.
The compounds of general formula (I) exhibit CGRP-antagonistic properties in the in vitro test model described, in a dosage range befinreen 10-'2 and 10-5 M.
In view of their pharmacological properties the compounds of general formula (I) and the salts thereof with physiologically acceptable acids are thus suitable for the acute and prophylactic treatment of headaches, particularly migraine or cluster headaches.
Moreover, the compounds of general formula (I) also have a positive effect on the following diseases: non-insulin-dependent diabetes mellitus ("NIDDM"), complex regional pain syndrome (CRPS1 ), cardiovascular diseases, morphine tolerance, diarrhoea caused by clostridium toxin, skin diseases, particularly thermal and radiation-induced skin damage including sunburn, inflammatory diseases, e.g.
inflammatory diseases of the joints (arthritis), neurogenic inflammation of the oral mucosa, inflammatory lung diseases, allergic rhinitis, asthma, diseases accompanied by excessive vasodilatation and resultant reduced blood supply to the tissues, e.g.
shock and sepsis. In addition, the compounds according to the invention have a general pain-relieving effect.
The symptoms of menopausal hot flushes caused by vasodilatation and increased blood flow in oestrogen-deficient women and hormone-treated patients with prostate 2o carcinoma are favourably affected by the CGRP-antagonists of the present application in a preventive and acute-therapeutic capacity, this therapeutic approach being distinguished from hormone replacement by the absence of side effects.
The dosage required to achieve a corresponding effect is conveniently 0.01 to 25 mg/kg of body weight, preferably 0.01 to 1 mg/kg of body weight, when administered intravenously or subcutaneousiy and 0.01 to 20 mg/kg of body weight, preferably 0.1 to 10 mg/kg of body weight when administered orally, and 0.01 to 10 mg/kg of body weight, preferably 0.1 to 10 mglkg of body weight when administered nasally or by inhalation, 1 to 3 x a day in each case.
If the treatment with CGRP antagonists and/or CGRP release inhibitors is given as a supplement to conventional hormone replacement, it is advisable to reduce the doses specified above, in which case the dosage may be from 1/5 of the lower limits mentioned above up to 1l1 of the upper limits specified.
The compounds prepared according to the invention may be administered either on their own or optionally in combination with other active substances for the treatment of migraine by intravenous, subcutaneous, intramuscular, intrarectal, intranasal route, by inhalation, transdermally or orally, while aerosol formulations are particularly suitable for inhalation. The combinations may be administered either simultaneously or sequentially.
Categories of active substance which may be used in the combination include e.g.
1o angiotensin II receptor antagonists, a-agonists and a-antagonists, 5-HT~B,~o agonists, AMPA antagonists, mild analgesics, antidepressants, antiemetics, anti-convulsants, antimuscarinics, ~i-blockers, calcium antagonists, corticosteroids, ergot alkaloids, histamine-H1 receptor antagonists, neurokinine antagonists, neurofeptics, non-steroidal antiinflammatories, NO-synthase inhibitors, prokinetics, selective ~s serotonin reuptake inhibitors or other anti-migraine agents, which may be formulated together with one or more inert conventional carriers and/or diluents, e.g.
with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, 2o carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, into conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, metered dose aerosols or suppositories.
Thus other active substances which may be used for the combinations mentioned 2s above include for example the non-steroidal antiinflammatories aceclofenac, acemetacin, acetylsalicylic acid, azathioprine, diclofenac, diflunisal, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, leflunomide, lornoxicam, mefenamic acid, naproxen, phenylbutazone, piroxicam, sulphasalazine, tenoxicam, zomepirac or the pharmaceutically acceptable salts thereof as well as meloxicam and so other selective COX2-inhibitors, such as for example rofecoxib and celecoxib.
It is also possible to use candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, valsartan, duloxetine, ergotamine, dihydroergotamine, metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine, chlorpromazine, vigabatrin, timolol, isometheptene, pizotifen, botox, gabapentin, topiramate, riboflavin, montelukast, lisinopril, prochloroperazine, dexamethasone, flunarizine, dextropropoxyphene, meperidine, metoprolol, propranolol, nadolol, atenolol, clonidine, indoramin, carbamazepine, phenytoin, valproate, amitryptiline, lidocaine or diltiazem and other 5-HT~B,»-agonists such as, for example, almotriptan, avitriptan, donitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan and the physiologically acceptable salts thereof.
The dosage of these active substances is expediently 1/5 of the lowest recommended dose to 1/1 of the normally recommended dose, i.e. for example 20 to 100 mg of sumatriptan.
The invention further relates to the use of the compounds according to the invention as valuable adjuvants for the production and purification (by affinity chromatography) of antibodies as well as in RIA and ELISA assays, after suitable radioactive labelling, for example by tritiation of suitable precursors, for example by catalytic hydrogenation with tritium or replacing halogen atoms with tritium, and as a diagnostic or analytical adjuvant in neurotransmitter research.
2o Experimental section As a rule, IR,'H-NMR and/or mass spectra have been obtained for the compounds prepared.
Unless otherwise stated, Rf values are obtained using ready-made silica gel TLC
plates 60 F254 (E. Merck, Darmstadt, Item no. 1.05714) without chamber saturation.
The ratios given for the eluants relate to units by volume of the solvent in question.
The units by volume specified for NH3 refer to a concentrated solution of NH3 in water.
Unless otherwise stated, the acid, base and salt solutions used for working up the 3o reaction solutions are aqueous systems of the concentrations specified.
For chromatographic purification, silica gel made by Millipore (MATREXT"", 35-70 pm) is used.
If there are no details of the configuration, it is unclear whether the substances are pure enantiomers or whether partial or even total racemisation has taken place.
The following abbreviations are used in the experimental descriptions:
Cyc cyclohexane DCM dichloromethane DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide EtOAc ethyl acetate HCI hydrochloric acid Hunig base ethyldiisopropylamine 1o LiOH lithium hydroxide MeOH methanol RT ambient temperature TBME tert.-butyl-methylether TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate THF tetrahydrofuran Example 1 (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-2o piperidin-1-yl]-2-oxo-ethyl1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate Fs NHZ
v 'CI
O N N O~-N~~N-v v0 HN
(1a) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-methoxycarbonyl-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate A mixture of 0.62 g (5.07 mmol) DMAP, 1.02 g (5.06 mmol) 4-nitrophenyl chloroformate and 20 mL pyridine was stirred for 40 min at RT, 1.50 g (5.04 mmol) methyl (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-hydroxy-propionate, so dissolved in 20 mL pyridine, was added dropwise thereto and the mixture was stirred for 2 h at RT. After the addition of 1.2 g (5.52 mmol) 2',3'-dihydro-2'-oxospiro-piperidin-4,4'(1'H)-quinazoline the mixture was stirred overnight at RT, combined with 60 mL TBME, washed three times with 1 M KHS04 solution and six times with 15%
K2C03 solution . The organic phase was dried over MgS04, filtered and evaporated down under reduced pressure. The residue was purified by column chromatography over silica gel.
Yield: 1.20 g (44% of theory) MS: (M+H)+ = 541/543 (CI) Rf = 0.61 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2) (1b) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate A mixture of 1.20 g (2.22 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-methoxycarbonyl-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate and 50 ml THF was combined with an aqueous solution of 100 mg (4.09 mmol) LiOH and stirred for 4 hours at RT. The reaction mixture was evaporated down under reduced pressure, combined with water and the aqueous phase was extracted twice with EtOAc . Then the aqueous phase was acidified by the addition of 1 molar hydrochloric acid and exhaustively extracted with DCM. The combined organic phases were dried over sodium sulphate and evaporated down under reduced pressure.
Yield: 0.90 g (77% of theory) MS: (M+H)+ = 5251527 (CI) Rf = 0.17 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2) (1c) (R)-1-(4-amino-3-chloro-5-triffuoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 1',2'-d ihydro-2'oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate 80 mg (0.24 mmol) TBTU and 0.05 mL (0.28 mmol) Hunig base were added to a 3o solution of 100 mg (0.19 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate in 15 mL THF and stirred for 30 min at RT . Then the mixture was combined with 40 mg (0.21 mmol) 1-methyl-4-piperidin-4-yl-piperazine dissolved in 5 mL THF and the reaction mixture was stirred for 4 h at RT . After the addition of 30 mL EtOAc the reaction mixture was washed twice with 20 mL 15% K2C03 solution.
The organic phase was dried over MgS04, filtered and evaporated down under reduced pressure. The residue was purified by column chromatography (silica gel, gradient DCM to DCM/MeOH/NH3 50:45:5).
Yield: 40 mg (31 % of theory) MS: (M+H)+ = 692/694 (CI) Rf = 0.36 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2) Example 2 (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-( 1-methyl-piperidin-4-yl)-piperazin-1-yIJ-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate Analogously to Example (1c) the product was obtained from 100 mg (0.19 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 1',2'-dihydro-2'-oxospiro-4H 3',1-quinazoline'-4,4'-piperidine-1-carboxylate and 40 mg (0.22 mmol) 1-(1-methyl-piperidin-4-yl)-piperazine.
Yield: 20 mg (15% of theory) MS: (M+H)+ = 692/694 (CI) 15 Rf = 0.30 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2) Example 3 (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1'-methyl-[4,4'Jbipiperidinyl-1-yl)-20 2-oxo-ethyl1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carbvxylate NHz CI
O N N~O~-N\_~N-O
HN
Analogously to Example (1 c) the product was obtained from 100 mg (0.19 mmol) (R)-25 2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate and 40 mg (0.22 mmol) 1-methyl-[4,4'Jbipiperidinyl.
Yield: 10 mg (8% of theory) MS: (M+H)+ = 691/693 (CI) Rf = 0.37 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2) Example 4 (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1,4')bipiperidinyl-1'-yl-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate NHz CI
O N N~O~N
~--~ ~O
HN
~l Analogously to Example (1 c) the product was obtained from 100 mg (0.19 mmol) (R)-~5 2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate and 40 mg (0.23 mmol) [1,4'Jbipiperidinyl.
Yield: 40 mg (31 % of theory) MS: (M+H)+ = 677/679 (CI) 2o Rf = 0.46 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2) Example 5 (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-2s piperidin-1-yIJ-2-oxo-ethyl1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate NHZ
v 'CI _ O O N O~~ N-HN
(5a) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-methoxycarbonyl-ethyl 1',2'-dihyd ro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate s Analogously to Example (1 a) the product was obtained from 1.5 g (5.04 mmol) methyl (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-hydroxy-propionate and 1.2 g (5.50 mmol) 1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine.
Yield: 0.85 g (31 % of theory) MS: (M+H)+ = 542/544 (CI) Rf = 0.56 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2) (5b) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate Analogously to Example (1 b) the product was obtained from 850 mg (1.57 mmol) (R)-~5 2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-methoxycarbonyl-ethyl1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate and 80 mg (3.27 mmol) LiOH.
Yield: 570 mg (69% of theory) MS: (M+H)+ = 528/530 (CI) 2o R, = 0.10 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2) (5c) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 1',2'-d ihyd ro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate 25 Analogously to Example (1c) the product was obtained from 100 mg (0.19 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 1',2'-d ihyd ro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate and 40 mg (0.21 mmol) 1-methyl-4-piperidin-4-yl-piperazine.
Yield: 70 mg (53% of theory) 3o MS: (M+H)+ = 693/695 (CI) Rf = 0.46 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2) Example 6 (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate F~
NHZ
v 'CI
O O N O~--~N~N-vO
HN
~l Analogously to Example (1 c) the product was obtained from 100 mg (0.19 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate and 40 mg (0.22 mmol) 1-( 1-methyl-piperidin-4-yl )-piperazine.
Yield: 50 mg (38% of theory) MS: (M+H)+ = 693/695 (C1) Rf = 0.34 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2) Example 7 (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1'-methyl-[4,4']bipiperidinyl-1-yl)-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate Analogously to Example (1c) the product was obtained from 100 mg (0.19 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate and 40 mg (0.22 mmol) 1-methyl-[4,4']bipiperidinyl.
Yield: 40 mg (30% of theory) MS: (M+H)+ = 692/694 (CI) Rf = 0.38 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2) Example 8 (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1,4']bipiperidinyl-1'-yl-2-oxo-ethyl 1',2'-d ihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate Analogously to Example (1c) the product was obtained from 100 mg (0.19 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 1',2'-d ihyd ro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate and 40 mg (0.23 mmol) [1,4']bipiperidinyl.
2o Yield: 40 mg (31 % of theory) MS: (M+H)+ = 678/680 (CI) Rf = 0.44 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2) The following Examples describe the preparation of pharmaceutical formulations which contain as active substance any desired compound of general formula (1):
Example I
Capsules for powder inhalation containing 1 mdof active ingredient Composition:
1 capsule for powder inhalation contains:
active ingredient 1.0 mg lactose 20.0 mg hard gelatine capsules 50.0 ma 71.0 mg ~5 Method of preparation:
The active ingredient is ground to the particle size required for inhaled substances.
The ground active ingredient is homogeneously mixed with the lactose. The mixture is transferred into hard gelatine capsules.
20 Example II
lnhalable solution for Respimat~ containing 1 ma of active ingredient Composition:
25 1 puff contains:
active ingredient 1.0 mg benzalkonium chloride 0.002 mg disodium edetate 0.0075 mg purified water ad 15.0 NI
Method of preparation:
The active ingredient and benzalkonium chloride are dissolved in water and transferred into Respimat~ cartridges.
Example III
Inhalable solution for nebulisers containing 1 mg of active ingredient Composition:
1 vial contains:
active ingredient 0.1 g sodium chloride 0.18 g benzalkonium chloride 0.002 g 1o purified water ad 20.0 ml Method of preparation:
The active ingredient, sodium chloride and benzalkonium chloride are dissolved in wate r.
Example IV
Propellant gas-operated metering aerosol containing 1 mg of active ingredient 2o Composition:
1 pufF contains:
active ingredient 1.0 mg lecithin 0.1 propellant gas ad 50.0 NI
Method of preparation:
The micronised active ingredient is homogeneously suspended in the mixture of lecithin and propellant gas. The suspension is transferred into a pressurised 3o container with a metering valve.
Example V
Nasal spray containing 1 mg of active in redient Composition:
active ingredient 1.0 mg sodium chloride 0.9 mg benzalkonium chloride 0.025 mg disodium edetate 0.05 mg 1o purified water ad 0.1 ml Method of preparation:
The active ingredient and the excipients are dissolved in water and transferred into a suitable container.
Example VI
Injectable solution containing 5 mg of active substance per 5 ml 2o Composition:
active substance 5 mg glucose 250 mg human serum albumin 10 mg glycofurol 250 mg water for injections ad 5 ml Preparation:
Glycofurol and glucose are dissolved in water for injections (Wfl); human serum 3o albumin is added; active ingredient is dissolved with heating; made up to specified volume with Wfl; transferred into ampoules under nitrogen gas.
Example VII
Iniectable solution containingi 100 mg of active substance per 20 ml Composition:
active substance 100 mg monopotassium dihydrogen phosphate = KH2P04 12 mg disodium hydrogen phosphate = Na2HP04~2H20 2 mg sodium chloride 180 mg 1o human serum albumin 50 mg Polysorbate 80 20 mg water for injections ad 20 ml Preparation:
Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate are dissolved in water for injections (Wfl); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with Wfl; transferred into ampoules.
Example VIII
Lyophilisate containing 10 mg of active substance Composition:
Active substance 10 mg Mannitol 300 mg human serum albumin 20 mg 3o Preparation:
Mannitol is dissolved in water for injections (Wfl); human serum albumin is added;
active ingredient is dissolved with heating; made up to specified volume with Wfl;
transferred into vials; freeze-dried.
Solvent for lyophilisate:
Polysorbate 80 = Tween 80 20 mg mannitol 200 mg water for injections ad 10 ml Preparation:
Polysorbate 80 and mannitol are dissolved in water for injections (Wfl);
transferred into ampoules.
Example IX
Tablets containinc~20 mq of active substance Composition:
~ 5 active substance 20 mg lactose 120 mg maize starch 40 mg magnesium stearate 2 mg Povidone K 25 18 mg Preparation:
Active substance, lactose and maize starch are homogeneously mixed; granulated with an aqueous solution of Povidone; mixed with magnesium stearate;
compressed in a tablet press; weight of tablet 200 mg.
Example X
Capsules containing 20 mgi active substance Composition:
active substance 20 mg maize starch 80 mg highly dispersed silica 5 mg magnesium stearate 2.5 mg Preparation:
Active substance, maize starch and silica are homogeneously mixed; mixed with magnesium stearate; the mixture is packed into size for 3 hard gelatine capsules in a capsule filling machine.
Example XI
Suppositories containinct 50 mg of active substance Composition:
active substance 50 mg hard fat (Adeps solidus) q.s. ad 1700 mg Preparation:
Hard fat is melted at about 38°C; ground active substance is homogeneously dispersed in the molten hard fat; after cooling to about 35°C it is poured into chilled moulds.
Exam~~le XII
Injectable solution containing 10 ma of active substance aer 1 ml Composition:
active substance 10 mg mannitol 50 mg human serum albumin 10 mg water for injections ad 1 ml Preparation:
Mannitol is dissolved in water for injections (Wfl); human serum albumin is added;
active ingredient is dissolved with heating; made up to specified volume with Wfl;
transferred into ampoules under nitrogen gas.
Claims (10)
1. CGRP antagonists of general formula wherein A denotes a group of formula the group lenotes a group of formula -NR2R3 denotes a group of formula the tautomers, the diastereomers, the enantiomers, the hydrates thereof, the mixtures thereof and the salts thereof as well as the hydrates of the salts.
2. The compounds of general formula (I) according to claim 1, which are numbered progressively from (1) to (258) in the Table in the specification, the tautomers, the diastereomers, the enantiomers, the hydrates thereof, the mixtures thereof and the salts thereof as well as the hydrates of the salts.
3. The following compounds of general formula (I) according to claim 1:
(1 ) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-
(1 ) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-
4,4'-piperidine-1-carboxylate, (2) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-methyl-piperidin-yl)-piperazin-1-yl]-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate, (3) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1'-methyl-[4,4']bipiperidinyl-1-yl)-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate, (4) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1,4']bipiperidinyl-1'-yl-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-quinazoline'-4,4'-piperidine-1-carboxylate, (5) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-yl)-piperidin-1-yl]-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate, (6) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate, (7) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1'-methyl-[4,4']bipiperidinyl-1-yl)-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate, (8) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1,4']bipiperidinyl-1'-yl-2-oxo-ethyl 1',2'-dihydro-2'-oxospiro-4H-3',1-benzoxazin-4,4'-piperidine-1-carboxylate, the tautomers, the diastereomers, the enantiomers, the hydrates thereof, the mixtures thereof and the salts thereof as well as the hydrates of the salts.
4. Physiologically acceptable salts of the compounds according to one of claims 1 to 3 with inorganic or organic acids.
4. Physiologically acceptable salts of the compounds according to one of claims 1 to 3 with inorganic or organic acids.
5. Pharmaceutical compositions containing a compound according to one of claims 1 to 3 or a physiologically acceptable salt according to claim 4, optionally together with one or more inert carriers and/or diluents.
6. Use of a compound according to at least one of claims 1 to 4 for preparing a pharmaceutical composition for the acute and prophylactic treatment of headaches, particularly migraine or cluster headaches.
7. Use of a compound according to at least one of claims 1 to 4 for preparing a pharmaceutical composition for the treatment of non-insulin-dependent diabetes mellitus (NIDDM).
8. Use of a compound according to at least one of claims 1 to 4 for preparing a pharmaceutical composition for the treatment of CRPS1 (complex regional pain syndrome), cardiovascular diseases, morphine tolerance, diarrhoea caused by clostridium toxin, skin diseases, particularly thermal and radiation-induced skin damage including sunburn, inflammatory diseases, e.g. in particular, inflammatory diseases of the joints such as arthritis, neurogenic inflammation of the oral mucosa, inflammatory lung diseases, allergic rhinitis, asthma, diseases accompanied by excessive vasodilatation and resultant reduced circulation of the blood, e.g.
shock and sepsis, for alleviating pain in general or for preventive or acute therapeutic treatment of the symptoms of menopausal hot flushes caused by vasodilatation and increased blood flow in oestrogen-deficient women and hormone-treated patients with prostate carcinoma.
shock and sepsis, for alleviating pain in general or for preventive or acute therapeutic treatment of the symptoms of menopausal hot flushes caused by vasodilatation and increased blood flow in oestrogen-deficient women and hormone-treated patients with prostate carcinoma.
9. Process for preparing a pharmaceutical composition according to claim 5, characterised in that a compound according to at least one of claims 1 to 4 is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
10. Process for preparing the compounds of general formula (I) according to at least one of claims 1 to 4, characterised in that (a) in order to prepare compounds of general formula wherein A and R1 to R3 are defined as in claim 1, a piperidine of general formula wherein R1 is defined as in claim 1, is reacted with a carbonic acid derivative of general formula wherein G denotes a nucleofugic group which may be identical or different, and with a compound of general formula wherein A, R2 and R3 are defined as in claim 1, with the proviso that R2 and R3 do r contain any other free, unprotected, primary or secondary aliphatic amino function;
(b) in order to prepare compounds of general formula wherein A and R1 to R3 are defined as in claim 1, a carboxylic acid of general formula wherein A and R1 are defined as in claim 1, is coupled with an amine of general formula HNR2R3, wherein R2 and R3 are defined as in claim 1, with the proviso that they do not contain any other unprotected primary or secondary aliphatic amino function; or (c) in order to prepare compounds of general formula wherein A and R1 to R3 are defined as in claim 1, a compound of general formula wherein A and R1 are defined as in claim 1 and Nu denotes a leaving group, is coupled with an amine of general formula HNR2R3, wherein R2 and R3 are defined as in claim 1, with the proviso that no other free, unprotected, primary or secondary aliphatic amino function is present, and if necessary any protective group used during the reactions described above is cleaved, and/or any precursor functions used are converted in a compound thus obtained, and/or if desired a compound of general formula (I) thus obtained is resolved into the stereoisomers thereof and/or a compound of general formula (I) thus obtained is converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof.
(b) in order to prepare compounds of general formula wherein A and R1 to R3 are defined as in claim 1, a carboxylic acid of general formula wherein A and R1 are defined as in claim 1, is coupled with an amine of general formula HNR2R3, wherein R2 and R3 are defined as in claim 1, with the proviso that they do not contain any other unprotected primary or secondary aliphatic amino function; or (c) in order to prepare compounds of general formula wherein A and R1 to R3 are defined as in claim 1, a compound of general formula wherein A and R1 are defined as in claim 1 and Nu denotes a leaving group, is coupled with an amine of general formula HNR2R3, wherein R2 and R3 are defined as in claim 1, with the proviso that no other free, unprotected, primary or secondary aliphatic amino function is present, and if necessary any protective group used during the reactions described above is cleaved, and/or any precursor functions used are converted in a compound thus obtained, and/or if desired a compound of general formula (I) thus obtained is resolved into the stereoisomers thereof and/or a compound of general formula (I) thus obtained is converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102004018794.0 | 2004-04-15 | ||
DE102004018794A DE102004018794A1 (en) | 2004-04-15 | 2004-04-15 | Selected CGRP antagonists, process for their preparation and their use as pharmaceuticals |
PCT/EP2005/003816 WO2005100360A1 (en) | 2004-04-15 | 2005-04-12 | Selected cgrp antagonists, methods for the production thereof, and use thereof as medicaments |
Publications (1)
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---|---|
CA2562529A1 true CA2562529A1 (en) | 2005-10-27 |
Family
ID=34964296
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CA002562529A Abandoned CA2562529A1 (en) | 2004-04-15 | 2005-04-12 | Selected cgrp antagonists, methods for the production thereof, and use thereof as medicaments |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1737864A1 (en) |
JP (1) | JP2007532602A (en) |
CA (1) | CA2562529A1 (en) |
DE (1) | DE102004018794A1 (en) |
WO (1) | WO2005100360A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8450327B2 (en) | 2007-10-18 | 2013-05-28 | Boehringer Ingelheim International Gmbh | CGRP antagonists |
Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
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US7220862B2 (en) | 2002-06-05 | 2007-05-22 | Bristol-Myers Squibb Company | Calcitonin gene related peptide receptor antagonists |
US7842808B2 (en) | 2002-06-05 | 2010-11-30 | Bristol-Myers Squibb Company | Anti-migraine spirocycles |
DE10250082A1 (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 |
AR046787A1 (en) | 2003-12-05 | 2005-12-21 | Bristol Myers Squibb Co | HETEROCICLIC ANTIMIGRAN AGENTS |
TW200533398A (en) | 2004-03-29 | 2005-10-16 | Bristol Myers Squibb Co | Novel therapeutic agents for the treatment of migraine |
US7384931B2 (en) | 2004-11-03 | 2008-06-10 | Bristol-Myers Squibb Company | Constrained compounds as CGRP-receptor antagonists |
US7384930B2 (en) | 2004-11-03 | 2008-06-10 | Bristol-Myers Squibb Company | Constrained compounds as CGRP-receptor antagonists |
US7449586B2 (en) | 2004-12-03 | 2008-11-11 | Bristol-Myers Squibb Company | Processes for the preparation of CGRP-receptor antagonists and intermediates thereof |
US7834007B2 (en) | 2005-08-25 | 2010-11-16 | Bristol-Myers Squibb Company | CGRP antagonists |
US8168592B2 (en) | 2005-10-21 | 2012-05-01 | Amgen Inc. | CGRP peptide antagonists and conjugates |
CN101309704B (en) | 2005-11-14 | 2012-10-10 | 礼纳特神经系统科学公司 | Antagonist antibodies directed against calcitonin gene-related peptide and methods using same |
WO2007076336A1 (en) * | 2005-12-22 | 2007-07-05 | Eli Lilly And Company | Treatment of migraine with anti-cgrp antibodies |
WO2008021375A2 (en) * | 2006-08-15 | 2008-02-21 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
WO2009034028A2 (en) * | 2007-09-07 | 2009-03-19 | Boehringer Ingelheim International Gmbh | Novel compounds |
EP2065381A1 (en) | 2007-10-18 | 2009-06-03 | Boehringer Ingelheim Pharma GmbH & Co. KG | CGRP antagonists |
EP2065386A1 (en) * | 2007-10-18 | 2009-06-03 | Boehringer Ingelheim Pharma GmbH & Co. KG | CGRP antagonists |
CA2716424C (en) | 2008-03-04 | 2015-04-28 | Pfizer Limited | Methods of treating chronic pain |
AU2010288194B2 (en) | 2009-08-28 | 2013-08-29 | Teva Pharmaceuticals International Gmbh | Methods for treating visceral pain by administering antagonist antibodies directed against calcitonin gene-related peptide |
AU2012258976B8 (en) | 2011-05-20 | 2017-07-20 | H. Lundbeck A/S | Use of anti-CGRP or anti-CGRP-R antibodies or antibody fragments to treat or prevent chronic and acute forms of diarrhea |
HUE055505T2 (en) | 2011-05-20 | 2021-11-29 | H Lundbeck As | Anti-cgrp compositions and use thereof |
DK2709663T3 (en) | 2011-05-20 | 2019-05-20 | Alderbio Holdings Llc | Use of anti-CGRP antibodies and antibody fragments to prevent or inhibit photophobia or aversion to light in individuals in need thereof, especially migraineurs |
US10556945B2 (en) | 2014-03-21 | 2020-02-11 | Teva Pharmaceuticals International Gmbh | Antagonist antibodies directed against calcitonin gene-related peptide and methods using same |
US9896502B2 (en) | 2014-03-21 | 2018-02-20 | Teva Pharmaceuticals International Gmbh | Antagonist antibodies directed against calcitonin gene-related peptide and methods using same |
KR20190066607A (en) | 2016-09-23 | 2019-06-13 | 테바 파마슈티컬스 인터내셔널 게엠베하 | Treatment of refractory migraine |
MX2021008267A (en) | 2019-01-08 | 2021-08-05 | H Lundbeck As | Acute treatment and rapid treatment of headache using anti-cgrp antibodies. |
Family Cites Families (5)
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TR199900537T2 (en) * | 1996-09-10 | 1999-07-21 | Dr. Karl Thomae Gmbh | Converted amino acids, pharmaceutical preparations containing them. |
AU6211499A (en) * | 1998-09-30 | 2000-04-17 | Merck & Co., Inc. | Benzimidazolinyl piperidines as cgrp ligands |
DE10211770A1 (en) * | 2002-03-14 | 2003-10-02 | Boehringer Ingelheim Pharma | Novel substituted piperidines, pharmaceutical compositions containing them and processes for their preparation |
CN100558728C (en) * | 2002-06-05 | 2009-11-11 | 布里斯托尔-迈尔斯斯奎布公司 | Calcitonin gene related peptide receptor antagonists |
TW200533398A (en) * | 2004-03-29 | 2005-10-16 | Bristol Myers Squibb Co | Novel therapeutic agents for the treatment of migraine |
-
2004
- 2004-04-15 DE DE102004018794A patent/DE102004018794A1/en not_active Withdrawn
-
2005
- 2005-04-12 CA CA002562529A patent/CA2562529A1/en not_active Abandoned
- 2005-04-12 WO PCT/EP2005/003816 patent/WO2005100360A1/en not_active Application Discontinuation
- 2005-04-12 JP JP2007507731A patent/JP2007532602A/en active Pending
- 2005-04-12 EP EP05731903A patent/EP1737864A1/en not_active Ceased
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8450327B2 (en) | 2007-10-18 | 2013-05-28 | Boehringer Ingelheim International Gmbh | CGRP antagonists |
Also Published As
Publication number | Publication date |
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EP1737864A1 (en) | 2007-01-03 |
JP2007532602A (en) | 2007-11-15 |
WO2005100360A1 (en) | 2005-10-27 |
DE102004018794A1 (en) | 2005-10-27 |
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