CA2217194A1 - Novel heterocyclic compounds - Google Patents
Novel heterocyclic compounds Download PDFInfo
- Publication number
- CA2217194A1 CA2217194A1 CA002217194A CA2217194A CA2217194A1 CA 2217194 A1 CA2217194 A1 CA 2217194A1 CA 002217194 A CA002217194 A CA 002217194A CA 2217194 A CA2217194 A CA 2217194A CA 2217194 A1 CA2217194 A1 CA 2217194A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- hydrogen
- ethyl
- dibenzo
- dihydro
- 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
- 150000002391 heterocyclic compounds Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 16
- 208000007920 Neurogenic Inflammation Diseases 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 14
- 239000003937 drug carrier Substances 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 230000032683 aging Effects 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 206010022489 Insulin Resistance Diseases 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- QECFHSWLBNSZQJ-UHFFFAOYSA-N 1-[2-(6,11-dihydro-5h-dibenzo[1,2-a:1',2'-e][7]annulen-11-yloxy)ethyl]-4-methyl-1,4-diazepane-6-carboxylic acid Chemical compound C1C(C(O)=O)CN(C)CCN1CCOC1C2=CC=CC=C2CCC2=CC=CC=C21 QECFHSWLBNSZQJ-UHFFFAOYSA-N 0.000 claims description 2
- ZLZTVHONDWGRPS-UHFFFAOYSA-N 1-[2-(6,11-dihydro-5h-dibenzo[1,2-a:1',2'-e][7]annulen-11-yloxy)ethyl]aziridine-2-carboxylic acid Chemical compound OC(=O)C1CN1CCOC1C2=CC=CC=C2CCC2=CC=CC=C21 ZLZTVHONDWGRPS-UHFFFAOYSA-N 0.000 claims description 2
- JGNOWDMIKGBNKB-UHFFFAOYSA-N 1-[2-(6,11-dihydro-5h-dibenzo[1,2-a:1',2'-e][7]annulen-11-yloxy)ethyl]piperidine-3-carboxamide Chemical compound C1C(C(=O)N)CCCN1CCOC1C2=CC=CC=C2CCC2=CC=CC=C21 JGNOWDMIKGBNKB-UHFFFAOYSA-N 0.000 claims description 2
- YUVRBGUIQSEEQH-UHFFFAOYSA-N 1-[2-(6,11-dihydro-5h-dibenzo[1,2-a:1',2'-e][7]annulen-11-yloxy)ethyl]piperidine-3-carboxylic acid Chemical compound C1C(C(=O)O)CCCN1CCOC1C2=CC=CC=C2CCC2=CC=CC=C21 YUVRBGUIQSEEQH-UHFFFAOYSA-N 0.000 claims description 2
- SJFRPOBSJLYNME-UHFFFAOYSA-N 1-[2-(6,11-dihydro-5h-dibenzo[1,2-a:1',2'-e][7]annulen-11-yloxy)ethyl]piperidine-4-carboxylic acid Chemical compound C1CC(C(=O)O)CCN1CCOC1C2=CC=CC=C2CCC2=CC=CC=C21 SJFRPOBSJLYNME-UHFFFAOYSA-N 0.000 claims description 2
- IFZUPGHXEXNSII-UHFFFAOYSA-N 2-[2-(6,11-dihydro-5h-dibenzo[1,2-a:1',2'-e][7]annulen-11-yloxy)ethyl]-3,4-dihydro-1h-isoquinoline-4-carboxylic acid Chemical compound C12=CC=CC=C2CCC2=CC=CC=C2C1OCCN1CC(C(=O)O)C2=CC=CC=C2C1 IFZUPGHXEXNSII-UHFFFAOYSA-N 0.000 claims description 2
- JXOHPIRZFYFZPM-UHFFFAOYSA-N 4-[2-(6,11-dihydro-5h-dibenzo[1,2-a:1',2'-e][7]annulen-11-yloxy)ethyl]morpholine-2-carboxylic acid Chemical compound C1COC(C(=O)O)CN1CCOC1C2=CC=CC=C2CCC2=CC=CC=C21 JXOHPIRZFYFZPM-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- MBZHYMBKOZCODO-UHFFFAOYSA-N [1-[2-(6,11-dihydro-5h-dibenzo[1,2-a:1',2'-e][7]annulen-11-yloxy)ethyl]piperidin-3-yl]methanol Chemical compound C1C(CO)CCCN1CCOC1C2=CC=CC=C2CCC2=CC=CC=C21 MBZHYMBKOZCODO-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 17
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 6
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- 208000032131 Diabetic Neuropathies Diseases 0.000 claims 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
- VFJKSTYPSMCNTC-XLIONFOSSA-N (2s,4r)-1-[2-(6,11-dihydro-5h-dibenzo[1,2-a:1',2'-e][7]annulen-11-yloxy)ethyl]-4-hydroxypyrrolidine-2-carboxylic acid Chemical compound C1[C@H](O)C[C@@H](C(O)=O)N1CCOC1C2=CC=CC=C2CCC2=CC=CC=C21 VFJKSTYPSMCNTC-XLIONFOSSA-N 0.000 claims 1
- PINBZXSCAZPXMP-UHFFFAOYSA-N 1-[2-(6,11-dihydro-5h-dibenzo[1,2-a:1',2'-e][7]annulen-11-yloxy)ethyl]piperidine-2-carboxylic acid Chemical compound OC(=O)C1CCCCN1CCOC1C2=CC=CC=C2CCC2=CC=CC=C21 PINBZXSCAZPXMP-UHFFFAOYSA-N 0.000 claims 1
- NVBYERWQPXXHAK-UHFFFAOYSA-N 2-[2-(6,11-dihydro-5h-dibenzo[1,2-a:1',2'-e][7]annulen-11-yloxy)ethyl]-3,4-dihydro-1h-isoquinoline-3-carboxylic acid Chemical compound C12=CC=CC=C2CCC2=CC=CC=C2C1OCCN1CC2=CC=CC=C2CC1C(=O)O NVBYERWQPXXHAK-UHFFFAOYSA-N 0.000 claims 1
- VEXNTZXEZGEQLK-UHFFFAOYSA-N 4-(4-chlorophenyl)-1-[2-(6,11-dihydro-5h-dibenzo[1,2-a:1',2'-e][7]annulen-11-yloxy)ethyl]piperidin-4-ol Chemical compound C1CN(CCOC2C3=CC=CC=C3CCC3=CC=CC=C32)CCC1(O)C1=CC=C(Cl)C=C1 VEXNTZXEZGEQLK-UHFFFAOYSA-N 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 10
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- 208000004296 neuralgia Diseases 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 5
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- 125000000547 substituted alkyl group Chemical group 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
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- 108090000932 Calcitonin Gene-Related Peptide Proteins 0.000 description 8
- 102100025588 Calcitonin gene-related peptide 1 Human genes 0.000 description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
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- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
- C07D203/10—Radicals substituted by singly bound oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
A compound of formula (1), in which Z is selected from (a), (b), (c), (d), (e), (f), (g), (h), (i), (j) and (k). The present invention relates to novel N-substituted azaheterocyclic carboxylic acids and esters thereof in which a substituted alkyl chain forms part of the N-substituent or salts thereof, to methods for their preparation, to composition containing them, and to their use for the clinical treatment of painful, hyperalgesic and/or inflammatory conditions in which C-fibers play a pathophysiological role by eliciting neurogenic pain or inflammation.
Description
W O 9~/31474 PCT~DK96/00151 Novel heterocvclic Comoounds Field of the Invention The present invention relates to novel N-substituted azaheterocyclic carbox-ylic acids and esters thereof in which a substituted alkyl chain forms part of 5 the N-substituent or salts thereof, to methods for their preparation, to compositions containing them, and to their use for the clinical treatment of painful, hyperalgesic and/or inflammatory conditions in which C-fibers play a pathophysiological role by eliciting neurogenic pain or inflammation. The invention also relates to the use of the present compounds for the treatment 10 of insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM) or aging, the present compounds knowing to interfere with neuropeptide con-taining C-fibres and hence inhibit the secretion and circulation of insulin an-tagonizing peptides like CGRP or amylin.
Backaround of the Invention 15 The nervous system exerts a profound effect on the inflammatory response.
Antidromic stimulation of sensory nerves results in localized vasodilation and increased vascular permeability (Janecso et al. Br. J. Pharmacol. 1967, 31, 138-151) and a similar response is observed following injection of peptides known to be present in sensory nerves. From this and other data it is postu-20 lated that peptides released from sensory nerve endings mediate manyinflammatory responses in tissues like skin, joint, urinary tract, eye, menin-ges, gastro-intestinal and respiratory tracts. Hence inhibition of sensory nervepeptide release and/or activity, may be useful in treatment of, for example arthritis, dermatitis, rhinitis, asthma, cystitis, gingivitis, thrombo-phlelitis, 25 glaucoma, gas~ro-intestinal diseases or migraine.
W O96/31474 PCT~DK~6/00151 Further, the potent effects of CGRP on skeletal muscle glycogen synthase ac-tivity and muscle glucose metabolism, together with the notion that this peptide is released from the neuromuscular junction by nerve excitation, suggest that CGRP may play a physiological role in skeletal muscle glucose 5 metabolism by directing the phosphorylated glucose away from glycogen storage and into the glycolytic and oxidative pathways (Rossetti et al. Am. J.
Physiol. 264, E1-E10, 1993). This peptide may represent an important physiological modulator of intracellular glucose trafficking in physiological conditions, such as exercise, and may also contribute to the decreased insulin 10 action and skeletal muscle glycogen synthase in pathophysiological condi-tions like NIDDM or aging-associated obesity (Melnyk et al. Obesity Res. 3, 337-344, 1995) where circulating plasma levels of CGRP are markedly increased. Hence inhibition of release and/or activity of the neuropeptide CGRP may be useful in the treatment of insulin resistance related to type 2 15 diabetes or aging.
In US Patent No. 4,383,999 and No. 4,514,414 and in EP 236342 as well as in EP 231996 some derivatives of N-(4,4-disubstituted-3-butenyl)-azaheterocyclic carboxylic acids are claimed as inhibitors of GABA uptake. In EP 342635 and EP 374801, N-substituted azaheterocyciic carboxylic acids in 20 which an oxime ether group and vinyl ether group forms part of the N-substituent respectively are claimed as inhibitors of GABA uptake. Further, in WO 9107389 and WO 9220658, N-substituted azacyclic carboxylic acids are claimed as GABA uptake inhibitors. EP 221572 claims that 1-aryloxyalkyl-pyridine-3-carboxylic acids are inhibitors of GABA uptake.
25 Descriction of the Invention The present invention relates to novel N-substituted azaheterocyclic carbo-xylic acids and esters thereof of formula I
R' R2 RGRs (I) ICH2) r wherein R', R2, R3, R4, Rs and R6 independently are hydrogen, halogen, trifluoromethyl, hydroxy, C1.6-alkyl, C1 6-alkoxy, -NR7R3 or -SO2NR7R8 wherein R7 and R3 independently are hydrogen or C1 6-alkyl; and 5 X is completion of an optional bond, -CH2-, -CH2CH2-, -CH=CH-, -O-, -S(O)z- wherein z is 0, 1 or 2, or -N(R9)- wherein R9 is hydrogen or C1 6-alkyl;and Y is -O-, -S(O)q- wherein q is 0, 1 or 2, or -N(R10)- wherein R'~ is hydrogen orCl ~-alkyl; and 10 ris 1, 2, 3 or4; and Z is selected from 11 ~ ~ ~N~ ~N~CH2) A
[~R~
~ R11 ~9~N--C~12--Rl 1 W 096/31474 PCTADK96/OOlSl wherein n is 1 or 2; and R" is -(CH2)mOH or-(CH2)tCOR'2 wherein m is 0, 1, 2, 3, 4, 5 or 6 and t is O
or 1 and wherein R12 is -OH, -NH2, -NHOH or C, 6-alkoxy; and R13 is hydrogen, halogen, trifluoromethyl, hydroxy, C, 6-alkyl or C, 6-alkoxy;
5 and R14 is hydrogen, C, 6-alkyl, C, 6-alkoxy or phenyl optionally substituted with haiogen, trifluoromethyl, hydroxy, C, 6-alkyl or C, 6-alkoxy; and R15 is hydrogen or C, 6-alkyl; and ... is optionally a single bond or a double bond;
or a pharmaceutically acceptable salt thereof.
The compounds of formula I may exist as geometric and optical isomers and all isomers and mixtures thereof are included herein. Isomers may be separ-ated by means of standard methods such as chromatographic techniques or fractional crystallization of suitable salts.
Preferably, the compounds of formula I exist as the individual geometric or optical isomers.
The compounds according to the invention may optionally exist as pharma-ceutically acceptable acid addition salts or - when the carboxylic acid group isnot esterified - as pharmaceutically acceptable metal salts or - optionally alkylated - ammonium salts.
Examples of such salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate or similar pharmaceutically accept-able inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) whlch are hereby incorporated by reference.
CA 022l7l94 l997-lO-Ol W O 96/31~74 PCTADK~6/00151 The term "Cl.6-alkyl" as used herein, alone or in combination, refers to a straight or branched, saturated hydrocarbon chain having 1 to 6 carbon atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-5 methylpentyl, neopentyl, n-hexyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and 1, 2, 2-trimethylpropyl .
The term "C1 6-alkoxy" as used herein, alone or in combination, refers to a straight or branched monovalent substituent comprising a Cl 6-alkyl group linked through an ether oxygen having its free valence bond from the ether 10 oxygen and having 1 to 6 carbon atoms e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy.
The term "halogen" means fluorine, chlorine, bromine or iodine.
Illustrative examples of compounds encompassed by the present invention include:
1 5 1-(2-(10,1 1-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-3-piperidinecarboxamide;
1-(2-(10,1 1-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-4-piperidinecarboxylic acid;
1-(2-(10,1 1-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-2-20 piperidinecarboxylic acid;
(1-(2-(10,1 1-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)piperidin-3-yl)methanol;
4-(4-Chlorophenyl)-1-(2-(10,1 1-Dihydro-5H-dibenzo[a,d]cyciohepten-5-yloxy)-ethyl)-4-piperidinol;
4-(2-(10,11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-4-piperazinecarboxylic acid;
(2S,4R)-1 -(2-(10,11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-4-5 hydroxy-2-pyrrolidinecarboxylic acid;
4-(2-(10,11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-2-morpholine-carboxylic acid;
1 -(2-(10,11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-2-aziridinecarboxylic acid;
Backaround of the Invention 15 The nervous system exerts a profound effect on the inflammatory response.
Antidromic stimulation of sensory nerves results in localized vasodilation and increased vascular permeability (Janecso et al. Br. J. Pharmacol. 1967, 31, 138-151) and a similar response is observed following injection of peptides known to be present in sensory nerves. From this and other data it is postu-20 lated that peptides released from sensory nerve endings mediate manyinflammatory responses in tissues like skin, joint, urinary tract, eye, menin-ges, gastro-intestinal and respiratory tracts. Hence inhibition of sensory nervepeptide release and/or activity, may be useful in treatment of, for example arthritis, dermatitis, rhinitis, asthma, cystitis, gingivitis, thrombo-phlelitis, 25 glaucoma, gas~ro-intestinal diseases or migraine.
W O96/31474 PCT~DK~6/00151 Further, the potent effects of CGRP on skeletal muscle glycogen synthase ac-tivity and muscle glucose metabolism, together with the notion that this peptide is released from the neuromuscular junction by nerve excitation, suggest that CGRP may play a physiological role in skeletal muscle glucose 5 metabolism by directing the phosphorylated glucose away from glycogen storage and into the glycolytic and oxidative pathways (Rossetti et al. Am. J.
Physiol. 264, E1-E10, 1993). This peptide may represent an important physiological modulator of intracellular glucose trafficking in physiological conditions, such as exercise, and may also contribute to the decreased insulin 10 action and skeletal muscle glycogen synthase in pathophysiological condi-tions like NIDDM or aging-associated obesity (Melnyk et al. Obesity Res. 3, 337-344, 1995) where circulating plasma levels of CGRP are markedly increased. Hence inhibition of release and/or activity of the neuropeptide CGRP may be useful in the treatment of insulin resistance related to type 2 15 diabetes or aging.
In US Patent No. 4,383,999 and No. 4,514,414 and in EP 236342 as well as in EP 231996 some derivatives of N-(4,4-disubstituted-3-butenyl)-azaheterocyclic carboxylic acids are claimed as inhibitors of GABA uptake. In EP 342635 and EP 374801, N-substituted azaheterocyciic carboxylic acids in 20 which an oxime ether group and vinyl ether group forms part of the N-substituent respectively are claimed as inhibitors of GABA uptake. Further, in WO 9107389 and WO 9220658, N-substituted azacyclic carboxylic acids are claimed as GABA uptake inhibitors. EP 221572 claims that 1-aryloxyalkyl-pyridine-3-carboxylic acids are inhibitors of GABA uptake.
25 Descriction of the Invention The present invention relates to novel N-substituted azaheterocyclic carbo-xylic acids and esters thereof of formula I
R' R2 RGRs (I) ICH2) r wherein R', R2, R3, R4, Rs and R6 independently are hydrogen, halogen, trifluoromethyl, hydroxy, C1.6-alkyl, C1 6-alkoxy, -NR7R3 or -SO2NR7R8 wherein R7 and R3 independently are hydrogen or C1 6-alkyl; and 5 X is completion of an optional bond, -CH2-, -CH2CH2-, -CH=CH-, -O-, -S(O)z- wherein z is 0, 1 or 2, or -N(R9)- wherein R9 is hydrogen or C1 6-alkyl;and Y is -O-, -S(O)q- wherein q is 0, 1 or 2, or -N(R10)- wherein R'~ is hydrogen orCl ~-alkyl; and 10 ris 1, 2, 3 or4; and Z is selected from 11 ~ ~ ~N~ ~N~CH2) A
[~R~
~ R11 ~9~N--C~12--Rl 1 W 096/31474 PCTADK96/OOlSl wherein n is 1 or 2; and R" is -(CH2)mOH or-(CH2)tCOR'2 wherein m is 0, 1, 2, 3, 4, 5 or 6 and t is O
or 1 and wherein R12 is -OH, -NH2, -NHOH or C, 6-alkoxy; and R13 is hydrogen, halogen, trifluoromethyl, hydroxy, C, 6-alkyl or C, 6-alkoxy;
5 and R14 is hydrogen, C, 6-alkyl, C, 6-alkoxy or phenyl optionally substituted with haiogen, trifluoromethyl, hydroxy, C, 6-alkyl or C, 6-alkoxy; and R15 is hydrogen or C, 6-alkyl; and ... is optionally a single bond or a double bond;
or a pharmaceutically acceptable salt thereof.
The compounds of formula I may exist as geometric and optical isomers and all isomers and mixtures thereof are included herein. Isomers may be separ-ated by means of standard methods such as chromatographic techniques or fractional crystallization of suitable salts.
Preferably, the compounds of formula I exist as the individual geometric or optical isomers.
The compounds according to the invention may optionally exist as pharma-ceutically acceptable acid addition salts or - when the carboxylic acid group isnot esterified - as pharmaceutically acceptable metal salts or - optionally alkylated - ammonium salts.
Examples of such salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate or similar pharmaceutically accept-able inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) whlch are hereby incorporated by reference.
CA 022l7l94 l997-lO-Ol W O 96/31~74 PCTADK~6/00151 The term "Cl.6-alkyl" as used herein, alone or in combination, refers to a straight or branched, saturated hydrocarbon chain having 1 to 6 carbon atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-5 methylpentyl, neopentyl, n-hexyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and 1, 2, 2-trimethylpropyl .
The term "C1 6-alkoxy" as used herein, alone or in combination, refers to a straight or branched monovalent substituent comprising a Cl 6-alkyl group linked through an ether oxygen having its free valence bond from the ether 10 oxygen and having 1 to 6 carbon atoms e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy.
The term "halogen" means fluorine, chlorine, bromine or iodine.
Illustrative examples of compounds encompassed by the present invention include:
1 5 1-(2-(10,1 1-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-3-piperidinecarboxamide;
1-(2-(10,1 1-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-4-piperidinecarboxylic acid;
1-(2-(10,1 1-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-2-20 piperidinecarboxylic acid;
(1-(2-(10,1 1-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)piperidin-3-yl)methanol;
4-(4-Chlorophenyl)-1-(2-(10,1 1-Dihydro-5H-dibenzo[a,d]cyciohepten-5-yloxy)-ethyl)-4-piperidinol;
4-(2-(10,11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-4-piperazinecarboxylic acid;
(2S,4R)-1 -(2-(10,11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-4-5 hydroxy-2-pyrrolidinecarboxylic acid;
4-(2-(10,11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-2-morpholine-carboxylic acid;
1 -(2-(10,11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-2-aziridinecarboxylic acid;
2-(2-(10,11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-1,2,3,4-tetrahydro-4-isoquinolinecarboxylic acid;
1 -(2-(10,11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-4-methyl- 1,4-diazepane-6-carboxylic acid;
2-(2-(10,11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-1,2,3,4-15 tetrahydro-3-isoquinolinecarboxylic acid;
1 -(2-(10,11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-3-piperidine-carboxylic acid hydroxamide;
(4-(2-(10,11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)piperazin-1 -yl)acetic acid;
20 or a pharmaceutically acceptable salt thereof.
wo 96/31474 PcT/DKg6/00151 As used herein, the term "patient" includes any mammal which could benefit from treatment of neurogenic pain or inflammation or insulin resistance in NIDDM. The term particularly refers to a human patient, but is not intended to be so limited.
5 It has been demonstrated that the novel compounds of formula I inhibit neurogenic inflammation which involves the release of neuropeptides from peripheral and central endings of sensory C-fibres. Experimentally this can be demonstrated in animal models of formalin induced pain or paw oedema (Wheeler and Cowan, Agents Actions 1991, 34, 264-269) in which the novel 10 compounds of formula I exhibit a potent inhibitory effect. Compounds of formula I may be used to treat all painful, hyperalgesic and/or inflammatory conditic~ns in which C-fibers play a pathophysiological role by eliciting neurogenic pain or inflammation, i.e.:
Acutely painful conditions exemplified by migraine, postoperative pain, burns, 15 bruises, post-herpetic pain (Zoster) and oain as it is generally associated with acute inflammation; chronic, painful and/or inflammatory conditions exemp-lified by various types of neuropathy (diabetic, post-traumatic, toxic), neural-gia, rheumatoid arthritis, spondylitis, gout, inflammatory bowel disease, prostatitis, cancer pain, chronic headache, coughing, asthma, chronic 20 pancreatitis, inflammatory sicin disease including psoriasis and autoimmune dermatoses, osteoporotic pain.
Further, it has been demonstrated that the compounds of general formula I
improves the glucose toierance in diabetic ob/ob mice and that this may result from the reduced release of CGRP from peripheral nervous endings.
25 Hence the compounds of general formula I may be used in the treatment of NIDDM as well as aging-associated obesity. Experimentally this has been demonstrated by the subcutaneous administration of glucose into ob/ob mice with or without previous oral treatment with a compound of general formula 1.
W O96/31474 PCTADK~6/00151 The compounds of formula I may be prepared by the following method:
R~
> (I) \ ~CH2) r W
(Il) (111) A compound of formula ll wherein R', R2, R3, R4, R5, R6, X, Y and r are as defined above and W is a suitable leaving group such as halogen, p-toluene sulphonate or mesylate may be reacted with an azaheterocyclic compound of 5 formula lll wherein Z is as defined above. This alkylation reaction may be carried out in a solvent such as acetone, dibutylether, 2-butanone, methyl ethyl ketone,ethyl acetate, tetrahydrofuran (THF) or toluene in the presence of a base e.g.
sodium hydride and a catalyst, e.g. an alkali metal iodide at a temperature up to reflux temperature for the solvent used for e.g. 1 to 120 h. If esters have been10 prepared in which R12 is alkoxy, compounds of formula I wherein R12 is OH maybe prepared by hydrolysis of the ester group, preferably at room temperature in a mixture of an aqueous alkali metal hydroxide solution and an alcohol such as methanol or ethanol, for example, for about 0.5 to 6 h.
Compounds of formula ll and lll may readily be prepared by methods familiar to 15 those skilled in the art.
Under certain circumstances it may be necessary to protect the intermediates used in the above methods e.g. a compound of formula lll with suitable protecting groups. The carboxylic acid group can, for example, be esterified.
Introduction and removal of such groups is described in "Protective Groups in 20 Organic Chemistry" J.F.W. McOrnie ed. (New York, 1973).
CA 022l7l94 l997-lO-Ol W O96/31'174 PCTADK~6/00151 Pharmacoloqical Methods Release of neurooeDtides from r herir heral and central endinqs of sensorv C-fibers A
Values for in vivo inhibition of formalin induced pain or oedema for the com-5 pounds of the present invention were assessed in mice essentially by the method of Wheeler-Aceto and Cowan (Agents Action 1991, 34, 265-269).
About 20 9 NMRI female mice were injected 20 ~l 1 % formalin into the left hind paw. The animals were then placed on a heated (31~C) table, and the pain response was scored. After 1 h they were killed and bled. Left and right hind 10 paws were removed and the weight difference between the paws was used as indication of the oedema response of the formalin injected paw.
Reduced release of CGRP from r herir heral nervous endings ob/ob female mice, 16 weeks of age, where injected glucose (2g/kg) subcutane-ously. At times hereafter blood glucose was determined in tail venous blood by 15 the gluGose oxidase method. At the end of the study the animals were decapita-ted and trunck blood collected. Immunoreactive CGRP was determined in plasma by radio-immuno-assay. Two groups of animals were used. The one group was vehicle treated, whereas the other group received a compound of formula I via drinkin~ water (100 mg/l) for five days before the test.
20 For the above indications the dosage will vary depending on the compound of formula I employed, on the mode of administration and on the therapy desired.
However, in general, satisfactory results are obtained with a dosage of from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of compounds of formula 1, conveniently given from 1 to 5 times daily, 25 optionally in sustained release form. Usually, dosage forms suitable for oraladministration comprise from about 0.5 mg to about 1000 mg, preferably from CA 022l7l94 l997-lO-Ol W O 96/31471 PCTADK~6/00151 about 1 mg to about 500 mg of the compounds of formula I admixed with a pharmaceutical carrier or diluent.
The compounds of formula I may be administered in a pharmaceutically accept-able acid addition salt form or where possible as a metal or a lower alkylammo-5 nium salt. Such salt forms exhibit approximately the same order of activity asthe free base forms.
This invention also relates to pharmaceutical compositions comprising a com-pound of formula I or a pharmaceutically acceptable salt thereof and, usually, such compositions also contain a pharmaceutical carrier or diluent. The composi-10 tions containing the compounds of this invention may be prepared by conven-tional techniques and appear in conventional forms, for example capsules, tablets, solutions or suspensions.
The pharmaceutical carrier employed may be a conventional solid or liquid carrier. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, 15 agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water.
Similarly, the carrier or diluent may include any time delay material known to the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with awax.
20 If a solid carrier for oral administration is used, the preparation can be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 9. If a liquid carrier is used, the prepara-tion may be in the form of a syrup, emulsion, soft gelatin capsule or sterile 25 injectable liquid such as an aqueous or non-aqueous liquid suspension or solution .
W O9G/31474 PCT~D~6100151 Generally, the compounds of this invention are dispensed in unit dosage form comprising 50-200 mg of active ingredient in or together with a pharmaceuti-cally acceptable carrier per unit dosage.
The dosage of the compounds according to this invention is 1-500 mg/day, e.g.
about 100 mg per dose, when administered to patients, e.g. humans, as a drug.
A typical tablet which may be prepared by conventional tabletting techniques contains Core:
Active compound (as free compound 100 mg or salt thereof) Colloidal silicon dioxide (Areosil$) 1.5 mg Cellulose, microcryst. (Avicel0) 70 mg Modified cellulose gum (Ac-Di-Sol~) 7.5 mg Magnesium stearate 1 5 Coating:
HPMC approx. 9 mg Mywacett~ 9-40 T approx. 0.9 mg Acylated monoglyceride used as plasticizer for film coating.
The route of administration may be any route which effectively transports the 20 active compound to the appropriate or desired site of action, such as oral orparenteral e.g. rectal, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.
EXAMPLES
W O96/31474 PCT~DK~6/00151 The process for preparing compounds of formula I and preparations containing them is further illustrated in the following examples, which, however, are not to be construed as limiting.
Hereinafter, TLC is thin layer chromatography and THF is tetrahydrofuran, CDCI3 5 is deuterio chloroform and DMSO-d5 is hexadeuterio dimethylsulfoxide. The structures of the compounds are confirmed by either elemental analysis or NMR, where peaks assigned to characteristic protons in the title compounds are presented where appropriate. 'H-NMR shifts (~) are given in parts per million (ppm). M.p. is melting point and is given in ~C and is not corrected. Column 10 chromatography was carried out using the technique described by W.C. Still etal, J. Org. Chem. (1978), 43, 2923-2925 on Merck silica gel 60 (Art. 9385).
Compounds used as starting materials are either known compounds or com-pounds which can readily be prepared by methods known ~er se.
1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)-1-ethyl)-4-piperidine-carboxylic acid hydrochloride ~ ,HC
A mixture of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol (10.0 9, 0.047 mol), 2-bromoethanol (8.6 9, 0.069 mol) and concentrated suiphuric acid (1.4 ml) in benzene (120 ml) was stirred for 0.5 h at room temperature. After cooling W O 96/31474 PCTADK~6/00151 (water/ice), crude 5-(2-bromoethoxy-10,11 -dihydro-5H-dibenzo[a,d]cyclohepten was filtered off, washed with petroleum ether and dried. This afforded 10.7 9 (72 %), which was used without purification for further reaction.
M.p. 62 - 70 ~C.
A mixture of 5-(2-bromoethoxy)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (9.5 g, 0.03 mol), ethyl 4-piperidinecarboxylate (4.7 9, 0.03 mol), potassium carbonate (8.1 9, 0.06 mol) and dimethylsulfoxide (120 ml) was stirred on a water bath at 40 - 50~C for 4 h. The mixture was cooled, filtered and the solid was washed with dimethylsulfoxide (10 ml) . The combined filtrates were diluted with water (720 ml) and extracted with diethyl ether (2 x 200 ml). The ether extract was washed with water, dried (MgS04), and the solvent was evaporated under vacuum. The residue was dissolved in 2-propanol, and a hot solution of oxalio acid (4.0 g) in 2-propanol was added. After cooling, crystals of ethyl 1 -(10,11 dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)-1-ethyl-4-piperidinecar-boxylate hydrogen oxalate precipitated. This afforded after filtration and drying 8.3 g (57 ~/0), which was used for further reaction without purification.
The above oxalate suspension (7.3 9, 0.015 mol) in water was made alkaline with a 25 % ammonia solution and extracted with diethyl ether (2 x 100 ml).
The organic layer was washed with water (2 x 50 ml), dried (MgS04 ) and evaporated in vacuum. This afforded 5.7 9 (96 %) of free ethyl ester as an oil.
A mixture of the above ester 2.01 9 (0.005 mol), 2.4 ml 20 % aqueous sodium hydroxide and ethanol (15 ml) was stirred at room temperature for 4 h and overnight. Dichloromethane (250 ml) was added, and under magnetic stirring and cooling (water/ice bath), ~ Z.5 N HCI was carefully added dropwise to pH
25 1. The water layer was separated, and the organic layer was dried (MgS04) and evaporated under vacuum. The solid residue was re-evaporated twice with acetone. This afforded 1.68 9 (83 %) tne title com~ound after crystallisation -from a mixture of ethanol and ether. Dichloromethane, which was present in the crystalline sample was removed under vacuum at elevated temperature.
M.p.192 -1 94~C.
'H NMR (DMSO-d6): 7.42 (bd, 2 H); 7.19 (m, 6 H); 5.62 (s, 1 H); 3.83 (t, 2 H);
1 -(2-(10,11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-4-methyl- 1,4-diazepane-6-carboxylic acid;
2-(2-(10,11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-1,2,3,4-15 tetrahydro-3-isoquinolinecarboxylic acid;
1 -(2-(10,11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-3-piperidine-carboxylic acid hydroxamide;
(4-(2-(10,11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)piperazin-1 -yl)acetic acid;
20 or a pharmaceutically acceptable salt thereof.
wo 96/31474 PcT/DKg6/00151 As used herein, the term "patient" includes any mammal which could benefit from treatment of neurogenic pain or inflammation or insulin resistance in NIDDM. The term particularly refers to a human patient, but is not intended to be so limited.
5 It has been demonstrated that the novel compounds of formula I inhibit neurogenic inflammation which involves the release of neuropeptides from peripheral and central endings of sensory C-fibres. Experimentally this can be demonstrated in animal models of formalin induced pain or paw oedema (Wheeler and Cowan, Agents Actions 1991, 34, 264-269) in which the novel 10 compounds of formula I exhibit a potent inhibitory effect. Compounds of formula I may be used to treat all painful, hyperalgesic and/or inflammatory conditic~ns in which C-fibers play a pathophysiological role by eliciting neurogenic pain or inflammation, i.e.:
Acutely painful conditions exemplified by migraine, postoperative pain, burns, 15 bruises, post-herpetic pain (Zoster) and oain as it is generally associated with acute inflammation; chronic, painful and/or inflammatory conditions exemp-lified by various types of neuropathy (diabetic, post-traumatic, toxic), neural-gia, rheumatoid arthritis, spondylitis, gout, inflammatory bowel disease, prostatitis, cancer pain, chronic headache, coughing, asthma, chronic 20 pancreatitis, inflammatory sicin disease including psoriasis and autoimmune dermatoses, osteoporotic pain.
Further, it has been demonstrated that the compounds of general formula I
improves the glucose toierance in diabetic ob/ob mice and that this may result from the reduced release of CGRP from peripheral nervous endings.
25 Hence the compounds of general formula I may be used in the treatment of NIDDM as well as aging-associated obesity. Experimentally this has been demonstrated by the subcutaneous administration of glucose into ob/ob mice with or without previous oral treatment with a compound of general formula 1.
W O96/31474 PCTADK~6/00151 The compounds of formula I may be prepared by the following method:
R~
> (I) \ ~CH2) r W
(Il) (111) A compound of formula ll wherein R', R2, R3, R4, R5, R6, X, Y and r are as defined above and W is a suitable leaving group such as halogen, p-toluene sulphonate or mesylate may be reacted with an azaheterocyclic compound of 5 formula lll wherein Z is as defined above. This alkylation reaction may be carried out in a solvent such as acetone, dibutylether, 2-butanone, methyl ethyl ketone,ethyl acetate, tetrahydrofuran (THF) or toluene in the presence of a base e.g.
sodium hydride and a catalyst, e.g. an alkali metal iodide at a temperature up to reflux temperature for the solvent used for e.g. 1 to 120 h. If esters have been10 prepared in which R12 is alkoxy, compounds of formula I wherein R12 is OH maybe prepared by hydrolysis of the ester group, preferably at room temperature in a mixture of an aqueous alkali metal hydroxide solution and an alcohol such as methanol or ethanol, for example, for about 0.5 to 6 h.
Compounds of formula ll and lll may readily be prepared by methods familiar to 15 those skilled in the art.
Under certain circumstances it may be necessary to protect the intermediates used in the above methods e.g. a compound of formula lll with suitable protecting groups. The carboxylic acid group can, for example, be esterified.
Introduction and removal of such groups is described in "Protective Groups in 20 Organic Chemistry" J.F.W. McOrnie ed. (New York, 1973).
CA 022l7l94 l997-lO-Ol W O96/31'174 PCTADK~6/00151 Pharmacoloqical Methods Release of neurooeDtides from r herir heral and central endinqs of sensorv C-fibers A
Values for in vivo inhibition of formalin induced pain or oedema for the com-5 pounds of the present invention were assessed in mice essentially by the method of Wheeler-Aceto and Cowan (Agents Action 1991, 34, 265-269).
About 20 9 NMRI female mice were injected 20 ~l 1 % formalin into the left hind paw. The animals were then placed on a heated (31~C) table, and the pain response was scored. After 1 h they were killed and bled. Left and right hind 10 paws were removed and the weight difference between the paws was used as indication of the oedema response of the formalin injected paw.
Reduced release of CGRP from r herir heral nervous endings ob/ob female mice, 16 weeks of age, where injected glucose (2g/kg) subcutane-ously. At times hereafter blood glucose was determined in tail venous blood by 15 the gluGose oxidase method. At the end of the study the animals were decapita-ted and trunck blood collected. Immunoreactive CGRP was determined in plasma by radio-immuno-assay. Two groups of animals were used. The one group was vehicle treated, whereas the other group received a compound of formula I via drinkin~ water (100 mg/l) for five days before the test.
20 For the above indications the dosage will vary depending on the compound of formula I employed, on the mode of administration and on the therapy desired.
However, in general, satisfactory results are obtained with a dosage of from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of compounds of formula 1, conveniently given from 1 to 5 times daily, 25 optionally in sustained release form. Usually, dosage forms suitable for oraladministration comprise from about 0.5 mg to about 1000 mg, preferably from CA 022l7l94 l997-lO-Ol W O 96/31471 PCTADK~6/00151 about 1 mg to about 500 mg of the compounds of formula I admixed with a pharmaceutical carrier or diluent.
The compounds of formula I may be administered in a pharmaceutically accept-able acid addition salt form or where possible as a metal or a lower alkylammo-5 nium salt. Such salt forms exhibit approximately the same order of activity asthe free base forms.
This invention also relates to pharmaceutical compositions comprising a com-pound of formula I or a pharmaceutically acceptable salt thereof and, usually, such compositions also contain a pharmaceutical carrier or diluent. The composi-10 tions containing the compounds of this invention may be prepared by conven-tional techniques and appear in conventional forms, for example capsules, tablets, solutions or suspensions.
The pharmaceutical carrier employed may be a conventional solid or liquid carrier. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, 15 agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water.
Similarly, the carrier or diluent may include any time delay material known to the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with awax.
20 If a solid carrier for oral administration is used, the preparation can be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 9. If a liquid carrier is used, the prepara-tion may be in the form of a syrup, emulsion, soft gelatin capsule or sterile 25 injectable liquid such as an aqueous or non-aqueous liquid suspension or solution .
W O9G/31474 PCT~D~6100151 Generally, the compounds of this invention are dispensed in unit dosage form comprising 50-200 mg of active ingredient in or together with a pharmaceuti-cally acceptable carrier per unit dosage.
The dosage of the compounds according to this invention is 1-500 mg/day, e.g.
about 100 mg per dose, when administered to patients, e.g. humans, as a drug.
A typical tablet which may be prepared by conventional tabletting techniques contains Core:
Active compound (as free compound 100 mg or salt thereof) Colloidal silicon dioxide (Areosil$) 1.5 mg Cellulose, microcryst. (Avicel0) 70 mg Modified cellulose gum (Ac-Di-Sol~) 7.5 mg Magnesium stearate 1 5 Coating:
HPMC approx. 9 mg Mywacett~ 9-40 T approx. 0.9 mg Acylated monoglyceride used as plasticizer for film coating.
The route of administration may be any route which effectively transports the 20 active compound to the appropriate or desired site of action, such as oral orparenteral e.g. rectal, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.
EXAMPLES
W O96/31474 PCT~DK~6/00151 The process for preparing compounds of formula I and preparations containing them is further illustrated in the following examples, which, however, are not to be construed as limiting.
Hereinafter, TLC is thin layer chromatography and THF is tetrahydrofuran, CDCI3 5 is deuterio chloroform and DMSO-d5 is hexadeuterio dimethylsulfoxide. The structures of the compounds are confirmed by either elemental analysis or NMR, where peaks assigned to characteristic protons in the title compounds are presented where appropriate. 'H-NMR shifts (~) are given in parts per million (ppm). M.p. is melting point and is given in ~C and is not corrected. Column 10 chromatography was carried out using the technique described by W.C. Still etal, J. Org. Chem. (1978), 43, 2923-2925 on Merck silica gel 60 (Art. 9385).
Compounds used as starting materials are either known compounds or com-pounds which can readily be prepared by methods known ~er se.
1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)-1-ethyl)-4-piperidine-carboxylic acid hydrochloride ~ ,HC
A mixture of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol (10.0 9, 0.047 mol), 2-bromoethanol (8.6 9, 0.069 mol) and concentrated suiphuric acid (1.4 ml) in benzene (120 ml) was stirred for 0.5 h at room temperature. After cooling W O 96/31474 PCTADK~6/00151 (water/ice), crude 5-(2-bromoethoxy-10,11 -dihydro-5H-dibenzo[a,d]cyclohepten was filtered off, washed with petroleum ether and dried. This afforded 10.7 9 (72 %), which was used without purification for further reaction.
M.p. 62 - 70 ~C.
A mixture of 5-(2-bromoethoxy)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (9.5 g, 0.03 mol), ethyl 4-piperidinecarboxylate (4.7 9, 0.03 mol), potassium carbonate (8.1 9, 0.06 mol) and dimethylsulfoxide (120 ml) was stirred on a water bath at 40 - 50~C for 4 h. The mixture was cooled, filtered and the solid was washed with dimethylsulfoxide (10 ml) . The combined filtrates were diluted with water (720 ml) and extracted with diethyl ether (2 x 200 ml). The ether extract was washed with water, dried (MgS04), and the solvent was evaporated under vacuum. The residue was dissolved in 2-propanol, and a hot solution of oxalio acid (4.0 g) in 2-propanol was added. After cooling, crystals of ethyl 1 -(10,11 dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)-1-ethyl-4-piperidinecar-boxylate hydrogen oxalate precipitated. This afforded after filtration and drying 8.3 g (57 ~/0), which was used for further reaction without purification.
The above oxalate suspension (7.3 9, 0.015 mol) in water was made alkaline with a 25 % ammonia solution and extracted with diethyl ether (2 x 100 ml).
The organic layer was washed with water (2 x 50 ml), dried (MgS04 ) and evaporated in vacuum. This afforded 5.7 9 (96 %) of free ethyl ester as an oil.
A mixture of the above ester 2.01 9 (0.005 mol), 2.4 ml 20 % aqueous sodium hydroxide and ethanol (15 ml) was stirred at room temperature for 4 h and overnight. Dichloromethane (250 ml) was added, and under magnetic stirring and cooling (water/ice bath), ~ Z.5 N HCI was carefully added dropwise to pH
25 1. The water layer was separated, and the organic layer was dried (MgS04) and evaporated under vacuum. The solid residue was re-evaporated twice with acetone. This afforded 1.68 9 (83 %) tne title com~ound after crystallisation -from a mixture of ethanol and ether. Dichloromethane, which was present in the crystalline sample was removed under vacuum at elevated temperature.
M.p.192 -1 94~C.
'H NMR (DMSO-d6): 7.42 (bd, 2 H); 7.19 (m, 6 H); 5.62 (s, 1 H); 3.83 (t, 2 H);
3.28 (t, 1 H); 4.96 (d, 1 H); 2.53 (m, 1 H); 3.37 (m, 6 H); 3.00 (m, 4 H); 1.99 (m, 4H).
Claims (17)
1. A compound of formula I
wherein R1, R2, R3, R4, R5 and R6 independently are hydrogen, halogen, trifluoromethyl, hydroxy, C1-6-alkyl, C1-6-alkoxy, -NR7R8 or -SO2NR7R8 wherein R7 and R8 independently are hydrogen or C1-6-alkyl; and X is completion of an optional bond, -CH2-, -CH2CH2-, -CH=CH-, -O-, -S(O)z- wherein z is 0, 1 or 2, or -N(R9)- wherein R9 is hydrogen or C1-6-alkyl; and Y is -O-, -S(O)q- wherein q is 0, 1 or 2, or -N(R10)- wherein R10 is hydrogen or C1-6-alkyl;
and r is 1, 2, 3 or 4; and Z is selected from wherein n is 1 or 2; and R11 is -(CH2)m OH or -(CH2)t COR12 wherein m is 0, 1, 2, 3, 4, 5 or 6 and t is 0 or 1 and wherein R12 is -OH, -NH2, -NHOH or C1-6-alkoxy; and R13 is hydrogen, halogen, trifluoromethyl, hydroxy, C1-6-alkyl or C1-6-alkoxy; and R14 is hydrogen, C1-6-alkyl, C1-6-alkoxy or phenyl optionally substituted with halogen, trifluoromethyl, hydroxy, C1-6-alkyl or C1-6-alkoxy; and R15 is hydrogen or C1-6-alkyl; and ... is optionally a single bond or a double bond;
or a pharmaceutically acceptable salt thereof, with the proviso that if X is a bond, then Y cannot be -N(R10)-, wherein R10 is hydrogen or C1-6-alkyl.
wherein R1, R2, R3, R4, R5 and R6 independently are hydrogen, halogen, trifluoromethyl, hydroxy, C1-6-alkyl, C1-6-alkoxy, -NR7R8 or -SO2NR7R8 wherein R7 and R8 independently are hydrogen or C1-6-alkyl; and X is completion of an optional bond, -CH2-, -CH2CH2-, -CH=CH-, -O-, -S(O)z- wherein z is 0, 1 or 2, or -N(R9)- wherein R9 is hydrogen or C1-6-alkyl; and Y is -O-, -S(O)q- wherein q is 0, 1 or 2, or -N(R10)- wherein R10 is hydrogen or C1-6-alkyl;
and r is 1, 2, 3 or 4; and Z is selected from wherein n is 1 or 2; and R11 is -(CH2)m OH or -(CH2)t COR12 wherein m is 0, 1, 2, 3, 4, 5 or 6 and t is 0 or 1 and wherein R12 is -OH, -NH2, -NHOH or C1-6-alkoxy; and R13 is hydrogen, halogen, trifluoromethyl, hydroxy, C1-6-alkyl or C1-6-alkoxy; and R14 is hydrogen, C1-6-alkyl, C1-6-alkoxy or phenyl optionally substituted with halogen, trifluoromethyl, hydroxy, C1-6-alkyl or C1-6-alkoxy; and R15 is hydrogen or C1-6-alkyl; and ... is optionally a single bond or a double bond;
or a pharmaceutically acceptable salt thereof, with the proviso that if X is a bond, then Y cannot be -N(R10)-, wherein R10 is hydrogen or C1-6-alkyl.
2. A compound according to claim 1 selected from the following:
1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-3-piperidine-carboxamide;
1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)4-piperidinecarboxylic acid;
1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-2-piperidinecarboxylic acid;
(1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)piperidin-3-yl)methanol;
4-(4-Chlorophenyl)-1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)4-piperidinol;
4-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-4-piperazinecarboxylic acid;
(2S,4R)-1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)4-hydroxy-2-pyrrolidinecarboxylic acid;
4-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-2-morpholinecarboxylic acid;
1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-2-aziridinecarboxylic acid;
2-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-1,2,3,4-tetrahydro-4-isoquinolinecarboxylic acid;
1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)4-methyl-1,4-diazepane-6-carboxylic acid;
2-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid;
1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-3-piperidinecarboxylic acid hydroxamide;
(4-(2-(10,11-Dihydro-5H-dibenzo[a,dlcyclohepten-5-yloxy)ethyl)piperazin-1-yl)acetic acid;
or a pharmaceutically acceptable salt thereof.
1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-3-piperidine-carboxamide;
1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)4-piperidinecarboxylic acid;
1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-2-piperidinecarboxylic acid;
(1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)piperidin-3-yl)methanol;
4-(4-Chlorophenyl)-1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)4-piperidinol;
4-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-4-piperazinecarboxylic acid;
(2S,4R)-1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)4-hydroxy-2-pyrrolidinecarboxylic acid;
4-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-2-morpholinecarboxylic acid;
1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-2-aziridinecarboxylic acid;
2-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-1,2,3,4-tetrahydro-4-isoquinolinecarboxylic acid;
1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)4-methyl-1,4-diazepane-6-carboxylic acid;
2-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid;
1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-3-piperidinecarboxylic acid hydroxamide;
(4-(2-(10,11-Dihydro-5H-dibenzo[a,dlcyclohepten-5-yloxy)ethyl)piperazin-1-yl)acetic acid;
or a pharmaceutically acceptable salt thereof.
3. A method of preparing a compound according to claim 1, CHARACTERIZED in a) reacting a compound of formula II
wherein R1, R2, R3, R4, R5, R6, X, Y and r are as defined above and W is a suitable leaving group such as halogen, p-toluene sulphonate or mesylate, with a compound of formula III
HZ (III) wherein Z is as defined above to form a compound of formula I; or b) hydrolyzing a compound of formula I, wherein R12 is C1-6-alkoxy, to form a compound of formula I wherein R12 is OH.
wherein R1, R2, R3, R4, R5, R6, X, Y and r are as defined above and W is a suitable leaving group such as halogen, p-toluene sulphonate or mesylate, with a compound of formula III
HZ (III) wherein Z is as defined above to form a compound of formula I; or b) hydrolyzing a compound of formula I, wherein R12 is C1-6-alkoxy, to form a compound of formula I wherein R12 is OH.
4. A pharmaceutical composition comprising as active component a compound according to claim 1 or 2 together with a pharmaceutically carrier or diluent.
5. A pharmaceutical composition suitable for treating neurogenic inflammation comprising an effective amount of a compound according to claim 1 or 2 together with a pharmaceutically acceptable carrier or diluent.
6 A pharmaceutical composition suitable for treating diabetic neuropathy comprising an effective amount of a compound according to claim 1 or 2 together with a pharmaceutically acceptable carrier or diluent.
7. A pharmaceutical composition suitable for treating rheumatoid arthritiscomprising an effective amount of a compound according to claim 1 or 2 together with a pharmaceutically acceptable carrier or diluent.
8. A pharmaceutical composition suitable for treating insulin resistance in NIDDM or aging comprising an effective amount of a compound according to claim 1 or 2 together with a pharmaceutically acceptable carrier or diluent.
9. The pharmaceutical composition according to claims 4, 5, 6, 7 or 8 comprising between 0.5 mg and 1000 mg of the compound according to claim 1 or 2 per unit.
dose.
dose.
10. The use of a compound according to claim 1 or 2 wherein in the formula (I) additionally X is a bond when Y is -N(R10)- wherein R10 is hydrogen or C1-6-alkyl; and Z is wherein R11 and R14 are as defined in claim 1 for preparing a medicament for treatment of neurogenic inflammation.
11. The use of a compound according to claim 1 or 2 wherein in the formula (I) additionally X is a bond when Y is -N(R10)-wherein R10 is hydrogen or C1-6-alkyl; and Z is wherein R11 and R14 are as defined in claim 1 for preparing a medicament for treatment of diabetic neuropathy.
12. The use of a compound according to claim 1 or 2 wherein in the formula (I) additionally X is a bond when Y is -N(R10)- wherein R10 is hydrogen or C1-6-alkyl; and Z is wherein R11 and R14 are as defined in claim 1 for preparing a medicament for treatment of rheumatoid arthritis.
13. The use of a compound according to claim 1 or 2 wherein in the formula (I) additionally X is a bond when Y is -N(R10)- wherein R10 is hydrogen or C1-6-alkyl; and Z is wherein R11 and R14 are as defined in claim 1 for preparing a medicament for treatment of insulin resistance in NIDDM or aging.
14. A method of treating neurogenic inflammation in a subject in need of such treatment comprising administering to said subject an effective amount of a compound according to claim 1 or 2 wherein in the formula (I) additionally X is a bond when Y is -N(R10)- wherein R10 is hydrogen or C1-6-alkyl; and Z is wherein R11 and R14 are as defined in claim 1.
15. A method of treating diabetic neuropathy in a subject in need of such treatment comprising administering to said subject an effective amount of a compound according to claim 1 or 2 wherein in the formula (I) additionally X is a bond when Y is -N(R10)- wherein R10 is hydrogen or C1-6-alkyl; and Z is wherein R11 and R14 are as defined in claim 1.
16. A method of treating rheumatoid arthritis in a subject in need of such treatment comprising administering to said subject an effective amount of a compound according to claim 1 or 2 wherein in the formula (I) additionally X is a bond when Y is -N(R10)- wherein R10 is hydrogen or C1-6-alkyl; and Z is wherein R11 and R14 are as defined in claim 1.
17. A method of treating insulin resistance in NIDDM or aging in a subject in need of such treatment comprising administering to said subject an effective amount of a compound according to claim 1 or 2 wherein in the formula (I) additionally X is a bond when Y is -N(R10)- wherein R10 is hydrogen or C1-6-alkyl; and Z is wherein R11 and R14 are as defined in claim 1.
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PT1622569E (en) | 2003-04-24 | 2016-03-03 | Incyte Corp | Aza spiro alkane derivatives as inhibitors of metallproteases |
TW201711999A (en) | 2015-09-03 | 2017-04-01 | 佛瑪治療公司 | [6,6] fused bicyclic HDAC8 inhibitors |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1176173A (en) * | 1966-11-14 | 1970-01-01 | Allen & Hanburys Ltd | Novel Fluorene Compounds |
FI864246A (en) * | 1985-11-08 | 1987-05-09 | Warner Lambert Co | N-SUBSTITUERADE 3-PIPERIDIN- ELLER 3-PYRIDINKARBOXYLSYROR SAMT DERAS DERIVAT. |
AU612437B2 (en) * | 1987-12-14 | 1991-07-11 | Kyowa Hakko Kogyo Co. Ltd. | Tricyclic compounds |
-
1996
- 1996-04-01 JP JP8529880A patent/JPH11503132A/en active Pending
- 1996-04-01 AU AU52716/96A patent/AU5271696A/en not_active Abandoned
- 1996-04-01 EP EP96909088A patent/EP0820442A1/en not_active Ceased
- 1996-04-01 CA CA002217194A patent/CA2217194A1/en not_active Abandoned
- 1996-04-01 WO PCT/DK1996/000151 patent/WO1996031474A1/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
AU5271696A (en) | 1996-10-23 |
EP0820442A1 (en) | 1998-01-28 |
WO1996031474A1 (en) | 1996-10-10 |
JPH11503132A (en) | 1999-03-23 |
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