CA1182818A - N-substituted mercaptoacyl propionamides - Google Patents
N-substituted mercaptoacyl propionamidesInfo
- Publication number
- CA1182818A CA1182818A CA000376389A CA376389A CA1182818A CA 1182818 A CA1182818 A CA 1182818A CA 000376389 A CA000376389 A CA 000376389A CA 376389 A CA376389 A CA 376389A CA 1182818 A CA1182818 A CA 1182818A
- Authority
- CA
- Canada
- Prior art keywords
- accordance
- compound
- methyl
- prepared
- hydrogen
- 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.)
- Expired
Links
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical class CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 74
- -1 1-piperazinyl Chemical group 0.000 claims abstract description 34
- 239000001257 hydrogen Substances 0.000 claims abstract description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 23
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 125000003118 aryl group Chemical group 0.000 claims abstract description 12
- 125000001589 carboacyl group Chemical group 0.000 claims abstract description 8
- 125000005129 aryl carbonyl group Chemical group 0.000 claims abstract description 7
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims abstract description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 19
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract 5
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract 3
- 238000000034 method Methods 0.000 claims description 47
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 239000000908 ammonium hydroxide Substances 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- WNWVKZTYMQWFHE-UHFFFAOYSA-N 4-ethylmorpholine Chemical group [CH2]CN1CCOCC1 WNWVKZTYMQWFHE-UHFFFAOYSA-N 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- BFWVKHNSUSMAGH-UHFFFAOYSA-N n-(2,2-dimethoxyethyl)-4-methyl-2-(sulfanylmethyl)pentanamide Chemical compound COC(OC)CNC(=O)C(CS)CC(C)C BFWVKHNSUSMAGH-UHFFFAOYSA-N 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 10
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 6
- WLBRRPKNFHYPFS-UHFFFAOYSA-N 4-methyl-n-(2-morpholin-4-ylethyl)-2-(sulfanylmethyl)pentanamide Chemical compound CC(C)CC(CS)C(=O)NCCN1CCOCC1 WLBRRPKNFHYPFS-UHFFFAOYSA-N 0.000 claims 1
- LIECSJNNNPCYRH-UHFFFAOYSA-N n-[4-(hydrazinylmethylideneamino)butyl]-4-methyl-2-(sulfanylmethyl)pentanamide Chemical compound CC(C)CC(CS)C(=O)NCCCCNC=NN LIECSJNNNPCYRH-UHFFFAOYSA-N 0.000 claims 1
- XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 claims 1
- AZPSXANBFIUMSS-UHFFFAOYSA-N s-[2-[4-(hydrazinylmethylideneamino)butylcarbamoyl]-4-methylpentyl] ethanethioate Chemical compound CC(=O)SCC(CC(C)C)C(=O)NCCCCN=CNN AZPSXANBFIUMSS-UHFFFAOYSA-N 0.000 claims 1
- 102000029816 Collagenase Human genes 0.000 abstract description 11
- 108060005980 Collagenase Proteins 0.000 abstract description 11
- 229960002424 collagenase Drugs 0.000 abstract description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 239000000243 solution Substances 0.000 description 18
- 239000000047 product Substances 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 102000008186 Collagen Human genes 0.000 description 4
- 108010035532 Collagen Proteins 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 229920001436 collagen Polymers 0.000 description 4
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 4
- FGKJLKRYENPLQH-UHFFFAOYSA-N isocaproic acid Chemical compound CC(C)CCC(O)=O FGKJLKRYENPLQH-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- RYNDYESLUKWOEE-UHFFFAOYSA-N 2-benzylprop-2-enoic acid Chemical compound OC(=O)C(=C)CC1=CC=CC=C1 RYNDYESLUKWOEE-UHFFFAOYSA-N 0.000 description 3
- CJNRGSHEMCMUOE-UHFFFAOYSA-N 2-piperidin-1-ylethanamine Chemical compound NCCN1CCCCC1 CJNRGSHEMCMUOE-UHFFFAOYSA-N 0.000 description 3
- XQIHFGYUMFFCFG-UHFFFAOYSA-N 4-methyl-2-methylidenepentanoic acid Chemical compound CC(C)CC(=C)C(O)=O XQIHFGYUMFFCFG-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000005587 bubbling Effects 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 3
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 3
- OVBFMEVBMNZIBR-UHFFFAOYSA-N -2-Methylpentanoic acid Natural products CCCC(C)C(O)=O OVBFMEVBMNZIBR-UHFFFAOYSA-N 0.000 description 2
- QKWWDTYDYOFRJL-UHFFFAOYSA-N 2,2-dimethoxyethanamine Chemical compound COC(CN)OC QKWWDTYDYOFRJL-UHFFFAOYSA-N 0.000 description 2
- AVFUGXZVSMKHDL-UHFFFAOYSA-N 2-(acetylsulfanylmethyl)-4-methylpentanoic acid Chemical compound CC(C)CC(C(O)=O)CSC(C)=O AVFUGXZVSMKHDL-UHFFFAOYSA-N 0.000 description 2
- JAEJSNFTJMYIEF-UHFFFAOYSA-N 2-benzylpropanedioic acid Chemical compound OC(=O)C(C(O)=O)CC1=CC=CC=C1 JAEJSNFTJMYIEF-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229910014033 C-OH Inorganic materials 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229910014570 C—OH Inorganic materials 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- DUYAAUVXQSMXQP-UHFFFAOYSA-N ethanethioic S-acid Chemical compound CC(S)=O DUYAAUVXQSMXQP-UHFFFAOYSA-N 0.000 description 2
- DLLJVQNYBYOKGS-UHFFFAOYSA-N ethoxyethane;pentane Chemical compound CCCCC.CCOCC DLLJVQNYBYOKGS-UHFFFAOYSA-N 0.000 description 2
- 229960004279 formaldehyde Drugs 0.000 description 2
- 235000019256 formaldehyde Nutrition 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- SNVLJLYUUXKWOJ-UHFFFAOYSA-N methylidenecarbene Chemical compound C=[C] SNVLJLYUUXKWOJ-UHFFFAOYSA-N 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 229940086542 triethylamine Drugs 0.000 description 2
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- YZWKKMVJZFACSU-UHFFFAOYSA-N 1-bromopentane Chemical compound CCCCCBr YZWKKMVJZFACSU-UHFFFAOYSA-N 0.000 description 1
- FTKIARCSSZWRFJ-UHFFFAOYSA-N 2-(2-methylpropyl)propanedioic acid Chemical compound CC(C)CC(C(O)=O)C(O)=O FTKIARCSSZWRFJ-UHFFFAOYSA-N 0.000 description 1
- BCAAXVOKLXDSPD-UHFFFAOYSA-N 2-(acetylsulfanylmethyl)-3-phenylpropanoic acid Chemical compound CC(=O)SCC(C(O)=O)CC1=CC=CC=C1 BCAAXVOKLXDSPD-UHFFFAOYSA-N 0.000 description 1
- VEDWGJFOCZOWGV-UHFFFAOYSA-N 2-[(dimethylamino)methyl]-2-(2-methylpropyl)propanedioic acid Chemical compound CC(C)CC(C(O)=O)(C(O)=O)CN(C)C VEDWGJFOCZOWGV-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- LYIIBVSRGJSHAV-UHFFFAOYSA-N 2-aminoacetaldehyde Chemical compound NCC=O LYIIBVSRGJSHAV-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- NTLKAXQBFYZMAH-UHFFFAOYSA-N 2-methylpentanamide Chemical compound CCCC(C)C(N)=O NTLKAXQBFYZMAH-UHFFFAOYSA-N 0.000 description 1
- PTAYFGHRDOMJGC-UHFFFAOYSA-N 4-aminobutyl(diaminomethylidene)azanium;hydrogen sulfate Chemical compound OS(O)(=O)=O.NCCCCN=C(N)N PTAYFGHRDOMJGC-UHFFFAOYSA-N 0.000 description 1
- ACMPWZQOUILVFB-UHFFFAOYSA-N 4-methylpentanamide Chemical compound CC(C)CCC(N)=O ACMPWZQOUILVFB-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 244000186140 Asperula odorata Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 101100381997 Danio rerio tbc1d32 gene Proteins 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 206010014989 Epidermolysis bullosa Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
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- 206010023203 Joint destruction Diseases 0.000 description 1
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- 239000007832 Na2SO4 Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 206010064996 Ulcerative keratitis Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
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- 239000013543 active substance Substances 0.000 description 1
- 239000011717 all-trans-retinol Substances 0.000 description 1
- 235000019169 all-trans-retinol Nutrition 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
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- 239000012298 atmosphere Substances 0.000 description 1
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
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- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
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- 238000001816 cooling Methods 0.000 description 1
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- 239000013058 crude material Substances 0.000 description 1
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- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- OFRFGNSZCYDFOH-UHFFFAOYSA-N diethyl 2-(2-methylpropyl)propanedioate Chemical compound CCOC(=O)C(CC(C)C)C(=O)OCC OFRFGNSZCYDFOH-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- SMBQBQBNOXIFSF-UHFFFAOYSA-N dilithium Chemical class [Li][Li] SMBQBQBNOXIFSF-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
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- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 108010052322 limitin Proteins 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
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- TWXDDNPPQUTEOV-FVGYRXGTSA-N methamphetamine hydrochloride Chemical compound Cl.CN[C@@H](C)CC1=CC=CC=C1 TWXDDNPPQUTEOV-FVGYRXGTSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 208000028169 periodontal disease Diseases 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940095574 propionic acid Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- QJOPKOMRAWGHPR-UHFFFAOYSA-N s-[2-(2,2-dimethoxyethylcarbamoyl)-4-methylpentyl] ethanethioate Chemical compound COC(OC)CNC(=O)C(CC(C)C)CSC(C)=O QJOPKOMRAWGHPR-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 229910000634 wood's metal Inorganic materials 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
Abstract
Abstract Mammalian collagenase is inhibited by compounds having the formula or a salt thereof, wherein R1 is hydrogen, alkanoyl of 2 to 10 carbon atoms, or arylcarbonyl; 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinyl or 4-alkyl-1-piperazinyl wherein R4 is hydrogen, alkyl or aryl; R3 is alkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, aryl or arylalkyl; and n is an integer of 1 to 20.
Description
QA170/170a/168 N-SUBSTITUI'ED MERCAPTOACYL PROPIONAMIDES
. , _ . _ _ .
Mammalian collagenase is inhibited by compounds having the formula 1 S C~2-~ C-NH-(cH2) -R
In formula I, and throughout the specification, the symbols are as defined below.
Rl is hydrogen, alkanoylo~ 2 to 10 ~rbon atcms (ace~y~ is p~e~erred) or arylcar~ benzoyl is preferred);
NH 1 l4 R2 is ~NH-~ H2, ~ R4, -C-(O-alkyl)2, ~4 ~ - CH2 -C/
~ O - CH2, l-pyrrolidinyl, l-piperidinyl, 4-morpholinyl, l-piperazinyl, or 4-alkyl-1-piperazinyl; wherein R4 is hydrogen, alkyl or aryl;
R3 is alkyl of 3 to 8 carbon atoMs, cycloalkyl of 3 to 7 carbon atoms, aryl or arylalkyl; and n is an integer of 1 to 20.
The term "aryl", as used throughout the specification, either individually or as part of a larger group, re~ers to phenyl or phenyl substituted with one, two or three alkyl, alkoxy, halogen, amino, hydroxy, or alkanoyloxy groups.
Phenyl and monosubstituted phenyl are the preferred aryl groups.
The terms "alkyl" and "alkoxy", as used throughout the speci~ication (unless otherwise defined), either individually or as part of a larger group, refer to groups having 1 to 8 ~arbon atoms.
~.
~ Q~170 /l7oa/l68 qhe term halogen, as used throughout -the specification, either individually or as part of a larger group, refers to fluorine, chlorine, bromi.ne and iodine.
The compounds of this invention can be prepared using as a starting material-a carboxylic acid having the formula .
II
HO-CH2-CH-C-OH.
Heating a carboxylic.acid of formula II with phosphoric acid yields a compound ha~ing the formula III
~3 CH2=C - C- OH, which can in turn be reacted with a thio acid having the formula IV
R -SH, wherein Rl is alkanoyl or arylcarbonyl, to yield a product having the formula ~d. `~ 3 ~ ~3 Q~170/170a/16 , 3 11 Rl-S-CH~-CH-C~OH.
5An acid of formula V, or ester thereoE, can be coupled with a compound having the formula VI
10NH2- (CH2) n~R2 ~
or a salt thereof, to yield the compounds of formula I wherein Rl is other than hydrogen.
The coupling reaction can be effected by first activating the acid of formula V, ~, by formation of a mixed or symmetrical anhydride, acid chloride, or active ester, or by the use of Woodward reagen~ R, EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline) or the like. A
preferred method of activation comprises first treating an acid of formula V with an organic base (e~., tr.iethyl.amine) and then adding ethyl chloroformate.
Those products of formula I wherein Rl is hydrogen can be prepared Erom corresponding compounds of formula I wherein Rl is alkanoyl or arylcarbony:L by treatment of the acylthio compound with concentrated ammonium hydroxide.
Alternatively, the compounds of this .
invention can be prepared using as a starting ~ Q~170/170a/168 material a malonic acicl ester derivative having the formula VII
O R O
1~ l3 ll alkyl-O-C-CH-C-O-alkyl.
Hydrolysis of a mak~nic acid ester derivative of formula VII yields the corresponding compound having the formula VIII
O R O
Il l3 11 HO-C-CH-C-OH.
Sequen-tial reaction of a diacid of formula VIII
with a secondary amine (such as dimethylamine) and formaldehyde yields the corresponding compound having the formula ~0 ~X
O R O
l3 li HO-C~C - C - OH
( 3 2 Con~ersion of a compound of formula IX to the corresponding compound having the formula III
R O
CH2=C~C--OH
~ r~ Q~170/170a/16 can be accomplished by melting the precursor compound. The compounds oE this inven-tion can be prepared from khe compounds of formula III
using the procedures described above.
Those compounds of Eorm~la I wherein R2 .is -C R4 can alternatively be prepared from the corresponding product o~ formula I wherein R2 j4 l4O - CH
is -C-(O-alkyl)~ or -C~ 1 2 O- CH2 by acid hydrolysis.
The compounds of formula I have at least one asymmetric carbon atom; the carbon noted with an asterisk (*) in formula I. The compounds accordingly exist in stereomeric forms or as racemic mixtures thereof. All of these are within the scope of this invention. The above described synthesis can utilize the starting compounds in the form of a racemic mixture or as a stereomer.
In mammals, collagenase is one of the key enzymes involved in the cartila~e and joint destruction of rheumatoid arthritis; see, for example, Arthritis and Rheumatism, ~0 (6):1231 (1977). It is, therefore, desirable to inhibit the action of the collagenase enzyme.
While not limitin~ the scope of this invention to a specific theory or mechanism of operation, it is nevertheless helpful to an understanding of the invention to revlew the possible reasons for the activi~y of the compounds of formula I. The main components of cartilage are the collagen polypeptide molecules. These polypeptides are cleaved by mammalian collagenase at a single site. The compounds of this invention ~ 170/170a~168 resemble the susceptibl~ sequence of the collagen molecules and, it is theorized, bind to the mammalian collagenase enzyme and inhibit its activity.
The mammalian collagenase enzyme contains zinc, which assists in the cleavage o-f a ~lycine-leucine or glycine-isoleucine bond and contains an extended cleft which interacts with an extended portion of the collagen molecule. This molecule in turn contains arginine as the last homolo~ous amino acid in the substrate sequence adjacent to the cleavage site, a sequence showing a high de~ree oE homology among the various types of collagen molecules. The inhibitors of this invention make use of these features of the enzyme and make modifications to enhance binding to the mammalian collagenase molecule~
The action of mammalian collagenase has also been implicated as a causative factor in several other diseases in mammals. These diseases include periodontal disease, corneal ulceration, tumor invasiveness, and epidermolysis bullosa; see, for example, Amerlcan Journal of P~tho~y, _ (2):509 (1978) and The New England Journal of Medicine, 291 (13):652 (1974).
For use in the treatment of rheumatoid arthritis, the compounds of this invention can be administered to a mammal in need thereof either orally or by injection intraarticularly into the affected joint. The daily dosage for a 70 kilogram mammal will be in the range of about 10 milligrams to 1 gram.
The compounds of this invention can be formulated in compositions such as tablets, QA170/170a/168 ~7 capsules or elixirs for oral administration or in sterile solutions or suspensions Eor parenteral administration. About 10 to 500 mg of a compound of formula I can be formulated with a pharma-ceutically acceptable vehicle, carrier, excipient,binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or prepaxations 0 i5 such that a suitable dosage in the ranye indicated is obtained.
Salts of the compounds of ormula I wherein ~ H
R2 is -NH-C-NH2 are also useful in the inhibition of mammalian collagenase and can be~used and formulated followiny the procedures described above. The compounds of formula I wherein R2 NH
is -NH-C-NH2 form acid-addition salts with organic and inorganic acids. These acid-addition salts are not only useful as inhibitors of mammalian collagenase but also frequently provide useful means for isolating the products from reaction mixtures by forming the salt in a medium in which it is insoluble, isolating the salt and then neutralizing the salt. Salts of the compounds NH
of formula I wherein R2 is -NH-C-NH2 can also be formed by utilizing a salt of a compound of formula VI as a reactant.
.a~r~3 QA170/170a/168 Exa~
~-(?,2-Dimethox~ethyl) -?- [(ace~_th:io)met yl~-4-methylpen_anamide .
A) Isocaproic Acid Potassium cyanide (28 y) is partly dissolved in 125 ml of ethanol and 30 ml of water. Amyl bromide (63.6 g) is added and the reaction mixture is digested on the steam cone for 24 hours. The solution is decanted from the potassium bromide on to 35 g of potassium hydroxide. This is digested on the steam cone for 20 hours, diluted with 50 ml of water and concentrated ln vacuo to remove the ethanol. A 1:1 mixture of sulfuric acid and water is added to the reaction mixture and product is extracted with petroleum ether to yield 60.6 g of crude product. Vacuum distillation yields 43.4 g of product boiling at 90-98C/9 mm of Hg.
B) 4-~lethyl-2-(hydroxymethyl)pentanoic acid Diisopropylamine (20.6 g) is dissolved in 80 ml of dry tetrahydrofuran. This solution is cooled to -30 C. n-Butyllithium (77 ml of 2.6M
in hexane) is added dropwise in a nitrogen atmosphere at a rate that maintains the reaction at -30 to -20C, and this solution is stirred at -20 C for 30 minutes. Isocaproic acid (11.6 g) in 10 ml of tetrahydrofuran is added dropwise at -20 to -10C, then stirred at -10C for 30 minutes. In a separate flask, paraformaldehyde (28 g) is heated to about 200C and the vapors ~ J~t~ QA170/170a~16 are carried in a stream of nitrogen over the surface of the tetrahydrofuran solution of the dilithium salt of isocaproic acid. During this procedure the temperature is kept between -10 5 and ~10C. After all oE the paraformaldehyde has vapori~ed the reaction mixture is cooled to 0C and 10~ hydrochloric acid is added dropwise until the reaction mix-ture becomes acidic.
Produc~ is extracted with 2 portions of et'ner (400 ml each). The ether is dried with magnesium sulfate, filtered and concentrated ln vacuo -to yield 13.2 g of crude material. Product is vacuum distilled to yield 9.0 g, boiling point 135-142 C/9 mm of Hg.
C) 4-Methyl-2-methylenepentanoic acid 4-Methyl-2-(hydroxymethyl)pentanoic acid (8.7 g) is heated with 10 drops of 85~ phosphoric acid in a Wood's metal bath at 220C for 20 minutes. A distillation head is attached and the pressure is slowly decreased to 60 mm while the temperature is increased to 270C.
Product starts to distill and the pressure is further decreased to 10 mm. The vapor temperature varies between 180 and 190C. The yield of the title compound as distillate is 7.0 g.
D~ 2-~Acetylthio)methyl~-4-methylpentanoic acid 4-Methyl-2-methylenepentanoic acid (6-.8 ~) is stirred with 5 ml of thiolacetic acid under argon for 5 days, concentrated ln vacuo and a portion is distilled. The product boils at 117-120 C at 9 mm of Hg.
~ .&3 QA170/170a/168 E) N-(2,2-Dimethoxyethyl)-2-[(acetylthio)methyl]-4-methylpentanamide A solution of 2~[(acetylthio~methyl~4~
methylpentanoic acid (2.0 g) and triethyl amine ~1.0 g) in 50 ml of -tetr~hydrof~ran (THF) is cooled to -5C. Ethyl chloroformate (1.1 g) in 5 ml of THF is added dropwise and the reaction mixture is stirred at -5C for 30 minutes.
Amino acetaldehyde dimethyl acetal (1.1 g) in 20 ml of THF is added dropwise to the mixed anhydride solution at -5C. After addition, it is stirred at 10-20C for 2 hours and stored at 0C for about 16 hours. Triethylamine hydrochloride is filtered off and the filtrate is concentrated in vacuo. The residue (2.1 g) is dissolved in 3 ml of ether. Silica gel (5 g) is added and ether is evaporated off. I'his is placed on top of 40 g of dry silica gel and washed through with pentane, l:l pentane:ether and finally ether. Product elutes with ether to yield 1.3 g of product which solidifies to give a low melting waxy solid.
Anal- calc'd for C13H25N4S--l5H2 H, 8.67; N/ 4.76; S, 10.90 Found: C, S3.09; H, 8.73; N, 4.67; S, 10.89 Q~170/170a/1~8 f"3 Exam~le 2 N-t2,2-Dimethoxye h~1)~2-(mercaptometh methylpentanamide The N-(2,2-dimethoxyethyl)-2-[(ace-tylthio)-methyl]~4-methylpentanamide obtained in Example 1 is dissolve~ in 15 ml of absolute ethanol and the atmosphere is purged with axgon. Concentrated ammonium hydroxide (2 ml) is added and this solution is stirred at room temperature for 3 hours, concentrated to dryness ln vacuo and dried at 50 C for 8 hours over phosphorous pentoxide.
The title compound (0.8 g) crystallizes, melting point 34-37C.
~nal. calc'd for CllH23N3S 25~l2 H, 9.33; N, 5.51; S, 12.63 Found: C, 52.09; H, 9.05; N, 5.64; S, 12.40 Example 3 N-[2-(Merca~_omethyl)-4-methyIpentanoyl]amino acetaldehyde The N-(2,2-dimethoxyethyl)-2-(mercaptomethyl)-4 methylpentanamide obtalned in Example 2 is - dissolved in 10 ml of water and treated with a few drops of 10% hydrochloric acid. After standlng for 1 hour at 25C, the water is removed ln vacuo and the product is obtained as a powder by triturating with acetonitrile~
Examples 4-7 Following the procedures of Example 1 and
. , _ . _ _ .
Mammalian collagenase is inhibited by compounds having the formula 1 S C~2-~ C-NH-(cH2) -R
In formula I, and throughout the specification, the symbols are as defined below.
Rl is hydrogen, alkanoylo~ 2 to 10 ~rbon atcms (ace~y~ is p~e~erred) or arylcar~ benzoyl is preferred);
NH 1 l4 R2 is ~NH-~ H2, ~ R4, -C-(O-alkyl)2, ~4 ~ - CH2 -C/
~ O - CH2, l-pyrrolidinyl, l-piperidinyl, 4-morpholinyl, l-piperazinyl, or 4-alkyl-1-piperazinyl; wherein R4 is hydrogen, alkyl or aryl;
R3 is alkyl of 3 to 8 carbon atoMs, cycloalkyl of 3 to 7 carbon atoms, aryl or arylalkyl; and n is an integer of 1 to 20.
The term "aryl", as used throughout the specification, either individually or as part of a larger group, re~ers to phenyl or phenyl substituted with one, two or three alkyl, alkoxy, halogen, amino, hydroxy, or alkanoyloxy groups.
Phenyl and monosubstituted phenyl are the preferred aryl groups.
The terms "alkyl" and "alkoxy", as used throughout the speci~ication (unless otherwise defined), either individually or as part of a larger group, refer to groups having 1 to 8 ~arbon atoms.
~.
~ Q~170 /l7oa/l68 qhe term halogen, as used throughout -the specification, either individually or as part of a larger group, refers to fluorine, chlorine, bromi.ne and iodine.
The compounds of this invention can be prepared using as a starting material-a carboxylic acid having the formula .
II
HO-CH2-CH-C-OH.
Heating a carboxylic.acid of formula II with phosphoric acid yields a compound ha~ing the formula III
~3 CH2=C - C- OH, which can in turn be reacted with a thio acid having the formula IV
R -SH, wherein Rl is alkanoyl or arylcarbonyl, to yield a product having the formula ~d. `~ 3 ~ ~3 Q~170/170a/16 , 3 11 Rl-S-CH~-CH-C~OH.
5An acid of formula V, or ester thereoE, can be coupled with a compound having the formula VI
10NH2- (CH2) n~R2 ~
or a salt thereof, to yield the compounds of formula I wherein Rl is other than hydrogen.
The coupling reaction can be effected by first activating the acid of formula V, ~, by formation of a mixed or symmetrical anhydride, acid chloride, or active ester, or by the use of Woodward reagen~ R, EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline) or the like. A
preferred method of activation comprises first treating an acid of formula V with an organic base (e~., tr.iethyl.amine) and then adding ethyl chloroformate.
Those products of formula I wherein Rl is hydrogen can be prepared Erom corresponding compounds of formula I wherein Rl is alkanoyl or arylcarbony:L by treatment of the acylthio compound with concentrated ammonium hydroxide.
Alternatively, the compounds of this .
invention can be prepared using as a starting ~ Q~170/170a/168 material a malonic acicl ester derivative having the formula VII
O R O
1~ l3 ll alkyl-O-C-CH-C-O-alkyl.
Hydrolysis of a mak~nic acid ester derivative of formula VII yields the corresponding compound having the formula VIII
O R O
Il l3 11 HO-C-CH-C-OH.
Sequen-tial reaction of a diacid of formula VIII
with a secondary amine (such as dimethylamine) and formaldehyde yields the corresponding compound having the formula ~0 ~X
O R O
l3 li HO-C~C - C - OH
( 3 2 Con~ersion of a compound of formula IX to the corresponding compound having the formula III
R O
CH2=C~C--OH
~ r~ Q~170/170a/16 can be accomplished by melting the precursor compound. The compounds oE this inven-tion can be prepared from khe compounds of formula III
using the procedures described above.
Those compounds of Eorm~la I wherein R2 .is -C R4 can alternatively be prepared from the corresponding product o~ formula I wherein R2 j4 l4O - CH
is -C-(O-alkyl)~ or -C~ 1 2 O- CH2 by acid hydrolysis.
The compounds of formula I have at least one asymmetric carbon atom; the carbon noted with an asterisk (*) in formula I. The compounds accordingly exist in stereomeric forms or as racemic mixtures thereof. All of these are within the scope of this invention. The above described synthesis can utilize the starting compounds in the form of a racemic mixture or as a stereomer.
In mammals, collagenase is one of the key enzymes involved in the cartila~e and joint destruction of rheumatoid arthritis; see, for example, Arthritis and Rheumatism, ~0 (6):1231 (1977). It is, therefore, desirable to inhibit the action of the collagenase enzyme.
While not limitin~ the scope of this invention to a specific theory or mechanism of operation, it is nevertheless helpful to an understanding of the invention to revlew the possible reasons for the activi~y of the compounds of formula I. The main components of cartilage are the collagen polypeptide molecules. These polypeptides are cleaved by mammalian collagenase at a single site. The compounds of this invention ~ 170/170a~168 resemble the susceptibl~ sequence of the collagen molecules and, it is theorized, bind to the mammalian collagenase enzyme and inhibit its activity.
The mammalian collagenase enzyme contains zinc, which assists in the cleavage o-f a ~lycine-leucine or glycine-isoleucine bond and contains an extended cleft which interacts with an extended portion of the collagen molecule. This molecule in turn contains arginine as the last homolo~ous amino acid in the substrate sequence adjacent to the cleavage site, a sequence showing a high de~ree oE homology among the various types of collagen molecules. The inhibitors of this invention make use of these features of the enzyme and make modifications to enhance binding to the mammalian collagenase molecule~
The action of mammalian collagenase has also been implicated as a causative factor in several other diseases in mammals. These diseases include periodontal disease, corneal ulceration, tumor invasiveness, and epidermolysis bullosa; see, for example, Amerlcan Journal of P~tho~y, _ (2):509 (1978) and The New England Journal of Medicine, 291 (13):652 (1974).
For use in the treatment of rheumatoid arthritis, the compounds of this invention can be administered to a mammal in need thereof either orally or by injection intraarticularly into the affected joint. The daily dosage for a 70 kilogram mammal will be in the range of about 10 milligrams to 1 gram.
The compounds of this invention can be formulated in compositions such as tablets, QA170/170a/168 ~7 capsules or elixirs for oral administration or in sterile solutions or suspensions Eor parenteral administration. About 10 to 500 mg of a compound of formula I can be formulated with a pharma-ceutically acceptable vehicle, carrier, excipient,binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or prepaxations 0 i5 such that a suitable dosage in the ranye indicated is obtained.
Salts of the compounds of ormula I wherein ~ H
R2 is -NH-C-NH2 are also useful in the inhibition of mammalian collagenase and can be~used and formulated followiny the procedures described above. The compounds of formula I wherein R2 NH
is -NH-C-NH2 form acid-addition salts with organic and inorganic acids. These acid-addition salts are not only useful as inhibitors of mammalian collagenase but also frequently provide useful means for isolating the products from reaction mixtures by forming the salt in a medium in which it is insoluble, isolating the salt and then neutralizing the salt. Salts of the compounds NH
of formula I wherein R2 is -NH-C-NH2 can also be formed by utilizing a salt of a compound of formula VI as a reactant.
.a~r~3 QA170/170a/168 Exa~
~-(?,2-Dimethox~ethyl) -?- [(ace~_th:io)met yl~-4-methylpen_anamide .
A) Isocaproic Acid Potassium cyanide (28 y) is partly dissolved in 125 ml of ethanol and 30 ml of water. Amyl bromide (63.6 g) is added and the reaction mixture is digested on the steam cone for 24 hours. The solution is decanted from the potassium bromide on to 35 g of potassium hydroxide. This is digested on the steam cone for 20 hours, diluted with 50 ml of water and concentrated ln vacuo to remove the ethanol. A 1:1 mixture of sulfuric acid and water is added to the reaction mixture and product is extracted with petroleum ether to yield 60.6 g of crude product. Vacuum distillation yields 43.4 g of product boiling at 90-98C/9 mm of Hg.
B) 4-~lethyl-2-(hydroxymethyl)pentanoic acid Diisopropylamine (20.6 g) is dissolved in 80 ml of dry tetrahydrofuran. This solution is cooled to -30 C. n-Butyllithium (77 ml of 2.6M
in hexane) is added dropwise in a nitrogen atmosphere at a rate that maintains the reaction at -30 to -20C, and this solution is stirred at -20 C for 30 minutes. Isocaproic acid (11.6 g) in 10 ml of tetrahydrofuran is added dropwise at -20 to -10C, then stirred at -10C for 30 minutes. In a separate flask, paraformaldehyde (28 g) is heated to about 200C and the vapors ~ J~t~ QA170/170a~16 are carried in a stream of nitrogen over the surface of the tetrahydrofuran solution of the dilithium salt of isocaproic acid. During this procedure the temperature is kept between -10 5 and ~10C. After all oE the paraformaldehyde has vapori~ed the reaction mixture is cooled to 0C and 10~ hydrochloric acid is added dropwise until the reaction mix-ture becomes acidic.
Produc~ is extracted with 2 portions of et'ner (400 ml each). The ether is dried with magnesium sulfate, filtered and concentrated ln vacuo -to yield 13.2 g of crude material. Product is vacuum distilled to yield 9.0 g, boiling point 135-142 C/9 mm of Hg.
C) 4-Methyl-2-methylenepentanoic acid 4-Methyl-2-(hydroxymethyl)pentanoic acid (8.7 g) is heated with 10 drops of 85~ phosphoric acid in a Wood's metal bath at 220C for 20 minutes. A distillation head is attached and the pressure is slowly decreased to 60 mm while the temperature is increased to 270C.
Product starts to distill and the pressure is further decreased to 10 mm. The vapor temperature varies between 180 and 190C. The yield of the title compound as distillate is 7.0 g.
D~ 2-~Acetylthio)methyl~-4-methylpentanoic acid 4-Methyl-2-methylenepentanoic acid (6-.8 ~) is stirred with 5 ml of thiolacetic acid under argon for 5 days, concentrated ln vacuo and a portion is distilled. The product boils at 117-120 C at 9 mm of Hg.
~ .&3 QA170/170a/168 E) N-(2,2-Dimethoxyethyl)-2-[(acetylthio)methyl]-4-methylpentanamide A solution of 2~[(acetylthio~methyl~4~
methylpentanoic acid (2.0 g) and triethyl amine ~1.0 g) in 50 ml of -tetr~hydrof~ran (THF) is cooled to -5C. Ethyl chloroformate (1.1 g) in 5 ml of THF is added dropwise and the reaction mixture is stirred at -5C for 30 minutes.
Amino acetaldehyde dimethyl acetal (1.1 g) in 20 ml of THF is added dropwise to the mixed anhydride solution at -5C. After addition, it is stirred at 10-20C for 2 hours and stored at 0C for about 16 hours. Triethylamine hydrochloride is filtered off and the filtrate is concentrated in vacuo. The residue (2.1 g) is dissolved in 3 ml of ether. Silica gel (5 g) is added and ether is evaporated off. I'his is placed on top of 40 g of dry silica gel and washed through with pentane, l:l pentane:ether and finally ether. Product elutes with ether to yield 1.3 g of product which solidifies to give a low melting waxy solid.
Anal- calc'd for C13H25N4S--l5H2 H, 8.67; N/ 4.76; S, 10.90 Found: C, S3.09; H, 8.73; N, 4.67; S, 10.89 Q~170/170a/1~8 f"3 Exam~le 2 N-t2,2-Dimethoxye h~1)~2-(mercaptometh methylpentanamide The N-(2,2-dimethoxyethyl)-2-[(ace-tylthio)-methyl]~4-methylpentanamide obtained in Example 1 is dissolve~ in 15 ml of absolute ethanol and the atmosphere is purged with axgon. Concentrated ammonium hydroxide (2 ml) is added and this solution is stirred at room temperature for 3 hours, concentrated to dryness ln vacuo and dried at 50 C for 8 hours over phosphorous pentoxide.
The title compound (0.8 g) crystallizes, melting point 34-37C.
~nal. calc'd for CllH23N3S 25~l2 H, 9.33; N, 5.51; S, 12.63 Found: C, 52.09; H, 9.05; N, 5.64; S, 12.40 Example 3 N-[2-(Merca~_omethyl)-4-methyIpentanoyl]amino acetaldehyde The N-(2,2-dimethoxyethyl)-2-(mercaptomethyl)-4 methylpentanamide obtalned in Example 2 is - dissolved in 10 ml of water and treated with a few drops of 10% hydrochloric acid. After standlng for 1 hour at 25C, the water is removed ln vacuo and the product is obtained as a powder by triturating with acetonitrile~
Examples 4-7 Following the procedures of Example 1 and
2 (sequentially), but substituting the compound listed in column I for amino acetaldehyde dimethyl acetal, yields the compound listed in column II, and on hydrolysis as in Example 3, the compound listed in column III.
d ~ Q~170/170a/168 U --U O = U
o = u o - ~ u u N N N N
~ y ~U y Y
H N ~ t :~ N 3:: N ~
~ ~ --Y U--u Il O _ O ~ O _ y UO U'~ U U--U--y U--U--y U--U--y X X ~ N N
U U U U
N N
:~ ~ N t`l t~ U--U ~ ~
U---U
:C~ l I
U N O
~ ~ U \U~
H UU ` ~ U U
N ~ N :~
~ O_U 3~ O=t.) ~ O=U ~ O--U
-- N ¦ `' ~ I -- N I `' ~N I
U U--y U--U--U U--U--y U U uN t~
~N ~N ~1 ~N
N U--U U_U
U
ol U U~~y y ~U
N ~N N ~
U~ U y U
~N ~N N t'~l ?~ Q~170/170a/1~8 ~-13-2 [(~cetyl~thlo) hyl] 4-me-th~l-N-[4-[(amino-iminomethyl)amino]butyl~E~anamide~ acetate (1:1) ~) 2-[(Acetylthio)methyl~-4-methylpentanoic acid, ~-nitrophenyl ester 2-[(Acetylthlo~methyl]-4-methylpentanoic acid (5.1 g, see Example lD) in 100 ml of ethyl acetate is cooled to 5C and treated with ~-nitrophenol (3.5 g) followed by 5.1 g of dicyclohexylcarbodiimide, in portions.
After stirring for four hours at 5C, the dicyclohexylurea is filtered and the ethyl acetate is removed in vacuo. The resulting .
solid is washed with hexane to give the title compound, 8.0 g, as an oil.
B) 4-[(Aminoiminomethyl)amlno~butylamine, acetate (1:1) A solution of agmatine sulfate (1.4 g) and sodium acetate (1.0 g) in 10 ml of water is cone~entrated in vacuo and the residue is slurried with hot absolute ethanol and filtered.
The filtrate is evaporated and washed with ethyl acetate to give 1.5 g of the title compound, melting point 132-136C.
~ 3~ `3 ~A170/170a/16R
C) 2-¦(Ace~yltlllo)m ~ -meth~ o-imlnomethxl)amino]butyl]pentanamide, acetate (1-1?
The ~-nitrophenyl ester of 2-[(acetylthio)-methyl]-4-methylpentanoic acid (3.S g) is dissolved in 75 ml of dimethylformamide, cooled to 5C, and treated with a solution of the monoacetate salt of 4-l(aminoiminomethyl)amino~butylamine (1.6 g) ln 10 ml oE water. The mixture is stirred, for about 16 hours at 25C, evaporated ln vacuo leaving an aqueous solution and extracted thorou~hly with ethyl acetate. The aqueous layer is lyophilized to a solid, which is washed with acetonitrile and dried in vacuo to give 2.8 g of the title compound.
Exam~le 9 2-(Mercaptomethyl)-4-methyl-N-[4-~[(aminoiminomethy-l) amino]butyl]pentanamide, acetate (1:1) 2-[(Acetylthio)methyl~-4-methyl-N-[4-[(amino-iminomethyl)amino]butyl]pentanamide, acetate (1:1) 11 g) is dissolved in 30 ml of water, cooled in ice, and purged with argon. Concentrated ammonium hydroxide (4 ml) is added, and the mixture is allowed to warm to 25C over 2 hours.
The solution is lyophilized, and the resulting solid is triturated with acetonitrile. Drying in vacuo at 40 C gives 0.8 g of the -title compound.
~ 3 QA170/170a/168 -15~
~ _0 and 11 Following the p.rocedures of Examples 8 and 9 (sequentially), but substituting the compound listed in column I for the.monoacetate salt of s 4-[~aminoiminomethyl)amino~butylamine, yields the acetate salt o the compound listed in column II.
Column I CD1~nrl II
Cfl(Cfl3)Z
NH ~Cf~2101 NH
10. H2N_CH2_CH2_NH C_NH2 HS~CH ~CH~C~NH~CH ~CH -NH~ ~NH
CH(Cff3)2 NH C~H2l0l NH
2 2 7 2 HS CH~_CH_C_NH_(CH2)7_NH_C_NH2 Exam~ 12 (+)-2-[(Acetylthio)meth ~ l-N-~2-~4-morpholinyl)ethyl]pentanamide 2-[(Acetylthio)methyl]-4-methyl pentanoic acid can be prepared as described in Example 1 or as follows:
d ~ Q~170/170a/168 U --U O = U
o = u o - ~ u u N N N N
~ y ~U y Y
H N ~ t :~ N 3:: N ~
~ ~ --Y U--u Il O _ O ~ O _ y UO U'~ U U--U--y U--U--y U--U--y X X ~ N N
U U U U
N N
:~ ~ N t`l t~ U--U ~ ~
U---U
:C~ l I
U N O
~ ~ U \U~
H UU ` ~ U U
N ~ N :~
~ O_U 3~ O=t.) ~ O=U ~ O--U
-- N ¦ `' ~ I -- N I `' ~N I
U U--y U--U--U U--U--y U U uN t~
~N ~N ~1 ~N
N U--U U_U
U
ol U U~~y y ~U
N ~N N ~
U~ U y U
~N ~N N t'~l ?~ Q~170/170a/1~8 ~-13-2 [(~cetyl~thlo) hyl] 4-me-th~l-N-[4-[(amino-iminomethyl)amino]butyl~E~anamide~ acetate (1:1) ~) 2-[(Acetylthio)methyl~-4-methylpentanoic acid, ~-nitrophenyl ester 2-[(Acetylthlo~methyl]-4-methylpentanoic acid (5.1 g, see Example lD) in 100 ml of ethyl acetate is cooled to 5C and treated with ~-nitrophenol (3.5 g) followed by 5.1 g of dicyclohexylcarbodiimide, in portions.
After stirring for four hours at 5C, the dicyclohexylurea is filtered and the ethyl acetate is removed in vacuo. The resulting .
solid is washed with hexane to give the title compound, 8.0 g, as an oil.
B) 4-[(Aminoiminomethyl)amlno~butylamine, acetate (1:1) A solution of agmatine sulfate (1.4 g) and sodium acetate (1.0 g) in 10 ml of water is cone~entrated in vacuo and the residue is slurried with hot absolute ethanol and filtered.
The filtrate is evaporated and washed with ethyl acetate to give 1.5 g of the title compound, melting point 132-136C.
~ 3~ `3 ~A170/170a/16R
C) 2-¦(Ace~yltlllo)m ~ -meth~ o-imlnomethxl)amino]butyl]pentanamide, acetate (1-1?
The ~-nitrophenyl ester of 2-[(acetylthio)-methyl]-4-methylpentanoic acid (3.S g) is dissolved in 75 ml of dimethylformamide, cooled to 5C, and treated with a solution of the monoacetate salt of 4-l(aminoiminomethyl)amino~butylamine (1.6 g) ln 10 ml oE water. The mixture is stirred, for about 16 hours at 25C, evaporated ln vacuo leaving an aqueous solution and extracted thorou~hly with ethyl acetate. The aqueous layer is lyophilized to a solid, which is washed with acetonitrile and dried in vacuo to give 2.8 g of the title compound.
Exam~le 9 2-(Mercaptomethyl)-4-methyl-N-[4-~[(aminoiminomethy-l) amino]butyl]pentanamide, acetate (1:1) 2-[(Acetylthio)methyl~-4-methyl-N-[4-[(amino-iminomethyl)amino]butyl]pentanamide, acetate (1:1) 11 g) is dissolved in 30 ml of water, cooled in ice, and purged with argon. Concentrated ammonium hydroxide (4 ml) is added, and the mixture is allowed to warm to 25C over 2 hours.
The solution is lyophilized, and the resulting solid is triturated with acetonitrile. Drying in vacuo at 40 C gives 0.8 g of the -title compound.
~ 3 QA170/170a/168 -15~
~ _0 and 11 Following the p.rocedures of Examples 8 and 9 (sequentially), but substituting the compound listed in column I for the.monoacetate salt of s 4-[~aminoiminomethyl)amino~butylamine, yields the acetate salt o the compound listed in column II.
Column I CD1~nrl II
Cfl(Cfl3)Z
NH ~Cf~2101 NH
10. H2N_CH2_CH2_NH C_NH2 HS~CH ~CH~C~NH~CH ~CH -NH~ ~NH
CH(Cff3)2 NH C~H2l0l NH
2 2 7 2 HS CH~_CH_C_NH_(CH2)7_NH_C_NH2 Exam~ 12 (+)-2-[(Acetylthio)meth ~ l-N-~2-~4-morpholinyl)ethyl]pentanamide 2-[(Acetylthio)methyl]-4-methyl pentanoic acid can be prepared as described in Example 1 or as follows:
3 QAl/0/170a/16 i) 3~_~tanoic acid . .
A solution of 91ol g of 2-(ethyl-oxycarbonyl)-4-methylpentanoic acid, ethyl ester in 300 ml of methanol is treated for 6 hours at 80C with 400 ml of 1096 sodium hydroxide. The solution is concentrated in vacuo to 400 ml and acidified with 10%
.
hydrochloric acid. The product is extracted with ethyl acetate to yield 67.6 g of the title compound, which crystallizes on standing.
Recrystallization Erom ethyl acetate-hexane yields the title compound, melting point 102 - 105C.
ii) 2-Carboxy-4-methyl-2~[~di~e~ n~
me~yl]pentanolc acid 2-Carboxy-4-methylpentanoic acid (67g) is suspended in 400 ml of water and coole~
to 5C~ Aqueous 40% dimethylamine (50 g) is added 2~ to the suspension followed by aqueous 37% formal-dehyde (3S.7 g). The resulting solution is stirred for about 16 hours and solid product is filtered and dried ln vacuo to yield 57.3 g of the title compound, melting point 134 - 137C
with carbon dioxide and dimethylamine given off~
iii) _-Methyl-2-methylenepentanolc acid 2 Carboxy-4-methyl-2-[(dimethylamino)-methyl]pentanoic acid (57.3 g) is suspended melted at 140 - 145C in an oil bath, and held at this temperature until bubbling ceases. The melt 170/170a/168 i5 cooled, taken up in water and acidified with 10~ hydrochloric acid. ~xtraction with hexane, drying and evaporation yields 30.5 g of the title compound.
B) 2-~(Acetylthio)methyl]-4-met-x~entanoic acid
A solution of 91ol g of 2-(ethyl-oxycarbonyl)-4-methylpentanoic acid, ethyl ester in 300 ml of methanol is treated for 6 hours at 80C with 400 ml of 1096 sodium hydroxide. The solution is concentrated in vacuo to 400 ml and acidified with 10%
.
hydrochloric acid. The product is extracted with ethyl acetate to yield 67.6 g of the title compound, which crystallizes on standing.
Recrystallization Erom ethyl acetate-hexane yields the title compound, melting point 102 - 105C.
ii) 2-Carboxy-4-methyl-2~[~di~e~ n~
me~yl]pentanolc acid 2-Carboxy-4-methylpentanoic acid (67g) is suspended in 400 ml of water and coole~
to 5C~ Aqueous 40% dimethylamine (50 g) is added 2~ to the suspension followed by aqueous 37% formal-dehyde (3S.7 g). The resulting solution is stirred for about 16 hours and solid product is filtered and dried ln vacuo to yield 57.3 g of the title compound, melting point 134 - 137C
with carbon dioxide and dimethylamine given off~
iii) _-Methyl-2-methylenepentanolc acid 2 Carboxy-4-methyl-2-[(dimethylamino)-methyl]pentanoic acid (57.3 g) is suspended melted at 140 - 145C in an oil bath, and held at this temperature until bubbling ceases. The melt 170/170a/168 i5 cooled, taken up in water and acidified with 10~ hydrochloric acid. ~xtraction with hexane, drying and evaporation yields 30.5 g of the title compound.
B) 2-~(Acetylthio)methyl]-4-met-x~entanoic acid
4-Methyl-2-methylenepentanoic acid (~.8 g) is stirred with 5 ml of thiolacetic acid for about 16 hours. The reaction mixture i5 concentrated ln vacuo until crystallization occurs, yielding 3.6 g of the title compound, melting point 42 - 47C.
C) (-)-2-[(Acetylthio)methyl]-4-methyl-N~
[2-(4-morpholinyl)e-thyl]pentanamide 2-[(~cetylthio)methyl]-4-metllylpentanoic acid (2.0 g) is dissolved in 40 ml of tetrahydro-furan (THF) and 1.0 g of triQthylamine. This solution is cooled to -5C and ethyl chloroformate in 5 ml of THF is added dropwise. The reaction mixture is .qtirred at -5C for 20 minutes and then N-(2-aminoethyl)morpholine [1.3 g] in 20 ml of THF is added dropwise. lt is stirred at 20C
for 4 hours and stored at 0C for about 16 hours.
Triethylamine hydrochloride is filtered off and the filtrate is concentrated _n vacuo. This residue is 'a.~3 QA170/170a/168 dissolved in e~her and washed once with aqueous Na~CO3 and twice with water. The ether is dried with MySO4 t filtered and concentrated in vacuo to yield 1.6 g of material. This is S purified by dissolving 0.6 g in 2 ml of ether and placing it on top of a pad of alumina (activity II 10 g). The column is washed through with 250 ml of ether which is concentrated ln vacuo. Product crystallizes and is washed with 1:5 ether-pentane. The remainder of the crude is seeded with a small crystal and ~len washed with 1:5 ether-pentane. Total yield is 1.0 g of the title compound, melting point 54-59C.
15H28N2O3S: C, 56.93; H, 8.92; N, 8 85 S, 10.13 Found: C, 56.76, H, 8.91; N, 9.10; S, 10.01 Example 13, (~)-2-[(Acetylthio)methyl~-4-meth~l-N-~2 (1-piperidinyl_e_ yl~pentanamide A solution of (~)-2~~(acetylthio)me ~yl]-4-methylpentanoic acid in 40 ml of THF is cooled to 5 C, followed by the dropwise addition of triethylamine (1.0 g) in 5 ml of THF. This solution i~ cooled to -5C and ethyl chloro-formate in 4 ml of THF is added dropwise at
C) (-)-2-[(Acetylthio)methyl]-4-methyl-N~
[2-(4-morpholinyl)e-thyl]pentanamide 2-[(~cetylthio)methyl]-4-metllylpentanoic acid (2.0 g) is dissolved in 40 ml of tetrahydro-furan (THF) and 1.0 g of triQthylamine. This solution is cooled to -5C and ethyl chloroformate in 5 ml of THF is added dropwise. The reaction mixture is .qtirred at -5C for 20 minutes and then N-(2-aminoethyl)morpholine [1.3 g] in 20 ml of THF is added dropwise. lt is stirred at 20C
for 4 hours and stored at 0C for about 16 hours.
Triethylamine hydrochloride is filtered off and the filtrate is concentrated _n vacuo. This residue is 'a.~3 QA170/170a/168 dissolved in e~her and washed once with aqueous Na~CO3 and twice with water. The ether is dried with MySO4 t filtered and concentrated in vacuo to yield 1.6 g of material. This is S purified by dissolving 0.6 g in 2 ml of ether and placing it on top of a pad of alumina (activity II 10 g). The column is washed through with 250 ml of ether which is concentrated ln vacuo. Product crystallizes and is washed with 1:5 ether-pentane. The remainder of the crude is seeded with a small crystal and ~len washed with 1:5 ether-pentane. Total yield is 1.0 g of the title compound, melting point 54-59C.
15H28N2O3S: C, 56.93; H, 8.92; N, 8 85 S, 10.13 Found: C, 56.76, H, 8.91; N, 9.10; S, 10.01 Example 13, (~)-2-[(Acetylthio)methyl~-4-meth~l-N-~2 (1-piperidinyl_e_ yl~pentanamide A solution of (~)-2~~(acetylthio)me ~yl]-4-methylpentanoic acid in 40 ml of THF is cooled to 5 C, followed by the dropwise addition of triethylamine (1.0 g) in 5 ml of THF. This solution i~ cooled to -5C and ethyl chloro-formate in 4 ml of THF is added dropwise at
-5 to 0C. It is stirred for 30 minutes and N-(2-aminoethyl)piperidine in 30 ml of THF is added dropwise. The reaction mixture is stirred ~A170/170a/168 at 20 C for 4 hours and stored at 0 C for about 16 hours. Triethylamine hydrochloride is filtered of and the filtrate i5 concentrated _ vacuo. The residue is dissolved in ether and washed with aqueous NaHCO3. Ether i~ dried with MgSO4, filtered and concentrated in vacuo to yield 2.1 g of crude productO This crude is absorbed on a 20-g pad of alumina act II
and washed through with ether ~o yield 1.4 g of product which Grystallizes from pen-tane, melting point 47-50C.
Calc. for C16H30N2O2S: C, 61.11; H, 9.62; N, 8.91;
S, lO.lg Found: C, 61.04; H, ~.82; N, 8.93; S, 9.91 Example 14 2-(Mercap-tomethyl)-4-methyl-N-~2-(4-morpholinyl)-ethyl]pentanamide -~ 2-[(Acetylthio)methyl]-4-methyl-N-[2-(4-morpholinyl)ethyl~pentanamide (0.6 g) is dissolved in 20 ml of 1:1 ethanol:water.
The solution is saturated with argon and 2 ml of 47% NH40H is added. This is stirred under argon for 2 hours at room temperature. The reaction mixture is concentrated in vacuo and lyophilized for about 16 hours. The residue is dissolved in ether and stirred with charcoal to decolorize the product, which i5 then filtered through diatomaceous earth and concentrated ln vacuo.
Q~170/170~/168 The oil is dried at 45C in vacuo for about 16 hours to yield analytical product.
CalC- for C13H26N22S 1/4 2 N, 10.04; S, 11.49 Found: C, 55.78; ~i, 9.48; N, 10.33; S, 11.41 E ~ 15 2-(Mercaptomethyl)-4-methyl-N-[2~ eridinyl)~
eth ~
(~)-2-[(Acetylthio)methyl]--4-methyl-N-[2~ piperidinyl~ethyl]pentanamide (0.8 g) is dissolved in 3 ml of water and 5 ml o~ absolute ethanol. After this solution is purged with argon, 2 ml of 56~ NH4OH is added and the reaction mixture is stirred at room temperature for 2.5 hours. It is first concentrated ln vacuo to get rid of excess ammonia and ethanol and then lyophilized for about 16 hours. The dark brown oil is dissol~ed in ether and stirred with a scoop of charcoal for 20 minutes. It is filtered through Celite and concentrated ln vacuo to yield an oil. ~rying in vacuo for 4 hours at 40C yields the analytical productO
cal~- for C14H28N2S 0-25 H2 ;
N, 10.12; S, 11.58 Found: C, 60.52; H, 10.38; N, 10.51; S, 11.20 ~a ~
QA170/170a/168 Examples 16 - 18 Followiny the procedure of Example 13,but substituting the compound lis-ted in column I for N-(2-aminoethyl)piperidine, yields the compound listed in column II
Column I Column II
5 N-(3-aminopropyl)- (-)-2-[(acetylthio)methyl]
piperaæinyl -4-methyl-N-[3-(l~piper-azinyl)propyl]pentanamide
and washed through with ether ~o yield 1.4 g of product which Grystallizes from pen-tane, melting point 47-50C.
Calc. for C16H30N2O2S: C, 61.11; H, 9.62; N, 8.91;
S, lO.lg Found: C, 61.04; H, ~.82; N, 8.93; S, 9.91 Example 14 2-(Mercap-tomethyl)-4-methyl-N-~2-(4-morpholinyl)-ethyl]pentanamide -~ 2-[(Acetylthio)methyl]-4-methyl-N-[2-(4-morpholinyl)ethyl~pentanamide (0.6 g) is dissolved in 20 ml of 1:1 ethanol:water.
The solution is saturated with argon and 2 ml of 47% NH40H is added. This is stirred under argon for 2 hours at room temperature. The reaction mixture is concentrated in vacuo and lyophilized for about 16 hours. The residue is dissolved in ether and stirred with charcoal to decolorize the product, which i5 then filtered through diatomaceous earth and concentrated ln vacuo.
Q~170/170~/168 The oil is dried at 45C in vacuo for about 16 hours to yield analytical product.
CalC- for C13H26N22S 1/4 2 N, 10.04; S, 11.49 Found: C, 55.78; ~i, 9.48; N, 10.33; S, 11.41 E ~ 15 2-(Mercaptomethyl)-4-methyl-N-[2~ eridinyl)~
eth ~
(~)-2-[(Acetylthio)methyl]--4-methyl-N-[2~ piperidinyl~ethyl]pentanamide (0.8 g) is dissolved in 3 ml of water and 5 ml o~ absolute ethanol. After this solution is purged with argon, 2 ml of 56~ NH4OH is added and the reaction mixture is stirred at room temperature for 2.5 hours. It is first concentrated ln vacuo to get rid of excess ammonia and ethanol and then lyophilized for about 16 hours. The dark brown oil is dissol~ed in ether and stirred with a scoop of charcoal for 20 minutes. It is filtered through Celite and concentrated ln vacuo to yield an oil. ~rying in vacuo for 4 hours at 40C yields the analytical productO
cal~- for C14H28N2S 0-25 H2 ;
N, 10.12; S, 11.58 Found: C, 60.52; H, 10.38; N, 10.51; S, 11.20 ~a ~
QA170/170a/168 Examples 16 - 18 Followiny the procedure of Example 13,but substituting the compound lis-ted in column I for N-(2-aminoethyl)piperidine, yields the compound listed in column II
Column I Column II
5 N-(3-aminopropyl)- (-)-2-[(acetylthio)methyl]
piperaæinyl -4-methyl-N-[3-(l~piper-azinyl)propyl]pentanamide
6 1-(4-aminobutyl)-4- ~-)-2-[(acetylthio)methyl]
methyl-piperazinyl -4-methyl-N-[4-(4-methyl-l-piperazinyl)butyl]pen-tanamide
methyl-piperazinyl -4-methyl-N-[4-(4-methyl-l-piperazinyl)butyl]pen-tanamide
7 N~2-aminoethyl)pyr- (~)-2-[(acetylthio)methyl]-rolidinyl 4-methyl-N-[2-(1-pyrroli-dinyl)ethyl]pentanamide 3-(Acetylthio)--N-[2-(1-piperi n ~ hyl]-2-(phenyl-methyl)propionarnide A) 2-Carboxyl-3-~dimethy_ mino)-2-(phenylmethyl3-pro~ionic acid . . . _ Benzyl malonic acid (13 g) is mixed wi-th 7.6 g of 40% aqueous dimethylamine and 5.4 g of 37~
for~alin in 150 ml of water. After 2 hours, the resulting solid is filtered, washed with water and partially dried in air to yield 2008 g of material.
B) Benzylacrylic acid The above material is melted in a 170C oil Q~170/170a/168 bath and heated for 10 minutes, until amine evolution stops and bubbling has vlrtually ceased. The cooled product, a mobile liquid, is acidified with 10~ pot~
assium bisulfate, extracted with hexane, dried (Na2SO4) S and evaporated to give 6.3 g of solid. The aqueous filtra-tes from the Mannich reaction of part A are allowed to stand for about 16 hours and then heated at 100C on a steam cone until bubbling ceases.
Cooling, acidification and extraction as above give an additi.onal 1.2 g of solid for a total yield of 7.5 g of benzyl acrylic acid.
C) 3-(Acetylthio)-2-(phenylmethyl)propionic acid ___ _ .
Following the procedure of Example lB, but substituting benzylacrylic acid for 4-methyl-2-methyl-enepentanoic acid~ yields the -title compound.
D) 3-(Acetylthio)-N-[2-(1-piperidinyl)ethyl]-2-. . . ~ . . _ _ . . . _ _ . .
(phenylmethyl)propionic acld 2~ Following the procedure of Example lC, but substituting 3-(acetylthio) -2-(phenylmethyl)pro-pionic acid for 2-[(acetyl-thio)me-thyl]-4-methylpentan-oic acid and N-(2-aminoethyl)piperidine for N-(2-aminoethyl)morpholine, yields the title compound.
Example 20 - 22 Following the procedure of Example 19, but substituting the compound listed in column I for benzyl malonic acid and the compound listed in column II for N-(2-aminoethyl)morpholine, yields the compound listed in column III.
- 2 2 a ~ r~
~ 1--~ ~ ~ n E.
, PJ , o o n ~. n ~.
Z z z g O r~ O
(D ~<: 1'--- g O ~. ~
O
~.
(D ~, w ~ ~ ~ w ~ w n 3 ~ ~
O ~ ~ O Q~ ~ H
~ ~ O ~ :~ ~ 5' H
1--~ 0 h~--O ~ ~ O
~ ~ æ' ~t z @ w æ
o n~:~ 3 n .1 ~
for~alin in 150 ml of water. After 2 hours, the resulting solid is filtered, washed with water and partially dried in air to yield 2008 g of material.
B) Benzylacrylic acid The above material is melted in a 170C oil Q~170/170a/168 bath and heated for 10 minutes, until amine evolution stops and bubbling has vlrtually ceased. The cooled product, a mobile liquid, is acidified with 10~ pot~
assium bisulfate, extracted with hexane, dried (Na2SO4) S and evaporated to give 6.3 g of solid. The aqueous filtra-tes from the Mannich reaction of part A are allowed to stand for about 16 hours and then heated at 100C on a steam cone until bubbling ceases.
Cooling, acidification and extraction as above give an additi.onal 1.2 g of solid for a total yield of 7.5 g of benzyl acrylic acid.
C) 3-(Acetylthio)-2-(phenylmethyl)propionic acid ___ _ .
Following the procedure of Example lB, but substituting benzylacrylic acid for 4-methyl-2-methyl-enepentanoic acid~ yields the -title compound.
D) 3-(Acetylthio)-N-[2-(1-piperidinyl)ethyl]-2-. . . ~ . . _ _ . . . _ _ . .
(phenylmethyl)propionic acld 2~ Following the procedure of Example lC, but substituting 3-(acetylthio) -2-(phenylmethyl)pro-pionic acid for 2-[(acetyl-thio)me-thyl]-4-methylpentan-oic acid and N-(2-aminoethyl)piperidine for N-(2-aminoethyl)morpholine, yields the title compound.
Example 20 - 22 Following the procedure of Example 19, but substituting the compound listed in column I for benzyl malonic acid and the compound listed in column II for N-(2-aminoethyl)morpholine, yields the compound listed in column III.
- 2 2 a ~ r~
~ 1--~ ~ ~ n E.
, PJ , o o n ~. n ~.
Z z z g O r~ O
(D ~<: 1'--- g O ~. ~
O
~.
(D ~, w ~ ~ ~ w ~ w n 3 ~ ~
O ~ ~ O Q~ ~ H
~ ~ O ~ :~ ~ 5' H
1--~ 0 h~--O ~ ~ O
~ ~ æ' ~t z @ w æ
o n~:~ 3 n .1 ~
Claims (19)
1. A method of preparing compounds having the formula:
I
or a salt thereof, wherein R1 is hydrogen, alkanoyl of 2 to 10 carbon atoms, or arylcarbonyl; R2 is 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinyl or 4-alkyl-1-piperazinyl; wherein R4 is hydrogen, alkyl or aryl; R3 is alkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, aryl or arylalkyl; and n is an integer of 1 to 20;
the term aryl being limited to phenyl or phenyl substituted with 1, 2 or 3 alkyl, alkoxy, halogen, amino, hydroxy or alkanoyloxy groups and the term alkyl being limited to a group having 1 to 8 car-bon atoms; which comprises, when R1 is other than hydrogen, reacting a compound of the formula:
V
or an ester thereof with a compound of the formula:
VI
or a salt thereof and when R1 is hydrogen reacting a compound of formula I wherein R1 is alkanoyl or arylcarbonyl with ammonium hydroxide to form a com-- 23a -pound of formula I wherein R1 is hydrogen.
I
or a salt thereof, wherein R1 is hydrogen, alkanoyl of 2 to 10 carbon atoms, or arylcarbonyl; R2 is 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinyl or 4-alkyl-1-piperazinyl; wherein R4 is hydrogen, alkyl or aryl; R3 is alkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, aryl or arylalkyl; and n is an integer of 1 to 20;
the term aryl being limited to phenyl or phenyl substituted with 1, 2 or 3 alkyl, alkoxy, halogen, amino, hydroxy or alkanoyloxy groups and the term alkyl being limited to a group having 1 to 8 car-bon atoms; which comprises, when R1 is other than hydrogen, reacting a compound of the formula:
V
or an ester thereof with a compound of the formula:
VI
or a salt thereof and when R1 is hydrogen reacting a compound of formula I wherein R1 is alkanoyl or arylcarbonyl with ammonium hydroxide to form a com-- 23a -pound of formula I wherein R1 is hydrogen.
2. A method in accordance with claim 1 wherein R1 is hydrogen, acetyl or benzoyl.
3. A method in accordance with claim 1 wherein R1 is alkanoyl of 2 to 10 carbon atoms.
4. A method in accordance with claim 1 wherein R1 is arylcarbonyl.
5. A method in accordance with claim 1 wherein R2 is .
6. A method in accordance with claim 1 wherein R2 is -?-R4.
7. A method in accordance with claim 1 wherein R2 is .
8. A method in accordance with claim 6 wherein R4 is hydrogen.
9. A method in accordance with claim 7 wherein R4 is hydrogen.
10. A method in accordance with claim 1 wherein n is 2, 3 or 4.
11. A method in accordance with claim 1 wherein R3 is 2-methylpropyl.
12. A method in accordance with claim 1 wherein R1 is acetyl, R2 is CH(OCH3)2, R3 is CH2CH(CH3)2 and n is one.
13. A method in accordance with claim 1 wherein R1 is hydrogen, R2 is CH(OCH3)2, R3 is CH2CH(CH3)2 and n is one.
14. A method in accordance with claim 1 wherein R1 is acetyl, R2 is , R3 is CH2CH(CH3)2 and n is four.
15. A method in accordance with claim 1 wherein R1 is hydrogen, R2 is , R3 is CH2CH(CH3)2 and n is four.
16. A method in accordance with claim 1 wherein R1 is acetyl, R2 is 4-morpholinyl, R3 is CH2CH(CH3)2 and n is two.
17. A method in accordance with claim 1 wherein R1 is acetyl, R2 is 1-piperidinyl, R3 is CH2CH(CH3)2 and n is two.
18. A method in accordance with claim 1 wherein R1 is hydrogen, R2 is 4-morpholinyl, R3 is CH2CH(CH3)2 and n is two.
19. A method in accordance with claim 1 wherein R1 is hydrogen, R2 is 1-piperidinyl, R3 is CH2CH(CH3)2 and n is two.
20. A compound having the formula:
or a salt thereof, wherein R1 is hydrogen, alkanoyl of 2 to 10 carbon atoms, or arylcarbonyl; R2 is 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinyl, or 4-alkyl-1-piperazinyl; wherein R4 is hydrogen, alkyl or aryl; R3 is alkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, aryl or arylalkyl; and n is an integer of 1 to 20;
the term aryl being limited to phenyl or phenyl substituted with 1, 2 or 3 alkyl, alkoxy, halogen, amino, hydroxy or alkanoyloxy groups and the term alkyl being limited to a group having 1 to 8 car-bon atoms; when prepared by the process of claim 1.
21. A compound in accordance with claim 20 wherein R1 is hydrogen, acetyl or benzoyl, when pre-pared by the process of claim 2.
22. A compound in accordance with claim 20 wherein R1 is alkanoyl of 2 to 10 carbon atoms when prepared by the process of claim 3.
- 25a -23. A compound in accordance with claim 20 wherein R1 is arylcarbonyl when prepared by the process of claim 4.
24. A compound in accordance with claim 20 wherein R2 is when prepared by the process of claim 5.
25. A compound in accordance with claim 20 wherein R2 is -?-R4 when prepared by the process of claim 6.
26. A compound in accordance with claim 20 wherein R2 is when prepared by the process of claim 7.
27. A compound in accordance with claim 25 wherein R4 is hydrogen when prepared by the process of claim 8.
28. A compound in accordance with claim 26 wherein R4 is hydrogen when prepared by the process of claim 9.
29. A compound in accordance with claim 20 wherein n is 2, 3 or 4 when prepared by the process of claim 10.
30. A compound in accordance with claim 20 wherein R3 is 2-methylpropyl whenever prepared by the process of claim 11.
31. The compound in accordance with claim 20 N-(2,2-dimethoxethyl)-2-[(acetylthio)methyl]-4-methylpentanamide when prepared by the process of claim 12.
32. The compound in accordance with claim 20 N-(2,2-dimethoxyethyl)-2-(mercaptomethyl)-4-methyl-pentanamide when prepared by the process of claim 13.
33. The compound in accordance with claim 20 2-[(acetylthio)methyl]-4-methyl-N-[4-[(aminoimino-methyl)amino]butyl]pentanamide, acetate (1:1) when prepared by the process of claim 14.
34. The compound in accordance with claim 20 2-(mercaptomethyl)-4-methyl-N-[4-[(aminoiminomethyl)-amino]butyl]pentanamide, acetate (1:1) when prepared by the process of claim 15.
35. The compound in accordance with claim 20 (?)-2-[(acetylthio)methyl]-4-methyl-N-[2-(4-morpholinyl)ethyl]pentanamide when prepared by the process of claim 16.
36. The compound in accordance with claim 20 (?)-2-[(acetylthio)methyl]-4-methyl-N-[2-(1-piperidinyl)ethyl]pentanamide when prepared by the process of claim 17.
37. The compound in accordance with claim 20 2-(mercaptomethyl)-4-methyl-N-[2-(4-morpholinyl)-ethyl]pentanamide when prepared by the process of
18. A method in accordance with claim 1 wherein R1 is hydrogen, R2 is 4-morpholinyl, R3 is CH2CH(CH3)2 and n is two.
19. A method in accordance with claim 1 wherein R1 is hydrogen, R2 is 1-piperidinyl, R3 is CH2CH(CH3)2 and n is two.
20. A compound having the formula:
or a salt thereof, wherein R1 is hydrogen, alkanoyl of 2 to 10 carbon atoms, or arylcarbonyl; R2 is 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinyl, or 4-alkyl-1-piperazinyl; wherein R4 is hydrogen, alkyl or aryl; R3 is alkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, aryl or arylalkyl; and n is an integer of 1 to 20;
the term aryl being limited to phenyl or phenyl substituted with 1, 2 or 3 alkyl, alkoxy, halogen, amino, hydroxy or alkanoyloxy groups and the term alkyl being limited to a group having 1 to 8 car-bon atoms; when prepared by the process of claim 1.
21. A compound in accordance with claim 20 wherein R1 is hydrogen, acetyl or benzoyl, when pre-pared by the process of claim 2.
22. A compound in accordance with claim 20 wherein R1 is alkanoyl of 2 to 10 carbon atoms when prepared by the process of claim 3.
- 25a -23. A compound in accordance with claim 20 wherein R1 is arylcarbonyl when prepared by the process of claim 4.
24. A compound in accordance with claim 20 wherein R2 is when prepared by the process of claim 5.
25. A compound in accordance with claim 20 wherein R2 is -?-R4 when prepared by the process of claim 6.
26. A compound in accordance with claim 20 wherein R2 is when prepared by the process of claim 7.
27. A compound in accordance with claim 25 wherein R4 is hydrogen when prepared by the process of claim 8.
28. A compound in accordance with claim 26 wherein R4 is hydrogen when prepared by the process of claim 9.
29. A compound in accordance with claim 20 wherein n is 2, 3 or 4 when prepared by the process of claim 10.
30. A compound in accordance with claim 20 wherein R3 is 2-methylpropyl whenever prepared by the process of claim 11.
31. The compound in accordance with claim 20 N-(2,2-dimethoxethyl)-2-[(acetylthio)methyl]-4-methylpentanamide when prepared by the process of claim 12.
32. The compound in accordance with claim 20 N-(2,2-dimethoxyethyl)-2-(mercaptomethyl)-4-methyl-pentanamide when prepared by the process of claim 13.
33. The compound in accordance with claim 20 2-[(acetylthio)methyl]-4-methyl-N-[4-[(aminoimino-methyl)amino]butyl]pentanamide, acetate (1:1) when prepared by the process of claim 14.
34. The compound in accordance with claim 20 2-(mercaptomethyl)-4-methyl-N-[4-[(aminoiminomethyl)-amino]butyl]pentanamide, acetate (1:1) when prepared by the process of claim 15.
35. The compound in accordance with claim 20 (?)-2-[(acetylthio)methyl]-4-methyl-N-[2-(4-morpholinyl)ethyl]pentanamide when prepared by the process of claim 16.
36. The compound in accordance with claim 20 (?)-2-[(acetylthio)methyl]-4-methyl-N-[2-(1-piperidinyl)ethyl]pentanamide when prepared by the process of claim 17.
37. The compound in accordance with claim 20 2-(mercaptomethyl)-4-methyl-N-[2-(4-morpholinyl)-ethyl]pentanamide when prepared by the process of
claim 18.
38. The compound in accordance with claim 20 2-(mercaptomethy])-4-methyl-N-[2-(1-piperidinyl)-ethyl]pentamide when prepared by the process of
38. The compound in accordance with claim 20 2-(mercaptomethy])-4-methyl-N-[2-(1-piperidinyl)-ethyl]pentamide when prepared by the process of
claim 19.
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/154,748 US4263293A (en) | 1980-05-30 | 1980-05-30 | Heterocyclic containing amides as inhibitors of mammalian collagenase |
US154,748 | 1980-05-30 | ||
US168,933 | 1980-07-14 | ||
US06/168,933 US4327111A (en) | 1980-07-14 | 1980-07-14 | N-Substituted mercaptoacyl pripionamides |
US20299880A | 1980-11-03 | 1980-11-03 | |
US202,998 | 1980-11-03 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1182818A true CA1182818A (en) | 1985-02-19 |
Family
ID=27387632
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000376389A Expired CA1182818A (en) | 1980-05-30 | 1981-04-28 | N-substituted mercaptoacyl propionamides |
Country Status (5)
Country | Link |
---|---|
CA (1) | CA1182818A (en) |
DE (1) | DE3121189A1 (en) |
FR (1) | FR2483411A1 (en) |
GB (1) | GB2076809B (en) |
IT (1) | IT1137485B (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2540495B1 (en) * | 1983-02-07 | 1986-02-14 | Roussel Uclaf | NOVEL DERIVATIVES OF O-MERCAPTOPROPANAMIDE AND ITS HOMOLOGUES, THEIR PREPARATION METHOD, THEIR APPLICATION AS MEDICAMENTS, THE COMPOSITIONS CONTAINING THEM AND THE NEW INTERMEDIATES OBTAINED |
FR2559770B1 (en) * | 1984-02-20 | 1986-10-24 | Roussel Uclaf | NOVEL N-ALKYL-O-MERCAPTOPROPANAMIDE DERIVATIVES, PROCESSES FOR THEIR PREPARATION, THEIR USE AS MEDICAMENTS, THE COMPOSITIONS CONTAINING THEM AND THE NEW INTERMEDIATES OBTAINED |
FR2562068B1 (en) * | 1984-03-29 | 1987-07-17 | Roussel Uclaf | NOVEL DERIVATIVES OF O-MERCAPTOPROPANAMIDE AND ITS HOMOLOGUES, THEIR PREPARATION METHOD, THEIR APPLICATION AS MEDICAMENTS, THE COMPOSITIONS CONTAINING THEM AND THE NEW INTERMEDIATES OBTAINED |
ATE30415T1 (en) * | 1984-04-02 | 1987-11-15 | Squibb & Sons Inc | ENKEPHALINAS INHIBITORS. |
FR2589468B1 (en) * | 1985-07-30 | 1987-12-31 | Roussel Uclaf | NOVEL 2-ACYLAMINO ETHANETHIOL 2-SUBSTITUTED DERIVATIVES, THEIR PREPARATION PROCESS, THEIR USE AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4113715A (en) * | 1977-01-17 | 1978-09-12 | E. R. Squibb & Sons, Inc. | Amino acid derivatives |
US4235885A (en) * | 1979-06-25 | 1980-11-25 | E. R. Squibb & Sons, Inc. | Inhibitors of mammalian collagenase |
-
1981
- 1981-04-28 CA CA000376389A patent/CA1182818A/en not_active Expired
- 1981-04-28 GB GB8113036A patent/GB2076809B/en not_active Expired
- 1981-05-20 FR FR8110073A patent/FR2483411A1/en active Granted
- 1981-05-26 IT IT21951/81A patent/IT1137485B/en active
- 1981-05-27 DE DE3121189A patent/DE3121189A1/en not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
IT1137485B (en) | 1986-09-10 |
GB2076809B (en) | 1984-03-14 |
FR2483411B1 (en) | 1983-05-13 |
GB2076809A (en) | 1981-12-09 |
DE3121189A1 (en) | 1982-02-25 |
FR2483411A1 (en) | 1981-12-04 |
IT8121951A0 (en) | 1981-05-26 |
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