TW200418488A

TW200418488A - Organic compounds

Info

Publication number: TW200418488A
Application number: TW092129433A
Authority: TW
Inventors: Christine Charman; John R Fozard
Original assignee: Novartis Ag
Priority date: 2002-10-24
Filing date: 2003-10-23
Publication date: 2004-10-01
Also published as: AU2003274067A1; WO2004037266A1; GB0224788D0

Abstract

The use of a compound of formula I, in free form or in the form of a pharmaceutically acceptable salt for the preparation of a medicament for the treatment of a cough, wherein R1, R2, R3, R4, R5, R6 and R7 have the meanings as indicated in the specification.

Description

200418488 5夂、發明說明：【發明所屬之技術領域】 I發明關於有機化合物，特別是關於其醫藥用途。【發明内容】本發明一方面提供自由形式的或醫藥上可接受的鹽的形式的式I化合物200418488 5) Description of the invention: [Technical field to which the invention belongs] I The invention relates to organic compounds, in particular to its medical use. SUMMARY OF THE INVENTION In one aspect, the present invention provides a compound of formula I in the form of a free form or a pharmaceutically acceptable salt.

7 R 'NIH I製備藥物以治療咳漱上的用途，其中7 R 'NIH I The use of a preparation for the treatment of cough, in which

Rl是苯基，其為未經取代的或以1，2或3個取代基取代的’而此等取代基是選自鹵素，C1-C7-燒基’三氟甲基，經基及C1-C7 -挺氧基， R2是氫或Ci-Cy-燒基， R3是氫或Ci-Cr烷基或苯基，其為未經取代的或以1，2 或3個取代基取代的，而此等取代基是選自鹵素，Ci-C7-烷基，三氟甲基，羥基及(^<7-烷氧基， R4是苯基，其為未經取代的或以1，2或3個取代基取代的，而此等取代基是選自鹵素，Ci-Cr烷基，三氟甲基，羥基及CVCV烷氧基；或為萘基，1H-吲哚-3-基或l-C^CV烷基哚-3-基， R5及R6各彼此獨立是氫或Ci-Cr烷基，至少R5及R6之一是氫，及 88769 〜基或L-氮環庚-2-酮疋C 3 - c 8 -環fe基’ D -氮環庚__ 2 -酉同 3、基。主，、 ΛΤ、％瑪主，特別是人病 %嚷的方法，此法包括給予該我士 ι 合物。丁 4届王有效量的前逑式I化根據本發明，咳嗷的治療可以是症狀性治療。、、f =教所致之情況。其形式為有聲地噴出氣體，其功能為 ’育除呼吸道内有刺激性的物質，如微粒、煙、化學品、及病聲的粘液等。咳嗽可能由一或多種潛伏的疾病， :且塞性肺病（COPD)，上呼吸道感染（URTI)，鼻滴液後，、、病每感朱，氣17而，肺癌，間質性肺病，胃食道回流病 ⑴取D)，血管緊張素轉化酶誘發的咳嗷及心衰竭所致。式 I化合物在治療無疫性（non-productive)咳漱，也叫乾咳，特別是由COPD或急性病毒感染所致的無痰咳漱上有效。【實施方式】前述及後述一般詞名有如下意義： CKC7-烷基是，例如，甲基，乙基，正-丙基，異丙基，正-丁基，異丁基，第二-丁基，第三-丁基，正-戊基，新戊基，正-己基，或正-庚基，特別是甲基或乙基’尤其是甲基。鹵素是，例如，氟，氯，溴或破。鹵苯基是，例如，（氟-，氯-，溴-或破-)苯基’較佳是敦苯基或氣苯基’特別是4 -氟笨基或4 -氣笨基尤其疋4 -氯苯基0 88769 200418488 二鹵苯基是，例如，二氯苯基，二氯苯基或氯氟苯基，較佳是二氯苯基或二氟苯基，特別是3,4-二氯苯基或3,4-二氟苯基，尤其是3,4-二氯苯基。二_苯基是^例如，二氣苯基或二氯苯基。 1-Ci-C7-烷基哚-3-基是，例如，1-甲基^丨哚-3-基。 C 3 _ C 8 _玉幕基-及類似的C 5 - C 7 -玉哀基-各是兩戶斤不5募竣原子數的環烷基。所以，c3-c8-環烷基是，例如，環丙基，環丁基，環戊基，環己基，環庚基或環辛基，較佳是環己基。 D-氮環庚-2-酮-3-基相當於如下的基團Rl is phenyl, which is unsubstituted or substituted with 1, 2 or 3 substituents, and these substituents are selected from halogen, C1-C7-alkyl, trifluoromethyl, triphenyl, and C1 -C7-quiteoxy, R2 is hydrogen or Ci-Cy-alkyl, R3 is hydrogen or Ci-Cr alkyl or phenyl, which is unsubstituted or substituted with 1, 2 or 3 substituents, These substituents are selected from the group consisting of halogen, Ci-C7-alkyl, trifluoromethyl, hydroxyl and (^ < 7-alkoxy, R4 is phenyl, which is unsubstituted or 1,2 Or 3 substituents, and these substituents are selected from halogen, Ci-Cr alkyl, trifluoromethyl, hydroxyl and CVCV alkoxy; or naphthyl, 1H-indole-3-yl or lC ^ CV alkyl indol-3-yl, R5 and R6 are each independently hydrogen or Ci-Cr alkyl, at least one of R5 and R6 is hydrogen, and 88769 ~ or phenylcycloheptan-2-one C 3-c 8 -cyclofe group 'D -azacycloheptene__ 2-different 3 groups. Master, ΔΤ,% ma master, especially human disease method, this method includes giving the According to the present invention, the treatment of cough can be a symptomatic treatment.,, f = teaching Caused by a form of audible gas, its function is to 'remove irritating substances in the respiratory tract, such as particles, smoke, chemicals, and mucus of sick sounds. Cough may be caused by one or more latent Diseases: COPD, upper respiratory tract infection (URTI), nasal drops, irritation, illness, qi, and lung cancer, interstitial lung disease, gastroesophageal reflux disease (D), Angiotensin-converting enzyme-induced cough and heart failure. Compounds of formula I are effective in the treatment of non-productive coughs, also called dry coughs, especially sputum-free coughs caused by COPD or acute viral infections. [Embodiment] The foregoing and the following general word names have the following meanings: CKC7-alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and second-butyl Radical, tert-butyl, n-pentyl, neopentyl, n-hexyl, or n-heptyl, especially methyl or ethyl ', especially methyl. Halogen is, for example, fluorine, chlorine, bromine or bromine. Halophenyl is, for example, (fluoro-, chloro-, bromo- or oxo-) phenyl 'preferably phenyl or phenyl', especially 4-fluorobenzyl or 4-phenylbenzyl, especially -Chlorophenyl 0 88769 200418488 dihalophenyl is, for example, dichlorophenyl, dichlorophenyl or chlorofluorophenyl, preferably dichlorophenyl or difluorophenyl, especially 3,4-diphenyl Chlorophenyl or 3,4-difluorophenyl, especially 3,4-dichlorophenyl. Di-phenyl is, for example, dioxophenyl or dichlorophenyl. 1-Ci-C7-alkylindol-3-yl is, for example, 1-methyl ^ indol-3-yl. C 3 _ C 8 _ Yumuji-and similar C 5-C 7-Yuaiji-each is a cycloalkyl group with two or less 5 atoms. Therefore, c3-c8-cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, and cyclohexyl is preferred. D-azepine-2-one-3-yl corresponds to the following group

其係衍生自於3-位經取代的D( + )-衣普西隆-己内醯胺（胺基 -)[-D-3-胺基-衣普西隆-己内醯胺=(R)-3-胺基-六氫-2-氮七環烯酮]。同樣，L-氮環庚-2-酮-3-基相當於如下的基團It is derived from the substituted 3-position D (+)-Ipsiron-caprolactam (amino-) [-D-3-amino-Ipsiron-caprolactam = ( R) -3-amino-hexahydro-2-azaheptazone]. Similarly, L-azacycloheptan-2-one-3-yl corresponds to the following group

其係衍生自於3-位經取代的L(-)-衣普西隆-己内醯胺（胺基 -)[ = L-3-胺基-衣普西隆-己内醯胺=(S)-3-胺基-六氫-2-氮七環烯酮]。式I化合物可以為式IA化合物 88769 200418488It is derived from the substituted L (-)-Ipsiron-caprolactam (amino-) at the 3-position [= L-3-amino-Ipsupiron-caprolactam = ( S) -3-Amino-hexahydro-2-azaheptazone]. A compound of formula I may be a compound of formula IA 88769 200418488

R \ N—HR \ N—H

IA 其中*是指R構形，或為式IB化合物IA where * refers to the R configuration, or a compound of formula IB

R \ N—HR \ N—H

IB 其中*是指S構形，此處R1，R2，R3，R4，R5，R6及R7之意義如前述。式IA化合物一般喜用於本發明。有鹼性基團的式I化合物可，例如，與適宜的礦物酸生成酸加成鹽，如與鹽酸，硫酸或磷酸生成鹽酸鹽，氫溴酸鹽，硫酸鹽，硫酸氫鹽，或碟酸鹽。在式I化合物含酸性基團時，也可與鹼，生成對應的鹽，例如對應的驗金屬或驗土金屬鹽，例如銷、鉀或鎂鹽，或與氨或有機胺生成鹽，如按鹽。本發明較佳是關於式I化合物的用途，其中 R1是苯基，3,5-貳三氟甲基-苯基或3,4,5-三甲氧基苯基， R2是氫或Ci-CV烷基， R3是氫或苯基， R4是苯基，鹵-苯基，二鹵-苯基，三鹵-苯基，2-萘基， 1H-H丨哚-3-基或l-Ci-CV烷基吲哚-3-基， 88769 200418488 R5及R6各獨立是氮或Ci-Cy-烷基，至少R5及R6之一是氫，及 117是(：5-(：7-環烷基，D-氮環庚-2-酮-3-基或L-氮環庚-2-酮 -3-基。本發明特別是關於式I化合物的用途，其中 R1是3,5-貳三氟甲基-苯基， R2是氫，甲基或乙基， R3是氫或苯基， R4是苯基，4-氯苯基，4-氟苯基，3,4-二氯苯基，3,4-二氣苯基’ 3 -氣-4-鼠"·苯基’ 3,4,5 -二氣苯基’ 2 -奈基’ 哚-3-基或1-甲基哚-3-基， R5及R6各獨立是氫或甲基，至少R5及R6之一是氫，及 R7是環己基，D-氮環庚-2-酮-3-基或L-氮環庚-2-酮-3-基。本發明更是關於式I化合物的用途，其中 Ri是3,5-貳三氟甲基-苯基， R2是氫或甲基， R3是氫或苯基， R4是苯基，4-氯苯基，3,4-二氣苯基，2-莕基，1H-W哚 -3-基或1-甲基丨哚-3-基， R5及R6是氫，及 R7是環己基，D-氮環庚-2-酮-3-基或L-氮環庚-2-酮-3-基。應特別提及的是下述次級式I化合物。 (1)式I化合物，其中R7是D-氮環庚-2-酮-3-基；（2)式I化合物，其中R5及R6是氫；（3)式I化合物，其中R1是苯基，3,5- 88769 -10- 200418488 貳三氟甲基-苯基或3，4,5-三甲氧基苯基；（4)自由態的式I化合物，即非鹽形式的。式I化合物的特定例包括： (4R)-[N、甲基-N、（3,5-貳三氟甲基-苯甲醯基）-胺基]-5-(1-甲基-啕哚-3-基）-戊-2-烯酸N-[(R)-衣普西隆-己内醯胺-3-基]-醯胺， (4R)-[NT-甲基-ΝΓ-(3,5-貳三氟曱基-苯甲醯基）-胺基]-5-(1-甲基-啕哚-3-基）-戊-2-烯酸N-[(S)-衣普西隆-己内醯胺-3-基]-醯胺， (4RHN、甲基-N、（3,5-貳三氟甲基-苯甲醯基）-胺基]-5-(1-甲基丨哚-3-基）-戊-2-烯酸N-環己基-醯胺， (411)-[^、甲基-^-(3,5-貳三氟甲基-苯甲醯基）-胺基]-5-(1-甲基哚-3-基）-2-甲基-戊-2-烯酸-環己基-醯胺， (4RHNT-甲基-ΝΓ-(3,5-貳三氟甲基-苯甲醯基）-胺基]-5-(1-甲基-喇哚-3-基）-2-甲基-戊-2-烯酸N-[(R)-衣普西隆-己内酿胺-3 -基]-酸胺， (411)-[1^-甲基小’-(3,5-貳三氟甲基-苯甲醯基）-胺基]-5-(1-甲基丨哚-3-基）-2-甲基-戊-2-烯酸N-[(S)-衣普西隆-己内醯胺-3 -基]-酸胺’ (4R)-(Nf-甲基-Ν’-苯甲醯基-胺基）-5-(1-甲基-吲哚-3-基）-2-甲基-戊-2-烯酸N-[(R)-衣普西隆-己内醯胺-3-基]-_胺， (4RMN’-甲基-N、（3,5-貳三氟甲基-苯甲醯基）-胺基]-5-(莕 -2-基）-戊-2-烯酸N-[(R)-衣普西隆-己内醯胺-3-基]-醯胺， (4R)-(N、甲基-1^-苯甲醯基胺基-5-(萘-2-基）-戊-2-烯酸 88769 -11 - 200418488 N-[(R) -衣普西隆-己内醒胺-3-基]-S篮胺’ (4R)-[N，-曱基-N’-(3,5-貳三氟甲基-苯甲醯基）-胺基]-5-(莕 -2-基）-2-甲基-戊-2-烯酸N-[(R)-衣普西隆-己内醯胺-3-基]-驗胺， (411)-[1^-甲基-1^-(3,4,5-三甲氧基-苯甲醯基）-胺基]-5-(莕 -2-基）-2-曱基-戊-2-烯酸N-[(R)-衣普西隆-己内醯胺-3-基]-醯胺， (4R)-[NT-甲基-N、（3,5-貳三氟甲基-苯甲醯基）-胺基]-5-(莕 -2-基）-2-甲基-戊-2-烯酸N-[(S)-衣普西隆-己内醯胺-3-基]-醯胺， (4R)-[N、甲基-N’-(3,5-貳三氟甲基-苯甲醯基）-胺基]-5-(莕 -2-基）-2-甲基-戊-2-烯酸N-環己基-醯胺， (4R)-[N’-甲基-N’-(3,5-貳三氟甲基-苯甲醯基）-胺基]-5-(1-甲基-吲哚-3-基）-戊-2-烯酸N-[(S)-衣普西隆-己内醯胺-3-基]-驢胺， (4R)-[Nf-甲基-N、（3,5-貳三氟甲基-苯甲醯基）-胺基]-4-(4-氯爷基）-丁 - 2-錦r酸N-[(R)-衣普西隆-己内酸胺-3-基]-S產胺， (4R)-[N、甲基-N、（3,5-貳三氟甲基-苯甲醯基胺基]-4-(4-氯芊基）-丁-2-烯酸N-[(S)-衣普西隆-己内醯胺-3-基]-醯胺， (411)-[1^-甲基-1^-(3,5-貳三氟甲基-苯甲醯基）-胺基]-4-(4-氯芊基）-丁-2-烯酸N-環己基-醯胺， (4R)-[N、甲基-N、（3,5-貳三氟甲基-苯甲醯基）-胺基]-4-(3,4-二氯爷基）-丁 - 2-晞酸N-環己基-驗胺， (4R)-[N’_曱基-N’-(3,5-貳三氟甲基-苯甲醯基）-胺基]- 88769 -12- 200418488 4-(3,4-二氟苄基）-丁-2-烯酸N-環己基-醯胺， (4R)-[N，-甲基-N、（3,5-貳三氟甲基-苯甲醯基）-胺基]-5-(4-氯苯基）-2-甲基-戊-2-烯酸N-環己基-醯胺， (4R)-[N、甲基-N、（3,5-貳三氟甲基-苯曱醯基）-胺基]-5-(4-氯苯基）-2-甲基-戊-2-烯酸N-[(R)-衣普西隆-己内醯胺-3-基]-醯胺， (411)-[1^-甲基-14’-(3,5-貳三氟甲基-苯甲醯基）-胺基]-4-(4-氯芊基）-2-甲基-丁 -2-烯酸N-[(S)-衣普西隆-己内醯胺-3-基]-醯胺， (4R)-[N’-乙基-N’-(3,5-貳三氟甲基-苯甲醯基）-胺基]-5-(4-氯苯基l·戊-2-烯酸N-[(S)-衣普西隆-己内醯胺-3-基]-醯胺， (4R)-[N’-甲基-Nf-(3,5-貳三氟甲基-苯甲醯基）-胺基]-5-(4-氯苯基）-3-甲基-戊-2-烯酸N-環己基-醯胺， (4R)-[N’_甲基-N、（3,5-貳三氟甲基-苯甲醯基）-胺基]-4-(4-氯芊基）-3 -甲基-丁 -2-烯酸N-[(R)-衣普西隆-己内醯胺-3-基]-驗胺’ (4RHN、甲基-N、（3,5-貳三氟甲基-苯甲醯基胺基]-4-(4-氣芊基）-丁-2-烯酸N-[(R)-衣普西隆-己内醯胺-3-基]-醯胺， (4R)-[Nf-甲基-N’-(3,5 -貳三氟甲基-苯甲醯基）-胺基]-4-(3,4-二氯芊基）-丁-2-烯酸1^[(11)-衣普西隆-己内醯胺-3-基]-醯胺， (4R)-及（4S)-4-[N’_甲基-N，-(3,5-貳三氟甲基-苯甲醯基）-胺基]-4-(3 -氣-4-氯卞基）-丁-2 -缔feN-[(R) -衣普西隆-己内驗胺-3-基]-醯胺， 88769 -13 - 200418488 (4R)声（4S)-4-[N，-甲基-ΝΑ5 -武二氟曱基苯甲驗基）-胺某]4 (3 4-二氟芊基丁烯酸N-[(R)-衣普西隆-己内醯胺 -3-基]-醯胺， (4R) 1 (4&4-[Ν，-甲基U3,5-武三氟甲基-苯曱醯基）_胺某]4 (3 二漠笮基）-丁 -2-烯酸N —[(R)_衣普西隆-己内醯胺 -3 -基]-酷胺’ (伙）及（43)-4-1^’-甲基-^-(3,5-武二氟甲基-苯甲驢基）_胺某]_4-(3,4,5-三氟苄基）_ 丁晞酸义[(11)-衣普西隆-己内醯胺-3-基]-醯胺， (4R) -及（4S)-4-[N’_甲基-N -(3,5 -武二氟甲基-苯甲酸基）·胺基]-4-(4-氟芊基）-丁 -2-烯酸衣普西隆-己内醯胺冬基]-SS胺， (4R)-及（4S)-4-[N，-(3,5-貳三氟甲基-苯曱醯基）-N，-甲基-胺基]-5，5-二苯基-戊-2-烯酸N-[(S)-衣普西隆-己内醯胺_3_ 基]-si胺， (4S)-4-[N，-甲基-N，-(3,5-貳三氟甲基-苯甲醯基）-胺基]-4-(3,4-二氯芊基）-丁-2-烯酸N-[(R)-衣普西隆-己内醯胺 -3 -基]-S區胺， (4R)-4-[NT-甲基W-(3,5-貳二氟甲基-苯甲醯基）_胺基]_4-(3,4-二氯苄基）-丁-2-晞酸1^[(8)-衣普西隆-己内驢胺_3-基]-胺，及 (4S)-4_[N’_甲基-N’-(3,5-貳三氟甲基·苯甲醯基）_胺基卜4_ (3,4-二氯芊基）-丁-2-烯酸义[(3)-衣普西隆_己内醯胺_3_ 基]-酿胺。 88769 -14- 200418488 本發明最重要的係關於（4RM-[N，-曱基-N、（3,l武三氣甲基苯甲酿基）胺基]-4-(3，4 -—鼠苯基）-丁-2 -缔酸N-[(r)衣晋西隆-己内驢胺-3 -基]-酸胺，即式η化合物之用途。IB where * refers to the S configuration, where R1, R2, R3, R4, R5, R6 and R7 have the same meanings as described above. Compounds of formula IA are generally preferred for use in the present invention. Compounds of formula I having a basic group can, for example, form acid addition salts with suitable mineral acids, such as hydrochloride, hydrobromide, sulfate, bisulfate, or dish with hydrochloric acid, sulfuric acid or phosphoric acid. Acid salt. When the compound of formula I contains an acidic group, it can also form a corresponding salt with a base, such as the corresponding metal test or soil test metal salt, such as a pin, potassium, or magnesium salt, or a salt with ammonia or an organic amine, such as salt. The invention preferably relates to the use of a compound of formula I, wherein R1 is phenyl, 3,5-fluorenetrifluoromethyl-phenyl or 3,4,5-trimethoxyphenyl, and R2 is hydrogen or Ci-CV Alkyl, R3 is hydrogen or phenyl, R4 is phenyl, halo-phenyl, dihalo-phenyl, trihalo-phenyl, 2-naphthyl, 1H-H, indol-3-yl, or l-Ci -CV alkyl indol-3-yl, 88769 200418488 R5 and R6 are each independently nitrogen or Ci-Cy-alkyl, at least one of R5 and R6 is hydrogen, and 117 is (: 5-(: 7-cycloalkane) D-azacycloheptan-2-one-3-yl or L-azacyclohept-2-one-3-yl. The present invention relates in particular to the use of compounds of formula I, wherein R1 is 3,5-pyridine Fluoromethyl-phenyl, R2 is hydrogen, methyl or ethyl, R3 is hydrogen or phenyl, R4 is phenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-dichlorophenyl, 3,4-Difluorophenyl '3-Ga-4-Rat " Phenyl' 3,4,5-Digasphenyl '2-Nylyl'indol-3-yl or 1-methylindole- 3-yl, R5 and R6 are each independently hydrogen or methyl, at least one of R5 and R6 is hydrogen, and R7 is cyclohexyl, D-azacyclohept-2-one-3-yl, or L-azepine- 2-keto-3-yl. The invention further relates to the use of compounds of formula I, wherein Ri is 3,5-fluorenetrifluoromethyl -Phenyl, R2 is hydrogen or methyl, R3 is hydrogen or phenyl, R4 is phenyl, 4-chlorophenyl, 3,4-diphenylphenyl, 2-fluorenyl, 1H-Windol-3- Or 1-methyl 丨 indol-3-yl, R5 and R6 are hydrogen, and R7 is cyclohexyl, D-azacyclohept-2-one-3-yl or L-azacyclohept-2-one-3 -Groups. Special mention should be made of the following compounds of the formula I. (1) Compounds of the formula I, wherein R7 is D-azacyclohept-2-one-3-yl; (2) Compounds of the formula I, wherein R5 And R6 is hydrogen; (3) a compound of formula I, wherein R1 is phenyl, 3,5- 88769 -10- 200418488 488 trifluoromethyl-phenyl or 3,4,5-trimethoxyphenyl; (4 ) Free state compounds of formula I, ie non-salt forms. Specific examples of compounds of formula I include: (4R)-[N, methyl-N, (3,5-fluorenetrifluoromethyl-benzyl) -Amine] -5- (1-methyl-pyridin-3-yl) -pent-2-enoic acid N-[(R) -Ipsiron-caprolactam-3-yl] -fluorene Amine, (4R)-[NT-methyl-NΓ- (3,5-fluorene trifluorofluorenyl-benzyl) -amino] -5- (1-methyl-fluorin-3-yl) -Pent-2-enoic acid N-[(S) -Ipsirone-caprolactam-3-yl] -amidamine, (4RHN, methyl-N, (3,5-fluorenetrifluoromethyl) -Benzylidene) -amino] -5- (1-methyl 丨Indol-3-yl) -pent-2-enoic acid N-cyclohexyl-fluorenamine, (411)-[^, methyl-^-(3,5-fluorenetrifluoromethyl-benzyl)- Amine] -5- (1-methylindol-3-yl) -2-methyl-pent-2-enoic acid-cyclohexyl-fluorenamine, (4RHNT-methyl-NΓ- (3,5-fluorene Trifluoromethyl-benzyl) -amino] -5- (1-methyl-ardol-3-yl) -2-methyl-pent-2-enoic acid N-[(R) -coating Pucillon-caprolactam-3-yl] -acid amine, (411)-[1 ^ -methyl small '-(3,5-fluorenetrifluoromethyl-benzyl) -amino group] -5- (1-methyl 丨 indol-3-yl) -2-methyl-pent-2-enoic acid N-[(S) -Ipsiron-caprolactam-3-yl] -acid Amine '(4R)-(Nf-methyl-N'-benzylidene-amino) -5- (1-methyl-indol-3-yl) -2-methyl-pent-2-ene N-[(R) -Ipsirone-caprolactam-3-yl] -amine, (4RMN'-methyl-N, (3,5-fluorenetrifluoromethyl-benzyl) ) -Amino] -5- (fluoren-2-yl) -pent-2-enoic acid N-[(R) -Ipsirone-caprolactam-3-yl] -amidamine, (4R) -(N, methyl-1 ^ -benzylideneamino-5- (naphthalene-2-yl) -pent-2-enoic acid 88769 -11-200418488 N-[(R) -Ipsirone- Caprolactam-3-yl] -S basket amine '(4R)-[N, -fluorenyl-N'-(3,5-fluorenetrifluoromethyl-benzyl) -Amine] -5- (fluoren-2-yl) -2-methyl-pent-2-enoic acid N-[(R) -Ipsirone-caprolactam-3-yl] -amine , (411)-[1 ^ -methyl-1 ^-(3,4,5-trimethoxy-benzylidene) -amino] -5- (fluoren-2-yl) -2-fluorenyl -Pent-2-enoic acid N-[(R) -Ipsirone-caprolactam-3-yl] -fluorenamine, (4R)-[NT-methyl-N, (3,5-fluorene Trifluoromethyl-benzyl) -amino] -5- (fluoren-2-yl) -2-methyl-pent-2-enoic acid N-[(S) -Ipsirone-caprolactone Fluorenamine-3-yl] -fluorenamine, (4R)-[N, methyl-N '-(3,5-fluorenetrifluoromethyl-benzylidene) -amino] -5- (fluorene- 2-yl) -2-methyl-pent-2-enoic acid N-cyclohexyl-fluorenamine, (4R)-[N'-methyl-N '-(3,5-fluorenetrifluoromethyl-benzene Formamyl) -amino] -5- (1-methyl-indol-3-yl) -pent-2-enoic acid N-[(S) -Ipsiron-caprolactam-3- []] Donylamine, (4R)-[Nf-methyl-N, (3,5-fluorenyltrifluoromethyl-benzyl) -amino] -4- (4-chloroethenyl) -butyl -N-[(R) -Ipsirone-Caprolactam-3-yl] -S produces amines, (4R)-[N, methyl-N, (3,5-fluorene) Trifluoromethyl-benzylideneamino] -4- (4-chlorofluorenyl) -but-2-enoic acid N-[(S) -Ipsiron-caprolactam-3-yl] -Amidamine, (411)-[1 ^ -methyl -1 ^-(3,5-fluorenetrifluoromethyl-benzylidene) -amino] -4- (4-chlorofluorenyl) -but-2-enoic acid N-cyclohexyl-fluorenamine, ( 4R)-[N, methyl-N, (3,5-fluorenetrifluoromethyl-benzylidene) -amino] -4- (3,4-dichloromethyl) -butan-2-ene Acid N-cyclohexyl-amine, (4R)-[N'_fluorenyl-N '-(3,5-fluorene trifluoromethyl-benzyl) -amino]-88769 -12- 200418488 4 -(3,4-difluorobenzyl) -but-2-enoic acid N-cyclohexyl-fluorenamine, (4R)-[N, -methyl-N, (3,5-fluorenetrifluoromethyl- Benzamidine) -amino] -5- (4-chlorophenyl) -2-methyl-pent-2-enoic acid N-cyclohexyl-fluorenamine, (4R)-[N, methyl-N , (3,5-fluorenetrifluoromethyl-phenylfluorenyl) -amino group] -5- (4-chlorophenyl) -2-methyl-pent-2-enoic acid N-[(R)- Ipsiron-caprolactam-3-yl] -amidamine, (411)-[1 ^ -methyl-14 '-(3,5-fluorenetrifluoromethyl-benzyl) -amine Group] -4- (4-chlorofluorenyl) -2-methyl-but-2-enoic acid N-[(S) -Ipsiron-caprolactam-3-yl] -fluorenamine, ( 4R)-[N'-ethyl-N '-(3,5-fluorenetrifluoromethyl-benzyl) -amino] -5- (4-chlorophenyl l-pent-2-enoic acid N-[(S) -Ipsirone-caprolactam-3-yl] -amidamine, (4R)-[N'-methyl-Nf- (3,5-fluorene) Methyl-benzyl) -amino] -5- (4-chlorophenyl) -3-methyl-pent-2-enoic acid N-cyclohexyl-fluorenamine, (4R)-[N'_ Methyl-N, (3,5-fluorenetrifluoromethyl-benzylidene) -amino] -4- (4-chlorofluorenyl) -3 -methyl-but-2-enoic acid N- [ (R) -Ipsirone-caprolactam-3-yl] -testamine '(4RHN, methyl-N, (3,5-fluorene trifluoromethyl-benzylamino)]-4 -(4-Arylidene) -but-2-enoic acid N-[(R) -Ipsiron-caprolactam-3-yl] -amidamine, (4R)-[Nf-methyl- N '-(3,5 -fluorenetrifluoromethyl-benzylidene) -amino] -4- (3,4-dichlorofluorenyl) -but-2-enoic acid 1 ^ [(11)- Ipsirone-caprolactam-3-yl] -amidamine, (4R)-and (4S) -4- [N'_methyl-N,-(3,5-fluorenetrifluoromethyl- Benzamidine) -amino] -4- (3-gas-4-chlorofluorenyl) -butan-2-associated feN-[(R) -Ipsirone-caprolactam-3-yl] -Amine, 88769 -13-200418488 (4R) Acoustic (4S) -4- [N, -Methyl-NA-5 -Carbondifluorobenzylbenzyl) -Amine] 4 (3 4-Difluoroamidine Butyric acid N-[(R) -Ipsirone-caprolactam-3-yl] -amidamine, (4R) 1 (4 & 4- [N, -methyl U3,5-wusan Fluoromethyl-phenylfluorenyl) _amine] 4 (3 dioxalyl) -but-2-ene Acid N — [(R) _Ipsirone-caprolactam-3 -yl] -coamine '(Partner) and (43) -4-1 ^'-methyl-^-(3,5- Difluoromethyl-benzylidene) _Amine] _4- (3,4,5-trifluorobenzyl) _ Butyric acid sense [(11) -Ipsiron-caprolactam-3 -Yl] -fluorenamine, (4R)-and (4S) -4- [N'_methyl-N-(3,5-wutrafluoromethyl-benzoate) · amino] -4- ( 4-fluorofluorenyl) -but-2-enoic acid isipiron-caprolactam tolyl] -SS amine, (4R)-and (4S) -4- [N,-(3,5-fluorene Trifluoromethyl-phenylfluorenyl) -N, -methyl-amino] -5,5-diphenyl-pent-2-enoic acid N-[(S) -Ipsiron-caprolide Amine_3_yl] -siamine, (4S) -4- [N, -methyl-N,-(3,5-fluorenetrifluoromethyl-benzylidene) -amino] -4- (3 , 4-Dichlorofluorenyl) -but-2-enoic acid N-[(R) -Ipsiron-caprolactam-3-yl] -S amine, (4R) -4- [NT- Methyl W- (3,5-fluorenedifluoromethyl-benzylidene) _amino group] _4- (3,4-dichlorobenzyl) -but-2-fluorenic acid 1 ^ [(8)- Ipsirone-caprolactam_3-yl] -amine, and (4S) -4_ [N'_methyl-N '-(3,5-fluorenetrifluoromethyl · benzyl)) _ Amino group 4_ (3,4-dichlorofluorenyl) -but-2-enoic acid sense [(3) -Ipsipron_caprolactam_3_yl]- Amine. 88769 -14- 200418488 The most important aspect of the present invention relates to (4RM- [N, -fluorenyl-N, (3,1 sulfanylmethylbenzyl) amino] -4- (3,4- Murine phenyl) -butan-2-associated acid N-[(r) Yijinxilong-caprolactam-3-yl] -acid amine, that is, the use of a compound of formula η.

自由態或醫藥上可接受的鹽的式{化合物可如w〇 98/07694或WO 01/85696所述製備。如其所述，其可為水人物形式及/或可包括其他溶劑，例如固體形式的化合物結晶所用的溶劑。視各性負的个同及對應的不對稱中心的數目及視選用的起始物料及製造方法不同，式I化合物可製成立體異構物混合物的形式，例如非鏡像立體異構物混合物或對映體混合物，如外消旋體，或者也可能是純立體異構物形式。根據本發明万法或某些其他方法所製得的非鏡像立體異構物混合物可以習用万式分離成對映體混合物，例如外消旋物，或分離成個別的非鏡像立體異構物，例如以已知方法藉分級結晶，蒸餾及/或色層分析基於各成分之物理_化學差異分離。較佳是分離較活性的異構物。 D象木些其他方&可製得的對晚體混合物，特別是外消旋物’可以已知方法分離成個別的對映體，例如用光學活性溶劑藉微生物之助作重結晶，用色層分析及/或與光學活 88769 -15- 200418488 性助劑化合物，例如驗、酸或醇反應，生成非鏡像立體異構物鹽混合物或官能衍生物，如酯，將其分離釋出所需對映體。較佳是分離較活性的異構物。根據本發明治療疾病時，可以任何適宜途徑給予自由態的醫藥上可接受的鹽的式I化合物，例如以錠、膠囊或液體形式作經口給予，或例如以可注射的溶液或懸浮液作非經腸給予，或經鼻給予，例如以喷霧劑或其他可霧化的調配物用適宜的鼻内投送裝置給予，例如用此技藝已知的鼻喷霧器給予，或作吸入給予。但較佳是經口給予。自由態或鹽形式的式I化合物，可與醫藥上可接受的稀釋劑或載劑製成醫藥組合物給予。此類組合物可如WO 98/07694内所述者，例如WO 98/07694實例A至E所述之乾散，錠，膠囊，液，注射溶液，輸液或吸入懸浮液，或用此技藝已知的調配成分及技術製備。自由態或鹽形式的式I化合物的劑量取決於多種因素，如活性成分的活性及作用時間，要治療的疾病的嚴重性，給予方式，物種，病主的性別，種族，年齡及體重及/或其個別情況。在正常情形下，給予的每日劑量，例如是給予溫血動物，特別是體重約75公斤的人，約為1毫克至約1000毫克，特別是約5毫克至約200毫克。此劑量可，例如，作一次給予，或分成數份，例如5毫克至200毫克，給予。式I化合物治療咳嗷，例如乾咳，的適宜性可藉式I化合物對天竺鼠釋出内生性神經肽之抑制測定。將未麻醉的、未約束的雄性Dunkin Hartley天竺鼠（250-500克）分別置於透 88769 -16- 200418488 明的塑膠整體體積描記器（Buxco, USA)内，測定2分鐘基線呼吸道功能。將天竺鼠曝露於霧化的（DeVilbiss ultrasonic, U S A)檸檬酸水溶液（0 · 6 Μ)下10分鐘。在以擰檬酸（0.6 Μ)激發10分鐘前2小時，經口給予式I化合物（0.3，3.0或10.0毫克/公斤）或載體（2%二甲基亞石風 (DMSO)，1:5 CREMOPHOR EL® :生理鹽水）。不對動物作選擇而是隨機分組。每一藥物治療組再按不同劑量分成次組。所有的實驗都有適宜的時間配合對照。所得值為平均值+標準平均誤差。用ANOVA及此後Tukey試驗分析數據作統計差（statistical difference)，P值 <0.05是為有意義。以下法測定咳嗷：體積描記器室裝有擴音器，聯於外部的擴音喇队及電腦上。觀察者持續看著動物並計數其咳嗷次數。咳嗽的評估特徵是開口發出大聲，這很易與噴嚏相區別。咳嗷時有快而大的腹部運動，此是以短時間的氣流增加超過正常氣流。以此法在曝露的10分鐘内測定咳嗷，曝露後5分鐘仍測定咳漱。先以載劑（0.9%生理鹽水）處理過的動物在曝露於0.6 Μ檸檬酸後發生咳嗷反應。分別與給予載劑（2% DMSO，1:5 CREMOPHOR EL® : 0.9%生理鹽水）治療白勺動物相較，經口給予（4R)-4-[N’_甲基-Ν’-(3,5-貳三氟甲基苯甲醯基）胺基]_4-(3,4-二氯苄基）-丁 -2-烯酸N-[(R)-衣普西隆-己内醯胺 -3-基]醯胺（0.3，3或10毫克/公斤，經口 2小時）明顯地 (Ρ<0·05)抑制咳嗷 62 ± 11，63 ± 8及 86 ± 4%)。 88769 -17-Compounds of the formula {free state or pharmaceutically acceptable salts can be prepared as described in WO 98/07694 or WO 01/85696. As described, it may be in the form of aquatic organisms and / or may include other solvents, such as those used to crystallize compounds in solid form. Depending on the number of asymmetric and corresponding asymmetric centers, and depending on the starting materials and methods used, the compounds of formula I can be made into the form of stereoisomer mixtures, such as Enantiomeric mixtures, such as racemates, or may also be in the form of pure stereoisomers. Mixtures of non-mirror stereoisomers prepared according to the method of the present invention or some other methods can be separated into enantiomeric mixtures, such as racemates, or into individual non-mirror stereoisomers by conventional methods, For example, by known methods, fractional crystallization, distillation, and / or chromatographic analysis are performed based on the physical-chemical differences of the components. It is preferred to separate the more active isomers. D like some other anti-night mixtures, especially the racemates, which can be prepared by known methods, can be separated into individual enantiomers, such as recrystallization using optically active solvents with the help of microorganisms. Chromatographic analysis and / or reaction with optical activity 88769 -15- 200418488 sex adjuvant compounds, such as test, acid or alcohol, to form non-mirrored stereoisomer salt mixtures or functional derivatives, such as esters, which are separated and released Enantiomers required. It is preferred to separate the more active isomers. In the treatment of diseases according to the present invention, the compounds of formula I can be administered in any suitable route as a freely acceptable pharmaceutically acceptable salt, such as orally in the form of tablets, capsules, or liquids, or, for example, as injectable solutions or suspensions. For parenteral or nasal administration, for example as a spray or other nebulizable formulation with a suitable intranasal delivery device, such as with a nasal sprayer known in the art, or by inhalation . However, oral administration is preferred. The compound of formula I in free form or in salt form can be administered in a pharmaceutical composition with a pharmaceutically acceptable diluent or carrier. Such compositions may be as described in WO 98/07694, such as dry powders, tablets, capsules, liquids, injectable solutions, infusions or inhaled suspensions as described in Examples 98 to E of WO 98/07694, or by using this technique Known blending ingredients and technical preparation. The dosage of the compound of formula I in free form or salt depends on a number of factors, such as the activity of the active ingredient and the duration of action, the severity of the disease to be treated, the mode of administration, the species, the sex of the subject, the race, age and weight and / Or its individual circumstances. Under normal circumstances, the daily dose administered is, for example, to a warm-blooded animal, particularly a human who weighs about 75 kg, from about 1 mg to about 1000 mg, particularly from about 5 mg to about 200 mg. This dose may be administered, for example, as a single administration, or divided into portions such as 5 mg to 200 mg. The suitability of a compound of formula I for the treatment of cough, such as dry cough, can be determined by the inhibition of endogenous neuropeptide release from guinea pigs by a compound of formula I. Unanesthetized and unconstrained male Dunkin Hartley guinea pigs (250-500 g) were placed in plastic plethysmographs (Buxco, USA), which were transparent at 88769-16-200418488, and baseline respiratory function was measured for 2 minutes. The guinea pigs were exposed to an atomized (DeVilbiss ultrasonic, US A) citric acid aqueous solution (0.6 M) for 10 minutes. Orally administer a compound of formula I (0.3, 3.0, or 10.0 mg / kg) or vehicle (2% dimethylsulfite (DMSO), 2: 5 2 hours before excitation with citric acid (0.6 M) for 10 minutes CREMOPHOR EL®: saline). Animals are not selected but grouped randomly. Each drug treatment group was divided into subgroups at different doses. All experiments are timed to match controls. The value obtained is the average + standard error. Data were analyzed using ANOVA and Tukey's test for statistical difference. A P value of <0.05 was considered significant. Cough is measured by the following method: The plethysmograph room is equipped with a loudspeaker, connected to an external loudspeaker team and a computer. The observer keeps looking at the animal and counts the number of coughs. The assessment of cough is characterized by a loud noise in the mouth, which is easily distinguished from sneezing. Fast and large abdominal movements when coughing. This is a short-term increase in airflow over normal airflow. By this method, cough was measured within 10 minutes of exposure, and cough was measured 5 minutes after exposure. Animals previously treated with a vehicle (0.9% physiological saline) developed a cough response after exposure to 0.6 M citric acid. Compared with vehicle (2% DMSO, 1: 5 CREMOPHOR EL®: 0.9% physiological saline) to treat animals, (4R) -4- [N'_methyl-N '-(3 , 5-fluorenetrifluoromethylbenzylidene) amino] 4- (3,4-dichlorobenzyl) -but-2-enoic acid N-[(R) -Ipsiron-caprolactam Amine-3-yl] amidamine (0.3, 3 or 10 mg / kg, 2 hours by mouth) significantly (P < 0.05) inhibited cough (62 ± 11, 63 ± 8 and 86 ± 4%). 88769 -17-

Claims

200418488 拾、申請專利範圍： 1 ·自由態形式或醫藥上可接受的鹽的形式的式τ化合物 R2 R5 Π200418488 Scope of patent application: 1. Compounds of formula τ in free form or pharmaceutically acceptable salt form R2 R5 Π

社製備樂物以治療咳漱上的用途，其中 R是苯基，其為未經取代的或以1，2或3個取代基取代的，而此等取代基是選自鹵素，Cl-c7-烷基，三氟甲基’羥基及CrC7-烷氧基， R2是氫或cvc7-燒基， R3是氫或cvcv烷基或苯基，其為未經取代的或以 1，2或3個取代基取代的，而此等取代基是選自鹵素， Ci-C”燒基，三氟甲基，輕基及Ci-GV燒氧基， R4是苯基，其為未經取代的或以1，2或3個取代基取代的，而此等取代基是選自鹵素，Ci-Cr烷基，三氟甲基，羥基及（^-(：7-烷氧基；或為萘基，1H4I哚-3-基或 KrCV烷基吲哚-3-基， R5及R6各彼此獨立是氫或CrCV烷基，至少R5及R6之 —是氫，及 R7是C-3-C8-環烷基，D-氮環庚-2-酮-3-基或L-氮環庚酮，3-基。 2 ·根據申請專利範圍第1項之用途，其中式I化合物為式IA 化合物 200418488 VO RThe use of the compound to treat cough, where R is phenyl, which is unsubstituted or substituted with 1, 2 or 3 substituents, and these substituents are selected from halogen, Cl-c7 -Alkyl, trifluoromethyl 'hydroxyl and CrC7-alkoxy, R2 is hydrogen or cvc7-alkyl, R3 is hydrogen or cvcv alkyl or phenyl, which is unsubstituted or starts with 1,2 or 3 With four substituents, and these substituents are selected from halogen, Ci-C "alkyl, trifluoromethyl, light and Ci-GV alkyl, R4 is phenyl, which is unsubstituted or Substituted with 1, 2 or 3 substituents, and these substituents are selected from halogen, Ci-Cr alkyl, trifluoromethyl, hydroxyl and (^-(: 7-alkoxy; or naphthyl) , 1H4I indol-3-yl or KrCV alkyl indol-3-yl, R5 and R6 are each independently hydrogen or CrCV alkyl, at least one of R5 and R6 is hydrogen, and R7 is C-3-C8-ring Alkyl, D-azacycloheptan-2-one-3-yl or L-azacycloheptanone 3-yl. 2 · Use according to item 1 of the scope of patent application, wherein the compound of formula I is a compound of formula IA 200418488 VO R

R \ N—H IA 此處*是指R構形，及R1，R2，R3，R4，R5，R6及R7之定義如根據申請專利範圍第1項所述。 3. 根據申請專利範圍第1或第2項之用途，其中 R1是苯基，3,5-貳三氟甲基-苯基或3,4,5-三甲氧基苯基， R2是氫或Q-CV烷基， R3是氫或苯基， R是苯基’卣_苯基’二卣'本基’二1¾ "本基’ 2 -奈基’ 1H-吲哚-3-基或l-CVC?-烷基吲哚-3-基， R5及R6各獨立是氫或CVCV烷基，至少R5及R6之一是氫，及 117是（：5-(：7-環烷基，D-氮環庚-2-酮-3-基或L-氮環庚 -2-酮-3-基。 4. 根據申請專利範圍第1或第2項之用途，其中 R1是3,5-貳三氟甲基-苯基， R2是氫，甲基或乙基， R3是氫或苯基， R4是苯基，4-氣苯基，4-氟苯基，3,4-二氯苯基，3,4-二氣苯基，3 -氣-4-鼠-苯基’ 3，4,5 -二氣苯基’ 2 -奈基’ 1H-H丨哚-3-基或1-甲基哚-3-基， 200418488 R5及R6各獨立是氫或甲基，至少R5及R6之一是氫，及 R是彡哀己基’ D-氣彡募庚-2-酬-3-基或L -氣緣庚-2-酬-3_ 基。 5. 根據申請專利範圍第1或第2項之用途，其中以是3,5-貳三氟甲基-苯基， R2是氫或甲基， R3是氫或苯基， R4是苯基，4-氯苯基，3,4-二氯苯基，2-莕基，1H-eh果-3-基或1-甲基丨嗓-3-基， R5及R6是氫，及 R1 2是環己基，D-氮環庚-2-酮-3-基或L-氮環庚-2-酮-3- 基。 6. 根據申請專利範圍第1項之用途，其中式I化合物是下式化合物R \ N—H IA Here * refers to the R configuration, and the definitions of R1, R2, R3, R4, R5, R6 and R7 are as described in accordance with item 1 of the scope of patent application. 3. Use according to item 1 or 2 of the scope of patent application, wherein R1 is phenyl, 3,5-fluorenetrifluoromethyl-phenyl or 3,4,5-trimethoxyphenyl, and R2 is hydrogen or Q-CV alkyl, R3 is hydrogen or phenyl, R is phenyl '卣 -phenyl' bis' 'benzyl' bis 1¾ " benzyl '2 -naphthyl' 1H-indol-3-yl or l-CVC? -alkylindol-3-yl, R5 and R6 are each independently hydrogen or CVCV alkyl, at least one of R5 and R6 is hydrogen, and 117 is (: 5-(: 7-cycloalkyl, D-azacyclohept-2-one-3-yl or L-azacyclohept-2-one-3-yl. 4. Use according to item 1 or 2 of the scope of patent application, where R1 is 3,5-贰 Trifluoromethyl-phenyl, R2 is hydrogen, methyl or ethyl, R3 is hydrogen or phenyl, R4 is phenyl, 4-fluorophenyl, 4-fluorophenyl, 3,4-dichlorobenzene , 3,4-Diaminophenyl, 3-Ga-4-murine-phenyl '3,4,5-Difluorophenyl' 2-naphthyl '1H-H 丨 indol-3-yl or 1- Methyl indol-3-yl, 200418488 R5 and R6 are each independently hydrogen or methyl, at least one of R5 and R6 is hydrogen, and R is hexadecyl ' Or L- 气缘庚 -2--2--3. 5. According to the first or second item of the scope of patent application Uses: 3,5-fluorene trifluoromethyl-phenyl, R2 is hydrogen or methyl, R3 is hydrogen or phenyl, R4 is phenyl, 4-chlorophenyl, 3,4-dichlorobenzene Group, 2-fluorenyl group, 1H-ehfol-3-yl group or 1-methyl group-3-yl group, R5 and R6 are hydrogen, and R1 2 is cyclohexyl, and D-azacycloheptan-2-one- 3-yl or L-azacycloheptan-2-one-3-yl. 6. Use according to item 1 of the scope of patent application, wherein the compound of formula I is a compound of formula

1 根據申請專利範圍第1至第6項任一項之用途，其中咳嗷是有痰的咳喷：。 2 根據申請專利範圍第1至第6項任一項之用途，其中咳嗷是乾咳。 9.根據申請專利範圍第8項之用途，其中咳嗷伴有慢性阻 200418488 基性肿病或急性病毒感染。 10.根據申請專利範圍第8項之用途，其中咳嗷伴有氣喘。 200418488 柒、指定代表圖： (一) 本案指定代表圖為：無 (二) 本代表圖之元件代表符號簡單說明：捌、本案若有化學式時，請揭示最能顯示發明特徵的化學式:1 The use according to any one of claims 1 to 6, wherein cough is a cough spray with sputum :. 2 The use according to any one of claims 1 to 6, wherein the cough is dry cough. 9. Use according to item 8 of the scope of patent application, in which cough is accompanied by chronic obstruction 200418488 basic swollen disease or acute viral infection. 10. Use according to item 8 of the scope of patent application, wherein cough is accompanied by asthma. 200418488 柒 Designated representative map: (1) The designated representative map in this case is: None. (2) Brief description of the component representative symbols in this representative map: 捌 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention:

VH 88769VH 88769