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1. 发明申请

WO1994008997A1 SUBSTITUTED BENZYLAMINOQUINUCLIDINES AS SUBSTANCE P ANTAGONISTS 审中-公开
标题翻译：作为物质的拮抗剂的取代苄基氨基
公开(公告)号：WO1994008997A1
公开(公告)日：1994-04-28
申请号：PCT/US1993009168
申请日：1993-09-30
申请人： PFIZER INC. , ITO, Fumitaka , SATAKE, Kunio , SHIMADA, Kaoru
发明人： PFIZER INC.
IPC分类号： C07D453/02
CPC分类号： C07F9/6561 , C07D453/02
摘要： Compounds useful in the treatment of inflammatory disorders, central nervous system disorders and other disorders of formula (I), and the pharmaceutically acceptable salts thereof, wherein Ar and Ar are each independently aryl or substituted aryl; R is alkyl having from 1 to 6 carbon atoms; R is hydrogen or alkyl having from 1 to 6 carbon atoms; and either X and Y are taken separately and they are each, independently, hydrogen, dialkylphosphoryl having 2 to 12 carbon atoms, alkyl having from 1 to 6 carbon atoms, alkenyl having from 2 to 6 carbon atoms or alkynyl having from 2 to 6 carbon atoms; or X and Y are taken together and they represent a hydrocarbon chain having 3, 4, or 5 carbon atoms, optionally containing up to 2 double bonds and optionally having 1 or 2 substituents selected from oxo, hydroxy and alkyl having from 1 to 6 carbon atoms; provided that when X and Y are taken together they are attached to adjacent carbon atoms; and provided that if either X or Y is hydrogen, then the other one must be alkenyl or alkynyl.
摘要翻译：用于治疗炎性疾病，中枢神经系统疾病和式（I）的其它病症的化合物及其药学上可接受的盐，其中Ar 1和Ar 2各自独立地为芳基或取代的芳基; R 1是具有1至6个碳原子的烷基; R 2是氢或具有1至6个碳原子的烷基; X和Y分别取代，它们各自独立地为氢，具有2至12个碳原子的二烷基磷酰基，具有1至6个碳原子的烷基，具有2至6个碳原子的烯基或具有2至6个碳原子的炔基原子; 或X和Y一起并且它们表示具有3,4或5个碳原子的烃链，任选地含有至多2个双键并且任选地具有1或2个选自氧代，羟基和具有1至6个碳原子的烷基的取代基原子; 条件是当X和Y一起取代时，它们连接到相邻的碳原子上; 并且条件是如果X或Y是氢，则另一个必须是烯基或炔基。

2. 发明申请

WO1994004496A1 SUBSTITUTED BENZYLAMINO NITROGEN CONTAINING NON-AROMATIC HETEROCYCLES 审中-公开
标题翻译：取代的苯甲酰胺含有非芳香杂环的氮
公开(公告)号：WO1994004496A1
公开(公告)日：1994-03-03
申请号：PCT/US1993004063
申请日：1993-05-05
申请人： PFIZER INC. , HOWARD, Harry, R., Jr. , IKUNAKA, Masaya , ITO, Fumitaka , LOWE, John, A., III , NAKANE, Masami , O'NEILL, Brian, T. , ROSEN, Terry, R. , SATAKE, Kunio
发明人： PFIZER INC.
IPC分类号： C07D211/56
CPC分类号： C07D401/12 , C07D211/56 , C07D417/12 , C07D453/02 , C07D487/08
摘要： The present invention relates to novel substituted benzylamino nitrogen containing non-aromatic heterocycles and, specifically, to compounds of formula (I) wherein W, R1, R2, R3 and A are as defined in the specification, and to intermediates used in the synthesis of such compounds. The novel compounds of formula (I) are useful in the treatment of inflammatory and central nervous system disorders, as well as other disorders.
摘要翻译：本发明涉及新的取代的苄基氨基氮的非芳族杂环，具体地说，涉及式（I）的化合物，其中W，R 1，R 2，R 3和A如说明书中所定义，以及用于合成这样的化合物。式（I）的新型化合物可用于治疗炎性和中枢神经系统疾病以及其它疾病。

3. 发明申请

WO1992020676A1 SUBSTITUTED 3-AMINOQUINUCLIDINES 审中-公开
标题翻译：取代的3-氨基胆碱
公开(公告)号：WO1992020676A1
公开(公告)日：1992-11-26
申请号：PCT/US1992004002
申请日：1992-05-19
申请人： PFIZER INC. , ITO, Fumitaka , KOKURA, Toshihide , NAKANE, Masami , SATAKE, Kunio , WAKABAYASHI, Hiroaki
发明人： PFIZER INC.
IPC分类号： C07D453/02
CPC分类号： C07D453/02
摘要： Compounds of formula (I), wherein W, Ar , Ar and Ar are defined as below; and the pharmaceutically acceptable salts of such compounds. These compounds are substance P antagonists and useful in the treatment of gastrointestinal disorders, inflammatory disorders, central nervous system disorders and pain.
摘要翻译：其中W，Ar 1，Ar 2和Ar 3的式（I）化合物定义如下：和这些化合物的药学上可接受的盐。这些化合物是物质P拮抗剂，可用于治疗胃肠道疾病，炎性疾病，中枢神经系统疾病和疼痛。

4. 发明申请

WO1994010170A1 SUBSTITUTED QUINUCLIDINES AS SUBSTANCE P ANTAGONISTS 审中-公开
标题翻译：作为物质拮抗剂的替代喹啉
公开(公告)号：WO1994010170A1
公开(公告)日：1994-05-11
申请号：PCT/US1993009169
申请日：1993-09-30
申请人： PFIZER INC. , ITO, Fumitaka , KOKURA, Toshihide , NAKANE, Masami , SATAKE, Kunio , WAKABAYASHI, Hiroaki
发明人： PFIZER INC.
IPC分类号： C07D453/02
CPC分类号： C07D453/02
摘要： Certain novel substituted quinuclidine compounds having the ability to antagonize substance P and having formula (I) wherein Ar and Ar are each, independently, thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl; X is -CONR R , -CO2R , -CH2OR , -CH2NR R or -CONR OR ; R , R and R are each, independently, hydrogen or alkyl having 1 to 4 carbon atoms; R is alkyl having 1 to 4 carbon atoms; Y is alkylsulfonyl having 1 to 4 carbon atoms, N-alkyl-N-alkanoylamino (which may be substituted by halogen in the alkanoyl moiety) having 1 to 4 carbon atoms in the alkyl and the alkanoyl moieties, N-alkyl-N-alkylsulfonylamino (which may be substituted by halogen in the alkylsulfonyl moiety) having 1 to 4 carbon atoms in the alkyl and the alkyl sulfonyl moieties, alkenyl having 2 to 4 carbon atoms, alkynyl having 2 to 4 carbon atoms, halosubstituted alkyl having 1 to 4 carbon atoms, alkylamino having 1 to 4 carbon atoms, alkanoylamino (which may be substituted by halogen) having 1 to 4 carbon atoms or alkylsulfonylamino (which may be substituted by halogen) having 1 to 4 carbon atoms. These compounds are useful in the treatment gastrointestinal or central nervous system disorders and the alleviation of inflammatory diseases, asthma, pain and migraine in mammals and as the active ingredient in pharmaceutical compositions for treating such conditions.
摘要翻译：具有拮抗物质P并具有其中Ar 1和Ar 2的式（I）的能力的某些新型取代的奎宁环化合物各自独立地为噻吩基，苯基，氟苯基，氯苯基或溴苯基; X是-CONR 3 R 4，-CO 2 R 3，-CH 2 OR 3，-CH 2 NR 3 R 4或-CONR 3 OR 4; R 1，R 3和R 4各自独立地为氢或具有1至4个碳原子的烷基; R 2是具有1至4个碳原子的烷基; Y是具有1至4个碳原子的烷基磺酰基，在烷基和烷酰基部分中具有1至4个碳原子的N-烷基-N-烷酰基氨基（其可被烷酰基部分中被卤素取代）为N-烷基-N-烷基磺酰基氨基（其可以被烷基磺酰基部分中的卤素取代）在烷基和烷基磺酰基部分中具有1至4个碳原子，具有2至4个碳原子的烯基，具有2至4个碳原子的炔基，具有1至4个碳原子的卤代烷基原子，具有1至4个碳原子的烷基氨基，具有1至4个碳原子的烷酰基氨基（其可以被卤素取代）或具有1至4个碳原子的烷基磺酰基氨基（可以被卤素取代）。这些化合物可用于治疗哺乳动物中的胃肠道或中枢神经系统疾病和减轻炎症性疾病，哮喘，疼痛和偏头痛，并用作用于治疗这些病症的药物组合物中的活性成分。

5. 发明申请

WO1992021677A1 bibNUCLIDINE DERIVATIVES 审中-公开
标题翻译： bibNUCLIDINE衍生物
公开(公告)号：WO1992021677A1
公开(公告)日：1992-12-10
申请号：PCT/US1992003317
申请日：1992-04-28
申请人： PFIZER INC. , ITO, Fumitaka , KONDO, Hiroshi , SHIMADA, Kaoru , NAKANE, Masami , LOWE, John, Adams, III , ROSEN, Terry, Jay , YANG, Bingwei, Vera
发明人： PFIZER INC.
IPC分类号： C07D453/02
CPC分类号： C07D453/02
摘要： Compounds of formula (I), wherein R is methoxy and R is selected from the group consisting of methyl, ethyl, isopropyl, sec-butyl and tert-butyl; and the pharmaceutically acceptable salts of such compounds. These compounds are substance P antagonists and useful in the treatment of gastrointestinal disorders, inflammatory disorders, central nervous system disorders and pain.
摘要翻译：式（I）化合物，其中R 1是甲氧基，R 2选自甲基，乙基，异丙基，仲丁基和叔丁基; 和这些化合物的药学上可接受的盐。这些化合物是物质P拮抗剂，可用于治疗胃肠道疾病，炎性疾病，中枢神经系统疾病和疼痛。

6. 发明申请

WO1994011368A1 QUINUCLIDINE DERIVATIVE AS SUBSTANCE P ANTAGONIST 审中-公开
标题翻译：喹诺酮衍生物作为物质P ANTAGONIST
公开(公告)号：WO1994011368A1
公开(公告)日：1994-05-26
申请号：PCT/US1993006624
申请日：1993-07-19
申请人： PFIZER INC. , ITO, Fumitaka , KONDO, Hiroshi , NAKANE, Masami , SHIMADA, Kaoru
发明人： PFIZER INC.
IPC分类号： C07D453/02
CPC分类号： A61K31/435 , C07D453/02
摘要： This invention relates to the quinuclidine derivative (2S, 3S)-N-(5-n-propyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine and its pharmaceutically acceptable salts. These compounds are substance P antagonists and are useful in the treatment of gastrointestinal disorders, inflammatory disorders, central nervous system disorders and pain.
摘要翻译：本发明涉及奎宁环衍生物（2S，3S）-N-（5-正丙基-2-甲氧基苯基）甲基-2-二苯基甲基-1-氮杂双环[2.2.2]辛-3-胺及其药学上可接受的盐。这些化合物是物质P拮抗剂，可用于治疗胃肠道疾病，炎性疾病，中枢神经系统疾病和疼痛。

7. 发明申请

WO1993019064A1 QUINUCLIDINE DERIVATIVES AS SUBSTANCE P ANTAGONISTS 审中-公开
标题翻译：喹啉衍生物作为物质拮抗剂
公开(公告)号：WO1993019064A1
公开(公告)日：1993-09-30
申请号：PCT/US1993001810
申请日：1993-03-05
申请人： PFIZER INC. , SATAKE, Kunio , WAKABAYASHI, Hiroaki , NAKANE, Masami
发明人： PFIZER INC.
IPC分类号： C07D453/02
CPC分类号： C07D453/02
摘要： Compounds useful in the treatment of inflammatory disorders, central nervous system disorders and other disorders of formula (I) and the pharmaceutically-acceptable salts thereof, wherein X is alkoxy or halosubstituted alkoxy; X is hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halosubstitued alkyl, halosubstituted alkoxy, alkylamino, dialkylamino, alkylsulfonylamino (which may be substituted), N-alkyl-N-alkylsulfonylamino (which may be substituted), alkanoylamino (which may be substituted) or N-alkyl-N-alkanoylamino (which may be substituted); Ar and Ar are each, independently, thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl; A is Y-(CH2)m-CH(R )-(CH2)n-NR -; R is hydrogen, alkyl, benzyl or -(CH2)p-Y; R is hydrogen, alkyl (which may be substituted), benzyl, 4-hydroxybenzyl, 3-indolylmethyl or -(CH2)p-Y; Y is -CN, -CH2Z or -COZ; Z is hydroxy, amino, alkoxy, alkylamino or dialkylamino; m, n and p are each, independently, 0, 1, 2 or 3; and R and R may be connected to form a ring.
摘要翻译：用于治疗炎症性疾病，中枢神经系统疾病和式（I）的其它病症的化合物及其药学上可接受的盐，其中X 1是烷氧基或卤素取代的烷氧基; X 2是氢，卤素，烷基，烯基，炔基，烷氧基，烷硫基，烷基亚磺酰基，烷基磺酰基，卤素取代的烷基，卤代烷氧基，烷基氨基，二烷基氨基，烷基磺酰基氨基（其可被取代的），N-烷基-N-烷基磺酰基氨基可以被取代），烷酰基氨基（其可以被取代）或N-烷基-N-烷酰基氨基（其可以被取代）; Ar 1和Ar 2各自独立地为噻吩基，苯基，氟苯基，氯苯基或溴苯基; A是Y-（CH 2）m -CH（R 2） - （CH 2）n -NR 1 - ; R 1是氢，烷基，苄基或 - （CH 2）p-Y; R 2是氢，烷基（其可以被取代），苄基，4-羟基苄基，3-吲哚基甲基或 - （CH 2）p-Y; Y是-CN，-CH2Z或-COZ; Z是羟基，氨基，烷氧基，烷基氨基或二烷基氨基; m，n和p各自独立地为0,1,2或3; R 1和R 2可以连接形成环。

8. 发明申请

WO1994026740A1 HETEROATOM SUBSTITUTED ALKYL BENZYLAMINOQUINUCLIDINES AS SUBSTANCE P ANTAGONISTS 审中-公开
标题翻译：异构体取代的烷基苯甲酰氨基胆碱作为物质的拮抗剂
公开(公告)号：WO1994026740A1
公开(公告)日：1994-11-24
申请号：PCT/JP1994000781
申请日：1994-05-13
申请人： PFIZER PHARMACEUTICALS INC. , PFIZER INC. , SATAKE, Kunio
发明人： PFIZER PHARMACEUTICALS INC. , PFIZER INC.
IPC分类号： C07D453/02
CPC分类号： C07D453/02
摘要： Compounds useful in the treatment of inflammatory disorders, central nervous system disorders and other disorders of formula (I) and the pharmaceutically-acceptable salts thereof; wherein R is C1-C6 alkyl; X is C1-C6 alkyl having one or more substituents which include at least one heteroatom; Ar and Ar are each, independently, aryl optionally substituted by one C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, nitro, phenoxy, mono C1-C6 alkylamino, di C1-C6 alkylamino, halosubstituted C1-C6 alkyl, or halosubstituted C1-C6 alkoxy; Y is hydrogen, C1-C6 akyl, C2-C6 alkenyl, C3-C8 cycloalkyl, Z-(CH2)p-, or W-(CH2)m-CHR (CH2)n-NR CO- wherein Y is at the 4-, 5- or 6-position on the quinuclidine ring; R is hydrogen, C1-C6 alkyl, benzyl or -(CH2)r-W; R is hydrogen or C1-C6 alkyl which may be substituted by one hydroxy, amino, methylthio, methylmercapto, benzyl, 4-hydroxybenzyl, 3-indolylmethyl or -(CH2)r-W; R may form a ring with R ; Z is C1-C6 alkoxy, -CONR R , -CO2R , -CHR OR , -CHR NR R , -COR , -CONR OR or optionally substituted aryl; each W is independently cyano, hydroxymethyl, C2-C6 alkoxymethyl, aminomethyl, mono C1-C6 alkylaminomethyl, di C1-C6 alkylaminomethyl, carboxyl, carbamoyl or C1-C6 alkoxycarbonyl; R , R and R are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or an optionally substituted aryl or heterocyclic group; p is 0 to 6; and m, n and r are each, independently, 0 to 3.
摘要翻译：用于治疗炎症性疾病，中枢神经系统疾病和式（I）的其它病症的化合物及其药学上可接受的盐; 其中R是C1-C6烷基; X是具有一个或多个包含至少一个杂原子的取代基的C 1 -C 6烷基; Ar 1和Ar 2各自独立地为任选被一个C 1 -C 6烷基，C 1 -C 6烷氧基，C 1 -C 6烷硫基，卤素，氰基，硝基，苯氧基，单C 1 -C 6烷基氨基，二C1 -C 1-6烷基氨基，卤代取代的C 1 -C 6烷基或卤素取代的C 1 -C 6烷氧基; Y是氢，C 1 -C 6烷基，C 2 -C 6烯基，C 3 -C 8环烷基，Z-（CH 2）p - 或W-（CH 2）m -CH 2（CH 2）n -NR A CO- 其中Y在奎宁环上的4-，5-或6-位; R 1是氢，C 1 -C 6烷基，苄基或 - （CH 2）r-W; R 2是氢或可被一个羟基，氨基，甲硫基，甲基巯基，苄基，4-羟基苄基，3-吲哚基甲基或 - （CH 2）r-W取代的C 1 -C 6烷基; R 1可以与R 2形成环; Z是C 1 -C 6烷氧基，-CONR 4 R 5，-CO 2 R 4，-CHR 4 OR 5，-CHR 4 NR 5 R 6， 4，-CONR 4或OR 5或任选取代的芳基; 每个W独立地是氰基，羟甲基，C2-C6烷氧基甲基，氨基甲基，单C1-C6烷基氨基甲基，二C1-C6烷基氨基甲基，羧基，氨基甲酰基或C1-C6烷氧基羰基; R 4，R 5和R 6独立地是氢，C 1 -C 6烷基，C 1 -C 6烷氧基，C 3 -C 8环烷基或任选取代的芳基或杂环基; p为0〜6; m，n和r各自独立地为0〜3。

9. 发明申请

WO1997008144A1 SUBSTITUTED BENZYLAMINOPIPERIDINE COMPOUNDS 审中-公开
标题翻译：取代的苄基苯胺化合物
公开(公告)号：WO1997008144A1
公开(公告)日：1997-03-06
申请号：PCT/IB1996000572
申请日：1996-06-10
申请人： PFIZER PHARMACEUTICALS INC. , PFIZER INC. , SATAKE, Kunio , SHISHIDO, Yuji , WAKABAYASHI, Hiroaki
发明人： PFIZER PHARMACEUTICALS INC. , PFIZER INC.
IPC分类号： C07D211/56
CPC分类号： C07D211/56
摘要： This invention provides a compound of formula (I) and its pharmaceutically acceptable salts, wherein R is halo C1-C8 alkyl, halo C2-C8 alkenyl, halo C2-C8 alkynyl or halo C1-C8 alkyl substituted by hydroxy or C1-C8 alkoxy; R is hydrogen, halo or C1-C6 alkoxy; or R and R , together with the two carbon atoms shared between the benzene ring and the R and R , complete a fused C4-C6 cycloalkyl wherein one carbon atom is optionally replaced by oxygen and wherein one or two of the carbon atoms are optionally substituted by up to five substituents selected from halo, C1-C6 alkyl and halo C1-C6 alkyl; X is C1-C6 alkoxy, halo C1-C6 alkoxy, phenoxy or halo; and Ar is phenyl optionally substituted by halo. These compounds are of use in treating a gastrointestinal disorder, a central nervous system (CNS) disorder, an inflammatory disease, emesis, urinary incontinence, pain, migraine, sunburn, diseases, disorders and adverse conditions caused by Helicobacter pylori, or angiogenesis especially CNS disorders in a mammalian subject, especially humans.
摘要翻译：本发明提供式（I）化合物及其药学上可接受的盐，其中R为卤代C 1 -C 8烷基，卤代C 2 -C 8烯基，卤代C 2 -C 8炔基或被羟基或C 1 -C 8烷氧基取代的卤代C 1 -C 8烷基 ; R 1是氢，卤素或C 1 -C 6烷氧基; 或R和R 1与苯环和R和R 1之间共享的两个碳原子一起形成稠合的C 4 -C 6环烷基，其中一个碳原子任选被氧代替，并且其中一个或两个碳原子任选被至多五个选自卤素，C 1 -C 6烷基和卤代C 1 -C 6烷基的取代基取代; X是C 1 -C 6烷氧基，卤代C 1 -C 6烷氧基，苯氧基或卤素; 且Ar为任选被卤素取代的苯基。这些化合物可用于治疗胃肠道疾病，中枢神经系统（CNS）障碍，炎性疾病，呕吐，尿失禁，疼痛，偏头痛，晒伤，疾病，病症和由幽门螺杆菌引起的不良状况，或血管发生，尤其是CNS 哺乳动物受试者，特别是人类的疾病。

10. 发明申请

WO1995002595A1 BENZYLOXYQUINUCLIDINES AS SUBSTANCE P ANTAGONISTS 审中-公开
标题翻译：苯甲酰胆碱作为物质拮抗剂
公开(公告)号：WO1995002595A1
公开(公告)日：1995-01-26
申请号：PCT/JP1994001092
申请日：1994-07-05
申请人： PFIZER PHARMACEUTICALS INC. , PFIZER INC. , SATAKE, Kunio , WAKABAYASHI, Hiroaki
发明人： PFIZER PHARMACEUTICALS INC. , PFIZER INC.
IPC分类号： C07D453/02
CPC分类号： C07D453/02
摘要： A compound of chemical formula (I) and its pharmaceutically acceptable salt, wherein X and Y are each hydrogen, halogen, C1-C6 alkyl, halosubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl or tri C1-C6 alkylsilyl; Ar and Ar are each aryl optionally substituted by halogen; A is -CO- or -(CH2)-; Z-A- is at 2 or 3 position on the quinuclidine ring; and Z is hydroxy, C1-C6 alkoxy, NR R or the like. Typical examples are (3S,4R,5S,6S)-5-(3,5-bis(trifluoromethyl)benzyloxy)-N,N-dimethyl-6-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-carboxamide; (3S,4R,5S,6S)-5-(3,5-bis(trifluoromethyl)benzyloxy)-6-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-carboxylic acid. The novel benzyloxyquinuclidines in this invention have substance P antagonistic activity and are thus useful for the treatment of gastrointestinal disorders, central nervous system disorders, allergy, inflammatory diseases, asthma, pain, emesis, migraine, urinary incontinence or angiogenesis in mammals, especially humans.
摘要翻译：化学式（I）的化合物及其药学上可接受的盐，其中X和Y各自为氢，卤素，C 1 -C 6烷基，卤素取代的C 1 -C 6烷基，C 1 -C 6烷氧基，C 1 -C 6烷硫基，C 1 -C 6烷基亚磺酰基， C1-C6烷基磺酰基或三C1-C6烷基甲硅烷基; Ar 1和Ar 2各自为任选被卤素取代的芳基; A是-CO-或 - （CH 2） - ; Z-A-位于奎宁环上2或3位; Z是羟基，C 1 -C 6烷氧基，NR 1 R 2等。典型实例是（3S，4R，5S，6S）-5-（3,5-双（三氟甲基）苄氧基）-N，N-二甲基-6-二苯基甲基-1-氮杂双环[2.2.2]辛-3-甲酰胺 ; （3S，4R，5S，6S）-5-（3,5-双（三氟甲基）苄氧基）-6-二苯基甲基-1-氮杂双环[2.2.2]辛-3-羧酸。本发明中的新型苄氧基奎宁类具有P物质拮抗作用，因此可用于治疗哺乳动物尤其是人类的胃肠疾病，中枢神经系统疾病，变态反应，炎性疾病，哮喘，疼痛，呕吐，偏头痛，尿失禁或血管发生。

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