1-Methylindazole-3-carboxylic acid

Iupac Name：1-methyl-N-[(1S,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl]indazole-3-carboxamide;hydrochloride

Molecular Weight：348.875

Modify Date.: 2022-11-22 16:09

Introduction: Granisetron hydrochloride is the second selective 5HT-3-antagonist approved for themanagement of nausea and vomiting induced by cancer chemotherapy.Likeondansetron, granisetron hydrochloride is superior to metoclopramide in both efficacyand side effect profile. The compound appears to be effective both as a prophylacticagent and in blocking vomiting once started. View more+

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1. Names and Identifiers

1.1 Name: 1-Methylindazole-3-carboxylic acid
1.2 Synonyms: 1H-Indazole-3-carboxamide, 1-methyl-N-[(1R,3S,6R)-9-methyl-9-azabicyclo[4.2.1]non-3-yl]-, hydrochloride (1:1) 1H-Indazole-3-carboxamide, 1-methyl-N-[(3-endo)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-, hydrochloride (1:1) 1H-indazole-3-carboxamide, 1-methyl-N-[(3-endo)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-, monohydrochloride 1-méthyl-N-[(3-endo)-9-méthyl-9-azabicyclo[3.3.1]non-3-yl]-1H-indazole-3-carboxamide chlorhydrate 1-methyl-N-((1R,3R,5S)-9-methyl-9-azabicyclo[3,3,1]nonan-3-yl)-1H-inzadole-3-carboxamide hydrochloride 1-methyl-n-(9-methyl-9-azabicyclo(3.3.1)non-3-yl)-1h-indazole-3-carboxamid 1-Methyl-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-1H-isoindole-3-carboxamide hydrochloride 1-Methyl-N-[(1R,3S,6R)-9-methyl-9-azabicyclo[4.2.1]non-3-yl]-1H-indazole-3-carboxamide hydrochloride (1:1) 1-methyl-N-[(1S,5R)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl]indazole-3-carboxamide,hydrochloride 1-Methyl-N-[(1β,3α,5β)-9-methyl-9-azabicyclo[3.3.1]nonane-3-yl]-1H-indazole-3-carboxamide·hydrochloride 1-Methyl-N-[(1β,5β)-9-methyl-9-azabicyclo[3.3.1]nonane-3α-yl]-1H-indazole-3-carboxamide·hydrochloride 1-Methyl-N-[(3-endo)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-1H-indazol-3-carboxamidhydrochlorid 1-Methyl-N-[(3-endo)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-1H-indazole-3-carboxamide 1-METHYL-N-[(3-ENDO)-9-METHYL-9-AZABICYCLO[3.3.1]NON-3-YL]-1H-INDAZOLE-3-CARBOXAMIDE HYDROCHLORIDE 1-Methyl-N-[(3-endo)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-1H-indazole-3-carboxamide hydrochloride (1:1) 1-methyl-N-[(3-endo)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-1H-Indazole-3-carboxamide, hydrochloride (1:1) endo-1-methyl-n-(9-methyl-9-azabicyclo(3.3.1)non-3-yl)-1h-indazole-3-carboxa endo-monohydrochlorid Granisetron (Hydrochloride) Granisetron HCl Granisetron hydrochloride MFCD01747034 midehydrochloride

1.3 CAS No.: 107007-99-8

1.4 CID: 49799997

1.5 EINECS(EC#): 1312995-182-4

1.6 Molecular Formula: C18H25ClN4O (isomer)

1.7 Inchi: InChI=1S/C18H24N4O.ClH/c1-21-13-6-5-7-14(21)11-12(10-13)19-18(23)17-15-8-3-4-9-16(15)22(2)20-17;/h3-4,8-9,12-14H,5-7,10-11H2,1-2H3,(H,19,23);1H/t13-,14-;/m0./s1

1.8 InChkey: QYZRTBKYBJRGJB-IODNYQNNSA-N

1.9 Canonical Smiles: CN1C2CCCC1CC(C2)NC(=O)C3=NN(C4=CC=CC=C43)C.Cl

1.10 Isomers Smiles: CN1[C@H]2CCC[C@H]1CC(C2)NC(=O)C3=NN(C4=CC=CC=C43)C.Cl

2. Properties

2.1 Density: 1.33

2.1 Melting point: 290-292°C

2.1 Boiling point: 532°Cat760mmHg

2.1 Refractive index: 1.69

2.1 Flash Point: 275.6°C

2.1 Precise Quality: 348.17200

2.1 PSA: 50.16000

2.1 logP: 3.44920

2.1 Solubility: H2O: >10mg/mL

2.2 Appearance: White to Off-White Crystalline Solid

2.3 Storage: Room temp

2.4 Color/Form: white to off-white

2.5 Water Solubility: H2O: >10mg/mL

2.6 StorageTemp: Room temp

3. Use and Manufacturing

3.1 Usage: It is the selective antagonist of the 5-serotonin 3 (5-HT3) in peripheral and central nervous system.

4. Safety and Handling

4.1 Symbol: GHS07

4.1 Hazard Codes: Xn; Xi

4.1 Signal Word: Warning

4.1 Risk Statements: R22

4.1 Safety Statements: 26-36-37

4.1 Hazard Declaration: H302

4.1 RIDADR: NONH for all modes of transport

4.1 Caution Statement: P301 + P312 + P330

4.1 WGK Germany: 3

4.1 RTECS: NK7882200

4.1 Safety: Hazard Codes:?Xn,Xi
Risk Statements: 22-62-37/38-36/37/38-36?
R22:Harmful if swallowed.?
R62:Risk of impaired fertility.?
R37/38:Irritating to respiratory system and skin.?
R36/37/38:Irritating to eyes, respiratory system and skin.?
R36:Irritating to eyes.
Safety Statements: 26-36-37?
S26: In case of contact with eyes, rinse immediately with plenty of water and seek medical advice.?
S36:Wear suitable protective clothing.?
S37:Wear suitable gloves.
RTECS: NK7882200

4.2 Specification: ? Granisetron hydrochloride (CAS NO.107007-99-8), its Synonyms are 1-Methyl-N-(9-methyl-endo-9-azabicyclo(3.3.1)non-3-yl)-1H-indazole-3-carboxamide monohydrochloride ; Granisetron HCl ; Granisetron hydrochloride preservative free ; Kytril ; Kytril Injection ; endo-1-Methyl-N-(9-methyl-9-azabicyclo(3.3.1)non-3-yl)-1H-indazole-3-carboxamide hydrochloride .

4.3 Toxicity

Organism	Test Type	Route	Reported Dose (Normalized Dose)	Effect	Source
dog	LDLo	intravenous	3mg/kg (3mg/kg)	SENSE ORGANS AND SPECIAL SENSES: OTHER: EYE BEHAVIORAL: TREMOR GASTROINTESTINAL: NAUSEA OR VOMITING	Yakkyoku. Pharmacy. Vol. 43, Pg. 589, 1992.
dog	LDLo	oral	15mg/kg (15mg/kg)	BEHAVIORAL: TREMOR GASTROINTESTINAL: NAUSEA OR VOMITING	Gekkan Yakuji. Pharmaceuticals Monthly. Vol. 37, Pg. 2697, 1995.
mouse	LD50	intravenous	17mg/kg (17mg/kg)	BEHAVIORAL: ALTERED SLEEP TIME (INCLUDING CHANGE IN RIGHTING REFLEX) BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD LUNGS, THORAX, OR RESPIRATION: RESPIRATORY STIMULATION	Kiso to Rinsho. Clinical Report. Vol. 24, Pg. 4991, 1990.
mouse	LD50	oral	350mg/kg (350mg/kg)	?	Iyakuhin Kenkyu. Study of Medical Supplies. Vol. 26, Pg. 740, 1995.
rat	LD50	intravenous	14mg/kg (14mg/kg)	BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD BEHAVIORAL: ATAXIA BEHAVIORAL: MUSCLE CONTRACTION OR SPASTICITY)	Kiso to Rinsho. Clinical Report. Vol. 24, Pg. 4991, 1990.
rat	LD50	oral	350mg/kg (350mg/kg)	?	Iyakuhin Kenkyu. Study of Medical Supplies. Vol. 26, Pg. 740, 1995.

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5. MSDS

2.Hazard identification

2.1 Classification of the substance or mixture

Acute toxicity - Oral, Category 4

2.2 GHS label elements, including precautionary statements

Pictogram(s)
Signal word	Warning
Hazard statement(s)	H302 Harmful if swallowed
Precautionary statement(s)
Prevention	P264 Wash ... thoroughly after handling. P270 Do not eat, drink or smoke when using this product.
Response	P301+P312 IF SWALLOWED: Call a POISON CENTER/doctor/\u2026if you feel unwell. P330 Rinse mouth.
Storage	none
Disposal	P501 Dispose of contents/container to ...

2.3 Other hazards which do not result in classification

none

View all

6. NMR Spectrum

Predict 1H proton NMR

7. Synthesis Route

107007-99-8Total: 2 Synthesis Route

109889-09-0 147 Suppliers

107007-99-8 385 Suppliers

Literatures:
INKE, S.A. Patent: WO2008/151677 A1, 2008 ; Location in patent: Page/Page column 13 ;
Yield: ~74%

76272-41-8 11 Suppliers

106649-02-9 12 Suppliers

107007-99-8 385 Suppliers

Literatures:
US4886808 A1, ;
Yield: null

8. Precursor and Product

precursor:

109889-09-0

106649-02-9

76272-41-8

product :

109889-09-0

9. Other Information

9.0 Outline of Granisetron hydrochloride: Granisetron hydrochloride was originally developed by the British Beecham company in the mid-1980s. At 1991, the merged Smithkline-Beecham (SB) Company had pushed for the first time of 3 mg of injection Kytri1 to the market in South Africa. To date, including 1 mg of oral tablets, 1mg of injections, granisetron hydrochloride has already entered into market in United States, Britain, France, Japan, Germany, Italy and other more than forty countries and regions around the world. When the Smithkline-Beecham (SB) Company was merged with Glaxo Company, it transferred this product to the Roche Company.
Foreign research data has shown that granisetron hydrochloride has a high selectivity to receptor. Its affinity to 5-HT3 receptor is 4000 to 10000 time as high as its affinity to other receptors, such as 5-HT1, 5-HT2, dopamine D1, D1, histamine H1, benzodiazepine and opioid receptor. For comparison, the difference for ondansetron is only about 1,000 times. For the test of its prevention of cisplatin-induced emesis in ferrets, the antiemetic rates in the three dose groups of granisetron hydrochloride 2 × 0.005,2 × 0.05 and 2 × 0.5mg/kg (iv) were 93%, 96% and 100 %, respectively while for ondansetron in 2 × 2.5mg/kg, this value was 89%, demonstrating that granisetron hydrochloride exhibited a at least five times stronger efficacy of anti-emetic than ondansetron. Toxicity studies suggest that granisetron hydrochloride can achieve very excellent antiemetic effect even in small dose with only minor side effects. However, there may be sth abnormal occurring in cardiovascular system upon large doses. Since the recommended clinical dose of granisetron hydrochloride is small (3mg/d), which is only 1/25 (<1 mg/kg) of the lowest dose used in animal studies, therefore, clinical application of it is very safe. Pharmacokinetic study has shown that granisetron hydrochloride has a half-life (t1/2) of 9 h in the body of patient while this value is 4 h at healthy people, 7.7 h in elderly people and 4.9h in young people. Granisetron hydrochloride is mainly metabolized in the liver and can be excreted through the feces and urine in the form of 7-hydroxy granisetron hydrochloride and other forms of metabolic product. For patients of liver damage or liver metastases, they have reduced plasma clearance rate with the scavenging rate upon renal insufficiency being 1/4 of the normal case. It has been observed of high first pass metabolism upon oral administration with the absolute bioavailability being 60%.

9.1 Description: Granisetron hydrochloride is the second selective 5HT_-3-antagonist approved for the management of nausea and vomiting induced by cancer chemotherapy.Like ondansetron, granisetron hydrochloride is superior to metoclopramide in both efficacy and side effect profile. The compound appears to be effective both as a prophylactic agent and in blocking vomiting once started.

9.2 Originator: SmithKline Beecham (United Kingdom)

9.3 Uses: These Secondary Standards are qualified as Certified Reference Materials. These are suitable for use in several analytical applications including but not limited to pharma release testing, pharma method development for qualitative and quantitative analyses, food and beverage quality control testing, and other calibration requirements.

9.4 Mesh: Drugs used to prevent NAUSEA or VOMITING. (See all compounds classified as Antiemetics.)|Drugs that bind to but do not activate serotonin receptors, thereby blocking the actions of serotonin or SEROTONIN RECEPTOR AGONISTS. (See all compounds classified as Serotonin Antagonists.)

9.5 Mesh Entry Terms: 1-Methyl-N-(endo-9-Methyl-9-Azabicyclo(3.3.1)non-3-yl)-1H-Indazole-3-Carboxamide

9.6 Use Classification: Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

9.7 Merck: 14,4536

9.8 Outline of Granisetron hydrochloride: Granisetron hydrochloride was originally developed by the British Beecham company in the mid-1980s. At 1991, the merged Smithkline-Beecham (SB) Company had pushed for the first time of 3 mg of injection Kytri1 to the market in South Africa. To date, including 1 mg of oral tablets, 1mg of injections, granisetron hydrochloride has already entered into market in United States, Britain, France, Japan, Germany, Italy and other more than forty countries and regions around the world. When the Smithkline-Beecham (SB) Company was merged with Glaxo Company, it transferred this product to the Roche Company.
Foreign research data has shown that granisetron hydrochloride has a high selectivity to receptor. Its affinity to 5-HT3 receptor is 4000 to 10000 time as high as its affinity to other receptors, such as 5-HT1, 5-HT2, dopamine D1, D1, histamine H1, benzodiazepine and opioid receptor. For comparison, the difference for ondansetron is only about 1,000 times. For the test of its prevention of cisplatin-induced emesis in ferrets, the antiemetic rates in the three dose groups of granisetron hydrochloride 2 × 0.005,2 × 0.05 and 2 × 0.5mg/kg (iv) were 93%, 96% and 100 %, respectively while for ondansetron in 2 × 2.5mg/kg, this value was 89%, demonstrating that granisetron hydrochloride exhibited a at least five times stronger efficacy of anti-emetic than ondansetron. Toxicity studies suggest that granisetron hydrochloride can achieve very excellent antiemetic effect even in small dose with only minor side effects. However, there may be sth abnormal occurring in cardiovascular system upon large doses. Since the recommended clinical dose of granisetron hydrochloride is small (3mg/d), which is only 1/25 (<1 mg/kg) of the lowest dose used in animal studies, therefore, clinical application of it is very safe. Pharmacokinetic study has shown that granisetron hydrochloride has a half-life (t1/2) of 9 h in the body of patient while this value is 4 h at healthy people, 7.7 h in elderly people and 4.9h in young people. Granisetron hydrochloride is mainly metabolized in the liver and can be excreted through the feces and urine in the form of 7-hydroxy granisetron hydrochloride and other forms of metabolic product. For patients of liver damage or liver metastases, they have reduced plasma clearance rate with the scavenging rate upon renal insufficiency being 1/4 of the normal case. It has been observed of high first pass metabolism upon oral administration with the absolute bioavailability being 60%.

9.9 Domestic Market Analysis: 1993, China has approved of the import of the Kytri1 injection (3 mg/ 3 mL) of British SB company, Registration No: X930279, and has allowed for in clinical trials. In 1994, the China-US Tianjin Smith Kline Pharmaceutical Co., Ltd. had used imported raw materials processing method for production of the injection of the 3mg granisetron hydrochloride and had obtained the approval of the Ministry of Health: (94) health medicine approved: J-10 number (fourth class) with the trade name being "Kay Reiter. " Currently there are a number of domestic manufacturers having their products enter into market with the number of manufacture which makes formulation being up to dozen, see Annex I for details.
China has a large population with the annual number of newly identified cancer patients being more than 1.6 million. The nausea and vomiting induced by chemotherapy and radiotherapy-induced have been one of the serious side effects that doctors and patients worry of. Therefore, new antiemetics are in urgent demand. Currently, ondansetron class of drugs has occupied most of the market antiemetic including ondansetron (ShufuLing), granisetron hydrochloride (Kytril) and tropisetron (Oubiting), wherein the ondansetron and granisetron has been accumulated of large number of clinical application experience with good response from the doctors and has played positive role on improving the domestic situation of the treatment of chemotherapy vomiting. With the localization of products, the decreasing price and the increasing income level of people, antiemetics market will be certainly greatly improved. In this case, granisetron hydrochloride, as the secondary antiemetic drug entering into market, will certainly have good market prospects.

9.10 Uses: It is the selective antagonist of the 5-serotonin 3 (5-HT3) in peripheral and central nervous system.

9.11 Chemical Properties: White to Off-White Crystalline Sold

9.12 Uses: anticoagulant

9.13 Uses: A specific serotonin (5HT3) receptor antagonist. Used as an antiemetic. Granisetron HCl is a serotonin 5-HT3 receptor antagonist used as an antiemetic to treat nausea and vomiting following chemothera py. Its main effect is to reduce the activity of the vagus nerve. It does not have much effect on vomiting due to motion sickness. This drug does not have any effect on dopamine receptors or muscarini c receptor

9.14 Brand name: Kytril (Roche).

9.15 Biological Activity: 5-HT 3 receptor antagonist that possesses potent antiemetic activity.

10. Computational chemical data

Molecular Weight: 348.875g/mol
Molecular Formula: C₁₈H₂₅ClN₄O
Compound Is Canonicalized: True
XLogP3-AA: null
Exact Mass: 348.1716891
Monoisotopic Mass: 348.1716891
Complexity: 442
Rotatable Bond Count: 2
Hydrogen Bond Donor Count: 2
Hydrogen Bond Acceptor Count: 3
Topological Polar Surface Area: 50.2
Heavy Atom Count: 24
Defined Atom Stereocenter Count: 2
Undefined Atom Stereocenter Count: 0
Defined Bond Stereocenter Count: 0
Undefined Bond Stereocenter Count: 0
Isotope Atom Count: 0
Covalently-Bonded Unit Count: 2
CACTVS Substructure Key Fingerprint: AAADceB7oAAEAAAAAAAAAAAAAAAAAWAAAAA8WIAAAAAYAFgB8AAAHgAYAAAADCjBngQywPPIAACqAyVyVACSBAAnggAY2KG4ZNgIYLLA1dGUpQhgngDIyQcciICOAAAAAAACAAAAAAAAAAQAAAAAAAAAAA==

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Granisetron hydrochloride CAS 107007-99-8 for API