CN1575169A - 用于治疗肥胖的mch拮抗剂 - Google Patents
用于治疗肥胖的mch拮抗剂 Download PDFInfo
- Publication number
- CN1575169A CN1575169A CNA028210697A CN02821069A CN1575169A CN 1575169 A CN1575169 A CN 1575169A CN A028210697 A CNA028210697 A CN A028210697A CN 02821069 A CN02821069 A CN 02821069A CN 1575169 A CN1575169 A CN 1575169A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- cycloalkyl
- chemical compound
- aryl
- alkoxyl
- 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.)
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- 208000008589 Obesity Diseases 0.000 title claims abstract description 12
- 235000020824 obesity Nutrition 0.000 title claims abstract description 12
- 239000005557 antagonist Substances 0.000 title abstract description 9
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- 238000000034 method Methods 0.000 claims abstract description 38
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
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- 208000019454 Feeding and Eating disease Diseases 0.000 claims abstract description 12
- 235000014632 disordered eating Nutrition 0.000 claims abstract description 12
- 208000030159 metabolic disease Diseases 0.000 claims abstract description 8
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 7
- 206010020710 Hyperphagia Diseases 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 177
- 125000003118 aryl group Chemical group 0.000 claims description 87
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 81
- 125000003545 alkoxy group Chemical group 0.000 claims description 80
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- 239000000203 mixture Substances 0.000 claims description 62
- -1 3-cyano-phenyl Chemical group 0.000 claims description 42
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 38
- 238000002360 preparation method Methods 0.000 claims description 37
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 36
- 229910052736 halogen Inorganic materials 0.000 claims description 36
- 150000002367 halogens Chemical class 0.000 claims description 36
- 125000001188 haloalkyl group Chemical group 0.000 claims description 33
- 239000012453 solvate Chemical class 0.000 claims description 31
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 30
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- 125000001424 substituent group Chemical group 0.000 claims description 22
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
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- 239000003112 inhibitor Substances 0.000 claims description 16
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 238000002372 labelling Methods 0.000 claims description 14
- 125000001118 alkylidene group Chemical group 0.000 claims description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
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- 230000001225 therapeutic effect Effects 0.000 claims description 11
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- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 claims description 10
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
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- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical group C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 claims description 8
- 229960001641 troglitazone Drugs 0.000 claims description 8
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 claims description 8
- 208000016097 disease of metabolism Diseases 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical group O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 claims description 5
- 229940118148 Aldose reductase inhibitor Drugs 0.000 claims description 5
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 claims description 5
- QTQMRBZOBKYXCG-MHZLTWQESA-N GW 1929 Chemical compound N([C@@H](CC1=CC=C(C=C1)OCCN(C)C=1N=CC=CC=1)C(O)=O)C1=CC=CC=C1C(=O)C1=CC=CC=C1 QTQMRBZOBKYXCG-MHZLTWQESA-N 0.000 claims description 5
- 102000007390 Glycogen Phosphorylase Human genes 0.000 claims description 5
- 108010046163 Glycogen Phosphorylase Proteins 0.000 claims description 5
- 108010016731 PPAR gamma Chemical group 0.000 claims description 5
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 claims description 5
- 102000002727 Protein Tyrosine Phosphatase Human genes 0.000 claims description 5
- 229940100389 Sulfonylurea Drugs 0.000 claims description 5
- 229960002632 acarbose Drugs 0.000 claims description 5
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Chemical group OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 claims description 5
- 239000003288 aldose reductase inhibitor Substances 0.000 claims description 5
- 229960001761 chlorpropamide Drugs 0.000 claims description 5
- 229960004580 glibenclamide Drugs 0.000 claims description 5
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 claims description 5
- 229960001381 glipizide Drugs 0.000 claims description 5
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 claims description 5
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical group CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims description 5
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- 102000000536 PPAR gamma Human genes 0.000 claims 2
- 101800002739 Melanin-concentrating hormone Proteins 0.000 abstract 3
- ORRDHOMWDPJSNL-UHFFFAOYSA-N melanin concentrating hormone Chemical compound N1C(=O)C(C(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)CNC(=O)C(C(C)C)NC(=O)C(CCSC)NC(=O)C(NC(=O)C(CCCNC(N)=N)NC(=O)C(NC(=O)C(NC(=O)C(N)CC(O)=O)C(C)O)CCSC)CSSCC(C(=O)NC(CC=2C3=CC=CC=C3NC=2)C(=O)NC(CCC(O)=O)C(=O)NC(C(C)C)C(O)=O)NC(=O)C2CCCN2C(=O)C(CCCNC(N)=N)NC(=O)C1CC1=CC=C(O)C=C1 ORRDHOMWDPJSNL-UHFFFAOYSA-N 0.000 abstract 3
- 102000047659 melanin-concentrating hormone Human genes 0.000 abstract 3
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- RBNBDIMXFJYDLQ-UHFFFAOYSA-N thieno[3,2-d]pyrimidine Chemical compound C1=NC=C2SC=CC2=N1 RBNBDIMXFJYDLQ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
- C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
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- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
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Abstract
本发明公开了式(I)和(II)的化合物,其是新的黑色素浓缩激素(MCH)的拮抗剂,以及制备上述化合物的方法。在另一实施方式中,本发明公开了含有所述MCH拮抗剂的药物组合物和理由它们治疗肥胖、代谢基本、饮食基本入饮食过多和糖尿病的方法。
Description
交叉参考的有关申请
本申请请求享受2001年10月25日提交的美国临时专利申请60/343,065的权益。
技术领域
本发明涉及黑色素浓缩激素(MCH)的拮抗剂及其在肥胖、饮食障碍和糖尿病中的用途,含义所述化合物的药物组合物,和使用所述化合物治疗的方法。
背景技术
MCH,一种环肽,十年前首次在硬骨鱼中被鉴定,其似乎调节颜色变化。最近,MCH已经成为研究其在哺乳动物中作为饮食行为的调控剂的可能作用的对象。据Shimada等,Nature,Vol.396(17 Dec.1998),pp.670-673报道,MCH-缺损小鼠由于饮食低下(减少饮食)而体重减轻且消瘦。从其发现看,暗示MCH作用的拮抗剂可有效用于肥胖的治疗。美国专利5,908,830公开了一种用于糖尿病或肥胖治疗的联合疗法,包括给代谢率增高剂和饮食行为调控剂的施用,后者的一个实例为MCH拮抗剂。
美国专利6,245,746(2001年6月12日提交)公开了抗微生物药物领域有关的具有流出泵抑制剂活性的酰胺化合物。
发明概述
在一种实施方式中,本发明提供了具有MCH拮抗活性的新化合物。这些化合物由结构式I表示:
式I
或该化合物的药学可接受盐或溶剂化物,其中:
X是单键,-C-,-CH-或亚烷基,并且当X是单键时,R6不存在并且标记1的碳原子直接连接于N-Y的N;
Y是单键,-C-,-CH-或亚烷基,并且当Y是单键,R5不存在并且标记7的碳原子直接相连于N-X的N;
R1是芳基或杂芳基,其中所述的芳基或杂芳基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自CN,CF3,卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;
R2是H,烷基,芳基或芳烷基其中所述的芳基或芳烷基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;
R3是H,烷基,芳基或芳烷基其中所述的芳基或芳烷基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自CF3,卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;
R4选自-亚烷基-N(R7)2,-N(H)亚烷基-N(R7)2,-O-亚烷基-N(R7)2,
和
其中该-N(R7)2中的各R7,可以相同或不同,各R7是H,烷基,环烷基或芳基,其中所述的烷基,芳基或环烷基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;或各R7可以连接在一起并且与其所连的氮构成3至7-元杂环环;
p是0-5并且当p>1时,p部分的数目可以相同或不同;R5是H或1或2个独立选自烷基或环烷基的取代基;
R6是H或1或2个独立选自烷基或环烷基的取代基;和
R8是H,OH,烷氧基,烷基,环烷基,芳基,-N(H)R7,-N(H)C(O)烷基,-N(H)C(O)芳基,-N(H)C(O)N(H)烷基,-N(H)C(O)N(H)芳基,-N(H)S(O2)烷基或-N(H)S(O2)芳基;
条件是芳环上标记1和6所示的碳,与X-R5一起,可以任选地构成4-8元环系。
一组优选的化合物是那些在详述中如式Ia、Ib和Ic所示的化合物。
本发明还涉及结构式II所示的化合物:
式II
或该化合物的药学可接受盐或溶剂化物,其中:
Y是单键,-C-,-CH-或亚烷基,并且当Y是单键,R5不存在并且标记7的碳原子直接相连于N-X的N;
Z是单键,-C-,-CH-或亚烷基,并且当Z是单键,R6不存在并且标记1的碳原子直接相连于标记8的碳原子;
R1是芳基或杂芳基,其中所述的芳基或杂芳基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自CN,CF3,卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;
R2是H,烷基,芳基或芳烷基其中所述的芳基或芳烷基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;
R3是H,烷基,芳基或芳烷基其中所述的芳基或芳烷基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自CF3,卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;
R5是H或1或2个独立选自烷基或环烷基的取代基;
R6是H或1或2个独立选自烷基或环烷基的取代基;
R10选自-亚烷基(R7)2,
和
其中所述-N(R7)2中的各R7,可以相同或不同,各R7是H,烷基,环烷基或芳基,其中所述的烷基,芳基或环烷基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;或各R7可以连接在一起并且与其所连的氮构成3至7-元杂环环;
n是0或1;
p是0-5并且当p>1时,p部分的数目可以相同或不同;和
R8是H,OH,烷氧基,烷基,环烷基,芳基,-N(H)R7,-N(H)C(O)烷基,-N(H)C(O)芳基,-N(H)C(O)N(H)烷基,-N(H)C(O)N(H)芳基,-N(H)S(O2)烷基或-N(H)S(O2)芳基;
条件是芳环上标记1和6的碳,与X-R6一起,可以任选地构成4-8元环系。
式I和II的化合物可以用作MCH受体拮抗剂并且用于代谢疾病例如肥胖和饮食疾病如饮食过多的治疗中。
本发明的另一实施方式涉及用于治疗肥胖的药物组合物,其含有肥胖治疗量的式I或II的化合物,或该化合物的药学可接受盐,以及药学可接受载体。
详述
在一种实施方式中,本发明公开了结构式I和II表示的MCH受体拮抗剂或其药学可接受盐或溶剂化物,其中多个部分如上所述。
一种优选实施方式是式Ia的化合物:
和Ia
式Ia或该化合物的药学可接受盐或溶剂化物,其中:
q是0-5并且当q>1时,q部分的数目可以相同或不同;
X是-CH-或亚烷基;
Y是CH2;
R2是H,烷基,芳基或芳烷基,其中所述的芳基或芳烷基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;
R3是H,烷基,芳基或芳烷基其中所述的芳基或芳烷基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自CF3,卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;
R4是-亚烷基-N(R7)2,其中两个R7部分可以相同或不同,各R7是H,烷基,环烷基或芳基,其中所述的烷基,芳基或环烷基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;或各R7可以连接在一起并且与其所连的氮构成3至7-元杂环环,或R4选自
R5和R6可以相同或不同,并且独立地是H或烷基;
R8是H,OH,烷氧基,烷基,环烷基,芳基,-N(H)R7,-N(H)C(O)烷基,-N(H)C(O)N(H)烷基或-N(H)S(O2)烷基;和
R9是烷基,F,Cl,Br,I,NO2,C(O)NH2,C(O)N(H)R或N(H)C(O)R,其中R是烷基,OCF3,CF3或CN。
另一优选实施方式是式Ib的化合物:
式Ib
或该化合物的药学可接受盐或溶剂化物,其中:
X是亚烷基;
R1是3-氰基苯基;
R2是H;
R3是苯基,其中该苯基被一个或多个可以相同或不同的部分取代,各部分独立地选自CF3,卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;
R4是-亚烷基-N(R7)2,其中两个R7部分可以相同或不同,各R7是H,烷基,环烷基或烷基,其中所述的烷基,芳基或环烷基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;或各R7可以连接在一起并且与其所连的氮构成3至7-元杂环环;或R4选自
和
R8是H,烷基,环烷基,芳基,-N(H)烷基,-N(H)芳基,OH,烷氧基,-N(H)C(O)烷基,-N(H)C(O)N(H)烷基或-N(H)S(O2)烷基。
另一优选实施方式是式Ic的化合物:
甲基是(S),(R)或消旋
式Ic
或该化合物的药学可接受盐或溶剂化物,其中:
R1是3-氰基苯基;
R2是H;
R3是苯基,其中该苯基被一个或多个可以相同或不同的部分取代,各部分独立地选自CF3,卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;
R4是-亚烷基-N(R7)2,其中两个R7部分可以相同或不同,各R7是H,烷基,环烷基或芳基,其中所述的烷基,芳基或环烷基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;或各R7可以连接在一起并且与其所连的氮构成3至7-元杂环环;或R4选自
或
和
R8是H,烷基,环烷基,芳基,-N(H)烷基,-N(H)芳基,OH,烷氧基,-N(H)C(O)烷基和-N(H)C(O)N(H)烷基或-N(H)S(O2)烷基。
另一优选实施方式是式IIa的化合物:
式IIa
或该化合物的药学可接受盐或溶剂化物,其中:
R1是3-氰基苯基;
R2是H;
R3是苯基,其中该苯基被一个或多个可以相同或不同的部分取代,各部分独立地选自CF3,卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;
R8是H,OH,烷基,环烷基,芳基,-N(H)烷基,-N(H)芳基,-N(H)C(O)烷基,N(H)C(O)N(H)烷基或-N(H)S(O2)烷基;和
R10选自-亚烷基(R7)2,
或
其中两个R7部分可以相同或不同,各R7是H,烷基,环烷基或芳基,其中所述的烷基,芳基或环烷基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;或各R7可以连接在一起并且与其所连的氮构成3至7-元杂环环。
一组特别优选的化合物是实施例1-65和实验实施例的表1、2和3中所示。
本发明的式I或II的拮抗剂可以作为外消旋混合物或对映体纯化合物给药。
如上所述,并且在本文全文中,下列术语,除非另外说明,应理解具有下列含义:
″患者″包括人和动物。
″哺乳动物″是指人和其他哺乳动物。
″烷基″是指脂族烃基,其可以是直链或支链且链中含有约1-约20碳原子。优选的烷基链中含有约1-约12个碳原子。更优选的烷基链中含有约1-约6个碳原子。支链是指一个或多个低级烷基例如甲基,乙基或丙基,连接于线性烷基链。″低级烷基″是指链中具有约1-约6个碳原子,其可以是直链或支链。术语″取代的烷基″是指可以被一个或多个可以相同或不同的取代基取代的烷基,各取代基独立地选自卤素,烷基,烷基,环烷基,氰基,羟基,烷氧基,烷硫基,氨基,-NH(烷基),-NH(环烷基),-N(烷基)2,羧基和-C(O)O-烷基。适当烷基的非限定实例包括甲基,乙基,正丙基,异丙基和叔丁基。
″芳基″是指含有约6-约14个碳原子、优选约6-约10个碳原子的芳族单环或多环环系。所述的烷基可以任选独立地被一个或多个″环系取代基″取代,取代基可以相同或不同,并且如本发明定义。适当烷基的非限定实例包括苯基和萘基。
″杂烷基″是指含有约5-14个环原子、优选约5-约10个环原子的芳族单环或多环环系,其中所述环原子的一个或多个是非碳元素,例如氮、氧或硫,单独或联合时。优选的杂芳基含有约5-约6环原子。″杂芳基″可以任选地被一个或多个可以相同或不同的″环系取代基″取代,并且如本文定义。杂芳基根名的前缀氮杂、氧杂或硫杂分别是指至少一个氮、氧或硫作为环原子存在。杂芳基的氮原子可以任选氧化为相应的N-氧化物。适当杂芳基的非限定实例包括吡啶基,吡嗪基,呋喃基,噻吩基,嘧啶基,异噁唑基,异噻唑基,噁唑基,噻唑基,吡唑基,呋咱基,吡咯基,吡唑基,三唑基,1,2,4-噻二唑基,吡嗪基,哒嗪基,喹喔啉基,酞嗪基,咪唑并[1,2-a]吡啶基,咪唑并[2,1-b]噻唑基,苯并呋咱基,吲哚基,氮杂吲哚基,苯并咪唑基,苯并噻吩基,喹啉基,咪唑基,噻吩并吡啶基,喹唑啉基,噻吩并嘧啶基,吡咯并吡啶基,咪唑并吡啶基,异喹啉基,苯并氮杂吲哚基,1,2,4-三嗪基,苯并噻唑基等。
″芳烷基″或″烷基烷基″是指烷基-烷基-,其中所述的烷基和烷基如上所述。优选的芳烷基包括低级烷基。适当芳烷基的非限定实例包括苄基,2-苯乙基和萘基甲基。甲基通过该烷基与母体部分相连。
″环烷基″是指含有约3-约10个碳原子、优选约3-约10个碳原子的非芳族单-或多环环系。优选的环烷基环含有约3-约7个环原子。所述的环烷基可以任选地被一个或多个可以相同或不同的″环系取代基″,并且定义如上。适当单环环烷基的非限定实例包括环丙基,环戊基,环己基,环庚基等。适当多环环烷基的非限定实例包括1-萘烷基,降冰片基,金刚烷基等。
″环烷基烷基″是指环烷基烷基。适当环烷基烷基的非限定实例包括环丙基甲基和环丙基乙基。价键通过烷基与母体部分相连。
″杂环基烷基″是指杂环基-烷基。适当杂环基烷基的非限定实例包括哌啶基甲基和哌嗪基甲基。价键通过烷基与母体部分相连。
″卤素″是指氟,氯,溴,或碘。优选氟,氯或溴,并且更优选是氟和氯。
″卤代″是指氟,氯,溴,或碘基。优选氟,氯或溴,并且更优选氟和氯。
″环系取代基″是指与芳族或非芳族环系相连的取代基,例如,其取代了环系上的可利用氢。环系取代基可以相同或不同,各自独立地选自芳烷基,杂芳烷基,羟基,羟基烷基,烷氧基,芳氧基,芳烷氧基,酰基,芳酰基,卤素,硝基,氰基,羧基,烷氧基羰基,芳氧基羰基,芳烷氧基羰基,烷基磺酰基,烷基磺酰基,杂芳基磺酰基,烷硫基,烷硫基,杂芳硫基,芳烷硫基,杂芳烷硫基,环烷基,杂环基,Y1Y2N-,Y1Y2N-烷基-,Y1Y2NC(O)-和Y1Y2NSO2-,其中
″杂环基″是指含有约3-约10碳原子、优选约5-约10个环原子的非芳族饱和单环或多环环系,其中环系中的一个或多个原子是非碳元素,例如氮、氧或硫,单用或合用。环系中不存在相邻的氧和/或硫原子。优选的杂环基含有约含有约5-约6环原子。杂环基根名之前的前缀氮杂,氧杂或硫杂分别是指至少一个氮、氧或硫原子作为环原子存在。该杂环基可以任选被一个或多个可以相同或不同的″环系取代基″取代,并且如本文定义。杂环基的氮或硫原子可以任选氧化为相应的N-氧化物,S-氧化物或S,S-二氧化物。适当单环杂环基环的非限定实例包括哌啶基,吡咯烷基,哌嗪基,吗啉基,硫代吗啉基,噻唑烷基,1,4-二噁烷基,四氢呋喃基,吡咯烷酮基,四氢硫代苯基等。
″杂芳烷基″是指杂芳基-烷基,其中该杂芳基和烷基如上定义。优选的杂芳烷基含有低级烷基。适当芳烷基的非限定实例包括吡啶基甲基,和喹啉-3-基甲基。价键通过烷基与母体部分相连。
″羟基烷基″是指HO-烷基-,其中烷基定义如上。
优选的羟基烷基含有低级烷基。适当羟基烷基的非限定实例包括羟基甲基和2-羟基乙基。
″酰基″是指H-C(O)-,烷基-C(O)-或环烷基-C(O)-,其中不同基团如上所述。母体部分的价键经过羰基。优选的酰基含有低级烷基。适当酰基的非限定实例包括甲酰基,乙酰基和丙酰基。
″芳酰基″是指烷基-C(O)-,其中该烷基如上定义。母体部分的价键经过羰基。适当基团的非限定实例包括苯甲酰基和1-萘酰基。
″烷氧基″是指烷基-O-基团,其中所述的烷基如上定义。适当烷氧基的非限定实例包括甲氧基,乙氧基,正丙氧基,异丙氧基和正丁氧基。母体部分的价键经醚氧。
″芳氧基″是指烷基-O-基团,其中该烷基如上定义。适当芳氧基的非限定实例包括苯氧基和萘氧基。母体部分的价键经过醚氧。
″烷硫基″是指烷基-S-,其中该烷基如上定义。适当烷硫基的非限定实例包括甲硫基和乙硫基。母体部分的价键经过硫。
″芳硫基″是指烷基-S-,其中该烷基如上定义。适当烷硫基的非限定实例包括苯硫基和萘硫基。母体部分的价键经过硫。
″芳烷硫基″是指芳烷基-S-,其中该芳烷基如上定义。适当芳烷硫基的非限定实例是是苄硫基。母体部分的价键经过硫。
″烷氧基羰基″是指烷基-O-CO-。适当烷氧基羰基的非限定实例包括甲氧基羰基和乙氧基羰基。母体部分的价键经过羰基。
″芳氧基羰基″是指烷基-O-C(O)-。适当芳氧基羰基的非限定实例包括苯氧基羰基和萘氧基羰基。母体部分的价键经过羰基。
″芳烷氧基羰基″是指芳烷基-O-C(O)-。适当芳烷氧基羰基的非限定实例是苄氧基羰基。母体部分的价键经过羰基。
″烷基磺酰基″是指烷基-S(O2)-。优选的基团是那些其中烷基是低级烷基的基团。母体部分的价键经过磺酰基。
″芳基磺酰基″是指烷基-S(O2)-。母体部分的价键经过磺酰基。
术语″取代的″是指指定原子上的一个或多个氢被自所示基团的选择取代,条件是指定原子的正常化合价在已有环境下没有满足,并且取代得到稳定的化合物。取代基和/或变量的联合只有在该联合可得到稳定化合物下允许。所谓″稳定化合物′或″稳定结构″是指足以坚定地由反应混合物分离保留达到可用纯度的化合物,并且配制为有效的治疗剂。
术语″任选取代的″是指被特定基团、原子团或部分的任选取代。
还应当注意,正文、路线、实施例和表中的任何具有不满化合价的杂原子被推定具有填满其化合价的氢原子。
当化合物中的官能团被称作″保护的″,这是指该基团为修饰形式以阻止当该混合物进行反应时在该保护位点的不利副反应。所属领域普通技术人员应懂得适当的保护基并且参考标准书籍,例如,T.W.Greene等,Protective Groups in organic Synthesis(1991),Wiley,NewYork。
当任何变量(例如,烷基,杂环,R2等)在组成或式中出现不止一次时,其在各种情况中的定义在每种不同情况中具有其独立定义。
在此使用的术语″组合物″包括含有特定含量的特定成分的产品,以及任何直接或间接由特定含量的特定成分的组合获得的产品。
在此还考虑本发明的化合物的前药和溶剂化物。在此使用的术语″前药″代表是药物前体的化合物,其在施用给对象时通过代谢或化学过程发生化学转化生成式I或II的化合物或其盐和/或溶剂化物。前药的讨论提供在T.Higuchi and V.Stella,Pro-drugs as Novel DeliverySystems(1987)14 of the A.C.S.Symposium Series中,和BioreversibleCarriers in Drug Design,(1987)Edward B.Roche,ed.,AmericanPharmaceutical Association and Pergamon Press中,这两者在此引入作为参考。
″溶剂化物″是指本发明的化合物与一种或多种溶剂分子的物理缔合物。该物理缔合物包括不同程度的离子和共价键,包括氢键。在某些情况中所述的溶剂化物应能够分离,例如当将一种或多种溶剂分子混合在结晶的晶格中时。″溶剂化物″包括溶液相和可分离溶剂化物两者。适当溶剂化物的非限定实例包括乙醇化物,甲醇化物等。″水合物″是指一种溶剂分钟是H2O的溶剂化物。
″有效量″或″治疗有效量″是指描述了本发明的化合物或组合物有效拮抗多巴胺受体并由此产生预期治疗、改善或预防作用的量。
式I和II的化合物可以形成盐,其也属于本发明的范围内。在此优选的式I和II的化合物包括参考其盐,除非另外说明。本文使用的术语″盐″代表与无机和/或有机酸形成的酸性盐,以及与无机和/或有机碱形成的碱性盐。此外,当式I和II的化合物同时含有碱性部分,例如但不限于吡啶或咪唑,和酸性部分,例如但不限于羧酸时,可以形成两性离子(″内盐″)并且包括在在此使用的术语″盐″内。虽然也使用前体盐,但优选药学可接受(即,无毒,生理可接受)盐。
式I和II的化合物盐可以,例如,通过式I和II的化合物与一定量的酸或碱的反应来形成,例如等量,在介质中,例如在沉淀该盐的介质中或者在含水介质中随后冷冻干燥。
实例酸加成盐包括乙酸盐,抗坏血酸盐,苯甲酸盐,苯磺酸盐,硫酸氢盐,硼酸盐,丁酸盐,柠檬酸盐,樟脑酸盐,樟脑磺酸盐,富马酸盐,盐酸盐,氢溴酸盐,氢碘酸盐,乳酸盐,马来酸盐,甲磺酸盐,萘磺酸盐,硝酸盐,草酸盐,磷酸盐,丙酸盐,水杨酸盐,琥珀酸盐,硫酸盐,酒石酸盐,硫氰酸盐,甲苯磺酸盐(也称作tosylates,)等。此外,一般考虑适于由碱性药学化合物形成可药用盐的酸由例如,S.Berge等在Journal of Pharmaceutical Sciences(1977)66IU 1-19;P.Gould,Intemational J.of Pharmaceutics(1986)33 201-217;Anderson等在The Practice of Medicinal Chemistry(1996),Academic Press,NewYork;和在The Orange Book(Food & Drug Administration,Washington,D.C.on their website)中讨论。这些出版物在此引入作为参考。
实例碱性盐包括铵盐,碱金属盐例如钠,锂,和钾盐,碱土金属盐例如钙和镁盐,与有机碱(例如,有机胺)例如二环己基胺类,叔丁胺类的盐,和与氨基酸例如精氨酸,赖氨酸等的盐。碱性含氮基团可以用试剂例如低级烷基卤化物(例如甲基,乙基,和丁基氯化物,溴化物和碘化物),二烷基硫酸盐(例如二甲基,二乙基,和二丁基硫酸盐),长链卤化物(例如癸基,十二烷基和硬脂基氯化物,溴化物和碘化物),芳烷基卤化物(例如苄基和苯乙基溴化物)和其他试剂季铵化。
所有这些酸性盐和碱性盐是属于本发明范围内的药学可接受盐并且所有酸性和碱性盐被认为等同于本发明目的的相应化合物的游离形式。
式I和II的化合物,和其盐和溶剂化物,可以以互变异构体形式存在(例如,如酰胺或亚氨醚)。所有这样的合并异构体在此被认为是本发明的组成部分。
本发明化合物的所有立体异构体(例如,几何异构体,光学异构体等)(包括所述化合物的盐和溶剂化物),例如由于取代基不同的不对称碳而存在的那些,包括对映异构体(其甚至可以在不存在不对称碳下存在),几何异构体,阻转异构体,和非对映异构体,被考虑在本发明的范围内。本发明的化合物的各种立体异构体可以,例如,基本上不含有其他异构体,或可以混合,例如,成为消旋体或含有所有其他,或其他选定的立体异构体。本发明的手性中心可以具有S或R构型,如IUPAC1974推荐的定义。术语″盐″,″溶剂化物″″前药″等的使用,同样用于本发明化合物的对映体、立体异构体、旋转异构体、互变异构体、消旋体和前药的盐,溶剂化物和前药。
N-氧化物可以在X1,R或R2取代基中存在的叔氮上,或杂芳基环取代基中存在的=N-上形成并且属于式I和II的化合物。
对于本发明具有至少一个不对称碳原子的化合物来说,所有异构体,包括非对映异构体、对映异构体和转动异构体考虑是本发明的组成部分。本发明纯净和混合形式的d和l异构体,包括外消旋混合物。异构体可以利用常规技术制备,或者通过光学醇或光学富集的起始原料反应或者通过分离式I或II的异构体。
式I和II的混合物可以以非溶剂化物和溶剂化物存在,包括水化形式。通常,与药学可接受盐溶剂如水、乙醇等的溶剂化形式等同于本发明目的的非溶剂化形式。
式I或II的化合物可以形成与有机和无机酸的药学可接受盐。例如,吡啶-氮原子可以与强酸形成盐,而且叔氨基可以与弱酸形成盐。适合形成盐的酸的实例是盐酸、硫酸、磷酸,柠檬酸、丙二酸、水杨酸、苹果酸、富马酸、琥珀酸、抗坏血酸、马来酸、甲黑色和所属领域技术人员熟知的其他无机酸和羧酸。所述的盐是通过使游离碱形式与足够量的所需酸以常规方式接触生成盐。游离碱形式可以通过用适当的稀释碱水溶液处理盐来制备,例如稀释氢氧化钠、碳酸钾、氨或碳酸氢钠水溶液。游离碱在某些物理性质上略不同于其各自的盐形式,例如在极性溶剂中的溶解度,但盐在本发明的目的上等同于其各自的游离形式。
本发明的另一方面是一种治疗患有MCH介导的疾病或病症的患者(例如,人)的方法,通过施用治疗有效量的式I或II的化合物,或该化合物的药学可接受盐给该患者。
优选的剂量是约0.001-100mg/kg/天的式I或II化合物。尤其优选的剂量是约0.01-25mg/kg/天的式I或II的化合物,或该化合物的药学可接受盐。
本发明的另一方面涉及一种治疗肥胖的方法,包括给需要此类治疗的患者施用治疗有效量式I或II的化合物,或该化合物的药学可接受盐。
本发明的另一方面涉及一种治疗代谢疾病例如肥胖和饮食疾病例如食欲过盛和厌食的方法,该方法包括给患者施用治疗有效量的式I或II的化合物,或该化合物的药学可接受盐。
本发明的另一方面涉及一种治疗高脂血症的方法,包括给对施用治疗有效量的式I或II的化合物,或该化合物的药学可接受盐。
本发明的另一方面涉及一种治疗蜂窝组织炎和脂肪蓄积的方法,包括给该对象施用治疗有效量的式I或II的化合物,或该化合物的药学可接受盐。
本发明的另一方面涉及一种治疗II型糖尿病的方法,该方法包括给患者施用治疗有效量的式I或II的化合物,或该化合物的药学可接受盐。
除了本发明的化合物对MCH亚型的″直接″作用,受益于体重损失的疾病和病症例如是胰岛素抗性、损害的葡萄糖耐受性、II型糖尿病、高血压、高脂血症、心血管疾病、胆结石、某些癌症和睡眠窒息。
本发明还涉及含有一定量的式I或II的化合物,或该化合物的药学可接受盐和药学可接受载体的药物组合物。
本发明还涉及用于治疗肥胖的药物组合物,其含有肥胖治疗量的式I或II的化合物,或该化合物的药学可接受盐和其药学可接受盐载体。
式I和II的化合物可以通过所属领域技术人员已知的方法利用下列反应路线中所示的溶液相或固相合成来制备,在下面的制备例和实施例中。
式Ia(其中R6是H)和Ib的化合物按照路线1所示的方法制备。
式Ia 式Ib
路线1
苯胺2用溴代乙酰溴酰化得到酰胺酰胺3。胺4,其中X是a-(C1-C2)亚烷基,与烷基硼酸的Suzuki偶联得到二烷基胺5。溴化物3与胺5的亲核性置换得到二级胺6,其随后在标准条件下偶联于酸其中n=1或2得到氯化物7。或者,胺6用溴代乙酰溴酰化得到溴化物7。氯化物和溴化物7用适当胺的亲核性置换得到所需二-酰胺Ib其中R4在详述中已经描述。或者,可以改变步骤的顺序使Suzuki偶联在该顺序的最后进行。
式Ia(其中R6是烷基)和Ic的是按照路线2所示的方法制备。
甲基是(S),(R)或消旋
式Ic
路线2
4-溴-α-甲基苄基胺8(手性或外消旋)与烷基硼酸的Suzuki偶联得到二烷基胺9。溴化物3和胺9的亲核性置换得到二级胺10,其随后在标准条件下偶联于酸其中n=1或2得到氯化物11。或者,胺10被溴代乙酰溴酰化得到溴化物11。氯化物或溴化物11与适当胺的亲核性置换生成所需二-酰胺Ic其中R4如详述中定义。
或者,式Ib和Ic(其中n=2)的化合物可以按照路线3制备。
路线3
胺6或10在碱如TEA的存在下用丙烯酰氯酰化得到烯烃12。适当胺的加入得到所需的二-酰胺Ib或Ic,其中R4如详述中的上述定义。
本发明的式II的化合物按照路线4所示方法制备。
路线4
胺13用酰卤化物14酰化得到酰胺15。15与胺的烷基化得到胺16,其随后可以与酸17在标准条件下偶联。18与适当烃基代硼酸的Suzuki偶联得到II型的化合物。
下列路线举例说明上述合成顺序(路线5)中使用的非市售有用起始原料的合成的同样方法。胺A用酸化酰化得到酰胺B。B的卤化得到烷基卤化物C,其随后用碱脱保护得到卤化中间体D。
式I和II的化合物具有MCH受体拮抗活性,它与治疗饮食疾病的药学活性有关,例如肥胖和饮食过多,和糖尿病。
式I和II的化合物在设计证明MCH受体拮抗活性的实验过程中表现出药理学活性。该化合物在药学治疗剂量下是无毒的。
本发明的另一方面是式I或II的化合物,或该药学可接受盐与一种或多种下列其他化合物的组合。
所以,本发明的另一方面是用于治疗肥胖的方法,包括施用给患者
a.一定量的第一化合物,该第一化合物是式I或II化合物,或该化合物的药学可接受盐;和
b.一定量的至少一种其他化合物,该其他化合物(b)选择抗肥胖和/或减食欲药例如β3激动剂,拟甲状腺药物,厌食(an anoretic)药物,和NPY拮抗剂其中该(a)和(b)化合物的量得到治疗效果。
本发明还涉及药学联合组合物含有:治疗有效量的含有第一化合物的组合物,该第一化合物是式I或II化合物,或该化合物的药学可接受盐;和至少一种其他化合物,其选自抗肥胖和/或减食欲药物例如β3激动剂,拟甲状腺药物,厌食物,和NPY拮抗剂;和/或任选的药学可接受载体,赋形剂或稀释剂。
本发明的另一方面是一种套盒包括:
a.在第一单位剂型中一定量的式I或II化合物,或该化合物的药学可接受盐和药学可接受载体,赋形剂或稀释剂;
b.在第二单位剂型中至少一种抗肥胖和/或减食欲药物例如β3激动剂,拟甲状腺药物,厌食物,和NPY拮抗剂和可接受药学载体,赋形剂或稀释剂;和
c.含有上述第一和第二剂型的装置,其中第一和第二化合物的量获得治疗效果。
在上述联合方法、联合组合物和组合套盒中优选的抗肥胖和/或减食欲药物(单独或联合使用)是:苯丙醇胺,麻黄碱,假麻黄碱,苯丁胺,缩胆囊肽-A(此后称作CCK-A)激动剂,单胺摄取硬脂基(例如西布茶明),拟交感神经药物,5-羟色胺能药物(例如右旋芬氟拉明或芬氟拉明),多巴胺激动剂(例如溴隐停),黑素细胞刺激激素受体激动剂或模拟物,黑素细胞刺激激素类似物,大麻碱(cannabinoid)受体拮抗剂,黑素浓缩激素拮抗剂,OB蛋白(此后称作″leptin″),leptin类似物,leptin受体激动剂,galanin拮抗剂或GI脂肪酶抑制剂或减少剂(例如orlistat)。其他减食欲药物包括铃蟾肽激动剂,脱氢表雄酮或其类似物,糖皮质激素受体激动剂和拮抗剂,阿立新受体拮抗剂,urocortin结合蛋白拮抗剂,高血糖素样肽-1受体的激动剂例如Exendin和睫状神经营养因子例如Axokine。
本发明的另一方面是一种治疗糖尿病的方法,包括给患者(例如,女性或男性人类)施用:
a.一定量的第一化合物,该第一化合物是式I或II化合物,或该化合物的药学可接受盐;和
b.至少一种其他化合物,选自醛糖还原酶抑制剂,糖原磷酸化酶抑制剂,山梨糖醇脱氢酶抑制剂,蛋白酪氨酸磷酸化酶1B抑制剂,二肽基蛋白酶抑制剂,胰岛素(包括口服利用的胰岛素制剂),胰岛素模拟物,甲福明,阿卡糖,PPAR-γ配体例如曲格列酮(troglitazone),罗格列酮(rosaglitazone),吡格列酮(pioglitazone)或GW-1929,磺酰脲,格列吡嗪(glipazide),格列苯脲和氯磺丙脲,其中(a)和(b)化合物的量产生治疗效果。
本发明还涉及药学联合组合物含有:治疗有效量的组合物含有第一化合物,该第一化合物是式I或II化合物,或该化合物的药学可接受盐;至少一种其他化合物,选自醛糖还原酶抑制剂,糖原磷酸化酶抑制剂,山梨糖醇脱氢酶抑制剂,蛋白酪氨酸磷酸化酶1B抑制剂,二肽基蛋白酶抑制剂,胰岛素(包括口服利用的胰岛素制剂),胰岛素模拟物,甲福明,阿卡糖,PPAR-γ配体例如曲格列酮(troglitazone),罗格列酮(rosaglitazone),吡格列酮(pioglitazone)或GW-1929,磺酰脲,格列吡嗪(glipazide),格列苯脲和氯磺丙脲;和任选的药学载体、赋形剂或稀释剂。
本发明的另一方面是一种套盒包括:
a.在第一单位剂型中一定量的式I或II化合物,或该化合物的药学可接受盐和药学可接受载体,赋形剂或稀释剂;
b.在第二单位剂型中至少一种其他化合物,选自醛糖还原酶抑制剂,糖原磷酸化酶抑制剂,山梨糖醇脱氢酶抑制剂,蛋白酪氨酸磷酸化酶1 B抑制剂,二肽基蛋白酶抑制剂,胰岛素(包括口服利用的胰岛素制剂),胰岛素模拟物,甲福明,阿卡糖,PPAR-γ配体例如曲格列酮(troglitazone),罗格列酮(rosaglitazone),吡格列酮(pioglitazone)或GW-1929,磺酰脲,格列吡嗪(glipazide),格列苯脲和氯磺丙脲和药学可接受载体、赋形剂或稀释剂;和
c.含有第一和第二剂型的装置,其中第一和第二化合物的量获得治疗效果。
活性化合物在制剂的单位剂量中的量可以在约1mg-约100mg,右旋约1mg-约50mg,更优选约1mg-约25mg根据具体应用来改变或调整。
实际使用的剂量可根据患者的需求和被治疗病症的严重性而变化。决定具体情况中的适当剂量方案属于所属领域的技术范畴内。为了方便,全天剂量可以再分吡嗪根据需要在1天内分次给药。
本发明的化合物和/或其药学可接受盐的给药的量和次数应根据主治医师考虑此类因素如患者年龄、状况和大小以及被治疗症状的严重性作出的判断进行调整。口服给药的典型推荐日剂量可以是自约1mg/天-约300mg/天,优选1mg/天-50mg/天,分2-4次给药。
为了从本发明所述的化合物制备药物组合物,惰性、药学可接受载体可以是固体或液体。
固体制剂包括散剂、片剂、可酚酸颗粒剂、胶囊、囊形片和栓剂。散剂和片剂可以含有约5-约95%活性成分。适当的固体载体是所属领域已知的,例如,碳酸镁,硬脂酸镁,滑石,蔗糖或乳糖。片剂,散剂,囊形片和胶囊可以用作适合口服给药的固体剂型。药学可接受载体和用于不同组合物的制备方法的实例可以参见A.Gennaro(ed.),Remington′s Pharmaceutical Sciences,18th Edition,(1990),Mack Publishing Co.,Easton,Pennsylvania.。
液体形式的制备包括溶液,混悬剂和乳剂。作为实例可以提及用于非肠道注射的水或水-丙二醇溶液或为口服溶液、混悬液和乳剂加入甜味剂和遮光剂。液体制剂还可以包括鼻内给药的溶液。
适合吸入的气雾剂制剂可以包括溶液和粉末形式的固体,其可以与药学可接受载体混合,例如惰性压缩气体,例如氮。
还包括使用之前短时间转化为液体制剂用于口服或非肠道给药的固体制剂。此类液体包括溶液、混悬剂和乳剂。
本发明的化合物还包括可透皮给药的。沟通组合物可以采取霜剂、洗剂、气雾剂和/或乳剂的形式且可以包括基质或储库型的透皮贴剂,这是该领域中此目的常规的。
优选化合物经口服给药。
优选地,药学制剂为单位剂型。在此类剂型中,制剂再分为适当大小的含有适量活性成分的单位剂量,例如,达到预期目的的有效量。
本发明还涉及治疗代谢疾病例如肥胖,和饮食疾病(例如饮食过多)的药物组合物例如。
为了从本发明所述的化合物制备药物组合物,惰性、药学可接受载体可以是固体或液体。固体制剂包括散剂、片剂、可酚酸颗粒剂、胶囊、囊形片和栓剂。散剂和片剂可以含有约5-约95%活性成分。适当的固体载体是所属领域已知的,例如,碳酸镁,硬脂酸镁,滑石,蔗糖或乳糖。片剂,散剂,囊形片和胶囊可以用作适合口服给药的固体剂型。药学可接受载体和用于不同组合物的制备方法的实例可以参见A.Gennaro(ed.),Remington′s Pharmaceutical Sciences,18th Edition,(1990),Mack Publishing Co.,Easton,Pennsylvania.。
液体形式的制备包括溶液,混悬剂和乳剂。作为实例可以提及用于非肠道注射的水或水-丙二醇溶液或为口服溶液、混悬液和乳剂加入甜味剂和遮光剂。液体制剂还可以包括鼻内给药的溶液。
适合吸入的气雾剂制剂可以包括溶液和粉末形式的固体,其可以与药学可接受载体混合,例如惰性压缩气体,例如氮。
还包括使用之前短时间转化为液体制剂用于口服或非肠道给药的固体制剂。此类液体包括溶液、混悬剂和乳剂。
本发明的化合物还包括可透皮给药的。沟通组合物可以采取霜剂、洗剂、气雾剂和/或乳剂的形式且可以包括基质或储库型的透皮贴剂,这是该领域中此目的常规的。
本发明的化合物还可以经皮下给药。
优选该化合物经口服给药。
本发明在此通过下列制备和实施例举例,其不应构成对内容范围的限定。其他机械途径和类似结构对于所属领域技术人员来说是显而易见的。
其中给出NMR数据,1H光谱是在Varian VXR-200(200MHz,1H),Varian Gemini-300(300MHz)或XL-400(400MHz)上获得并且报告为距离Me4Si低场的ppm,同时质子的数目、多重态和偶合常数以赫兹(Hertz)表示在括号内。其中给出LC/MS数据,分析是利用AppliedBiosystemsAPI-100质谱仪和ShimadzuSCL-10A LC柱进行:Altech铂C18,3微米,33mm×7mm ID;梯度流量:0min-10%CH3CN,5min-95%CH3CN,7min-95%CH3CN,7.5min-10%CH3CN,9min-停止。给出保留时间和观察的母体离子。
本发明的化合物通过下列制备实施例举例说明,其不应构成对本发明范围的限定。或者e其他机械途径和类似结构对于所属领域技术人员来说是显而易见的。
起始原料是通过已知方法和/或制备例中所述的方法来制成。
下列溶剂和实际可以参考其在圆括号中的缩写:
乙酸乙酯(EtOAc);
甲醇(MeOH);
三乙胺(TEA);
核磁共振光谱(H NMR);
液体色谱质谱(LCMS);
高分辨质谱(HRMS);
毫升(mL);
毫摩尔(mmol);
微升(μl)
克(g);
毫克(mg);
室温(常温)约25℃(rt);
1,2-二甲氧基乙烷(DME);
乙醇(EtOH);
N,N-二甲基甲酰胺(DMF);
1-羟基苯并三唑(HOBt);
2-1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI);
3-叔丁醇羰基(Boc)。
试验实施例
下列实施例举例说明某些本发明的化合物的制备并且不构成对本发明的限定。
实施例1
步骤1:
向3,5-二氯苯胺(10.4g,64.18mmol)在冷却至0℃的二氯甲烷中的搅拌溶液内滴加溴代乙酰溴(6.71mL,77.02mmol)。将该混合物在0℃下轻轻搅拌1小时。该反应混合物用10%NaOH猝灭且用二氯甲烷萃取。合并的萃取液用Na2SO4干燥且浓缩得到16.21g(90%)的溴化物,全文固体。
步骤2:
向4-溴代苄基胺盐酸化物(12.2g,54.82mmol)在250mL甲苯∶乙醇∶H2O(3∶1∶1)中的搅拌溶液内加入3-氰基苯基硼酸(16.11g,109.65mmol),Pd(PPh3)4(6.3g,5.48mmol)和Na2CO3(35g,330mmol)。该混合物用N2脱气,随后加热至100℃达24小时。该反应混合物浓缩,随后用EtOAc稀释,用H2O洗涤,用MgSO4干燥,过滤,浓缩和用硅胶层析(用MeOH/CH2Cl2洗脱)得到7.44g(65%)的二烷基胺,其为油。
步骤3:
向步骤2中形成的胺(3.88g,18.65mmol)和步骤1中形成的溴化物(2.64g,9.32mmol)在DMF(20mL)中的搅拌溶液内加入K2CO3(3.86g,27.98mmol)且加热至50℃达6小时。该反应混合物被浓缩,随后用EtOAc稀释,用H2O洗涤,用Na2SO4干燥,浓缩并用硅胶层析(用EtOAc/己烷洗脱)得到2.92g(76%)的胺。
步骤4:
向步骤3中形成的胺(0.41g,1.01mmol)在二氯甲烷(3mL)中的搅拌溶液内加入3-氯丙酸(0.22g,2.03mmol)和EDCI(0.38g,2.03mmol)并且在rt下搅拌24小时。该反应混合物浓缩且用作步骤5的粗混合物。
步骤5:
向步骤4中形成的氯化物(0.06g,0.12mmol)在吡咯烷酮(1mL)中的搅拌溶液内加入K2CO3(0.02g,0.12mmol)和NaI(0.02g,0.12mmol)并加热至80℃达2.5小时。该反应混合物用EtOAc稀释,用NaHCO3溶液洗涤,用MgSO4干燥,过滤并层析(用EtOH/EtOAc洗脱)得到0.03g(51%)胺,其为固体。
300MHz-1H NMR(CDCl3)-9.08,*8.23(s,1H);7.83(s,1H);7.80-7.76(m,1H);7.66-7.46(m,4H);7.43-7.42(d,2H);7.33-7.26(d,2H);7.05(s,1H);4.78,*4.73(s,2H);*4.16,4.13(s,2H);2.93-2.77(m,2H);2.75-2.53(m,2H);1.81-1.75(m,4H)。提供的数据是旋转异构体的混合物,*表示次裂分峰。
HRMS(M+H+)535.1663
MCH Ki=21nm
而且,下列是表1中实施例9的方法,其也按照路线1制备。
步骤1:
向3,5-二氯苯胺(10.4g,64.18mmol)在冷却至0℃的二氯甲烷中的搅拌溶液内滴加溴代乙酰溴(6.71mL,77.02mmol)。沉淀的混合物在0℃下搅拌1小时。该反应混合物用10%NaOH终止且用二氯甲烷萃取。合并的萃取液用Na2SO4干燥且浓缩得到16.21g(90%)的溴化物,其为固体。
步骤2:
向4-溴苯基乙基胺盐酸化物(12.6g,63.00mmol)在250mL甲苯∶乙醇∶H2O(3∶1∶1)中的搅拌溶液内加入3-氰基苯基硼酸(13.71g,109.65mmol),Pd(PPh3)4(7.2g,6.3mmol)和Na2CO3(33g,330mmol)。该混合物用N2脱气,随后加热至100℃达24小时。该反应混合物被浓缩,随后用EtOAc稀释,用H2O洗涤,用MgSO4干燥,过滤,浓缩并用硅胶层析(用MeOH/CH2Cl2洗脱)得到8.2g(58%)的联烷基胺,其为油。
步骤3:
向步骤2中形成的胺(2.0g,9.0mmol)和步骤1中形成的溴化物(1.69g,6.00mmol)在CH3CN(30mL)中的搅拌溶液内加入K2CO3(1.65g,12.0mmol)并加热至50℃达6小时。该反应混合物被浓缩,随后用EtOAc稀释,用H2O洗涤,用Na2SO4干燥,浓缩并用硅胶层析(用EtOAc/己烷洗脱)得到1.6g(64%)的胺。
步骤4:
向步骤3中形成的胺(0.54g,1.27mmol)在二氯甲烷(10mL)中的搅拌溶液内加入丙烯酰氯(0.114g,1.91mmol)和三乙胺(0.266mL,1.99mmol)且在rt下搅拌24小时。该反应混合物用二氯甲烷稀释,用水洗涤,用MgSO4干燥,过滤,浓缩且用于下面步骤无需纯化。
步骤5:
向步骤4中的烯烃(0.030,0.62mmol)在二氯甲烷(1mL)中的搅拌溶液内加入吡咯烷(0.1mL)且在rt下搅拌24小时。该反应混合物被浓缩且纯化得到0.02g(59%)的胺。
300MHz-1H NMR(CDCl3)-9.28(s,1H);7.83(s,1H);7.80-7.76(m,1H);7.66-7.46(m,4H);7.43-7.42(d,2H);7.33-7.26(d,2H);7.05(s,1H);4.42,*4.52(s,2H);*4.16,4.13(s,2H);3.73(m,2H),3.44-2.77(m,2H);2.75-2.53(m,2H);1.81-1.75(m,4H).提供的数据是旋转异构体的混合物,*表示次裂分峰。
HRMS(M+H+)549.1835
实施例2--39
所用制备方法硫酸盐实施例1和实施例9所述的方法,制备下列化合物:
表1
实施例 结构 HRMS MCH Ki(nm)
3
535.1919 3.7
4
519.1957 5.3
6
565.1617 7.2
7
549.1830 9.3
10
585.1872 11.0
13
550.1768 13.0
14
551.1607 15.0
15
535.1658 19.0
16
537.1816 24.0
19
553.2230 28.0
20
535.1662 32.0
21
521.1500 35.0
23
549.1835 37.0
27
537.1452 61.0
28
564.1933 63.0
31
592.1875 82.0
33
551.1612
36
565.1777 8
37
563.1975 9
39
564.1940
实施例40-60式按照路线2和3制备
实施例40
步骤1:
向3,5-二氯苯胺(10.4g,64.18mmol)在冷却至0℃的二氯甲烷中搅拌溶液内滴加溴代乙酰溴(6.71mL,77.02mmol)。沉淀的混合物在0℃搅拌1小时。该反应混合物用10%NaOH终止且用二氯甲烷萃取。合并的萃取液用Na2SO4干燥且浓缩得到16.21g(90%)的溴化物,其为固体。
步骤2:
向4-溴-α-甲基苯基胺(1.0mL,6.98mmol)在25mL甲苯∶乙醇∶H2O(3∶1∶1)中的搅拌溶液内加入3-氰基苯基硼酸(2.05g,13.96mmol),Pd(PPh3)4(0.81g,0.698mmol)和Na2CO3(7.39g,69.8mmol)。该混合物用N2脱气,随后加热至100℃达24小时。该反应混合物被浓缩,随后用EtOAc稀释,用H2O洗涤,用MgSO4干燥,过滤,浓缩并用硅胶层析(用MeOH/CH2Cl2洗脱)得到1.14g(73%)的联烷基胺,其为油。
步骤3:
向步骤2中形成的胺(0.51g,2.28mmol)和步骤中形成的溴化物(0.32g,1.14mmol)在CH3CN(8mL)中的搅拌溶液加入K2CO3(0.47g,3.42mmol)和加热至50℃6小时。该反应混合物被浓缩,随后用EtOAc稀释,用H2O洗涤,用Na2SO4干燥,浓缩并用硅胶层析(用EtOAc/己烷烯烃)得到0.34g(35%)的胺。
步骤4:
向步骤3中形成的胺(0.20g,0.48mmol)在二氯甲烷(3mL)中的搅拌溶液内加入氯乙酸(0.09g,0.97mmol)和EDCl(0.18g,0.97mmol)并且在rt下搅拌24小时。该反应混合物被浓缩且用作步骤5的粗混合物。
步骤5:
向步骤4中形成的氯化物(0.48mmol)在CH3CN(3mL)中的搅拌溶液加入吡咯烷(0.2mL,2.41mmol),K2CO3(0.33g,2.41mmol)和NaI(0.14g,0.96mmol)且加热至80℃达24小时。该反应混合物用EtOAc稀释,用NaHCO3溶液洗涤,用MgSO4干燥,过滤和层析(用EtOH/EtOAc洗脱)得到0.12g(47%)胺,其为固体。
300MHz-H NMR(CDC13)-*9.23,7.18(s,1H);7.82-7.77(m,2H);7.67-7.44(m,6H);7.40-7.37(d,2H);7.01(s,1H);*6.11-6.08,5.66-5.64(m,1H);*4.08,3.70(s,2H);3.59,*3.47(s,2H);*2.90-2.88,2.69-2.67(m,4H);1.89-1.58(m,4H),1.27-1.21(t,3H).提供的数据是旋转异构体的混合物,*表示次裂分峰。
HRMS(M+H+)535.1658
MCH Ki=21nm
实施例41-60
举例的制备方法类似于实施例39所述的方法,制备下列化合物:
表2
实施例 结构 HRMS Ki(MCH)
45
537.1824 22.0
46
549.1819 22.0
50
551.1987 34.0
51
523.1658 45.0
53
509.1519 78.0
56
549.1835
57
563.1621
58
561.1829
实施例61-65按照路线5制备。
实施例61
步骤1:
3,5-二氯苯胺(1.5g,9.26mmol)在CH2Cl2(100mL)中的溶液在0℃下用溴代乙酰溴(1.05mL,12.0mmol)处理。45分钟后,该反应混合物用1N NaOH,H2O洗涤,干燥且真空浓缩得到粗溴化物(2.66g),其为白色固体。
步骤2:
粗溴化物(300mg,1.06mmol)在CH3CN(10mL)中的溶液用1-(3-氨基丙基)吡咯烷(280
2.20mmol)处理且加热至60℃。7小时后,该反应混合物冷却至室温,用饱和NH4Cl水溶液稀释且用EtOAc(3x)萃取。合并的有机萃取液用饱和NaHCO3水溶液,盐水洗涤,干燥且真空浓缩。粗产物溶解在二氯乙烷(6mL)中且用4-碘代苯基乙酸(160mg,0.610mmol)处理,随后用二异丙基乙基胺(348
2.00mmol)处理。加入EDCI(156mg,0.790mmol)和HOBT(107mg,0.790mmol)且该反应混合物加热至60℃。5小时后,该反应混合物冷却至室温,用饱和NaHCO3水溶液稀释,并且用CH2Cl2(3x)萃取。合并的有机萃取液干燥且真空浓缩。闪式色谱(2%MeOH/CH2Cl2→95∶4.5∶0.5 CH2Cl2,MeOH,NH4OH梯度)得到X碘代烷基酰胺(220mg,63%共2步),其为黄色油。
步骤3:
烷基碘化物(100mg,0.174mmol)在DME/H2O(2∶1,3mL)中的溶液用碳酸钠处理(28mg,0.261mmol),随后用3-氰基苯基硼酸(38mg,0.261mmol)处理。加入Pd(dppf)Cl2(16mg,0.020mmol)且将该反应混合物加热至80℃。4小时后,该反应混合物冷却至室温,用饱和NaHCO3水溶液稀释且用EtOAc(2x)萃取。用合并的有机萃取液干燥且真空浓缩。制备薄层色谱(10%MeOH/CH2Cl2),得到联烷基酰胺(32.4mg,34%),其为澄清油:1H NMR(300MHz,CDCl3)δ9.16(s,1H),7.84(s,1H),7.78(d,J=7.8Hz,1H),7.62(d,J=7.5Hz,1H),7.56-7.50(m,3H),7.39-7.35(m,4H),7.02(s,1H),4.12(s,2H),3.97(s,2H),3.58(t,J=6.0Hz,2H),2.48-2.43(m,6H),1.85-1.78(m,6H).LCMS:549.1,rt.=5.01min(M+1),HRMSm/z549.1831[(M+H)+].
MCH Ki=62nM
实施例62-65
所用制备方法类似于实施例61所述的那些,制备下列化合物:
表3
实施例 结构 HRMS Ki(MCH)
62
519.1967
63
553.2236
64
521.1515
65
526.1669
MCH受体结合试验:
由CHO细胞通过在4℃下用5mM HEPES溶解细胞15分钟制备表达MCH受体的膜。细胞溶解产物被离心(12.5000xg,15min)且沉淀再次悬浮在5mM HEPES中。对于各96-孔平板(Microlite,DynexTechnologies),1mg的细胞膜与10mg的小麦胚凝集素SPA珠(Amersham)在4℃下在10ml结合缓冲液(25mM HEPES,10mM MGCI2,10mM NaCI,5mM MnCl2,0.1%BSA)的体积中温育5分钟。膜/珠混合物被离心(1500xg,3.5min),抽吸上清液,且沉淀再次悬浮在10ml结合缓冲液中。随后重复离心,抽吸且再次悬浮。膜/珠混合物(100μl)随后加入到含50μl的500pM[125I]-MCH(NEN)和50ml的适当浓度的化合物(4X所需终浓度)的96-孔平板。非特异性结合通过杂结合反应中包括1μM MCH来测定。该结合反应在室温下温育2小时。随后平板在TOPCOUNT微量平板闪烁计数器(Packard)中分析。分析数据且用GraphPad Prim测定Ki值。
对于本发明的化合物,观察到MCH受体结合活性(Ki值)的范围是约3nM-约1500nM。本发明的化合物具有的结合活性在约3nM-约1000nM的范围内。
虽然本发明已经结合上述具体实施方式加以描述,许多变化、改进和其他方案对于所属领域普通技术人员来说是显而易见的。所有这些变化、改进和方案属于本发明的实质和范围内。
Claims (33)
1.式I的化合物:
式I
或该化合物的药学可接受盐或溶剂化物,其中:
X是单键,-C-,-CH-或亚烷基,并且当X是单键时,R6不存在并且标记1的碳原子直接连接于N-Y的N;
Y是单键,-C-,-CH-或亚烷基,并且当Y是单键,R5不存在并且标记7的碳原子直接相连于N-X的N;
R1是芳基或杂芳基,其中所述的芳基或杂芳基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自CN,CF3,卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;
R2是H,烷基,芳基或芳烷基,其中所述的芳基或芳烷基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;
R3是H,烷基,芳基或芳烷基,其中所述的芳基或芳烷基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自CF3,卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;
R4选自-亚烷基-N(R7)2,-N(H)亚烷基-N(R7)2,-O-亚烷基-N(R7)2,
和
其中该-N(R7)2中的各R7,可以相同或不同,各R7是H,烷基,环烷基或芳基,其中所述的烷基,芳基或环烷基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;或各R7可以连接在一起并且与其所连的氮构成3至7-元杂环环;
n是0或1;
p是0-5并且当p>1时,p部分的数目可以相同或不同;
R5是H或1或2个独立选自烷基或环烷基的取代基;
R6是H或1或2个独立选自烷基或环烷基的取代基;和
R8是H,OH,烷氧基,烷基,环烷基,芳基,-N(H)R7,-N(H)C(O)烷基,-N(H)C(O)烷基,-N(H)C(O)N(H)烷基,-N(H)C(O)N(H)芳基,-N(H)S(O2)烷基或-N(H)S(O2)芳基;
条件是芳环上标记1和6所示的碳,与X-R5一起,可以任选地构成4-8元环系。
2.权利要求1的式Ia的化合物:
式 Ia
或该化合物的药学可接受盐或溶剂化物,其中:
q是0-5并且当q>1时,q部分的数目可以相同或不同;
X是-CH-或亚烷基;
Y是CH2;
R2是H,烷基,芳基或芳烷基,其中所述的芳基或芳烷基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;
R3是H,烷基,芳基或芳烷基其中所述的芳基或芳烷基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自CF3,卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;
R4是-亚烷基-N(R7)2,其中两个R7部分可以相同或不同,各R7是H,烷基,环烷基或芳基,其中所述的烷基,芳基或环烷基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;或各R7可以连接在一起并且与其所连的氮构成3至7-元杂环环,或R4选自
R5和R6可以相同或不同,并且独立地是H或烷基;
R8是H,OH,烷氧基,烷基,环烷基,芳基,-N(H)R7,-N(H)C(O)烷基,-N(H)C(O)N(H)烷基或-N(H)S(O2)烷基;和
R9是烷基,F,Cl,Br,I,NO2,C(O)NH2,C(O)N(H)R或N(H)C(O)R,其中R是烷基,OCF3,CF3或CN。
3.权利要求2的化合物,其中R9是3或4-取代的芳基。
4.权利要求2的化合物,其中R9是3-氰基取代的芳基。
5.权利要求1的式Ib的化合物:
式Ib
或该化合物的药学可接受盐或溶剂化物,其中:
X是亚烷基;
R1是3-氰基苯基;
R2是H;
R3是苯基,其中该苯基被一个或多个可以相同或不同的部分取代,各部分独立地选自CF3,卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;
R4是-亚烷基-N(R7)2,其中两个R7部分可以相同或不同,各R7是H,烷基,环烷基或烷基,其中所述的烷基,芳基或环烷基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;或各R7可以连接在一起并且与其所连的氮构成3至7-元杂环环;或R4选自
和
R8是H,烷基,环烷基,芳基,-N(H)烷基,-N(H)芳基,OH,烷氧基,-N(H)C(O)烷基,-N(H)C(O)N(H)烷基或-N(H)S(O2)烷基。
6.权利要求1的式Ic的化合物:
甲基是(S),(R)或消旋
式Ic
或该化合物的药学可接受盐或溶剂化物,其中:
R1是3-氰基苯基;
R2是H;
R3是苯基,其中该苯基被一个或多个可以相同或不同的部分取代,各部分独立地选自CF3,卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;
R4是-亚烷基-N(R7)2,其中两个R7部分可以相同或不同,各R7是H,烷基,环烷基或芳基,其中所述的烷基,芳基或环烷基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;或各R7可以连接在一起并且与其所连的氮构成3至7-元杂环环;或R4选自
或
和
R8是H,烷基,环烷基,芳基,-N(H)烷基,-N(H)芳基,OH,烷氧基,-N(H)C(O)烷基和-N(H)C(O)N(H)烷基或-N(H)S(O2)烷基。
9.权利要求1的下式的化合物
或该化合物的药学可接受盐或溶剂化物。
10.权利要求1的下式的化合物
或该化合物的药学可接受盐或溶剂化物。
11.权利要求1的下式的化合物
或该化合物的药学可接受盐或溶剂化物。
12.式II的化合物
式II
或该化合物的药学可接受盐或溶剂化物,其中:
Y是单键,-C-,-CH-或亚烷基,并且当Y是单键,R5不存在并且标记7的碳原子直接相连于N-X的N;
Z是单键,-C-,-CH-或亚烷基,并且当Z是单键,R6不存在并且标记1的碳原子直接相连于标记8的碳原子;
R1是芳基或杂芳基,其中所述的芳基或杂芳基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自CN,CF3,卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;
R2是H,烷基,芳基或芳烷基其中所述的芳基或芳烷基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;
R3是H,烷基,芳基或芳烷基其中所述的芳基或芳烷基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自CF3,卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;
R5是H或1或2个独立选自烷基或环烷基的取代基;
R6是H或1或2个独立选自烷基或环烷基的取代基;
R10选自-亚烷基(R7)2,
是n是0或1;
p是0-5并且当p>1时,p部分的数目可以相同或不同;和
R8是H,OH,烷氧基,烷基,环烷基,芳基,-N(H)R7,-N(H)C(O)烷基,-N(H)C(O)芳基,-N(H)C(O)N(H)烷基,-N(H)C(O)N(H)芳基,-N(H)S(O2)烷基或-N(H)S(O2)芳基;
条件是芳环上标记1和6的碳,与X-R6一起,可以任选地构成4-8元环系。
13.权利要求12的式IIa的化合物:
式IIa
或该化合物的药学可接受盐或溶剂化物,其中:
R1是3-氰基苯基;
R2是H;
R3是苯基,其中该苯基被一个或多个可以相同或不同的部分取代,各部分独立地选自CF3,卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;
R8是H,OH,烷基,环烷基,芳基,-N(H)烷基,-N(H)烷基,-N(H)C(O)烷基,N(H)C(O)N(H)烷基或-N(H)S(O2)烷基;和
R10选自-亚烷基(R7)2,
其中两个R7部分可以相同或不同,各R7是H,烷基,环烷基或芳基,其中所述的烷基,芳基或环烷基各自可以未取代或任选独立地被一个或多个可以相同或不同的部分取代,各部分独立地选自卤素,烷基,环烷基,环烷基烷基,卤代烷基,卤代烷氧基,烷氧基和OH;或各R7可以连接在一起并且与其所连的氮构成3至7-元杂环环。
15.一种治疗代谢疾病、饮食疾病或糖尿病的方法,包括将有效量的权利要求1的化合物施用给需此治疗的患者。
16.一种治疗代谢疾病、饮食疾病或糖尿病的方法,包括将有效量的权利要求12的化合物施用给需此治疗的患者。
17.权利要求15的方法,其中该饮食疾病是饮食过多。
18.权利要求16的方法,其中所述的饮食疾病是饮食过多。
19.权利要求15的方法,其中该代谢疾病是肥胖。
20.权利要求16的方法,其中该代谢疾病是肥胖。
21.一种治疗与肥胖有关的疾病的方法,包括包括将有效量的权利要求1的化合物或其药用盐施用给需此治疗的患者。
22.一种治疗与肥胖有关的疾病的方法,包括包括将有效量的权利要求12的化合物或其药用盐施用给需此治疗的患者。
23.权利要求21的方法,其中该与肥胖有关的疾病是II型糖尿病、胰岛素抗性、高脂血症和高血压。
24.权利要求22的方法,其中该与肥胖有关的疾病是II型糖尿病、胰岛素抗性、高脂血症和高血压。
25.一种治疗饮食疾病的方法,其包括给需要此治疗的患者
一定量的第一化合物,该第一化合物是权利要求1的化合物,或该化合物的药学可接受盐;
一定量的至少一种其他化合物,该其他化合物(b)选自抗肥胖和/或减食欲药物例如β3激动剂,拟甲状腺药物,厌食(an anoretic)药物,和NPY拮抗剂;
其中(a)和(b)化合物的量获得治疗效果。
26.一种治疗饮食疾病的方法,其包括给需要该治疗的患者施用:
一定量的第一化合物,该第一化合物是权利要求12的化合物,或该化合物的药学可接受盐;
一定量的至少一种其他化合物,该其他化合物(b)选自抗肥胖和/或减食欲药物例如β3激动剂,拟甲状腺药物,厌食药物,和NPY拮抗剂其中;
其中(a)和(b)化合物的量获得治疗效果。
27.一种药物组合物,其含有治疗有效量的组合物,该组合物包含:
一定量的第一化合物,该第一化合物是权利要求1的化合物,或该化合物的药学可接受盐;
一定量的至少一种其他化合物,该其他化合物(b)选自抗肥胖和/或减食欲药物例如β3激动剂,拟甲状腺药物,厌食药物,和NPY拮抗剂;
药学可接受载体。
28.一种药物组合物,其含有治疗有效量的组合物,该组合物包含:
一定量的第一化合物,该第一化合物是权利要求12的化合物,或该化合物的药学可接受盐;
一定量的至少一种其他化合物,该其他化合物(b)选自抗肥胖和/或减食欲药物例如β3激动剂,拟甲状腺药物,厌食药物,和NPY拮抗剂;
药学可接受载体。
29.一种药物组合物,其含有治疗有效量的组合物,该组合物包含:
第一化合物,该第一化合物是权利要求1的化合物,或该化合物的药学可接受盐;和
至少一种其他化合物,选自醛糖还原酶抑制剂,糖原磷酸化酶抑制剂,山梨糖醇脱氢酶抑制剂,蛋白酪氨酸磷酸化酶1B抑制剂,二肽基蛋白酶抑制剂,胰岛素(包括口服利用的胰岛素制剂),胰岛素模拟物,甲福明,阿卡糖,PPAR-γ配体例如曲格列酮,罗格列酮,吡格列酮或GW-1929,磺酰脲,格列吡嗪,格列苯脲和氯磺丙脲;和药学可接受载体。
30.一种药物组合物,其含有治疗有效量的组合物,该组合物包含:
第一化合物,该第一化合物是权利要求12的化合物,或该化合物的药学可接受盐;和
至少一种其他化合物,选自醛糖还原酶抑制剂,糖原磷酸化酶抑制剂,山梨糖醇脱氢酶抑制剂,蛋白酪氨酸磷酸化酶1B抑制剂,二肽基蛋白酶抑制剂,胰岛素(包括口服利用的胰岛素制剂),胰岛素模拟物,甲福明,阿卡糖,PPAR-γ配体例如曲格列酮,罗格列酮,吡格列酮或GW-1929,磺酰脲,格列吡嗪,格列苯脲和氯磺丙脲;药学可接受载体。
31.一种药物组合物,其含有治疗有效量的至少一种与至少一种药学可接受载体组合的权利要求1的化合物。
32.一种药物组合物,其含有治疗有效量的至少一种与至少一种药学可接受载体组合的权利要求12的化合物。
33.一种制备药物组合物的方法,其包括将至少一种权利要求1的化合物和至少一种药学可接受载体组合。
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WO2006104136A1 (ja) * | 2005-03-29 | 2006-10-05 | Banyu Pharmaceutical Co., Ltd. | 非アルコール性脂肪性肝疾患の治療剤、及び非アルコール性脂肪性肝疾患の治療又は予防のための薬剤の候補化合物のスクリーニング方法 |
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