TW202300154A - Pde10化合物之前藥 - Google Patents
Pde10化合物之前藥 Download PDFInfo
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- TW202300154A TW202300154A TW111109390A TW111109390A TW202300154A TW 202300154 A TW202300154 A TW 202300154A TW 111109390 A TW111109390 A TW 111109390A TW 111109390 A TW111109390 A TW 111109390A TW 202300154 A TW202300154 A TW 202300154A
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- Prior art keywords
- methyl
- compound
- pharmaceutically acceptable
- acceptable salt
- cyclopropyl
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- BWPIARFWQZKAIA-UHFFFAOYSA-N protriptyline Chemical compound C1=CC2=CC=CC=C2C(CCCNC)C2=CC=CC=C21 BWPIARFWQZKAIA-UHFFFAOYSA-N 0.000 description 1
- 239000003368 psychostimulant agent Substances 0.000 description 1
- 239000000296 purinergic P1 receptor antagonist Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229960001964 quazepam Drugs 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
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012465 retentate Substances 0.000 description 1
- 229950004692 roletamide Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- KQPKPCNLIDLUMF-UHFFFAOYSA-N secobarbital Chemical compound CCCC(C)C1(CC=C)C(=O)NC(=O)NC1=O KQPKPCNLIDLUMF-UHFFFAOYSA-N 0.000 description 1
- 229960002060 secobarbital Drugs 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 1
- 229960003946 selegiline Drugs 0.000 description 1
- 208000025874 separation anxiety disease Diseases 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000003215 serotonin 5-HT2 receptor antagonist Substances 0.000 description 1
- 229940121356 serotonin receptor antagonist Drugs 0.000 description 1
- 230000000697 serotonin reuptake Effects 0.000 description 1
- 229940126570 serotonin reuptake inhibitor Drugs 0.000 description 1
- 239000003772 serotonin uptake inhibitor Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 208000022925 sleep disturbance Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 230000001148 spastic effect Effects 0.000 description 1
- 208000018198 spasticity Diseases 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 201000001716 specific phobia Diseases 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- WZAIVXXKOAWTGQ-UHFFFAOYSA-N spiro[2,3-dihydronaphthalene-4,3'-piperidine]-1,2',6'-trione Chemical compound O=C1NC(=O)CCC11C2=CC=CC=C2C(=O)CC1 WZAIVXXKOAWTGQ-UHFFFAOYSA-N 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 229940032330 sulfuric acid Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 229960003188 temazepam Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- NZFNXWQNBYZDAQ-UHFFFAOYSA-N thioridazine hydrochloride Chemical compound Cl.C12=CC(SC)=CC=C2SC2=CC=CC=C2N1CCC1CCCCN1C NZFNXWQNBYZDAQ-UHFFFAOYSA-N 0.000 description 1
- 229960004098 thioridazine hydrochloride Drugs 0.000 description 1
- 208000016686 tic disease Diseases 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229950002859 tracazolate Drugs 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229960003741 tranylcypromine Drugs 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 229950002464 trepipam Drugs 0.000 description 1
- 229960003386 triazolam Drugs 0.000 description 1
- JOFWLTCLBGQGBO-UHFFFAOYSA-N triazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl JOFWLTCLBGQGBO-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229960001147 triclofos Drugs 0.000 description 1
- ZEWQUBUPAILYHI-UHFFFAOYSA-N trifluoperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 ZEWQUBUPAILYHI-UHFFFAOYSA-N 0.000 description 1
- 229960002324 trifluoperazine Drugs 0.000 description 1
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 description 1
- 229960003962 trifluridine Drugs 0.000 description 1
- 229950001577 trimetozine Drugs 0.000 description 1
- 229950004526 uldazepam Drugs 0.000 description 1
- DTMPGSXFUXZBDK-UHFFFAOYSA-N uldazepam Chemical compound C12=CC(Cl)=CC=C2N=C(NOCC=C)CN=C1C1=CC=CC=C1Cl DTMPGSXFUXZBDK-UHFFFAOYSA-N 0.000 description 1
- 238000001195 ultra high performance liquid chromatography Methods 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229960001255 viloxazine Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
- 229960004010 zaleplon Drugs 0.000 description 1
- HUNXMJYCHXQEGX-UHFFFAOYSA-N zaleplon Chemical compound CCN(C(C)=O)C1=CC=CC(C=2N3N=CC(=C3N=CC=2)C#N)=C1 HUNXMJYCHXQEGX-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本發明係關於2-甲基-
N -((5-甲基-1,3,4-噻二唑-2-基)甲基)-6-(((1
S,2
S)-2-(5-甲基吡啶-2-基)環丙基)甲氧基)嘧啶-4-胺之前藥,其可用作治療與磷酸二酯酶10 (PDE10)相關之中樞神經系統病症的治療劑。本發明亦係關於此類化合物之用途,其用於治療神經及精神病症,諸如精神分裂症、精神病或亨廷頓氏病(Huntington's disease)及彼等與紋狀體功能低下或基底神經節功能障礙相關之病症。
Description
精神分裂症為影響大腦之心理及運動功能的衰弱性病症。其通常在個體二十歲早期至中期診斷且症狀包括幻覺及妄想或處於另一極端,快感缺乏或社交退縮。在譜系中,症狀指示認知障礙及功能性殘疾。儘管抗精神病治療在改良,但包括典型(氟哌啶醇)及非典型(氯氮平或奧氮平)抗精神病藥之當前療法已不可接受且引起極高的藥物療法不順從或中斷比率。對療法之不滿歸因於缺乏療效或不耐受及不可接受之副作用。副作用已與大量代謝、錐體外、催乳激素及心臟不良事件相關。參見Lieberman等人,
N . Engl . J . Med . (2005) 353:1209-1223。
咸信儘管多個路徑涉及導致精神病及認知缺陷之精神分裂症的致病機制,許多注意力已集中於與環單磷酸鳥苷(cyclic guanosine monophosphate,cGMP)含量相關之麩胺酸/NMDA功能障礙及與環單磷酸腺苷(cyclic adenosine monophosphate,cAMP)相關之多巴胺激導性D2受體的作用。此等普遍存在的第二信使負責改變許多胞內蛋白之功能。認為環狀AMP調節cAMP依賴性蛋白激酶(protein kinase,PKA)之活性,cAMP依賴性蛋白激酶轉而磷酸化且調節多種類型的蛋白,包括離子通道、酶及轉錄因子。類似地,cGMP亦負責激酶及離子通道之下游調節。
一種影響環狀核苷酸(諸如cAMP及cGMP)之含量的路徑為改變或調節使此等稱為3',5'-環狀核苷酸特異性磷酸二酯酶(phosphodiesterase,PDE)之酶降解的酶。PDE10之認定由三個組獨立報告且基於其胺基酸序列、功能特性及組織分佈而區別於其他PDE (Fujishige等人,
J . Biol . Chem. (1999) 274:18438-18445;Loughney等人,
Gene(1999) 234: 109-117;Soderling等人,
PNAS .USA (1999) 96: 7071-7076)。目前PDE10亞型由唯一成員PDE10A組成,其在N端(三個變體)及C端(兩個變體)均具有替代性剪接變體,但並不影響N端中之GAF域或C端中之催化位點。N端剪接變體PDE10A1及PDE10A2不同之處在於A2變體在活化後具有PK.A磷酸化位點,亦即PK.A磷酸化響應於升高的cAMP含量,產生酶定位之胞內變化。相對於亦具有保守性GAF域之其他PDE家族,PDE10A之獨特性在於其配位子為cAMP,而其他GAF域PDE之配位子為cGMP (Kehler等人,
Expert Opin . Ther . Patents(2007) 17(2): 147-158)。PDE10A在大腦及睪丸中具有受限但較高表現。PDE10獨一無二的在大腦及尤其紋狀體之神經元中的較高表現表明針對其之抑制劑可能非常適合治療神經及精神病症及病狀。
咸信抑制PDE10適用於治療精神分裂症及將得益於提高神經元內的cAMP及/或cGMP含量之廣泛多種病狀或病症,包括多種神經病症、精神病性病症、焦慮症及/或運動障礙。美國專利9,062,059 (全文併入本文中)揭示包括2-甲基-
N -((5-甲基-1,3,4-噻二唑-2-基)甲基)-6-(((1
S,2
S)-2-(5-甲基吡啶-2-基)環丙基)甲氧基)嘧啶-4-胺之PDE10抑制劑作為神經及精神病症之治療劑。
本發明係關於環嘧啶胺衍生物之某些衍生物。咸信式I化合物為可活體內代謝成2-甲基-
N -((5-甲基-1,3,4-噻二唑-2-基)甲基)-6-(((1
S,2
S)-2-(5-甲基吡啶-2-基)環丙基)甲氧基)嘧啶-4-胺(化合物A)且抑制PDE10之前藥。化合物A抑制PDE10之聚合酶功能,且更特定言之抑制與PDE10之cAMP相關的多巴胺激導性D2受體活性。因此,式I化合物適用於(例如)抑制磷酸二酯酶10 (PDE10),用於治療與磷酸二酯酶10 (PDE10)相關的中樞神經系統病症,用於促進化合物A之投與及用於治療精神分裂症以及多種神經病症、精神病性病症、焦慮症及/或運動障礙。
本發明係關於結構式I之化合物:
或其醫藥學上可接受之鹽,其中:
R
1選自由以下組成之群:
1)-C(O)OCH
2OC(O)R
2;
2)-C(O)OC
1 - 6烷基,該烷基視情況經1至3個R
a基團取代;
3)-C(O)-C
6 - 10芳基、C(O)-C
6 - 10雜芳基、-C(O)-C
1 - 6烷基、-C(O)-C
3 - 6環烷基,該芳基、雜芳基、烷基及環烷基視情況經1至3個R
a基團取代;
4)-S-C
6 - 10芳基、-S-C
4 - 10雜芳基、-S-C
1 - 6烷基、-S-C
3 - 6環烷基,該芳基、雜芳基、烷基及環烷基視情況經1至3個R
a基團取代;及
5)-C(O)OCH
2間二氧雜環戊烯基,視情況經1至2個R
a基團取代;
R
2選自由以下組成之群:C
1 - 6烷基、C
6 - 10芳基、C
4 - 10雜芳基及C
3 - 6環烷基;該烷基、芳基、雜芳基及環烷基視情況經1至3個R
a基團取代;
R
a獨立地選自由以下組成之群:C
1 - 6烷基、OC
1 - 6烷基、側氧基及鹵素;
n為1、2、3或4。
本發明之另一實施例係在R
1為-C(O)OCH
2OC(O)R
2時實現。本發明之此態樣之一子實施例係在R
2為C
1 - 6烷基時實現,該烷基未經取代或經1至3個R
a基團取代。本發明之此態樣之另一子實施例係在R
2為C
6 - 10芳基時實現,該芳基未經取代或經1至3個R
a基團取代。本發明之此態樣之另一子實施例係在芳基為未經取代或經取代之苯基或萘基時實現。本發明之此態樣之另一子實施例係在R
2為C
6 - 10雜芳基時實現,該雜芳基未經取代或經1至3個R
a基團取代。本發明之此態樣之另一子實施例係在雜芳基為未經取代或經取代之吡啶基或嘧啶基時實現。本發明之此態樣之又一子實施例係在R
2為C
3 - 6環烷基時實現;該環烷基未經取代或經1至3個R
a基團取代。本發明之此態樣之另一子實施例係在環烷基為未經取代或經取代之環丁基、環戊基或環己基時實現。
本發明之另一實施例係在R
2選自由C
1 - 6烷基、苯基、吡啶基及環己基組成之群時實現,該等基團未經取代或經1至3個R
a基團取代。
本發明之另一實施例係在R
1為C(O)OC
1 - 6時實現,該烷基視情況經1至3個R
a基團取代。
本發明之一實施例係在R
1為-C(O)OCH
2間二氧雜環戊烯基時實現,該間二氧雜環戊烯基視情況經1至3個R
a基團取代。本發明之此態樣之一子實施例係在間二氧雜環戊烯基未經取代或經1至2個獨立地選自R
a基團取代時實現。本發明之此態樣之另一子實施例係在間二氧雜環戊烯基未經取代時實現。本發明之此態樣之另一子實施例係在間二氧雜環戊烯基獨立地經1至2個C
1 - 6烷基或側氧基之基團取代時實現。本發明之此態樣之另一子實施例係在間二氧雜環戊烯基獨立地經1至2個C
1 - 6烷基及側氧基之基團取代時實現。本發明之此態樣之另一子實施例係在間二氧雜環戊烯基經CH
3及側氧基取代時實現。本發明之此態樣之另一子實施例係在R
1由(i)表示時實現:
其中彎曲線表示連接點。
本發明之另一實施例係在R
1為-S-C
6 - 10芳基時實現,該芳基視情況經1至3個R
a基團取代。本發明之此態樣之一子實施例係在芳基為苯基或萘基時實現,該苯基及萘基未經取代或經1至3個R
a基團取代。本發明之此態樣之另一子實施例係在R
1為未經取代或經1至3個R
a基團取代之苯基時實現。本發明之此態樣之另一子實施例係在R
1為未經取代之苯基時實現。本發明之此態樣之另一子實施例係在R
1為經取代之苯基時實現。本發明之此態樣之一子實施例係在芳基為未經取代或經取代之萘基時實現。
本發明之另一實施例係在R
1為-S-C
4 - 10雜芳基時實現,該雜芳基視情況經1至3個R
a基團取代。本發明之此態樣之一子實施例係在雜芳基選自吡啶基、嘧啶基、吡咯基、吡唑基、㗁唑基及類似基團時實現,該吡啶基、嘧啶基、吡咯基、吡唑基及㗁唑基未經取代或經1至3個R
a基團取代。本發明之此態樣之另一子實施例係在R
1為未經取代或經1至3個R
a基團取代之吡啶基時實現。本發明之此態樣之另一子實施例係在R
1為未經取代或經取代之嘧啶基時實現。本發明之此態樣之另一子實施例係在R
1為未經取代或經取代之吡咯基時實現。本發明之此態樣之另一子實施例係在R
1為未經取代或經取代之吡唑基時實現。本發明之此態樣之另一子實施例係在R
1為未經取代或經取代之㗁唑基時實現。
本發明之另一實施例係在R
1為-S-C
1 - 6烷基時實現,該烷基視情況經1至3個R
a基團取代。本發明之另一實施例係在R
1為-S-C
3 - 6環烷基時實現,該環烷基視情況經1至3個R
a基團取代。本發明之此態樣之一子實施例係在環烷基選自由環丙基、環丁基、環戊基及環己基組成之群時實現。
本發明之另一實施例係在R
1為-C(O)-C
6 - 10芳基時實現,該芳基視情況經1至3個R
a基團取代。本發明之此態樣之一子實施例係在芳基為苯基或萘基時實現,該苯基及萘基未經取代或經1至3個R
a基團取代。本發明之此態樣之另一子實施例係在R
1為未經取代或經1至3個R
a基團取代之苯基時實現。本發明之此態樣之另一子實施例係在R
1為未經取代之苯基時實現。本發明之此態樣之另一子實施例係在R
1為經取代之苯基時實現。本發明之此態樣之一子實施例係在芳基為未經取代或經取代之萘基時實現。
本發明之另一實施例係在R
1為-C(O)-C
4 - 10雜芳基時實現,該雜芳基視情況經1至3個R
a基團取代。本發明之此態樣之一子實施例係在雜芳基選自吡啶基、嘧啶基、吡咯基、吡唑基、㗁唑基及類似基團時實現,該吡啶基、嘧啶基、吡咯基、吡唑基及㗁唑基未經取代或經1至3個R
a基團取代。本發明之此態樣之另一子實施例係在R
1為未經取代或經1至3個R
a基團取代之吡啶基時實現。本發明之此態樣之另一子實施例係在R
1為未經取代或經取代之嘧啶基時實現。本發明之此態樣之另一子實施例係在R
1為未經取代或經取代之吡咯基時實現。本發明之此態樣之另一子實施例係在R
1為未經取代或經取代之吡唑基時實現。本發明之此態樣之另一子實施例係在R
1為未經取代或經取代之㗁唑基時實現。
本發明之另一實施例係在R
1為-C(O)-C
1 - 6烷基時實現,該烷基視情況經1至3個R
a基團取代。本發明之另一實施例係在R
1為-C(O)-C
3 - 6環烷基時實現,該環烷基視情況經1至3個R
a基團取代。本發明之此態樣之一子實施例係在環烷基選自由環丙基、環丁基、環戊基及環己基組成之群時實現。
本發明包括所有結構式中所定義之化合物的醫藥學上可接受之鹽、本文所述之其實施例及類別。本文所提及之式I化合物涵蓋式I化合物及其所有實施例及類別。除非另外規定,否則本發明所提及之化合物,如本文所描述或主張的特定式之化合物或實施例(例如式I化合物或其實施例)或任何其他通用結構式之化合物或特定化合物意欲涵蓋特定化合物或屬於式或實施例範圍內之化合物,包括其鹽,尤其醫藥學上可接受之鹽、此類化合物之溶劑合物(包括水合物)及其溶劑化鹽形式(當此類形式可能時)。
本發明包括本文所述之實例中之各者及其醫藥學上可接受之鹽。本發明亦涵蓋醫藥組合物,其包含有效量之本發明化合物或其藥學上可接受之鹽及醫藥學上可接受的載劑。
除非明確地作相反陳述,否則經指定取代基取代准許在鏈或環中任何原子上進行,限制條件為此類取代允許以化學方式進行且產生穩定化合物。「穩定」化合物為可製備及分離的化合物且其結構及特性保持或可基本上保持不變持續足以允許將化合物用於本文所述之目的(例如對個體進行治療或預防性投與)的時間段。本發明化合物限於式I及其實施例所包涵的穩定化合物。
在式I化合物中,原子可展現其天然同位素豐度,或原子中之一或多者可以原子序數相同但原子質量或質量數與自然界中主要存在之原子質量或質量數不同的特定同位素形式人工富集。本發明意欲包括式I之化合物之所有合適的同位素變體。舉例而言,氫(H)之不同同位素形式包括氕(
1H)及氘(
2H)。氕為自然界中存在之主要氫同位素。富集氘可獲得某些治療優勢,諸如延長活體內半衰期或減少劑量需求,或可提供適用作表徵生物樣本之標準物的化合物。式I內之同位素富集化合物可在無過度實驗情況下藉由熟習此項技術者熟知的習知技術或藉由與本文中之流程及實例中所描述類似的製程使用適當同位素富集反應劑及/或中間物來製備。
實例及本文中所揭示之特定化合物作為本發明之例示。本發明化合物適用於治療患者(諸如需要此類抑制之哺乳動物)之與PDE10功能障礙相關之神經或精神病症的方法中,該方法包含投與有效量之化合物。除靈長類動物(尤其人類)以外,多種其他哺乳動物可根據本發明之方法治療,包括彼等研究動物及伴侶動物,諸如小鼠、大鼠、靈長類動物、猴、黑猩猩、巨猿、犬及家貓。本發明化合物適用於抑制患者(諸如需要此類抑制之哺乳動物)之PDE10活性的方法中,該方法包含投與有效量之化合物。本發明化合物亦適用於治療有需要之哺乳動物患者之與紋狀體功能低下或基底神經節功能障礙相關的神經或精神病症。
本發明係關於用於藥物之本發明化合物或其醫藥學上可接受之鹽。本發明進一步係關於本發明化合物或其醫藥學上可接受之鹽的用途,其用於製造用以治療有需要之哺乳動物患者之與PDE10功能障礙相關的神經或精神病症之藥物。本發明進一步係關於本發明化合物或其醫藥學上可接受之鹽之用途,其用於製造用以治療有需要之哺乳動物患者之與紋狀體功能低下或基底神經節功能障礙相關的神經或精神病症之藥物。
如本文所用,「烷基」係指具有指定範圍內之指定碳原子數之分支鏈及直鏈飽和脂族烴基。舉例而言,術語「C
1 - 10烷基」意謂具有1、2、3、4、5、7、8、9或10個碳原子之直鏈或分支鏈烷基,包括所有可能的異構體,且包括癸基,壬基,辛基,庚基,己基及戊基異構體以及
正、
異、
二級及
三級丁基(丁基、
s-丁基、
i-丁基、
t -丁基,Bu = 丁基,統稱為「-C
4烷基」),
正及
異丙基(丙基、
i-丙基,Pr = 丙基,統稱為「-C
3烷基」),乙基(Et)及甲基(Me)中之各者。「C
1 - 4烷基」具有1、2、3或4個碳原子,且包括
正、
異、
二級及
三級丁基,
n -及
i-丙基,乙基及甲基中之各者。
「環烷基」係指具有指定範圍內之指定碳原子數的環化烷基環。因此,舉例而言,「C
3 - 8環烷基」涵蓋環丙基、環丁基、環戊基、環己基、環庚基及環辛基中之各者。「C
3 - 6環烷基」涵蓋環丙基、環丁基、環戊基及環己基中之各者。當環烷基為式I化合物之烷基之取代基時,環烷基取代基可鍵合至烷基中任何可供使用之碳。如下圖示-C
3 - 6環烷基取代基,其中取代基為粗體的環丙基:
「芳基」係指(i)苯基,(ii)至少一個環為芳族之9或10員雙環稠合羧基環系統及(iii)至少一個環為芳族之11至14員三環稠合碳環系統。合適芳基包括例如經取代及未經取代之苯基及經取代及未經取代之萘基。備受關注之芳基為未經取代或經取代之苯基。
「雜芳基」係指(i)含有1至4個獨立地選自N、O及S之雜原子的5或6員雜芳環,其中各N視情況呈氧化物形式;及(ii) 9或10員雙環稠環系統,其中(ii)之稠環系統含有1至6個獨立地選自N、O及S之雜原子,其中稠環系統中之各環含有零、一個或多於一個雜原子,至少一個環為芳族,各N視情況呈氧化物形式,且非芳族環中的各S視情況為S(O)或S(O)
2。合適5及6員雜芳環包括例如吡啶基、3-氟吡啶基、4-氟吡啶基、3-甲氧基吡啶基、4-甲氧基吡啶基、吡咯基、吡𠯤基、嘧啶基、嗒𠯤基、三𠯤基、噻吩基、呋喃基、咪唑基、吡唑基、三唑基(亦即1,2,3-三唑基或1,2,4-三唑基)、四唑基、㗁唑基、異㗁唑基、㗁二唑基(亦即1,2,3-、1,2,4-、1,2,5-(呋呫基)或1,3,4-異構體)、㗁三唑基、噻唑基、異噻唑基及噻二唑基。合適9及10員雜雙環稠環系統包括例如苯并呋喃基、吲哚基、吲唑基、㖠啶基、異苯并呋喃基、苯并哌啶基、苯并異㗁唑基、苯并㗁唑基、𠳭烯基、喹啉基、異喹啉基、異吲哚基、苯并哌啶基、苯并呋喃基、咪唑并[1,2-a]吡啶基、苯并三唑基、吲唑基、吲哚啉基及異吲哚啉基。雜芳基類別包括未經取代或經取代之吡啶基或嘧啶基,且尤其為未經取代或經取代之吡啶基。
術語「雜環」或「雜環基」係指(i) 飽和4至7員環化環及(ii)不飽和的非芳族4至7員環化環,包含碳原子及1至4個獨立地選自O、N及S之雜原子。本發明範疇內之雜環包括例如氮雜環丁烷基、哌啶基、𠰌啉基、硫代𠰌啉基、噻唑啶基、異噻唑啶基、㗁唑啶基、異㗁唑啶基、吡咯啶基、咪唑啶基、哌𠯤基、四氫呋喃基、四氫噻吩基、吡唑啶基、六氫嘧啶基、噻𠯤烷基、噻氮雜環庚烷基、氮雜環庚烷基、二氮雜環庚烷基、四氫哌喃基、四氫硫代哌喃基及二氧雜環己烷基。本發明範疇內之4至7員不飽和非芳族雜環之實例包括對應於前句所列之飽和雜環的單不飽和雜環,其中單鍵由雙鍵所替換(例如碳-碳單鍵由碳-碳雙鍵所替換)。雜環類別為4至6員飽和單環,其包含碳原子及1或2個雜原子,其中雜原子選自N、O及S。4至6員雜環之實例包括(但不限於)氮雜環丁烷基、吡咯啶基、哌啶基、哌𠯤基、𠰌啉基、硫代𠰌啉基、四氫呋喃基、四氫哌喃基及四氫硫代哌喃基,且其子類別為哌啶基、吡咯啶基、四氫呋喃基或四氫哌喃基。
因為可藉由一般技術者辨識,故本發明之特定化合物可以互變異構體之形式存在。此等化合物之所有互變異構形式不論個別地經分離或呈混合物形式均在本發明之範疇內。舉例而言,在雜芳環上准許存在-OH取代基且酮-烯醇互變異構為可能的情形中,應理解取代基實際上可全部或部分以側氧基(=O)形式存在。
「穩定」化合物為可製備及分離的化合物且其結構及特性保持或可基本上保持不變持續足以允許將化合物用於本文所述之目的(例如對個體進行治療或預防性投與)的時間段。本發明化合物限於式I及其實施例所包涵的穩定化合物。舉例而言,式I中所定義之某些部分可未經取代或經取代,且後者意欲涵蓋對於部分在化學上可能且產生穩定化合物之取代模式(亦即取代基之數目及種類)。
式I化合物可具有多個對掌性中心(亦稱作不對稱或立體對稱中心)。本發明涵蓋具有(
R)或(
S)立體組態之化合物,該組態出現於可存在於式I化合物以及其立體異構混合物中的磷不對稱中心及任何其他不對稱中心處。
本發明包括個別非對映異構體,尤其差向異構體,亦即具有相同化學式但單原子周圍的空間排列不同之化合物。本發明亦包括所有比率之非對映異構體混合物,尤其差向異構體混合物。本發明之實施例亦包括富集有差向異構體中之一者51%或更多的差向異構體混合物,包括(例如)一種差向異構體為60%或更多、70%或更多、80%或更多或90%或更多。單差向異構體為較佳的。個別或單一差向異構體係指藉由對掌性合成及/或使用一般已知之分離及純化技術所獲得之差向異構體,且該差向異構體可具有100%的一種差向異構體或可含有少量(例如10%或以下)的相反差向異構體。因此,個別非對映異構體為本發明之主題,其呈純淨形式(以左旋及以右旋對映體形式)、呈外消旋體形式及呈兩種非對映異構體的所有比率之混合物形式。在順/反異構情況中,本發明包括順形式及反形式兩者以及此等形式的所有比率之混合物。
視需要,可藉由慣用方法(例如藉由層析或結晶)分離混合物、藉由使用立體化學性均一的起始材料合成或藉由立體選擇性合成來進行個別立體異構體之製備。視情況,可在分離立體異構體之前進行衍生化。立體異構體混合物之分離可在式I化合物合成期間在中間步驟進行或可對最終外消旋產物進行。絕對立體化學可藉由結晶產物或結晶中間物之X射線結晶來測定,必要時該等結晶產物或結晶中間物用含有已知組態之立體對稱中心的反應劑衍生。或者,絕對立體化學可藉由振動圓二色性(Vibrational Circular Dichroism,VCD)光譜學分析來測定。本發明包括所有此類異構體以及此類外消旋體、對映異構體、非對映異構體及互變異構體及其混合物的鹽、溶劑合物(包括水合物)及溶劑化鹽。
化合物可以醫藥學上可接受之鹽的形式投與。術語「醫藥學上可接受之鹽」係指生物或其他方面沒有不合需要之鹽(例如對其接受者既無毒性,其他方面又無害)。因為式I化合物按照定義含有至少一個鹼基,故本發明包括相對應的醫藥學上可接受之鹽。當式I化合物含有一或多個酸基時,本發明亦包括相應醫藥學上可接受之鹽。因此,根據本發明,含有酸基(例如-COOH)之式I化合物可用作例如(但不限於)鹼金屬鹽、鹼土金屬鹽或用作銨鹽。此類鹽之實例包括(但不限於)鈉鹽、鉀鹽、鈣鹽、鎂鹽或與氨或有機胺(諸如乙胺、乙醇胺、三乙醇胺或胺基酸)之鹽。含有一或多個鹼基(亦即可質子化之基團)的式I化合物可根據本發明以其與無機或有機酸的酸加成鹽形式使用,例如(但不限於)與以下之鹽:鹽酸、溴化氫、磷酸、硫酸、硝酸、苯磺酸、甲磺酸、對甲苯磺酸、萘二磺酸、乙二酸、乙酸、三氟乙酸、酒石酸、乳酸、水楊酸、苯甲酸、甲酸、丙酸、特戊酸、二乙基乙酸、丙二酸、丁二酸、庚二酸、反丁烯二酸、順丁烯二酸、蘋果酸、胺基磺酸、苯基丙酸、葡萄糖酸、抗壞血酸、異菸酸、檸檬酸、己二酸等。若式I化合物的分子中同時含有酸基及鹼基,則除了所提及之鹽形式外,本發明亦包括內鹽或甜菜鹼(兩性離子)。可藉由熟習此項技術者已知的慣用方法,例如藉由與有機或無機酸或鹼在溶劑或分散劑中組合,或藉由與其他鹽陰離子交換或陽離子交換,自式I化合物獲得鹽。本發明亦包括式I化合物的所有鹽,其由於低生理學相容性而不適於直接用於醫藥中,但其可例如用作化學反應之中間物或用於製備醫藥學上可接受之鹽。
此外,本發明化合物可以非晶形式及/或一或多種結晶形式存在,且因而式I化合物的所有非晶及結晶形式及其混合物意欲包括於本發明之範疇內。此外,本發明之一些化合物可與水(亦即水合物)或常見有機溶劑形成溶劑合物。本發明之化合物的此類溶劑合物及水合物(尤其醫藥學上可接受之溶劑合物及水合物)連同此類化合物之非溶劑化及無水形式亦涵蓋在式I定義的化合物及其醫藥學上可接受之鹽的範疇內。
因此,除非另外規定,否則本文所描述及主張之通用結構式內的化合物、實施例及特定化合物涵蓋鹽,所有可能的立體異構體及互變異構體,物理形式(例如非晶及結晶形式),其溶劑合物及水合形式及此等形式之任何組合以及其鹽(當此類形式可能時)。
本發明涵蓋包含式I化合物或化合物之鹽的任何組合物,包括例如(但不限於)包含與一或多個其他分子及/或離子組分締合之該化合物(可稱作「共晶體」)的組合物。如本文所用,術語「共晶體」係指固相(可為或可不為結晶),其中兩個或更多個不同分子及/或離子組分(一般以化學計量比率)藉由非離子交互(包括(但不限於)氫鍵、偶極子-偶極子交互、偶極子-四極子交互或分散力(凡得瓦爾力(van der Waals)))而結合在一起。相異組分之間不存在質子轉移且固相既非單一鹽亦非溶劑合物。共晶體之論述可參見例如S. Aitipamula等人,
Crystal Growth and Design, 2012, 12 (5), 第2147-2152頁。
更確切而言,參考本發明,共晶體包含式I化合物或其醫藥學上可接受之鹽及一或多種生物上或其他方面無不合需要(例如對其接受者既無毒性,其他方面又無害)之非醫藥活性組分。共晶體可藉由化學領域中已知之慣用方法自式I化合物或其醫藥學上可接受之鹽獲得。舉例而言,包含本發明化合物之共晶體可藉由向化合物中添加所需要的化學計量之酸性或中性分子、添加適當溶劑來溶解且(例如)沈澱、凍乾或濃縮溶液從而獲得固體組合物來製備。共晶體可為(但不限於)一實施例,其中組合物包含中性式I化合物(亦即非鹽形式)及一或多種非醫藥活性組分;且在另一實施例中,共晶體組合物為結晶。舉例而言,結晶組合物可藉由向式I化合物中添加所需化學計量之酸性或中性分子、添加適當溶劑且加熱來完全溶解,且接著使溶液冷卻且使晶體生長來製備。本發明亦包括本發明化合物之所有共晶體,其由於低生理學相容性而不適合直接用於醫藥中,但其可(例如)用作化學反應之中間物或用於製備醫藥學上可接受之共晶體或鹽。
因此,本文所描述及主張之式I化合物、其實施例及特定化合物涵蓋所有可能的醫藥學上可接受之鹽、立體異構體、互變異構體、物理形式(例如非晶及結晶形式)、共晶體組合物、溶劑合物及水合形式及前述形式之任何組合(當此類形式可能時)。
本文所述之式I化合物為前藥。前藥之論述提供於(a) Stella, V. J.; Borchardt, R. T.; Hageman, M. J.; Oliyai, R.; Maag, H.等人
Prodrugs : Challenges and Rewards 部分 1 及部分 2; Springer, 第726頁: New York, NY, USA, 2007,(b) Rautio, J.; Kumpulainen, H.; Heimbach, T.; Oliyai, R.; Oh, D.等人 Prodrugs: design and clinical applications.
Nat . Rev . Drug Discov .2008,
7, 255,(c) T. Higuchi及V. Stella,
Pro - drugs as Novel Delivery Systems(1987) 14 of the A.C.S. Symposium Series中,及(d)
Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, 編, American Pharmaceutical Association and Pergamon Press中。更具體言之,式I化合物(或其任一實施例及其醫藥學上可接受之鹽)為化合物A之前藥變體。式I化合物可胞內(活體內或活體外)轉化成對應的化合物A。轉化可藉由一或多種機制發生,例如酶催化化學反應、代謝化學反應及/或自發化學反應(例如溶劑分解),諸如經由在血液中水解。儘管不希望受任何特定理論束縛,但化合物A一般應理解為負責抑制PDE10。
本發明之另一實施例為式I化合物,其中該化合物或其鹽為實質上純形式。如本文所用,「實質上純」意謂適合地至少約60 wt%,通常至少約70 wt%,較佳至少約80 wt%,更佳至少約90 wt% (例如約90 wt%至約99 wt%),甚至更佳至少約95 wt% (例如約95 wt%至約99 wt%,或約98 wt%至100 wt%),且最佳至少約99 wt% (例如100 wt%)之含有式I化合物或其鹽的產物(例如自反應混合物分離獲得化合物或鹽之產物)係由該化合物或鹽組成。化合物及鹽之純度水準可使用諸如高效液相層析及/或質譜或NMR技術之標準分析方法來測定。若採用超過一種分析方法且該等方法在所測定純度水準方面存在實驗上顯著差異,則以得到最高純度水準之方法為準。100%純度之化合物或鹽為如藉由標準分析方法所測定不含可偵測雜質的化合物或鹽。關於具有一或多個不對稱中心且可呈立體異構體之混合物形式存在的本發明化合物,實質上純化合物可為立體異構體的實質上純混合物或可為實質上純的個別立體異構體。
本文中之式I化合物及其醫藥學上可接受之鹽可用於活體外及活體內抑制PDE10。「治療疾病病況」或「疾病病況之治療」包括:1)預防疾病病況,亦即不讓疾病病況之臨床症狀在可能曝露到或易患疾病病況但尚未經歷或顯示疾病病況之症狀的個體內發展;2)抑制疾病病況,即遏制疾病病況或其臨床症狀之發展;3)或緩解疾病病況,亦即使得疾病病況或其臨床症狀暫時性或永久性消退。
本發明方法中所治療之個體一般為需要治療的哺乳動物,尤其人類(男性或女性)。術語「治療有效量」意謂研究人員、獸醫、醫生或其他臨床醫師所探求會引起組織、系統、動物或人類之生物學或醫學反應的本發明化合物之量。應認識到,熟習此項技術者可藉由用有效量之本發明化合物治療目前罹患神經及精神病症的患者或藉由預防性治療罹患此類病症之患者來影響該等病症。如本文所用,術語「治療(treatment/treating)」係指可減緩、中斷、遏制、控制或遏止本文所述之神經及精神病症之進展,但不一定指示所有病症症狀完全消除的所有方法,以及尤其在易患此類疾病或病症之患者中用以延緩所提及病狀之惡化或降低所提及病狀之風險的預防性療法。
申請者提出PDE10之抑制劑及尤其PDE10A之抑制劑可為患有精神及認知病症的個體提供治療效益。紋狀體之中型多棘投射神經元中PDE10A之獨特及獨佔式分佈在基底神經節內形成皮層及多巴胺激導性輸入之原理位點,表明或許有可能及有希望識別PDE10之抑制劑以減輕或消除此位點內的非所需細胞信號傳導。不希望受任何理論束縛,申請人咸信抑制紋狀體中之PDE10A可使cAMP/cGMP信號傳導及紋狀體輸出增加,有可能恢復在諸如精神分裂症之認知疾病中受損的行為抑制。麩胺酸激導性及多巴胺激導性輸入之調節及整合可提昇認知行為,同時遏制或減少非所需行為。因此,在一個實施例中,本發明化合物提供一種用於治療或改善疾病或病狀的方法,該等疾病或病狀中紋狀體功能低下為顯著特徵或基底神經節功能障礙起某種作用,諸如帕金森氏病(Parkinson's disease)、亨廷頓氏病、精神分裂症、強迫症、成癮及精神病。本文所述之抑制劑可具有所期望及有用效果的其他病狀包括需要降低活性及減少對精神運動刺激的反應之病狀或期望減少條件回避反應的情況,其常常預示臨床抗精神病藥活性。如本文所用,術語「選擇性PDE10抑制劑」係指相比來自PDE1-9或PDE11家族之酶而言更大程度地有效抑制來自PDE10家族之酶的有機分子。在一個實施例中,選擇性PDE10抑制劑為有機分子,其抑制PDE10之Ki低於用作另一PDE酶之抑制劑的物質之Ki或約為其十分之一。
包括PDE10之磷酸二酯酶已涉及各種生物功能。此已表明此等酶在人類或其他物種之多種病程中的潛在作用。本發明化合物在治療多種神經及精神病症中具有效用。
在一特定實施例中,本發明化合物提供一種治療精神分裂症或精神病之方法,其包含向有需要之患者投與有效量之本發明化合物。精神病症診斷與統計手冊(DSM-IV-TR) (2000,美國精神病協會,華盛頓)提供一種包括偏執型、錯亂型、緊張型或未分型精神分裂症及物質誘發的精神病性病症之診斷工具。如本文所用,術語「精神分裂症或精神病」包括如DSM-IV-TR中所描述之此等精神病症之診斷及分類且該術語意欲包括其他來源中所描述的類似病症。本文中涵蓋之病症及病狀包括(但不限於)諸如精神分裂症或精神病之病狀或疾病,包括精神分裂症(偏執型、錯亂型、緊張型、未分型或剩餘類型)、類精神分裂症、分裂情感精神病症,例如妄想型或抑鬱型、妄想症、精神病性病症、短暫性精神病性病症、共有型精神病性病症、因一般醫學病狀所致及物質誘發或藥物誘發之精神病性病症(例如由酒精、安非他命、大麻、可卡因、迷幻藥、吸入劑、類鴉片、苯環己哌啶、氯胺酮及其他分離型麻醉劑以及其他精神興奮劑誘發的精神病);精神病性精神病症、與情感障礙相關的精神病、短暫反應性精神病、分裂情感性精神病;「精神分裂症譜系」,諸如類分裂型或分裂型人格障礙、偏執型人格障礙、類分裂型人格障礙;與精神病相關的疾病(諸如嚴重抑鬱症、躁鬱(雙相)症、阿茲海默氏病(Alzheimer's disease)及創傷後壓力症候群),包括精神分裂症及其他精神病之正面及負面症狀。
在另一特定實施例中,本發明化合物提供一種用於治療認知病症之方法,其包含向有需要之患者投與有效量之本發明化合物。DSM-IV-TR亦提供一種包括認知病症之診斷工具,認知病症包括癡呆、譫妄、健忘症及老年性認知減退。如本文所用,術語「認知病症」包括如DSM-IV-TR中所描述之此等病症的診斷及分類,且該術語意欲包括其他來源中所描述之類似病症。本文中涵蓋之病症及病狀包括(但不限於)包含如注意力及/或認知缺陷症狀之病症,諸如癡呆(與阿茲海默氏病、缺血、多梗塞性癡呆、創傷、顱內腫瘤、大腦創傷、血管問題或中風、酒精性癡呆或其他藥物相關癡呆、AIDS、HIV病、帕金森氏病、亨廷頓氏病、匹克氏病(Pick's disease)、庫賈氏病(Creutzfeldt Jacob disease)、圍產期缺氧、其他一般醫學病狀或物質濫用相關)、阿茲海默氏病、多梗塞性癡呆、AIDS相關癡呆及額顳葉癡呆、譫妄、健忘症或老年性認知減退。
在另一特定實施例中,本發明化合物提供一種用於治療焦慮症之方法,其包含向有需要之患者投與有效量的本發明化合物。DSM-IV-TR亦提供一種包括如廣泛性焦慮症、強迫症及焦慮發作之焦慮症的診斷工具。如本文所用,術語「焦慮症」包括如DSM-IV-TR中所描述之此等精神病症之診斷及分類且該術語意欲包括其他來源中所描述的類似病症。本文中涵蓋之病症及病狀包括(但不限於)焦慮症,諸如急性壓力症、畏曠症、廣泛性焦慮症、強迫症、焦慮發作、恐慌症、創傷後壓力症、分離焦慮症、社交恐懼症、特定恐懼症、物質誘發之焦慮症及因一般醫學病狀所致的焦慮。
在另一特定實施例中,本發明化合物提供一種用於治療物質相關病症及成癮行為之方法,其包含向有需要之患者投與有效量的本發明化合物。DSM-IV-TR亦提供一種包括持續性癡呆、持續性健忘症、由物質濫用誘發之精神病性病症或焦慮症及對濫用物質的耐受、依賴性或戒斷反應之診斷工具。如本文所用,術語「物質相關病症及成癮行為」包括如DSM-IV-TR中所描述之此等精神病症之診斷及分類且該術語意欲包括其他來源中所描述的類似病症。本文中涵蓋之病症及病狀包括(但不限於)物質相關病症及成癮行為,諸如物質誘發之譫妄、持續性癡呆、持續性健忘症、精神病性病症或焦慮症、藥物成癮、對物質(包括酒精、安非他命、大麻、可卡因、迷幻藥、吸入劑、菸鹼、類鴉片、苯環己哌啶、鎮定劑、安眠藥或抗焦慮劑)之耐受及依賴性或戒斷反應。
在另一特定實施例中,本發明化合物提供一種用於治療與過量食物攝入相關之肥胖或進食障礙及與此相關的併發症之方法,其包含向有需要之患者投與有效量之本發明化合物。目前,肥胖作為一般醫學病狀包括於疾病及相關健康問題之國際分類第十版(tenth edition of the International Classification of Diseases and Related Health Problems,ICD-10) (1992世界衛生組織)中。DSM-IV-TR亦提供一種包括在影響醫學病狀之精神因素存在下之肥胖之診斷工具。如本文所用,術語「與過量食物攝入相關之肥胖或進食障礙」包括ICD-10及DSM-IV-TR中所描述之此等醫學病狀及病症之診斷及分類,且該術語意欲包括其他來源中所描述之類似病症。本文中涵蓋之病症及病狀包括(但不限於)肥胖、神經性貪食症及強迫性進食障礙。
在另一特定實施例中,本發明化合物提供一種用於治療情緒障礙及抑鬱症之方法,其包含向有需要之患者投與有效量的本發明化合物。如本文所用,術語「情緒障礙及抑鬱症」包括DSM-IV-TR中所描述之此等醫學病狀及病症之診斷及分類且該術語意欲包括其他來源中所描述之類似病症。本文中涵蓋之病症及病狀包括(但不限於)雙相障礙、情緒障礙,其包括抑鬱症,輕度、中度或重度型之嚴重抑鬱發作,躁狂或混合情緒發作,輕症躁狂情緒發作,具有非典型性特徵的抑鬱發作,具有憂鬱性特徵的抑鬱發作,具有緊張性特徵的抑鬱發作,產後發病情況下之情緒發作,中風後抑鬱;嚴重抑鬱症,精神抑鬱症,輕微抑鬱症,經前焦慮症,精神分裂症之精神病後抑鬱症,與諸如妄想症或精神分裂症之精神病性病症疊加的嚴重抑鬱症,雙相障礙(例如雙相I型障礙、雙相II型障礙),循環情感症,抑鬱(包括單相抑鬱、季節性抑鬱及產後抑鬱),經前症候群(premenstrual syndrome,PMS)及經前焦慮症(premenstrual dysphoric disorder,PDD),因一般醫學病狀所致的情緒障礙及物質誘發之情緒障礙。
在另一特定實施例中,本發明化合物提供一種用於治療疼痛之方法,其包含向有需要之患者投與有效量的本發明化合物。特定疼痛實施例為骨骼及關節疼痛(骨關節炎)、反覆性運動疼痛、牙齒疼痛、癌症疼痛、肌筋膜疼痛(肌肉損傷、肌肉纖維疼痛)、手術期間疼痛(一般手術、婦產科)、慢性疼痛及神經痛。
在其他特定實施例中,本發明化合物提供用於治療其他類型之認知、學習及精神相關病症的方法,包括(但不限於)學習障礙(諸如閱讀障礙、數學障礙或書面表達障礙)、注意力缺陷/過動症、年齡相關之認知衰退、廣泛性發育障礙(包括自閉症)、注意力障礙(諸如注意力缺陷過動症(attention-deficit hyperactivity disorder,ADHD)及品行障礙;NMDA受體相關病症,諸如自閉症、抑鬱、良性健忘、兒童學習障礙及閉合性顱腦損傷;神經退化性病症或病況,諸如與腦創傷、中風、腦梗塞、癲癇發作、神經毒素中毒相關的神經退化或低血糖誘發的神經退化;多系統萎縮;運動障礙,諸如運動不能及強直症候群(包括帕金森氏病、藥物誘發之帕金森氏病、腦炎後帕金森氏病、進行性核上麻痹、多發性系統萎縮症、皮質基底核退化、帕金森氏病-ALS癡呆綜合症及基底神經節鈣化)、藥物誘發之帕金森氏病(諸如精神安定劑誘發之帕金森氏病、精神安定劑惡性症候群、精神安定劑誘發之急性肌肉張力不足、精神安定劑誘發之急性靜坐不能、精神安定劑誘發之遲發性運動不能及藥物誘發之姿勢性震顫)、亨廷頓氏病、與多巴胺促效劑療法相關的運動困難、妥瑞氏症候群(Gilles de la Tourette's syndrome)、癲癇、肌肉痙攣及與肌肉痙攣或無力相關的病症(包括震顫);運動困難,包括震顫(諸如靜止性震顫、姿勢性震顫、意向震顫及特發性震顫)、腿不寧症候群、舞蹈病(諸如西登哈姆氏舞蹈病(Sydenham's chorea)、亨廷頓氏病、良性遺傳性舞蹈病、神經性棘紅細胞增多症、症狀性舞蹈病、藥物誘發之舞蹈病及偏身顫搐)、肌陣攣(包括廣泛性肌陣攣及局灶性肌陣攣)、抽動(包括簡單抽動、複雜抽動及症狀性抽動)、肌肉張力不足(包括廣泛性、特發性、藥物誘發的、症狀性、發作性及局灶性(諸如眼瞼痙攣、口下頜、痙攣、痙攣性斜頸、軸向肌肉張力不足、偏癱性及肌肉張力不足性書寫痙攣));尿失禁;神經元損壞(包括眼部損壞、眼睛視網膜病變或黃斑變性、耳鳴、聽覺減弱及喪失以及大腦水腫);嘔吐;及睡眠障礙,包括失眠及嗜睡症。在以上病症中,精神分裂症、雙相障礙、抑鬱(包括單相抑鬱、季節性抑鬱及產後抑鬱)、經前症候群(PMS)及經前焦慮症(PDD)、學習障礙、廣泛性發育障礙(包括自閉症)、注意力障礙(包括注意力缺陷/過動症)、自閉症、抽動症(包括妥瑞氏症候群)、焦慮症(包括恐懼症及創傷後壓力症)、與癡呆相關之認知病症、AIDS癡呆、阿茲海默氏病、帕金森氏病、亨廷頓氏病、痙攣、肌陣攣、肌肉痙攣、耳鳴及聽覺減弱及喪失的治療尤其重要。
本發明之化合物作為PDE10抑制劑之活性可容易地使用此項技術中熟知的螢光偏振(fluorescence polarization,FP)方法來測定而無需過度實驗(Huang, W., 等人,
J . Biomol Screen, 2002, 7: 215)。特定言之,如本文所揭示之化合物在所提及檢驗中具有活性,其展現抑制環狀核苷酸之磷酸酯鍵水解的能力。展現低於1 μM之Ki (抑制常量)的任何化合物(例如化合物A)將視為如本文所定義之PDE10抑制劑。
本發明化合物為化合物A之前藥且適用作(例如)抑制磷酸二酯酶10 (PDE10)的藥劑,用於治療與磷酸二酯酶10 (PDE10)相關之中樞神經系統病症,用於促進化合物A之投與及治療精神分裂症(包括多種神經病症、精神病症、焦慮症及/或運動障礙)。
在典型實驗中,化合物(諸如化合物A)之PDE10抑制活性係根據以下實驗方法測定。使用對應於人類PDE10A2 (登錄號AF127480,Genbank標識符4894716)之核苷酸56-77的含有Kozak共同序列之正向引子及對應於人類PDE10A2 (登錄號AF127480,Genbank標識符4894716)之核苷酸2406-2413的反向引子自人類胚胎大腦cDNA (Clontech,Mountain View,CA)擴增PDE10A2。用Easy-A聚合酶(Stratagene,La Jolla,CA)擴增係95℃持續2分鐘,接著為95℃持續40秒、55℃持續30秒及72℃持續2分鐘48秒之循環三十三次。最終延長部分為72℃持續7分鐘。PCR產物根據標準協定將TA選殖至pcDNA3.2-TOPO (lnvitrogen,Carlsbad,CA)中。根據製造商說明書(Invitrogen,Carlsbad,CA)使用Lipofectamine 2000使具有70-80%融合度之AD293細胞經人類PDE10A2/pcDNA3.2-TOPO暫時轉染。轉染後48小時採集細胞且藉由在含有20 mM HEPES、1 mM EDTA及蛋白酶抑制劑混合物(Roche)之緩衝液中進行音波處理(設定3,10×5秒脈波)來裂解。藉由在75,000 xg下離心20分鐘來收集裂解物。將含有細胞質部分之清液層用於評估PDE10A2活性。環狀核苷酸磷酸二酯酶之螢光偏振檢驗係使用Molecular Devices, Sunnyvale, CA供應之IMAP® FP套組(產品號R8139)進行。IMAP®技術先前已應用於磷酸二酯酶檢驗(Huang, W., 等人,
J . Biomol Screen ,2002, 7: 215)。檢驗係在室溫下在384孔微量滴定盤中以20.2 μL之培育體積進行。測試化合物之溶液係在DMSO中製備且經DMSO連續稀釋以得到10份8 μL之溶液,其中各者的濃度相差3倍,每盤32次連續稀釋。100%抑制係使用已知的PDE10抑制劑確定,該已知的PDE10抑制劑可為在如下文所描述之檢驗中以其Ki值5,000倍存在的任何化合物,諸如罌粟鹼(參見Siuciak, 等人
Neuropharmacology(2006) 51:386-396;Becker, 等人
Behav Brain Res(2008) 186(2):155-60;Threlfell, 等人, J
Pharmacol Exp Ther(2009) 328(3):785-795)、2-{4-[吡啶-4-基-1-(2,2,2-三氟乙基)-1H-吡唑-3-基]苯氧基甲基}喹啉丁二酸或2-[4-(1-甲基-4-吡啶-4-基-1H-吡唑-3-基)-苯氧基甲基]喹啉丁二酸(參見Schmidt, 等人
Pharmacol Exp Ther(2008) 325:681-690;Threlfell, 等人,
J Pharmacol Exp Ther(2009) 328(3): 785-795)。0%抑制係藉由使用DMSO (1%最終濃度)來確定。
Labcyte Echo 555 (Labcyte,Sunnyvale,CA)用於將200 nL自滴定盤之各孔分配至384孔分析盤。在檢驗緩衝液(10 mM Tris HCl,pH 7.2,10 mM MgCl
2,0.05% NaN
30.01% Tween-20及1 mM DTT)中製得最終濃度為50 nM之酶溶液(自等分試樣1/1600稀釋;足以製備產生20%基質轉化率)及來自Molecular Devices之經FAM標記的cAMP PDE (產品號R7506)之單獨溶液。隨後以連續兩次添加10 μL將酶及基質添加至檢驗盤,且隨後進行振盪以混合。允許反應在室溫下進行30分鐘。隨後由包含80%溶液A、20%溶液B及結合試劑之套組組分以總體結合溶液之1/600的體積製得結合溶液。藉由向檢驗盤之各孔添加60 μL結合溶液使酶反應停止且將盤密封且振盪10秒。在測定螢光偏振(fluorescence polarization,FP)之前將盤在室溫下培育至少一小時。使用Perkin Elmer EnVision™盤讀取器(Waltham,MA)來量測盤之各孔的平行及垂直螢光。
螢光偏振(mP)係依據各樣品孔之平行(S)及垂直(P)螢光及僅含有基質的中間對照孔之類似值(So及Po),使用以下等式:偏振(mP) = 1000×(S/So-P/Po)/(S/So+P/Po)來計算。
各化合物之劑量-抑制曲線藉由將mP資料擬合於下文給出之四參數等式來表徵。表觀抑制常數(KI)、對應於「100%抑制對照」之低平線區處的最大抑制(Imax;例如1=>與此對照相同)、對應於「0%抑制對照」之高平線區處的最小抑制(Imin,例如0=>與無藥物對照相同)及希爾斜率(nH)係藉由隨化合物之劑量而變的mP值之非線性最小平方擬合,使用基於Mosser等人,
JALA, 2003, 8: 54-63所描述之程序的自產軟體使用以下等式來測定:
「0%抑制對照」之中間信號(0%mP)及「100%抑制對照」之中間信號(100%mP)為依據位於各檢驗盤之第1-2行及第23-24行的對照所測定之常數。150 nM之經FAM標記之cAMP的表觀(K
m)係在單獨實驗中經由基質及所選藥物濃度之同步變化來測定。
PDE10相比於其他PDE家族之選擇率係使用IMAP®技術評估。恆河猴PDE2A3及人類PDE10A2酶係由經短暫轉染之HEK細胞的胞溶質部分製備。所有其他PDE為在昆蟲細胞中表現之GST Tag人類酶且係獲自BPS Bioscience (San Diego,CA):PDElA (目錄號60010)、PDE3A (目錄號60030)、PDE4A1A (目錄號60040)、PDE5Al (目錄號60050)、PDE6C (目錄號60060)、PDE7A (目錄號60070)、PDE8Al (目錄號60080)、PDE9A2 (目錄號60090)、PDE11A4 (目錄號60110)。
PDE 1至11之檢驗係在室溫下在384孔微量滴定盤中以20.2 μL之培育體積同時進行。測試化合物之溶液係在DMSO中製備且經DMSO連續稀釋以得到30 μL之溶液,各溶液的濃度常常相差3倍,每盤32次連續稀釋。100%抑制係藉由添加緩衝液而非酶來測定且0%抑制係藉由使用DMSO (1%最終濃度)來測定。將Labcyte POD 810 (Labcyte,Sunnyvale,CA)用於自滴定盤之各孔分配200 nL以製得十一個用於各滴定之檢驗盤之複製物、一個各PDE酶之複製物。在檢驗緩衝液(10 mM Tris HCI,pH 7.2,10 mM MgCh,0.05% NaN
30.01% Tween-20及1 mM DTT)中製得最終濃度為50 nM之各酶溶液(自等分試樣稀釋,足以產生20%基質轉化率)及來自Molecular Devices (Sunnyvale,CA,產品號R7506或cGMP號R7508)的經FAM標記之cAMP或經FAM標記之cGMP的單獨溶液。應注意PDE2之基質為含有1000 nM之cGMP的50 nM FAM cAMP。隨後以連續兩次添加10 μL將酶及基質添加至檢驗盤,且隨後進行振盪以混合。允許反應在室溫下進行60分鐘。隨後由包含80%溶液A、20%溶液B及結合試劑之套組組件以總體結合溶液之1/600的體積製得結合溶液。藉由向檢驗盤之各孔添加60 μL結合溶液使酶反應停止。將盤密封且振盪10秒。將盤在室溫下培育一小時,隨後使用Tecan Genios Pro盤讀取器(Tecan,Switzerland)來量測平行及垂直螢光。化合物對抗所有11種PDE之表觀抑制常數係依據如關於PDE10 FP檢驗所描述之平行及垂直螢光讀數使用以下各酶及基質組合的表觀KM值來測定:PDElA (FAM cGMP) 70 nM、恆河猴PD2A3 (FAM cAMP) 10,000 nM、PDE3A (FAM cAMP) 50 nM、PDE4AlA (FAM cAMP) 1500 nM、PDE5Al (FAM cGMP) 400 nM、PDE6C (FAM cGMP) 700 nM、PDE7A (FAM cAMP) 150 nM、PDE8Al (FAM cAMP) 50 nM、PDE9A2 (FAM cGMP) 60 nM、PDE10A2 (FAM cAMP) 150nM、PDE11A4 (FAM cAMP) 1000 nM。可根據本發明使用之化合物之內在PDE10抑制活性可藉由此等檢驗測定。
化合物A具有抑制人類PDE10酶之活性,其Ki一般低於約1 μM。該結果指示化合物在用作PDE10酶之抑制劑時的內在活性。關於化合物A之前藥的資料提供於以下實例中。
本發明化合物進一步適用於預防、治療、控制、改善本文所提及之疾病、病症及病狀或降低其風險的方法。本發明化合物進一步適用於與其他藥劑組合預防、治療、控制、改善前述疾病、病症及病狀或降低其風險的方法。本發明化合物可與一或多種其他藥物組合,用於治療、預防、控制、改善本發明化合物或其他藥物可具有效用之疾病或病狀或降低其風險,其中該等藥物組合在一起比任一藥物單獨更安全或更有效。此類其他藥物可藉由其常用之途徑且以其常用之量來與本發明化合物同時或依序投與。當本發明化合物與一或多種其他藥物同時使用時,可能需要呈單位劑型的含有此類其他藥物及本發明化合物之醫藥組合物。然而,組合療法亦可包括本發明化合物及一或多種其他藥物以不同重疊時程投與之療法。亦考慮當與一或多種其他活性成分組合使用時,本發明化合物及其他活性成分可以比各自單獨使用時之劑量更低的劑量使用。因此,本發明醫藥組合物包括除本發明化合物以外含有一或多種其他活性成分之醫藥組合物。以上組合不僅包括本發明化合物與一種其他活性化合物之組合,且亦包括本發明化合物與兩種或更多種其他活性化合物的組合。同樣地,本發明化合物可與用於預防、治療、控制、改善本發明化合物適用之疾病或病狀或降低其風險的其他藥物組合使用。此類其他藥物可藉由其常用之途徑且以其常用之量來與本發明化合物同時或依序投與。因此,本發明醫藥組合物包括除本發明化合物以外亦含有一或多種其他活性成分之醫藥組合物。本發明化合物與第二活性成分之重量比可發生改變且將視各成分之有效劑量而定。一般而言,將使用各自之有效劑量。因此,舉例而言,當本發明化合物與另一藥劑組合時,本發明化合物與另一種藥劑之重量比一般將在約1000:1至約1:1000,諸如約200:1至約1:200之範圍內。
本發明化合物與其他活性成分之組合一般亦將在前述範圍內,但在各情況下,應使用各活性成分之有效劑量。在此類組合中,本發明化合物及其他活性劑可分別或結合投與。此外,投與一個要素可在投與其他藥劑之前、同時或之後進行。
因此,本發明化合物可單獨或與已知有益於個體適應症之其他藥劑或影響受體或酶之其他藥物組合使用,該等受體或酶增加本發明化合物之功效、安全、便利性或降低非所需副作用或毒性。本發明化合物與其他藥劑可以伴隨療法或以固定組合共同投與。
在一個實施例中,本發明化合物可與抗阿茲海默氏藥劑、β-分泌酵素抑制劑、γ分泌酵素抑制劑、HMG-CoA還原酶抑制劑、包括布洛芬之NSAID、維生素E及抗類澱粉蛋白抗體組合使用。
在另一實施例中,本發明化合物可與鎮靜劑、安眠藥、抗焦慮劑(anxiolytics)、抗精神病劑、抗焦慮劑(antianxiety agent)、環吡咯啶酮、咪唑并吡啶、吡唑并嘧啶、微量安神劑、褪黑激素促效劑及拮抗劑、褪黑激素作用劑、苯并二氮呯、巴比妥酸鹽、5HT-2拮抗劑及其類似物組合使用,諸如:阿地唑侖(adinazolam)、阿洛巴比妥(allobarbital)、阿洛米酮(alonimid)、阿普唑侖(alprazolam)、胺磺必利(amisulpride)、阿米曲替林(amitriptyline)、異戊巴比妥(amobarbital)、阿莫沙平(amoxapine)、阿立哌唑(aripiprazole)、非典型性抗精神病劑、苯他西泮(bentazepam)、苯佐他明(benzoctamine)、溴替唑侖(brotizolam)、安非他酮(bupropion)、丁螺環酮(busprione)、布塔巴比妥(butabarbital)、布他比妥(butalbital)、卡普脲(capuride)、卡波氯醛(carbocloral)、氯醛甜菜鹼、氯醛水合物、氯米帕明(clomipramine)、氯硝西泮(clonazepam)、氯哌瑞噸(cloperidone)、氯氮平酸鹽(clorazepate)、氯二氮平(chlordiazepoxide)、氯乙雙酯(clorethate)、氯丙𠯤(chlorpromazine)、氯氮平(clozapine)、環丙西泮(cyprazepam)、地昔帕明(desipramine)、德克拉莫(dexclamol)、安定(diazepam)、氯醛比林(dichloralphenazone)、雙丙戊酸鈉(divalproex)、苯海拉明(diphenhydramine)、多塞平(doxepin)、艾司唑侖(estazolam)、乙氯維諾(ethchlorvynol)、依託咪酯(etomidate)、非諾班(fenobam)、氟硝西泮(flunitrazepam)、氟哌噻噸(flupentixol)、氟奮乃靜(fluphenazine)、弗拉西泮(flurazepam)、氟伏沙明(fluvoxamine)、氟西汀(fluoxetine)、弗沙西泮(fosazepam)、格魯米特(glutethimide)、哈拉西泮(halazepam)、氟哌啶醇(haloperidol)、安泰樂(hydroxyzine)、丙咪𠯤(imipramine)、鋰、勞拉西泮(lorazepam)、氯甲西泮(lormetazepam)、麥普替林(maprotiline)、甲氯喹酮(mecloqualone)、褪黑激素(melatonin)、甲苯巴比妥(mephobarbital)、安寧(meprobamate)、甲喹酮(methaqualone)、咪達氟(midaflur)、咪達唑侖(midazolam)、奈法唑酮(nefazodone)、尼索胺酯(nisobamate)、硝西泮(nitrazepam)、去甲替林(nortriptyline)、奧氮平(olanzapine)、奧沙西泮(oxazepam)、三聚乙醛(paraldehyde)、帕羅西汀(paroxetine)、戊巴比妥(pentobarbital)、哌拉平(perlapine)、奮乃靜(perphenazine)、苯乙肼(phenelzine)、苯巴比妥(phenobarbital)、普拉西泮(prazepam)、普魯米近(promethazine)、異丙酚、普羅替林(protriptyline)、誇西泮(quazepam)、喹硫平(quetiapine)、尼拉西泮(reclazepam)、利培酮(risperidone)、羅來米特(roletamide)、司可巴比妥(secobarbital)、舍曲林(sertraline)、舒普立酮(suproelone)、替馬西泮替馬西(temazepam)、硫利達𠯤(thioridazine)、胺碸噻𠮿(thiothixene)、曲卡唑酯(tracazolate)、強內心百樂明(tranylcypromaine)、曲唑酮(trazodone)、三唑侖(triazolam)、曲匹泮(trepipam)、三西米特(tricetamide)、三氯福司(triclofos)、三氟吡啦𠯤(trifluoperazine)、曲美托𠯤(trimetozine)、曲米帕明(trimipramine)、烏達西泮(uldazepam)、文拉法辛(venlafaxine)、紮來普隆(zaleplon)、齊拉西酮(ziprasidone)、唑拉西泮(zolazepam)、唑吡坦(zolpidem)及其鹽、及其組合、及其類似物,或本發明化合物可與使用諸如光療法或電刺激之物理方法來一起投與。
在另一實施例中,本發明化合物可與左旋多巴(存在或不存在選擇性腦外去羧酶抑制劑,諸如卡比多巴(carbidopa)或苄絲肼(benserazide))、諸如比哌立登(biperiden)之抗膽鹼激導性劑(視情況呈其鹽酸鹽或乳酸鹽形式)及三己芬迪(trihexyphenidyl)(苯海索(benzhexol))鹽酸鹽、COMT抑制劑(諸如恩他卡朋(entacapone))、MOA-B抑制劑、抗氧化劑、A2a腺苷受體拮抗劑、膽鹼激導性促效劑、NMDA受體拮抗劑、血清素受體拮抗劑及多巴胺受體促效劑(諸如阿侖替莫(alentemol)、溴麥角環肽(bromocriptine)、非諾多泮(fenoldopam)、麥角乙脲(lisuride)、那高利特(naxagolide)、培高利特(pergolide)或普拉克索(pramipexole))組合使用。應瞭解,多巴胺促效劑可呈醫藥學上可接受之鹽的形式,例如阿侖替莫氫溴酸鹽、溴麥角環肽甲磺酸鹽、非諾多泮甲磺酸鹽、那高利特鹽酸鹽及培高利特甲磺酸鹽。麥角乙脲及普拉克索通常以非鹽形式使用。
在另一實施例中,本發明化合物可與來自以下之化合物組合使用:啡噻𠯤(phenothiazine)、噻𠮿(thioxanthene)、雜環二苯并氮呯、苯丁酮、二苯基丁基哌啶及吲哚酮類精神安定劑。啡噻𠯤之適合實例包括氯丙𠯤、美索噠𠯤(mesoridazine)、硫利達𠯤、乙醯奮乃靜(acetophenazine)、氟奮乃靜、奮乃靜及三氟吡啦𠯤。噻𠮿之適合實例包括氯普噻𠮿(chlorprothixene)及胺碸噻𠮿。二苯并氮呯之實例為氯氮平。苯丁酮之實例為氟哌啶醇。二苯基丁基哌啶之實例為哌迷清(pimozide)。吲哚酮之實例為嗎茚酮(molindolone)。其他精神安定劑包括洛沙平(loxapine)、舒必利(sulpiride)及利培酮。應瞭解,當精神安定劑與本發明化合物組合使用時可呈醫藥學上可接受之鹽的形式,例如氯丙𠯤鹽酸鹽、美索嗒𠯤苯磺酸鹽、硫利達𠯤鹽酸鹽、乙醯奮乃靜順丁烯二酸鹽、氟奮乃靜鹽酸鹽、氟奮乃靜庚酸鹽、氟奮乃靜癸酸鹽、三氟吡啦𠯤鹽酸鹽、胺碸噻𠮿鹽酸鹽、氟哌啶醇癸酸鹽、洛沙平丁二酸鹽及嗎茚酮鹽酸鹽。奮乃靜、氯普噻𠮿、氯氮平、氟哌啶醇、哌迷清及利培酮一般通常以非鹽形式使用。因此,本發明化合物可與以下組合使用:乙醯奮乃靜、阿侖替莫、阿立哌唑、胺磺必利、苯海索、溴麥角環肽、比哌立登、氯丙𠯤、氯普噻𠮿、氯氮平、安定、非諾多泮、氟奮乃靜、氟哌啶醇、左旋多巴、含苄絲肼之左旋多巴、含卡比多巴之左旋多巴、麥角乙脲、洛沙平、美索嗒𠯤、嗎茚酮、那高利特、奧氮平、培高利特、奮乃靜、哌迷清、普拉克索、喹硫平、利培酮、舒必利、丁苯那𠯤、三己芬迪、硫利達𠯤、胺碸噻𠮿、三氟吡啦𠯤或齊拉西酮。
在另一實施例中,本發明化合物可與抗抑鬱劑或抗焦慮劑組合使用,包括正腎上腺素再吸收抑制劑(包括三級胺三環化合物及二級胺三環化合物)、選擇性血清素再吸收抑制劑(selective serotonin reuptake inhibitor,SSRi)、單胺氧化酶抑制劑(monoamine oxidase inhibitor,MAOi)、單胺氧化酶之可逆性抑制劑(reversible inhibitor of monoamine oxidase,RIMA)、血清素及正腎上腺素再吸收抑制劑(serotonin and noradrenaline reuptake inhibitor,SNRi)、促皮質素釋放因子(corticotropin releasing factor,CRF)拮抗劑、α-腎上腺素受體拮抗劑、神經激肽-1受體拮抗劑、非典型抗抑鬱劑、苯并二氮呯、5-HT
1A促效劑或拮抗劑,尤其5-HT
1A部分促效劑,及促皮質素釋放因子(corticotropin releasing factor,CRF)拮抗劑。特定藥劑包括:阿米曲替林、氯米帕明、多塞平、丙咪𠯤及曲米帕明;阿莫沙平、地昔帕明、麥普替林、去甲替林及普羅替林;氟西汀、氟伏沙明、帕羅西汀及舍曲林;異卡波肼(isocarboxazid)、苯乙肼(phenelzine)、反苯環丙胺(tranylcypromine)及司來吉蘭(selegiline);嗎氯貝胺(moclobemide);文拉法辛(venlafaxine);度洛西汀(duloxetine);阿匹坦(aprepitant);安非他酮、鋰、奈法唑酮、曲唑酮及維洛沙𠯤(viloxazine);阿普唑侖、氯二氮平、氯硝西泮、氯氮卓鹽(chlorazepate)、安定、哈拉西泮、勞拉西泮、奧沙西泮及普拉西泮;丁螺環酮(buspirone)、氟辛克生(flesinoxan)、吉哌隆(gepirone)及伊沙匹隆(ipsapirone),及其醫藥學上可接受之鹽。
本發明化合物可藉由口服、非經腸(例如肌肉內、腹膜內、靜脈內、腦室內(intracerebroventricular,ICV)、腦池內注射或輸注、皮下注射或植入)、藉由吸入噴霧、經鼻、經陰道、經直腸、舌下或局部投與途徑投與,且可呈合適劑量單位調配物形式單獨或一起調配,調配物含有適合各投與途徑的習知醫藥學上可接受之無毒載劑、佐劑及媒劑。除了治療溫血動物(諸如小鼠、大鼠、馬、牛、綿羊、犬、貓、猴等)以外,本發明化合物可有效用於人類。術語「投與」化合物應理解為意謂向需要治療之個體提供本發明化合物或本發明化合物之前藥。
如本文所用之術語「組合物」意欲涵蓋包含預定量或比例之指定成分的產物,以及直接或間接由指定量之指定成分之組合所產生的任何產物。關於醫藥組合物之此類術語意欲涵蓋包含活性成分及構成載劑之惰性成分的產物,以及直接或間接由任何兩種或更多種上述成分之組合、複合或聚集而產生、或由一或多種成分之解離而產生、或由一或多種成分之其他反應或相互作用類型而產生的任何產物。一般而言,藉由使活性成分與液體載劑或細粉狀固體載劑或兩者均勻且緊密地結合,且隨後必要時使產物成形為所需調配物來製備醫藥組合物。在醫藥組合物中,活性化合物以足以對疾病之過程或病狀起所需作用的量包括在內。因此,本發明醫藥組合物涵蓋藉由將本發明化合物與醫藥學上可接受之載劑混合而製得的任何組合物。
意欲用於口服使用之醫藥組合物可根據用於製造醫藥組合物之此項技術已知之任何方法製備,且此類組合物可含有一或多種選自由以下組成之群的藥劑:甜味劑、調味劑、著色劑及保藏劑以便提供醫藥學上精緻且適口之製劑。錠劑含有與適合於製造錠劑之醫藥學上可接受之無毒賦形劑混合的活性成分。錠劑可未經包覆,或其可藉由已知技術包覆以延緩在胃腸道中之崩解及吸收,且藉此提供更長時間段之持續作用。用於口服使用之組合物亦可以硬明膠膠囊形式呈現,其中活性成分與惰性固體稀釋劑(例如碳酸鈣、磷酸鈣或高嶺土)混合;或以軟明膠膠囊形式呈現,其中活性成分與水或油狀介質(例如花生油、液體石蠟或橄欖油)混合。水性懸浮液、油性懸浮液、可分散散劑或顆粒、水包油乳液及無菌可注射的水性懸浮液或油性懸浮液可藉由此項技術中已知之標準方法製備。「醫藥學上可接受之」意謂載劑、稀釋劑或賦形劑必須與調配物之其他成分相容且對其接受者無害。
本發明化合物進一步適用於預防、治療、控制、改善本文所提及之疾病、病症及病狀或降低其風險的方法。本發明組合物中活性成分之劑量可改變,然而活性成分之量必需使得獲得適合劑型。可向需要此類治療之患者(動物及人類)投與將提供最佳醫藥功效之劑量的活性成分。所選劑量視所需治療效應、投與途徑及治療持續時間而定。劑量將視疾病之性質及嚴重程度、患者之體重、隨後患者所採用之特定膳食、並行藥物及熟習此項技術者將認可之其他因素而定隨各患者而變化。一般而言,向患者(例如人類及老年人類)投與每日0.001至10 mg/kg體重之間的劑量水準。劑量範圍一般將為每患者每天約0.5 mg至1.0 g, 其可以單次或多次劑量投與。在一個實施例中,劑量範圍將為每患者每天約0.5 mg至500 mg;在另一實施例中,每患者每天約0.5 mg至200 mg;且在又一實施例中,每患者每天約5 mg至50 mg。本發明醫藥組合物可以諸如包含約0.5 mg至500 mg活性成分或包含約1 mg至250 mg活性成分之固體劑型提供。醫藥組合物可以包含約1 mg、5 mg、10 mg、25 mg、50 mg、100 mg、200 mg或250 mg活性成分之固體劑型提供。對於口服投與,組合物可以含有1.0至1000毫克活性成分,諸如1、5、10、15、20、25、50、75、100、150、200、250、300、400、500、600、750、800、900及1000毫克活性成分之錠劑形式提供給待治療之患者以進行劑量之對症調整。化合物可按每天1至4次,諸如每天一次或兩次之方案投與。
用於製備本發明化合物之若干方法說明於以下流程及實例中。起始材料及必備中間物在一些情況下可商購,或可根據文獻程序或如本文中所說明來製備。除文獻中已知的或實驗程序中例示的其他標準操作以外本發明化合物可藉由採用如以下流程中所展示之反應製備。如流程中所展示之取代基編號不必與申請專利範圍中所使用的取代基編號相關,且常常出於明晰之目的,單個取代基展示為連接至根據上文定義允許有多個取代基之化合物。除文獻中可能已知的或實驗程序中例示之其他標準操作(諸如酯水解、保護基斷裂等)以外,用於生成本發明化合物之反應物係藉由採用如本文之流程及實例中所展示的反應來製備。起始材料根據此項技術中已知或如本文中所說明之程序製得。本文使用以下縮寫:Me:甲基;Et:乙基;t-Bu:
三級丁基;Ar:芳基;Ph:苯基;Bn:苯甲基;Ac:乙醯基;THF:四氫呋喃;Boe:三級丁氧基羰基;DIPEA:
N , N-二異丙基乙胺;DPPA:二苯基磷醯基疊氮化物;EDC:N-(3-二甲胺基丙基)-N'-乙基碳化二亞胺;EtOAc:乙酸乙酯;HOBt:羥基苯并三唑水合物;TEA:三乙胺;DMF:N,N-二甲基甲醯胺;rt:室溫;HPLC:高效液相層析;NMR:核磁共振;TLC:薄層層析;DMSO:二甲亞碸;TFA:三氟乙酸;aqu.:水溶液;CELITE:矽藻土;,ACN:乙腈;,UPLC:超高效液相層析;XRPD:x射線粉末繞射。
在一些情況下,最終產物可例如藉由操作取代基進一步修飾。此等操作可包括(但不限於)熟習此項技術者通常已知之還原、氧化、烷化、醯化及水解反應。在一些情況下,可改變實施前述反應流程之次序以有助於反應或避免不合需要之反應產物。提供以下實例,從而可更全面地理解本發明。此等實例僅為說明性的且不應視為以任何方式限制本發明。
用於製備本發明化合物之若干方法描述於以下流程及實例中。
實例
一般方法
可商購的溶劑、反應劑及中間物按原樣使用。不可商購的反應劑及中間物以如下文所描述之方式製備。
1H NMR光譜報告為距Me
4Si之低場ppm以及質子數、多峰性及圓括號指示的以赫茲為單位之偶合常數。當提供LC/MS資料時,指定觀測到之原始離子。急驟管柱層析係使用預裝填正相二氧化矽或塊狀二氧化矽,通常使用己烷或石油醚與乙酸乙酯自100%己烷/石油醚至100%乙酸乙酯之梯度溶離進行。逆相純化係使用Sunfire Prep C18 OBD 5 μm (30×150 mm)或10 μm (50×150 mm)管柱,通常使用含0.1%三氟乙酸作為改質劑的乙腈與水之梯度溶離進行。
實例1
((5-甲基-1,3,4-噻二唑-2-基)甲基)(2-甲基-6-(((1
S,2
S)-2-(5-甲基吡啶-2-基)環丙基)甲氧基)嘧啶-4-基)胺甲酸(5-甲基-2-側氧基-1,3-間二氧雜環戊烯-4-基)甲酯
步驟A -合成化合物1
將2-甲基-
N-((5-甲基-1,3,4-噻二唑-2-基)甲基)-6-(((1
S,2
S)-2-(5-甲基吡啶-2-基)環丙基)甲氧基)嘧啶-4-胺(1a,500 mg,1.31 mmol)及(5-甲基-2-側氧基-1,3-間二氧雜環戊烯-4-基)甲基4-硝基苯基碳酸酯[CAS 173604-87-0] (867 mg,2.94 mmol)於DMF (6.5 mL)中之溶液用三乙胺(729 μL,5.23 mmol)處理,且隨後在70℃下加熱4.5 h。再添加4-硝基苯基碳酸(5-甲基-2-側氧基-1,3-間二氧雜環戊烯-4-基)甲酯(490 mg,1.66 mmol)及三乙胺(600 μL,4.30 mmol)且繼續加熱整夜。添加額外4-硝基苯基碳酸(5-甲基-2-側氧基-1,3-間二氧雜環戊烯-4-基)甲酯(300 mg)及三乙胺(400 μL)且繼續再加熱6.5 h。添加額外4-硝基苯基碳酸(5-甲基-2-側氧基-1,3-間二氧雜環戊烯-4-基)甲酯(260 mg)且再次繼續加熱整夜。
將經冷卻反應物用水稀釋且用飽和Na
2CO
3水溶液鹼化,隨後用乙酸乙酯萃取兩次。將經合併之有機物用鹽水與飽和Na
2CO
3水溶液之組合洗滌,經MgSO
4乾燥且濃縮。使用製備型HPLC (逆相C-18),用乙腈/水+ 0.1% TFA 10-50%溶離來純化殘餘物。將含有目標化合物之溶離份合併,用飽和NaHCO
3水溶液鹼化且用乙酸乙酯萃取。將有機物用鹽水洗滌,經MgSO
4乾燥且濃縮得到
1 。MS:
m/
z539.2 = [M+H]。
1H NMR (600 MHz, CDCl
3, ppm): δ 8.27 (s, 1H), 7.36 (d,
J= 8.4 Hz, 1H), 7.14 (s, 1H), 7.05 (d,
J= 8.4 Hz, 1H), 5.58 (s, 2H), 4.98 (S, 2H), 4.40-4.42 (m, 1H), 4.31-4.34 (m, 1H), 2.73 (s, 3H), 2.54 (s, 3H), 2.28 (s, 3H), 2.20 (s, 3H), 2.05-2.09 (m, 1H), 1.87-1.92 (m, 1H), 1.29-1.33 (m, 1H), 1.04-1.07 (m, 1H)。
步驟A -合成化合物2
將1a (300 mg,0.784 mmol)及
N-(苯硫基)鄰苯二甲醯亞胺(220 mg,0.863 mmol)於DMF (6.5 mL)中之溶液在100℃下攪拌整夜。將經冷卻之反應物濃縮,且使用製備型HPLC (逆相C-18)、用乙腈/水+ 0.1% TFA 10-55%溶離來純化殘餘物。將含有目標之溶離份合併,用飽和NaHCO
3水溶液鹼化且用乙酸乙酯萃取。將有機物用鹽水洗滌,經MgSO
4乾燥且濃縮。使用製備型HPLC (逆相C-18),用乙腈/水+ 0.1% TFA 10-55%溶離第二次純化殘餘物。將含有目標化合物之溶離份合併,用飽和NaHCO
3水溶液鹼化且用乙酸乙酯萃取。將有機物用鹽水洗滌,經MgSO
4乾燥且濃縮得到2
。MS:
m/
z491.1 = [M+H]。
1H NMR (600 MHz, CDCl
3, ppm): δ 8.26 (s, 1H), 7.34 (d,
J= 7.2 Hz, 1H), 7.26-7.29 (m, 2H), 7.17-7.20 (m, 1H), 7.11 (d,
J= 8.4 Hz, 2H), 7.02 (d,
J= 7.8 Hz, 1H), 6.58 (s, 1H), 5.46 (s, 2H), 4.31-4.34 (m, 1H), 4.26-4.29 (m, 1H), 2.71 (s, 3H), 2.54 (s, 3H), 2.26 (s, 3H), 2.02-2.05 (m, 1H), 1.82-1.88 (m, 1H), 1.25-1.30 (m, 1H), 1.01-1.04 (m, 1H)。
步驟A -合成化合物3
將1a (250 mg,0.654 mmol)於二㗁烷(2.61 mL)中之溶液用二異丙基乙胺(171 μL,0.980 mmol)及苯甲醯氯(99 μL,0.85 mmol)處理且在室溫攪拌。在3.5 h之後,添加額外二異丙基乙胺(57 μL)及苯甲醯氯(38 μL)且繼續攪拌整夜。將反應物用鹽水及飽和NaHCO
3水溶液稀釋,隨後用乙酸乙酯萃取,用鹽水洗滌,經MgSO
4乾燥且濃縮。使用製備型HPLC (逆相C-18),用乙腈/水+ 0.1% TFA 10-45%溶離來純化殘餘物。將含有目標之溶離份合併,用飽和NaHCO
3水溶液鹼化且用乙酸乙酯萃取。將有機物用鹽水洗滌,經MgSO
4乾燥且濃縮得到3
。MS:
m/
z487.2 = [M+H].
1H NMR (600 MHz, CDCl
3, ppm): δ 8.25 (s, 1H), 7.39-7.44 (m, 3H), 7.33-7.35 (m, 1H), 7.30 (t,
J= 7.8 Hz, 2H), 6.99 (d,
J= 7.8 Hz, 1H), 5.92 (s, 1H), 5.61 (s, 2H), 4.18-4.25 (m, 2H), 2.73 (s, 3H), 2.50 (s, 3H), 2.27 (s, 3H), 1.94-1.97 (m, 1H), 1.74-1.80 (m, 1H), 1.22-1.26 (m, 1H), 0.93-0.96 (m, 1H).
步驟A -合成化合物4
將1a (150 mg,0.392 mmol)於DMF (1.12 mL)中之溶液用4-二甲胺基吡啶(9.6 mg,0.078 mmol)、三乙胺(131 μL,0.941 mmol)及氯甲酸戊酯(227 μL,1.57 mmol)處理,且隨後在60℃下加熱4.5 h。添加額外氯甲酸戊酯(114 μL)且繼續加熱整夜。在次日早晨添加額外三乙胺(131 μL)及氯甲酸戊酯(227 μL)且在下午再次添加,且繼續加熱整夜。在次日早晨添加更多三乙胺(131 μL)及氯甲酸戊酯(227 μL)且在下午再次添加,且繼續加熱整夜。
將經冷卻反應物用水稀釋且用飽和NaHCO
3水溶液鹼化,隨後用乙酸乙酯萃取兩次。將經合併之有機物用鹽水與飽和Na
2CO
3水溶液之組合洗滌,經MgSO
4乾燥且濃縮。將殘餘物藉由矽膠層析用0-65% EtOAc/己烷溶離來純化得到4。MS:
m/
z497.3 = [M+H]。
1H NMR (600 MHz, CDCl
3, ppm): δ 8.27 (s, 1H), 7.35 (dd,
J= 8.4, 1.8 Hz, 1H), 7.21 (s, 1H), 7.04 (d,
J= 8.4 Hz, 1H), 5.58 (s, 2H), 4.37-4.40 (m, 1H), 4.30-4.33 (m, 1H), 4.21 (t,
J= 6.6 Hz, 2H), 2.72 (s, 3H), 2.53 (s, 3H), 2.27 (s, 3H), 2.04-2.07 (m, 1H), 1.86-1.89 (m, 1H), 1.65-1.69 (m, 2H), 1.25-1.33 (m, 5H), 1.03-1.06 (m, 1H), 0.88 (t,
J= 6.6 Hz, 3H)。
步驟A -合成化合物5
將1a (150 mg,0.392 mmol)於二氯甲烷(980 μL)中之溶液在0 ℃下冷卻且用氯甲酸氯甲酯(105 μL,1.18 mmol)快速逐滴處理,隨後升溫至室溫。在2 h之後,將反應物用二氯甲烷及飽和NaHCO
3水溶液稀釋。將有機物分離且用二氯甲烷第二次萃取水相。將經合併之有機物用鹽水洗滌,經MgSO
4乾燥且濃縮。將殘餘物溶解於DMF (2 mL)中且添加苯甲酸(144 mg,1.18 mmol)及碳酸銫(192 mg,0.588 mmol)且將反應物在70℃下加熱3 h。將經冷卻反應物使用製備型HPLC (逆相C-18)用乙腈/水+ 0.1% TFA 10-70%溶離來純化。將含有目標之溶離份合併,用飽和NaHCO
3水溶液鹼化且用乙酸乙酯萃取。將有機物用鹽水洗滌,經MgSO
4乾燥且濃縮得到5
。MS:
m/
z561.3 = [M+H]。
1H NMR (600 MHz, CDCl
3, ppm): δ 8.27 (s, 1H), 8.04 (d,
J= 7.2 Hz, 2H), 7.60 (t,
J= 6.6 Hz, 1H), 7.45 (t,
J= 7.8 Hz, 2H), 7.36 (d,
J= 6.6 Hz, 1H), 7.19 (s, 1H), 7.05 (d,
J= 7.8 Hz, 1H), 6.11 (s, 2H), 5.61 (s, 2H), 4.37-4.40 (m, 1H), 4.30-4.33 (m, 1H), 2.60 (s, 3H), 2.52 (s, 3H), 2.28 (s, 3H), 2.05-2.08 (m, 1H), 1.85-1.91 (m, 1H), 1.29-1.32 (m, 1H), 1.03-1.06 (m, 1H)。
步驟A -合成化合物6b
將6a (5.00 g,21.6 mmol)於丙酮(54.0 mL)中之溶液用碘化鈉(9.71 g,64.8 mmol)及碳酸氫鈉(0.363 g,4.32 mmol)處理,且將所得懸浮液在40℃下加熱12 h。添加額外6a (5.00 g,21.6 mmol)、碘化鈉(9.71 g,64.8 mmol)、碳酸氫鈉(0.363 g,4.32 mmol)及丙酮(25 mL),且繼續加熱整夜。將經冷卻反應物用丙酮稀釋且經由Celite
TM過濾,用丙酮洗滌。將黃色濾液濃縮且將所得固體溶解於水中且用乙酸乙酯萃取三次。將經合併之有機物用Na
2SO
3飽和水溶液洗滌,隨後用鹽水洗滌,經MgSO
4乾燥且濃縮得到呈油狀物之6b,其不經進一步純化即使用。
1H NMR (600 MHz, CDCl
3, ppm): δ 8.30-8.32 (m, 2H), 7.42-7.44 (m, 2H), 6.07 (s, 2H)。
步驟B -合成化合物6c
將6b (13.2 g,40.9 mmol)、苯甲酸(7.49 g,61.3 mmol)及碳酸銀(16.90 g,61.3 mmol)於甲苯(272 mL)中之混合物在80℃下加熱4 h及15 min。將經冷卻反應物經由Celite
TM過濾,用甲苯洗滌。將過濾物用水隨後用鹽水洗滌,經MgSO
4乾燥且濃縮。藉由矽膠層析用0-30% EtOAc/己烷溶離純化殘餘物,得到呈油狀物之
6c。
1H NMR (600 MHz, CDCl
3, ppm): δ 8.28-8.31 (m, 2H), 8.11-8.13 (m, 2H), 7.63-7.66 (m, 1H), 7.48-7.51 (m, 2H), 7.41-7.44 (m, 2H), 6.14 (s, 2H).
步驟C -合成化合物5
添加1a (100 mg,0.261 mmol)及6c (190 mg,0.588 mmol)於二氯乙烷(800 μL)及環己烷(800 μL)中之混合物且在85℃下加熱整夜。將經冷卻反應物用二氯甲烷稀釋且用半飽和Na
2CO
3水溶液洗滌。將有機物分離且將水性部分用二氯甲烷萃取三次。將經合併之有機物用半飽和Na
2CO
3水溶液洗滌,經MgSO
4乾燥且濃縮。藉由矽膠層析用10-100% EtOAc/己烷溶離來純化殘餘物。將所分離之材料藉由矽膠層析用10-100% EtOAc/己烷溶離第二次純化得到5。
本發明之以下化合物係使用上文實例5或6中所描述之方法替換適當反應物及/或反應試劑而製得:
化合物 | 結構 | 名稱 | MS [M+H] |
6 | 己酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 | 555.3 | |
7 | 丙酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 | 513.3 | |
8 | 吡啶-4-甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 | 562.4 | |
9 | 吡啶-2-甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 | 562.4 | |
10 | 吡啶-3-甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 | 562.5 | |
11 | 4-氟苯甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 | 579.5 | |
12 | 3-氟苯甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 | 579.5 | |
13 | 2-氟苯甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 | 579.5 | |
14 | 2-甲氧基苯甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 | 591.5 | |
15 | 3-甲氧基苯甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 | 591.5 | |
16 | 4-甲氧基苯甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 | 591.5 | |
17 | 2-甲基丙酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 | 527.5 | |
18 | 環己烷甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 | 567.5 | |
19 | 2-乙基丁酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 | 555.5 |
溶解度及穩定性化合物之水溶解度藉由在pH 7下之磷酸鹽緩衝鹽水(或等效pH 7緩衝液)中懸浮、音波處理(30分鐘)及漿化(2小時,1000 rpm)多餘固體(通常5-10 mg)來量測。隨後將懸浮液再次音波處理30分鐘且在1000 rpm下再攪拌至少6-24小時。移出大約400 μL樣品且將其放入旋轉過濾器中。使用0.45 μm PVDF旋轉過濾器將各樣品在14K rpm下旋轉10分鐘。將一部分濾液移出且用1:1 ACN:H
2O稀釋。使用UPLC分析來分析所得樣品。藉由XRPD檢驗固體保留物以確定材料為結晶亦或非晶。在140 μg/mL在pH 7.4下於PBS緩衝溶液中量測化合物A之溶解度。如表1中所揭示之化合物1至19展現較低水溶解度由此允許在延長的時間段內控制釋放。在140 μg/mL在pH 7.4下於PBS緩衝溶液中量測化合物A之溶解度。如表1中所揭示之化合物1至19展現較低水溶解度由此允許在延長的時間段內(例如在數天或數週之時間段)控制釋放。
化合物1至19 (1 μM)之血漿穩定性係在冷凍猴血漿及人類血漿中在37℃下於10% CO
2環境中評估。分析物之穩定性係藉由測定在0、0.25、0.5、1及3小時之過程內藥物損耗之百分比來評估。此外,測定化合物A之外觀持續相同時程。藥物損耗之百分比以與內部標準物之比率計。分析物濃度藉由LC/MS/MS來量測。線性回歸用平均T0值及線性時間值之對數轉換百分比進行。消除速率常數(ke)係根據此回歸線之斜率計算且半衰期(T
1 / 2)基於消除速率常數計算。
表1
a = 非晶材料在pH 7.0磷酸鹽緩衝液中之μg/mL
BLQ = 低於定量極限值
化合物 | 水溶解度 µg/mL a | T 1/2人類血漿 (小時) | T 1/2猴血漿 (小時) |
1 | 2.3 | 0.06 | 0.11 |
2 | BLQ | 0.29 | 0.08 |
3 | 19 | 3.03 | 1.15 |
4 | 0.008 | 6.86 | 1.73 |
5 | 0.02 | 1.74 | 1.31 |
6 | 0.02 | 0.35 | 0.24 |
7 | 15 | 0.08 | 0.09 |
8 | 0.139 | 0.19 | 0.16 |
9 | 0.058 | 0.12 | 0.10 |
10 | 0.050 | 0.93 | 0.51 |
11 | 0.07 | 1.08 | 0.72 |
12 | 0.18 | 1.32 | 0.59 |
13 | 0.08 | 0.45 | 0.28 |
14 | 0.02 | 2.10 | 0.90 |
15 | 0.12 | 3.30 | 1.12 |
16 | 0.16 | 3.78 | 1.67 |
17 | 0.16 | 0.13 | 0.12 |
18 | 0.07 | 0.35 | 0.28 |
19 | 0.03 | 2.47 | 0.59 |
Claims (38)
- 一種結構式I之化合物或其立體異構體、水合物或醫藥學上可接受之鹽, 其中: R 1選自由以下組成之群: 6) -C(O)OCH 2OC(O)R 2; 7) -C(O)OC 1 - 6烷基,該烷基視情況經1至3個R a基團取代; 8) -C(O)-C 6 - 10芳基、C(O)-C 6 - 10雜芳基、-C(O)-C 1 - 6烷基、-C(O)-C 3 - 6環烷基,該芳基、雜芳基、烷基及環烷基視情況經1至3個R a基團取代; 9) -S-C 6 - 10芳基、-S-C 4 - 10雜芳基、-S-C 1 - 6烷基、-S-C 3 - 6環烷基,該芳基、雜芳基、烷基及環烷基視情況經1至3個R a基團取代;及 10) -C(O)OCH 2間二氧雜環戊烯基,視情況經1至2個R a基團取代; R 2係選自由以下組成之群:C 1 - 6烷基、C 6 - 10芳基、C 6 - 10雜芳基及C 3 - 6環烷基;該烷基、芳基、雜芳基及環烷基視情況經1至3個R a基團取代; R a獨立地選自由以下組成之群:C 1 - 6烷基、OC 1 - 6烷基、側氧基及鹵素; n為1、2、3或4。
- 如請求項1之化合物或其立體異構體、水合物或醫藥學上可接受之鹽,其中R 1為-C(O)OCH 2OC(O)R 2。
- 如請求項1之化合物或其立體異構體、水合物或醫藥學上可接受之鹽,其中R 2為C 6 - 10芳基,該芳基未經取代或經1至3個R a基團取代。
- 如請求項1之化合物或其立體異構體、水合物或醫藥學上可接受之鹽,其中該芳基為苯基或萘基,該苯基及萘基未經取代或經1至3個R a基團取代。
- 如請求項1之化合物或其立體異構體、水合物或醫藥學上可接受之鹽,其中該芳基為苯基,該苯基未經取代或經1至3個R a基團取代。
- 如請求項1之化合物或其立體異構體、水合物或醫藥學上可接受之鹽,其中R 2為C 1 - 6烷基,該烷基未經取代或經1至3個R a基團取代。
- 如請求項1之化合物或其立體異構體、水合物或醫藥學上可接受之鹽,其中R 2為C 4 - 10雜芳基,該雜芳基未經取代或經1至3個R a基團取代。
- 如請求項7之化合物或其立體異構體、水合物或醫藥學上可接受之鹽,其中該雜芳基為未經取代或經1至3個R a基團取代之吡啶基及嘧啶基。
- 如請求項1之化合物或其立體異構體、水合物或醫藥學上可接受之鹽,其中R 2為C 3 - 6環烷基;該環烷基未經取代或經1至3個R a基團取代。
- 如請求項9之化合物或其立體異構體、水合物或醫藥學上可接受之鹽,其中該環烷基選自由未經取代或經取代之環丁基、環戊基或環己基組成之群。
- 如請求項1之化合物或其立體異構體、水合物或醫藥學上可接受之鹽,其中R 1為C(O)OC 1 - 6烷基,該烷基視情況經1至3個R a基團取代。
- 如請求項1之化合物或其立體異構體、水合物或醫藥學上可接受之鹽,其中R 1為-S-C 6 - 10芳基或-C(O)-C 6 - 10芳基,該芳基視情況經1至3個R a基團取代。
- 如請求項12之化合物或其立體異構體、水合物或醫藥學上可接受之鹽,其中芳基為苯基或萘基,該苯基及萘基未經取代或經1至3個R a基團取代。
- 如請求項1之化合物或其立體異構體、水合物或醫藥學上可接受之鹽,其中R 1為C(O)OCH 2間二氧雜環戊烯基,該間二氧雜環戊烯基未經取代或經1至3個R a基團取代。
- 如請求項1之化合物或其立體異構體、水合物或醫藥學上可接受之鹽,其為: ((5-甲基-1,3,4-噻二唑-2-基)甲基)(2-甲基-6-(((1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基)甲氧基)嘧啶-4-基)胺甲酸(5-甲基-2-側氧基-1,3-間二氧雜環戊烯-4-基)甲酯; N-((5-甲基-1,3,4-噻二唑-2-基)甲基)- N-(2-甲基-6-(((1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基)甲氧基)嘧啶-4-基)- S-苯基硫代羥胺; N-((5-甲基-1,3,4-噻二唑-2-基)甲基)- N-(2-甲基-6-(((1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基)甲氧基)嘧啶-4-基)苯甲醯胺; ((5-甲基-1,3,4-噻二唑-2-基)甲基)(2-甲基-6-(((1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基)甲氧基)嘧啶-4-基)胺甲酸戊酯; 苯甲酸((((5-甲基-1,3,4-噻二唑-2-基)甲基)(2-甲基-6-(((1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基)甲氧基)嘧啶-4-基)胺甲醯基)氧基)甲酯; 己酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯; 丙酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯; 吡啶-4-甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯; 吡啶-2-甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯; 吡啶-3-甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯; 4-氟苯甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯; 3-氟苯甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯; 2-氟苯甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯; 2-甲氧基苯甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯; 3-甲氧基苯甲酸({(2-甲基-6-{[( 1S , 2S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯; 4-甲氧基苯甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯; 2-甲基丙酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯; 環己烷甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯;及 2-乙基丁酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯;或 其立體異構體、水合物或醫藥學上可接受之鹽。
- 一種化合物或其立體異構體、水合物或醫藥學上可接受之鹽,其中該化合物係選自
結構 名稱 苯甲酸((((5-甲基-1,3,4-噻二唑-2-基)甲基)(2-甲基-6-(((1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基)甲氧基)嘧啶-4-基)胺甲醯基)氧基)甲酯 4-氟苯甲酸({(2-甲基-6-{[(1 S ,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 3-氟苯甲酸({(2-甲基-6-{[(1 S ,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 2-氟苯甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 2-甲氧基苯甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 3-甲氧基苯甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 4-甲氧基苯甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 及 2-甲基丙酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 。 - 一種醫藥組合物,其包含醫藥學上可接受之載劑及如請求項1至15中任一項之化合物或其立體異構體、水合物或醫藥學上可接受之鹽。
- 一種醫藥組合物,其包含醫藥學上可接受之載劑及化合物或其立體異構體、水合物或醫藥學上可接受之鹽,其中該化合物係選自:
結構 名稱 苯甲酸((((5-甲基-1,3,4-噻二唑-2-基)甲基)(2-甲基-6-(((1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基)甲氧基)嘧啶-4-基)胺甲醯基)氧基)甲酯 4-氟苯甲酸({(2-甲基-6-{[(1 S ,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 3-氟苯甲酸({(2-甲基-6-{[(1 S ,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 2-氟苯甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 2-甲氧基苯甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 3-甲氧基苯甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 4-甲氧基苯甲酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 及 2-甲基丙酸({(2-甲基-6-{[(1 S,2 S)-2-(5-甲基吡啶-2-基)環丙基]甲氧基}嘧啶-4-基)[(5-甲基-1,3,4-噻二唑-2-基)甲基]胺甲醯基}氧基)甲酯 。 - 一種如請求項1至24中任一項之化合物或其立體異構體、水合物或醫藥學上可接受之鹽的用途,其用於製造用以治療選自精神病性病症、妄想症及藥物誘發的精神病;焦慮症、運動障礙、情緒障礙及神經退化性病症之病症之藥物。
- 一種如請求項1至24中任一項之化合物或其立體異構體、水合物或醫藥學上可接受之鹽的用途,其用於製造用以治療與PDE10功能障礙相關之神經或精神病症之藥物。
- 一種如請求項1至24中任一項之化合物或其立體異構體、水合物或醫藥學上可接受之鹽的用途,其用於製造用以治療與紋狀體功能低下或基底神經節功能障礙相關之神經或精神病症之藥物。
- 一種如請求項1至24中任一項之化合物或其立體異構體、水合物或醫藥學上可接受之鹽的用途,其用於製造用以治療精神分裂症之藥物。
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