AU3210899A

AU3210899A - Antagonists of gonadotropin releasing hormone

Antagonists of gonadotropin releasing hormone Download PDF

Info

Publication number: AU3210899A
Authority: AU; Australia
Prior art keywords: substituted; alkyl; aryl; compound; aralkyl
Prior art date: 1998-04-02
Legal status : Abandoned

Application number

AU32108/99A

Other languages

English (en)

Inventor

Mark T. Goulet

Feroze Ujjainwalla

Thomas F. Walsh

Current Assignee

Merck and Co Inc

Original Assignee

Merck and Co Inc

Priority date

1998-04-02

Filing date

1999-03-29

Publication date

1999-10-25

1998-06-05 Priority claimed from GBGB9812217.9A external-priority patent/GB9812217D0/en

1999-03-29 Application filed by Merck and Co Inc filed Critical Merck and Co Inc

1999-10-25 Publication of AU3210899A publication Critical patent/AU3210899A/en

Status Abandoned legal-status Critical Current

Links

239000000579 Gonadotropin-Releasing Hormone Substances 0.000 title claims description 23
XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 title claims description 22
101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 title claims description 17
229940035638 gonadotropin-releasing hormone Drugs 0.000 title claims description 17
239000005557 antagonist Substances 0.000 title description 8
150000001875 compounds Chemical class 0.000 claims description 128
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 78
125000003118 aryl group Chemical group 0.000 claims description 43
238000000034 method Methods 0.000 claims description 43
239000000203 mixture Substances 0.000 claims description 40
125000003710 aryl alkyl group Chemical group 0.000 claims description 36
229910052739 hydrogen Inorganic materials 0.000 claims description 34
125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 34
125000003107 substituted aryl group Chemical group 0.000 claims description 34
239000001257 hydrogen Substances 0.000 claims description 33
125000000623 heterocyclic group Chemical group 0.000 claims description 25
125000004429 atom Chemical group 0.000 claims description 21
125000005842 heteroatom Chemical group 0.000 claims description 21
125000001424 substituent group Chemical group 0.000 claims description 19
125000000217 alkyl group Chemical group 0.000 claims description 18
229910052760 oxygen Inorganic materials 0.000 claims description 18
108090000765 processed proteins & peptides Proteins 0.000 claims description 18
102000018997 Growth Hormone Human genes 0.000 claims description 16
108010051696 Growth Hormone Proteins 0.000 claims description 16
125000002837 carbocyclic group Chemical group 0.000 claims description 16
239000000122 growth hormone Substances 0.000 claims description 16
125000005010 perfluoroalkyl group Chemical group 0.000 claims description 16
238000002560 therapeutic procedure Methods 0.000 claims description 15
150000003839 salts Chemical class 0.000 claims description 14
229910052736 halogen Inorganic materials 0.000 claims description 13
150000002367 halogens Chemical class 0.000 claims description 13
229910052717 sulfur Inorganic materials 0.000 claims description 13
229940088597 hormone Drugs 0.000 claims description 12
239000005556 hormone Substances 0.000 claims description 12
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 11
125000004432 carbon atom Chemical group C* 0.000 claims description 11
239000003163 gonadal steroid hormone Substances 0.000 claims description 11
229910052799 carbon Inorganic materials 0.000 claims description 9
239000008194 pharmaceutical composition Substances 0.000 claims description 9
206010028980 Neoplasm Diseases 0.000 claims description 8
125000000753 cycloalkyl group Chemical group 0.000 claims description 8
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
206010046798 Uterine leiomyoma Diseases 0.000 claims description 7
125000003342 alkenyl group Chemical group 0.000 claims description 7
229960002719 buserelin Drugs 0.000 claims description 7
230000001419 dependent effect Effects 0.000 claims description 7
201000010260 leiomyoma Diseases 0.000 claims description 7
238000004519 manufacturing process Methods 0.000 claims description 7
230000003287 optical effect Effects 0.000 claims description 7
108010037003 Buserelin Proteins 0.000 claims description 6
108700012941 GNRH1 Proteins 0.000 claims description 6
229920001774 Perfluoroether Polymers 0.000 claims description 6
125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 6
CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 claims description 6
230000008569 process Effects 0.000 claims description 6
GJKXGJCSJWBJEZ-XRSSZCMZSA-N Deslorelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CNC2=CC=CC=C12 GJKXGJCSJWBJEZ-XRSSZCMZSA-N 0.000 claims description 5
201000009273 Endometriosis Diseases 0.000 claims description 5
102400000932 Gonadoliberin-1 Human genes 0.000 claims description 5
BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 claims description 5
108010069236 Goserelin Proteins 0.000 claims description 5
101500026183 Homo sapiens Gonadoliberin-1 Proteins 0.000 claims description 5
108010000817 Leuprolide Proteins 0.000 claims description 5
108010021717 Nafarelin Proteins 0.000 claims description 5
108010050144 Triptorelin Pamoate Proteins 0.000 claims description 5
229960005408 deslorelin Drugs 0.000 claims description 5
108700025485 deslorelin Proteins 0.000 claims description 5
229960001442 gonadorelin Drugs 0.000 claims description 5
229960002913 goserelin Drugs 0.000 claims description 5
HHXHVIJIIXKSOE-QILQGKCVSA-N histrelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC(N=C1)=CN1CC1=CC=CC=C1 HHXHVIJIIXKSOE-QILQGKCVSA-N 0.000 claims description 5
108700020746 histrelin Proteins 0.000 claims description 5
229960002193 histrelin Drugs 0.000 claims description 5
GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 claims description 5
229960004338 leuprorelin Drugs 0.000 claims description 5
RWHUEXWOYVBUCI-ITQXDASVSA-N nafarelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 RWHUEXWOYVBUCI-ITQXDASVSA-N 0.000 claims description 5
229960002333 nafarelin Drugs 0.000 claims description 5
VXKHXGOKWPXYNA-PGBVPBMZSA-N triptorelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 VXKHXGOKWPXYNA-PGBVPBMZSA-N 0.000 claims description 5
229960004824 triptorelin Drugs 0.000 claims description 5
125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
206010020112 Hirsutism Diseases 0.000 claims description 4
102220517591 Methyl-CpG-binding domain protein 3-like 2B_R11C_mutation Human genes 0.000 claims description 4
206010036618 Premenstrual syndrome Diseases 0.000 claims description 4
125000000304 alkynyl group Chemical group 0.000 claims description 4
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
208000002551 irritable bowel syndrome Diseases 0.000 claims description 4
125000000896 monocarboxylic acid group Chemical group 0.000 claims description 4
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
201000010065 polycystic ovary syndrome Diseases 0.000 claims description 4
208000006155 precocious puberty Diseases 0.000 claims description 4
201000002859 sleep apnea Diseases 0.000 claims description 4
208000019116 sleep disease Diseases 0.000 claims description 4
208000003200 Adenoma Diseases 0.000 claims description 3
206010025135 lupus erythematosus Diseases 0.000 claims description 3
230000001817 pituitary effect Effects 0.000 claims description 3
206010061692 Benign muscle neoplasm Diseases 0.000 claims description 2
206010006187 Breast cancer Diseases 0.000 claims description 2
208000026310 Breast neoplasm Diseases 0.000 claims description 2
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
206010056438 Growth hormone deficiency Diseases 0.000 claims description 2
201000004458 Myoma Diseases 0.000 claims description 2
JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 2
206010060862 Prostate cancer Diseases 0.000 claims description 2
208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
208000020221 Short stature Diseases 0.000 claims description 2
208000002495 Uterine Neoplasms Diseases 0.000 claims description 2
125000004093 cyano group Chemical group *C#N 0.000 claims description 2
125000001153 fluoro group Chemical group F* 0.000 claims description 2
125000004043 oxo group Chemical group O=* 0.000 claims description 2
230000035935 pregnancy Effects 0.000 claims description 2
206010046766 uterine cancer Diseases 0.000 claims description 2
210000004291 uterus Anatomy 0.000 claims description 2
230000003054 hormonal effect Effects 0.000 claims 4
208000035475 disorder Diseases 0.000 claims 3
239000003937 drug carrier Substances 0.000 claims 3
HJNZCKLMRAOTMA-BRBGIFQRSA-N (2s)-n-[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2r)-1-[[(2s)-1-[[(2s)-5-(diaminomethylideneamino)-1-[(2s)-2-(ethylcarbamoyl)pyrrolidin-1-yl]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(2-methyl-1h-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(4-hydr Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=C(C)NC2=CC=CC=C12 HJNZCKLMRAOTMA-BRBGIFQRSA-N 0.000 claims 2
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125000003545 alkoxy group Chemical group 0.000 claims 1
230000003042 antagnostic effect Effects 0.000 claims 1
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238000002648 combination therapy Methods 0.000 claims 1
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XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 122
238000006243 chemical reaction Methods 0.000 description 60
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WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
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229940121381 gonadotrophin releasing hormone (gnrh) antagonists Drugs 0.000 description 12
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
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